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Bibliography on: Publications by FHCRC Researchers

The Electronic Scholarly Publishing Project: Providing world-wide, free access to classic scientific papers and other scholarly materials, since 1993.


ESP: PubMed Auto Bibliography 20 Jul 2019 at 01:38 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2019-07-19

Feldstein LR, Ellis EM, Rowhani-Rahbar A, et al (2019)

Estimating the cost of illness and burden of disease associated with the 2014-2015 chikungunya outbreak in the U.S. Virgin Islands.

PLoS neglected tropical diseases, 13(7):e0007563 pii:PNTD-D-19-00592 [Epub ahead of print].

Chikungunya virus (CHIKV), an alphavirus that causes fever and severe polyarthralgia, swept through the Americas in 2014 with almost 2 million suspected or confirmed cases reported by April 2016. In this study, we estimate the direct medical costs, cost of lost wages due to absenteeism, and years lived with disability (YLD) associated with the 2014-2015 CHIKV outbreak in the U.S. Virgin Islands (USVI). For this analysis, we used surveillance data from the USVI Department of Health, medical cost data from three public hospitals in USVI, and data from two studies of laboratory-positive cases up to 12 months post illness. On average, employed case-patients missed 9 days of work in the 12 months following their disease onset, which resulted in an estimated cost of $15.5 million. Estimated direct healthcare costs were $2.9 million for the first 2 months and $0.6 million for 3-12 months following the outbreak. The total estimated cost associated with the outbreak ranged from $14.8 to $33.4 million (approximately 1% of gross domestic product), depending on the proportion of the population infected with symptomatic disease, degree of underreporting, and proportion of cases who were employed. The estimated YLDs associated with long-term sequelae from the CHIKV outbreak in the USVI ranged from 599-1,322. These findings highlight the significant economic burden of the recent CHIKV outbreak in the USVI and will aid policy-makers in making informed decisions about prevention and control measures for inevitable, future CHIKV outbreaks.

RevDate: 2019-07-18

Li A, Wu Q, Luo S, et al (2019)

Derivation and Validation of a Risk Assessment Model for Immunomodulatory Drug-Associated Thrombosis Among Patients With Multiple Myeloma.

Journal of the National Comprehensive Cancer Network : JNCCN, 17(7):840-847.

BACKGROUND: Although venous thromboembolism (VTE) is a significant complication for patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs), no validated clinical model predicts VTE in this population. This study aimed to derive and validate a new risk assessment model (RAM) for IMiD-associated VTE.

METHODS: Patients with newly diagnosed MM receiving IMiDs were selected from the SEER-Medicare database (n=2,397) to derive a RAM and then data from the Veterans Health Administration database (n=1,251) were used to externally validate the model. A multivariable cause-specific Cox regression model was used for model development.

RESULTS: The final RAM, named the "SAVED" score, included 5 clinical variables: prior surgery, Asian race, VTE history, age ≥80 years, and dexamethasone dose. The model stratified approximately 30% of patients in both the derivation and the validation cohorts as high-risk. Hazard ratios (HRs) were 1.85 (P<.01) and 1.98 (P<.01) for high- versus low-risk groups in the derivation and validation cohorts, respectively. In contrast, the method of stratification recommended in the current NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease had HRs of 1.21 (P=.17) and 1.41 (P=.07) for the corresponding risk groups in the 2 datasets.

CONCLUSIONS: The SAVED score outperformed the current NCCN Guidelines in risk-stratification of patients with MM receiving IMiD therapy. This clinical model can help inform providers and patients of VTE risk before IMiD initiation and provides a simplified clinical backbone for further prognostic biomarker development in this population.

RevDate: 2019-07-18

Hansen SG, Marshall EE, Malouli D, et al (2019)

A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge.

Science translational medicine, 11(501):.

Previous studies have established that strain 68-1-derived rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) proteins (RhCMV/SIV) are able to elicit and maintain cellular immune responses that provide protection against mucosal challenge of highly pathogenic SIV in rhesus monkeys (RMs). However, these efficacious RhCMV/SIV vectors were replication and spread competent and therefore have the potential to cause disease in immunocompromised subjects. To develop a safer CMV-based vaccine for clinical use, we attenuated 68-1 RhCMV/SIV vectors by deletion of the Rh110 gene encoding the pp71 tegument protein (ΔRh110), allowing for suppression of lytic gene expression. ΔRh110 RhCMV/SIV vectors are highly spread deficient in vivo (~1000-fold compared to the parent vector) yet are still able to superinfect RhCMV+ RMs and generate high-frequency effector-memory-biased T cell responses. Here, we demonstrate that ΔRh110 68-1 RhCMV/SIV-expressing homologous or heterologous SIV antigens are highly efficacious against intravaginal (IVag) SIVmac239 challenge, providing control and progressive clearance of SIV infection in 59% of vaccinated RMs. Moreover, among 12 ΔRh110 RhCMV/SIV-vaccinated RMs that controlled and progressively cleared an initial SIV challenge, 9 were able to stringently control a second SIV challenge ~3 years after last vaccination, demonstrating the durability of this vaccine. Thus, ΔRh110 RhCMV/SIV vectors have a safety and efficacy profile that warrants adaptation and clinical evaluation of corresponding HCMV vectors as a prophylactic HIV/AIDS vaccine.

RevDate: 2019-07-18

Marshall EE, Malouli D, Hansen SG, et al (2019)

Enhancing safety of cytomegalovirus-based vaccine vectors by engaging host intrinsic immunity.

Science translational medicine, 11(501):.

Rhesus cytomegalovirus (RhCMV)-based vaccines maintain effector memory T cell responses (TEM) that protect ~50% of rhesus monkeys (RMs) challenged with simian immunodeficiency virus (SIV). Because human CMV (HCMV) causes disease in immunodeficient subjects, clinical translation will depend upon attenuation strategies that reduce pathogenic potential without sacrificing CMV's unique immunological properties. We demonstrate that "intrinsic" immunity can be used to attenuate strain 68-1 RhCMV vectors without impairment of immunogenicity. The tegument proteins pp71 and UL35 encoded by UL82 and UL35 of HCMV counteract cell-intrinsic restriction via degradation of host transcriptional repressors. When the corresponding RhCMV genes, Rh110 and Rh59, were deleted from 68-1 RhCMV (ΔRh110 and ΔRh59), we observed only a modest growth defect in vitro, but in vivo, these modified vectors manifested little to no amplification at the injection site and dissemination to distant sites, in contrast to parental 68-1 RhCMV. ΔRh110 was not shed at any time after infection and was not transmitted to naïve hosts either by close contact (mother to infant) or by leukocyte transfusion. In contrast, ΔRh59 was both shed and transmitted by leukocyte transfusion, indicating less effective attenuation than pp71 deletion. The T cell immunogenicity of ΔRh110 was essentially identical to 68-1 RhCMV with respect to magnitude, TEM phenotype, epitope targeting, and durability. Thus, pp71 deletion preserves CMV vector immunogenicity while stringently limiting vector spread, making pp71 deletion an attractive attenuation strategy for HCMV vectors.

RevDate: 2019-07-18

Krok-Schoen JL, Bernardo BM, Elena JW, et al (2019)

An Environmental Scan of Biopsychosocial and Clinical Variables in Cohort Studies of Cancer Survivors.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-18-0541 [Epub ahead of print].

BACKGROUND: An inventory of cancer survivorship cohorts is necessary to identify important gaps in what is being studied among cancer survivors.

METHODS: We conducted an environmental scan of cancer survivor cohorts, to determine the scope and scale of information collected on demographic, biopsychosocial, and selected clinical variables from cancer survivors. Cohorts were eligible for inclusion in the environmental scan if the study was conducted in the United States, reported in English, and consisted of data collected from cancer survivors post-diagnosis and followed for at least one year.

RESULTS: Out of the 131 cohorts identified, 62 were eligible. There were 23 cancer sites represented and more than half of the studies included breast cancer survivors (n=34). The next most commonly included cancers were leukemia (n=22) and lymphoma (n=23). The majority (n=59) collected information on clinical characteristics and basic diagnostic information, patient demographic characteristics (n=57), patient-reported symptoms (n=44), lifestyle (n=45), and psychological (n=42) characteristics. Half collected biospecimens (n=35) and biomarkers (n=35); fewer collected CAM use (n=19) and social characteristics (n=27).

CONCLUSIONS: Extensive data are available in cancer cohorts to study important questions relevant to cancer survivors. Cohorts should consider collecting information on social and environmental factors, as well as biospecimen collection and biomarker analyses, and should include survivors from cancer sites less likely to be studied.

IMPACT: This information can assist researchers in understanding the types of information currently being gathered from cancer survivors for further analysis and identify areas where more research is needed.

RevDate: 2019-07-17

McDonald GB, Sarmiento JI, Rees-Lui G, et al (2019)

Cytomegalovirus hepatitis after bone marrow transplantation: An autopsy study with clinical, histologic, and laboratory correlates.

Journal of viral hepatitis [Epub ahead of print].

Mortality from Cytomegalovirus disease after marrow transplantation can be reduced by treatment with anti-viral drugs based on detection of viremia and organ involvement. We examined autopsy liver specimens to determine the frequency, extent, and outcome of cytomegalovirus hepatitis and whether cytomegalovirus hepatitis occurred in the absence of cytomegalovirus disease elsewhere. Autopsy specimens from 50 transplant patients were evaluated for cytomegalovirus-infected cells, in five groups of 10, according to extent of CMV during life and at autopsy. Liver sections were examined by routine light microscopy, immunohistochemistry, and in situ DNA hybridization. Clinical and laboratory data collected during the last 30 days of life were analyzed as markers of liver cytomegalovirus infection. Cytomegalovirus-infected cells were detected in the livers of 10/10 patients with cytomegalovirus infection during life and wide-spread cytomegalovirus at autopsy; in 3/20 livers from patients with cytomegalovirus infection during life but negative liver cultures at autopsy; and in 1/10 livers from cytomegalovirus-seropositive patients who had been without other evidence of cytomegalovirus infection. Histology detected a lower density of cytomegalovirus-bearing cells per unit area of liver, compared to immunohistochemistry and in-situ hybridiation. No cytomegalovirus-infected cells were detected in livers from cytomegalovirus-seronegative controls. No distinctive clinical or laboratory findings correlated with liver cytomegalovirus detection. CMV liver disease is common in allografted patients with disseminated CMV but may rarely be isolated to the liver, best demonstrated with IHC and ISH. Massive hepatic necrosis from CMV was not seen in any autopsy liver in this study. This article is protected by copyright. All rights reserved.

RevDate: 2019-07-17

Lansigan F, Horwitz SM, Pinter-Brown LC, et al (2019)

Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry.

Acta haematologica pii:000500666 [Epub ahead of print].

BACKGROUND: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data.

OBJECTIVES: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease.

METHODS: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days.

RESULTS: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months.

CONCLUSIONS: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.

RevDate: 2019-07-17

Hayes RJ, Donnell D, Floyd S, et al (2019)

Effect of Universal Testing and Treatment on HIV Incidence - HPTN 071 (PopART).

The New England journal of medicine, 381(3):207-218.

BACKGROUND: A universal testing and treatment strategy is a potential approach to reduce the incidence of human immunodeficiency virus (HIV) infection, yet previous trial results are inconsistent.

METHODS: In the HPTN 071 (PopART) community-randomized trial conducted from 2013 through 2018, we randomly assigned 21 communities in Zambia and South Africa (total population, approximately 1 million) to group A (combination prevention intervention with universal antiretroviral therapy [ART]), group B (the prevention intervention with ART provided according to local guidelines [universal since 2016]), or group C (standard care). The prevention intervention included home-based HIV testing delivered by community workers, who also supported linkage to HIV care and ART adherence. The primary outcome, HIV incidence between months 12 and 36, was measured in a population cohort of approximately 2000 randomly sampled adults (18 to 44 years of age) per community. Viral suppression (<400 copies of HIV RNA per milliliter) was assessed in all HIV-positive participants at 24 months.

RESULTS: The population cohort included 48,301 participants. Baseline HIV prevalence was 21% or 22% in each group. Between months 12 and 36, a total of 553 new HIV infections were observed during 39,702 person-years (1.4 per 100 person-years; women, 1.7; men, 0.8). The adjusted rate ratio for group A as compared with group C was 0.93 (95% confidence interval [CI], 0.74 to 1.18; P = 0.51) and for group B as compared with group C was 0.70 (95% CI, 0.55 to 0.88; P = 0.006). The percentage of HIV-positive participants with viral suppression at 24 months was 71.9% in group A, 67.5% in group B, and 60.2% in group C. The estimated percentage of HIV-positive adults in the community who were receiving ART at 36 months was 81% in group A and 80% in group B.

CONCLUSIONS: A combination prevention intervention with ART provided according to local guidelines resulted in a 30% lower incidence of HIV infection than standard care. The lack of effect with universal ART was unanticipated and not consistent with the data on viral suppression. In this trial setting, universal testing and treatment reduced the population-level incidence of HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 071 [PopArt] number, NCT01900977.).

RevDate: 2019-07-17

Gilbert PB, Zhang Y, Rudnicki E, et al (2019)

Assessing pharmacokinetic marker correlates of outcome, with application to antibody prevention efficacy trials.

Statistics in medicine [Epub ahead of print].

The Antibody Mediated Prevention efficacy trials are the first studies to evaluate whether passive administration of a broadly neutralizing monoclonal antibody can prevent human immunodeficiency virus (HIV) acquisition. The trials randomize 4600 HIV-negative volunteers to receive 10 infusions of the monoclonal antibody VRC01 or placebo. The primary objective compares the incidence of HIV infection between the study groups. The secondary objective assesses whether and how a marker defined as the serum concentration of VRC01 over time associates with the instantaneous rate of HIV infection, using a two-phase sampling design, a pharmacokinetic model for the time-concentration curve, and an estimator of HIV infection times. While a Cox model with a time-dependent covariate constitutes an important approach to this problem, the low interindividual versus intraindividual marker variability limits its power, motivating us to develop two alternative methods that condition on outcome status: (1) an indirect method that checks whether HIV-infected cases have unexpectedly long times from the most recent infusion to the estimated infection date and (2) a direct method that checks whether the marker itself is unexpectedly low at estimated infection dates. In simulations and a pseudo Antibody Mediated Prevention application, we find that method (2) (but not (1)) has greater power than the Cox model. We also find that the quality of the infection time estimator majorly impacts method performance, and thus, incorporating details of an optimized estimator is critical. The methods apply more generally for assessing a time-dependent longitudinal marker as a correlate of risk when the marker trajectory is modeled pharmacokinetically.

RevDate: 2019-07-17

Pattacini L, Woodward Davis A, Czartoski J, et al (2019)

A pro-inflammatory CD8+ T-cell subset patrols the cervicovaginal tract.

Mucosal immunology pii:10.1038/s41385-019-0186-9 [Epub ahead of print].

The immune system of the cervicovaginal tract (CVT) must balance immunosurveillance and active immunity against pathogens with maintenance of tolerance to resident microbiota and to fetal and partner antigens for reproductive purposes. Thus, we predicted that CVT immunity is characterized by distinctive features compared to blood and other tissue compartments. Indeed, we found that CVT CD8+ T-cells had unique transcriptional profiles, particularly in their cytokine signature, compared to that reported for CD8+ T-cells in other tissue sites. Among these CVT CD8+ T-cells, we identified a CD69- CD103- subset that was characterized by reduced migration in response to tissue-exit signals and higher pro-inflammatory potential as compared to their blood counterpart. These inflammatory mucosal CD8+ T-cells (Tim) were increased in frequency in the CVT of individuals with chronic infection, pointing to a potential role in perpetuating inflammation. Our findings highlight the specialized nature of immunity within the CVT and identify Tim cells as potential therapeutic targets to tame tissue inflammation upon chronic infection.

RevDate: 2019-07-16

Flint Brodsly N, Bitman-Lotan E, Boico O, et al (2019)

The transcription factor Hey and nuclear lamins specify and maintain cell identity.

eLife, 8: pii:44745.

The inability of differentiated cells to maintain their identity is a hallmark of age-related diseases. We found that the transcription factor Hey supervises the identity of differentiated enterocytes (ECs) in the adult Drosophila midgut. Lineage tracing established that Hey-deficient ECs are unable to maintain their unique nuclear organization and identity. To supervise cell identity, Hey determines the expression of nuclear lamins, switching from a stem-cell lamin configuration to a differentiated lamin configuration. Moreover, continued Hey expression is required to conserve large-scale nuclear organization. During aging, Hey levels decline, and EC identity and gut homeostasis are impaired, including pathological reprograming and compromised gut integrity. These phenotypes are highly similar to those observed upon acute targeting of Hey or perturbation of lamin expression in ECs in young adults. Indeed, aging phenotypes were suppressed by continued expression of Hey in ECs, suggesting that a Hey-lamin network safeguards nuclear organization and differentiated cell identity.

RevDate: 2019-07-16

Hedden L, Pollock P, Bryan S, et al (2019)

Correction to: Patterns and predictors of registration and participation at a supportive care program for prostate cancer survivors.

The name of Stirling Bryan was incorrectly captured in the original manuscript.

RevDate: 2019-07-16

Lazarus E, Otwombe K, Dietrich J, et al (2019)

Vaginal practices among women at risk for HIV acquisition in Soweto, South Africa.

Southern African journal of HIV medicine, 20(1):866 pii:HIVMED-20-866.

Background: Vaginal practices (VP) may adversely affect normal vaginal flora and mucosal integrity, and increase acquisition risk of HIV and other genital tract infections.

Objective: The aim of this study was to describe self-reported VP, changes in the reported number of VP over time and factors associated with VP in a cohort of young Sowetan women enrolled in the HVTN 915 observational study.

Method: We longitudinally assessed self-reported VP in 50 young women at risk of HIV acquisition aged 18-25 years in a prospective study over 3 months in Soweto, South Africa. Interviewer-administered HIV behavioural risk questionnaires were completed. No intervention to reduce VP was specified per protocol, but clinicians provided education at their discretion. The generalised estimating equation with inverse probability weights assessed VP over time.

Results: The mean age at screening was 22 years; women reported multiple sexual partnerships with a mean of one main and 2 casual partners in the last 30 days. Consistent condom use was 2% (n = 1), 25% (n = 12) and 43% (n = 3) with main, casual and new partners, respectively. Commonly reported VP included washing the vagina with water (44%) and using fingers (48%). VP decreased significantly over time (p < 0.001). Women who used condoms inconsistently or whose last sex was with a casual partner were 3 times more likely to report VP (p = 0.001).

Conclusion: Despite the high incidence of HIV in our setting, VP are still common and are associated with other behavioural risks for HIV. Further study is needed to assess whether clinician education may reduce VP and therefore should be included in HIV risk reduction counselling.

RevDate: 2019-07-16

Moschini M, Xylinas E, Zamboni S, et al (2019)

Efficacy of Surgery in the Primary Tumor Site for Metastatic Urothelial Cancer: Analysis of an International, Multicenter, Multidisciplinary Database.

European urology oncology pii:S2588-9311(19)30095-1 [Epub ahead of print].

BACKGROUND: The effect of local treatment on survival in advanced-stage patients has gained interest in several malignancies; however, limited data exist regarding urothelial carcinoma (UC).

OBJECTIVE: To test the impact of surgery of the primary tumor site on cancer-specific mortality (CSM) and overall mortality (OM) in patients affected by metastatic UC.

Individual patient-level data from a multicenter collaboration, including metastatic UC patients treated with first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011 from hospitals in the USA, Europe, Israel, and Canada.

Univariable and multivariable Cox regression analyses were used to assess the effect of surgery on CSM and OM in patients affected by metastatic UC using 3-mo landmark analyses. Subgroup analyses were performed on the basis of the number of metastasis sites involved and including only patients treated with surgery before the start of chemotherapy.

RESULTS AND LIMITATIONS: Of the 326 patients included in the study, 47 (14%) were treated with surgery of the primary tumor site. Median (interquartile range) follow-up was 43 (33-45)mo. Of the patients treated with surgery, 28 (60%) were affected by a primary bladder cancer and 19 (40%) by a primary upper urinary tract tumor. On multivariable analyses, surgery was associated with a protective effect on CSM (hazard ratio [HR]: 0.59, confidence interval [CI]: 0.35-0.98, p=0.04) and OM (HR: 0.45, CI: 0.37-0.99, p=0.04) compared with patients treated with chemotherapy only. Similar results were found considering patients only surgically treated before the start of chemotherapy. After stratifying according to the number of metastatic sites, surgery has an effect on survival in patients with only one metastatic site, while no survival benefit was observed in patients with two or more metastatic sites. The study is limited by its retrospective nature.

CONCLUSIONS: We found that surgery of the primary tumor site is associated with improved survival in patients with metastatic UC who received standard chemotherapy. This effect disappears in patients affected by two or more metastatic sites. Our results need to be validated in a high-quality prospective trial.

PATIENT SUMMARY: In our multicenter, retrospective series, surgery in metastatic urothelial cancer patients improve survival compared with patients treated with chemotherapy only. This effect was evident in patients with limited disease extent, identified as one metastatic site.

RevDate: 2019-07-15

Palanee-Phillips T, Brown ER, Szydlo D, et al (2019)

Risk of HIV-1 acquisition among South African women using a variety of contraceptive methods in a prospective study.

AIDS (London, England), 33(10):1619-1622.

OBJECTIVE: Observational studies have associated use of intramuscular injectable depot medroxyprogesterone acetate (DMPA-IM) with increased risk of HIV-1 acquisition, but limited data are available to assess HIV-1 risk for alternate contraceptive methods.

METHODS: Within a randomized trial of the dapivirine vaginal ring for HIV-1 prevention, we assessed HIV-1 incidence by contraceptive method. We limited analyses to participants from South African sites and to women who used DMPA-IM, the alternative injectable norethisterone enanthate, implants, or copper intrauterine devices (IUDs). Contraceptive method was assessed as a time-dependent exposure and multivariate models adjusted for trial randomization arm, age, sexual behaviour, and incident sexually transmitted infections.

RESULTS: A total of 95 incident HIV-1 infections were observed: incidence 5.8 (DMPA-IM, n = 52), 6.2 (norethisterone enanthate, n = 28), 1.9 (implant, n = 3), and 4.5 (IUD, n = 12) cases per 100 woman-years. In multivariable models, there were no statistically significant differences between contraceptive methods in the risk of HIV-1 acquisition. However, compared with the IUD, the three hormonal methods each had point estimates near 1 while the implant had risk that was approximately half that of the IUD. When the three hormonal methods were combined, their relative risk compared with IUD was 0.90 (95% confidence interval 0.45-1.76).

CONCLUSION: Among women at risk of HIV-1 infections in South Africa, we found no statistically significant differences in HIV-1 incidence by contraceptive method. Implants had the lowest point estimate for HIV-1 incidence, and IUDs had risk comparable with injectable methods in multivariate models. Large, prospective studies are needed to define better the relative HIV-1 risks across different contraceptive methods.

RevDate: 2019-07-15

Pederzoli F, Bandini M, Briganti A, et al (2019)

Incremental Utility of Adjuvant Chemotherapy in Muscle-invasive Bladder Cancer: Quantifying the Relapse Risk Associated with Therapeutic Effect.

European urology pii:S0302-2838(19)30522-6 [Epub ahead of print].

The availability of new potent systemic therapies for urothelial carcinoma may change the way we use standard chemotherapy perioperatively. In particular, identifying which patients with muscle-invasive bladder cancer (MIBC) would benefit from adjuvant chemotherapy (AC) is compelling. From a multicenter database we selected 950 patients with cT2-4N0M0 MIBC treated with radical cystectomy (RC), with or without neoadjuvant chemotherapy (NAC), and AC. We used Kaplan-Meier analyses to test 1-yr recurrence-free survival (RFS) rates according to AC use. Nomogram-derived probabilities of 1-yr recurrence after RC were plotted against actual recurrence rates according to AC use. Overall, we did not see evidence of an AC effect on the 1-yr RFS rate (p=0.6). Conversely, the 1-yr RFS rate was higher among patients with pT3-4 or pN1 disease who received AC (75% vs 54%; p<0.001). We were unable to demonstrate a difference between AC and no AC among patients who received prior NAC (1-yr RFS 57% vs 76%; p=0.057). As the most important finding, AC was associated with incremental RFS benefits only for patients with a nomogram-derived 1-yr recurrence probability of >40%. Patient summary: Maximizing disease control with adjuvant chemotherapy was beneficial for patients with muscle-invasive bladder cancer who had a calculated recurrence risk of >40% and did not impact cancer recurrence in lower-risk disease. Therefore, patient stratification using the nomogram available for predicting recurrence is advisable pending external validation.

RevDate: 2019-07-13

Boppana S, Sterrett S, Files J, et al (2019)

HLA-I associated adaptation dampens the CD8 T-cell response in HIV Ad5-vectored vaccine recipients.

The Journal of infectious diseases pii:5532017 [Epub ahead of print].

HLA-I associated HIV adaptation is known to negatively impact disease progression and CD8 T-cell responses. We aimed to assess how HLA-I associated adaptation impacts HIV vaccine-induced CD8 T-cell responses in two past vaccine efficacy trials. We found that vaccine-encoded adapted epitopes were less immunogenic than vaccine-encoded non-adapted epitopes, and adapted epitope-specific responses were less polyfunctional than non-adapted epitope-specific responses. Along those lines, vaccine recipients with higher HLA-I adaptation to the Gag vaccine insert mounted less polyfunctional CD8 T-cell responses at the protein-level. Response breadth, which correlated with viral control in recipients who became infected, is also dampened by HLA-I adaptation. These findings suggest that HLA-I associated adaptation is an important consideration for strategies aiming to induce robust CD8 T-cell responses.

RevDate: 2019-07-13

Naik S, Riches M, Hari P, et al (2019)

Survival Outcomes of Allogeneic Hematopoietic Cell Transplants with EBV positive or EBV negative Post Transplant Lymphoproliferative Disorder (PTLD), A CIBMTR Study.

Transplant infectious disease : an official journal of the Transplantation Society [Epub ahead of print].

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) are associated with significant morbidity and mortality following allogeneic hematopoietic cell transplant (alloHCT). Although most PTLD is EBV-positive (EBVpos), EBV-negative (EBVneg) PTLD is reported; yet its incidence and clinical impact remain largely undefined. Furthermore, factors at the time of transplant impacting survival following PTLD are not well described.

METHODS: Between 2002 and 2014, 432 cases of PTLD following alloHCT were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). After exclusions, 267 cases (EBVpos = 222, 83%; EBVneg = 45, 17%) were analyzed.

RESULTS: Two-hundred and eight patients (78%) received in vivo T-cell depletion (TCD) with either anti-thymocyte globulin (ATG) or alemtuzumab. Incidence of PTLD was highest using umbilical cord donors (UCB, 1.60%) and lowest using matched related donors (MRD, 0.40%). Clinical features and histology did not significantly differ among EBVpos or EBVneg PTLD cases except that absolute lymphocyte count recovery was slower and CMV reactivation was later in EBVneg PTLD [EBVpos 32 (5 - 95) days versus EBVneg 47 (10 - 70) days, p=0.016]. There was no impact on survival by EBV-status in multivariable analysis [EBVneg RR 1.42, 95% CI 0.94-2.15, p = 0.097].

CONCLUSIONS: There is no difference in survival outcomes for patients with EBVpos or EBVneg PTLD occurring following alloHCT and 1-year survival is poor. Features of conditioning and use of serotherapy remain important. This article is protected by copyright. All rights reserved.

RevDate: 2019-07-13

Long JE, Ulrich A, White E, et al (2019)

Characterizing Men Who Have Sex with Transgender Women in Lima, Peru: Sexual Behavior and Partnership Profiles.

AIDS and behavior pii:10.1007/s10461-019-02590-w [Epub ahead of print].

HIV prevalence is high among transgender women (TW), but how HIV is transmitted to this population is not well understood. This analysis aims to characterize sexual partners of TW (PTW) to understand how their behavior contributes to HIV risk among TW. We examined baseline data from TW, PTW, and men who have sex with men (MSM) from a treatment-as-prevention study in Lima, Peru. Individual and partnership characteristics were compared across groups, and Poisson regression was used to calculate prevalence ratios for associations between sexual concurrency and potential correlates. We found that 81% of PTW had no cisgender male partners. Prevalence of alcohol dependency, concurrency, and condomless anal intercourse was high and HIV testing was low compared to the other groups. Our results suggest that PTW are a distinct population from MSM and TW, engage in behavior associated with HIV transmission, and are likely not well reached by HIV prevention interventions.

RevDate: 2019-07-13

Meers MP, Tenenbaum D, S Henikoff (2019)

Peak calling by Sparse Enrichment Analysis for CUT&RUN chromatin profiling.

Epigenetics & chromatin, 12(1):42 pii:10.1186/s13072-019-0287-4.

BACKGROUND: CUT&RUN is an efficient epigenome profiling method that identifies sites of DNA binding protein enrichment genome-wide with high signal to noise and low sequencing requirements. Currently, the analysis of CUT&RUN data is complicated by its exceptionally low background, which renders programs designed for analysis of ChIP-seq data vulnerable to oversensitivity in identifying sites of protein binding.

RESULTS: Here we introduce Sparse Enrichment Analysis for CUT&RUN (SEACR), an analysis strategy that uses the global distribution of background signal to calibrate a simple threshold for peak calling. SEACR discriminates between true and false-positive peaks with near-perfect specificity from "gold standard" CUT&RUN datasets and efficiently identifies enriched regions for several different protein targets. We also introduce a web server ( for plug-and-play analysis with SEACR that facilitates maximum accessibility across users of all skill levels.

CONCLUSIONS: SEACR is a highly selective peak caller that definitively validates the accuracy of CUT&RUN for datasets with known true negatives. Its ease of use and performance in comparison with existing peak calling strategies make it an ideal choice for analyzing CUT&RUN data.

RevDate: 2019-07-12

Liu AY, Norwood A, Gundacker H, et al (2019)

Brief Report: Routine Use of Oral PrEP in a Phase 2 Rectal Microbicide Study of Tenofovir Reduced-Glycerin 1% Gel (MTN-017).

Journal of acquired immune deficiency syndromes (1999), 81(5):516-520.

BACKGROUND: As daily oral preexposure prophylaxis (PrEP) becomes standard for HIV prevention, routine use of PrEP is likely to increase within clinical trials of novel preventive agents. We describe the prevalence and characteristics of participants reporting nonstudy oral PrEP use within Microbicide Trials Network-017 (MTN-017), a phase 2 trial of a rectal microbicide.

SETTING AND METHODS: One hundred ninety-five HIV-uninfected men who have sex with men and transgender women were enrolled and followed in MTN-017 across 8 sites in the United States, Thailand, South Africa, and Peru from 2013 to 2015. Nonstudy oral PrEP use was recorded on case report forms and progress notes. Characteristics of PrEP users and non-PrEP users were compared using tests of statistical significance.

RESULTS: Overall, 11% of participants reported nonstudy oral PrEP use, all from the San Francisco (SF) site, accounting for 58% (22/38) of participants enrolled in SF. There was a higher median number of sex partners reported in the past 8 weeks before enrollment among oral PrEP users vs. nonusers (7 vs. 2, P = 0.02). Most PrEP users (18/22, 82%) began PrEP treatment during screening/after enrollment, and most (19/22, 86%) decided to continue oral PrEP after study completion.

CONCLUSION: Nonstudy oral PrEP use in the first phase 2 study of tenofovir reduced-glycerin 1% gel was high at a single site in SF where community PrEP availability and use was expanding. Investigators should consider the evolving context of nonstudy oral PrEP use across trial sites when designing and interpreting trials of novel biomedical prevention modalities.

RevDate: 2019-07-12

Triplette M, Donovan LM, Crothers K, et al (2019)

Prediction of Lung Cancer Screening Eligibility Using Simplified Criteria.

Annals of the American Thoracic Society [Epub ahead of print].

RATIONALE: Lung cancer screening with low-dose chest CT decreases mortality for high-risk current or former smokers. An essential eligibility criteria, lifetime smoking intensity (cigarette pack-years) is poorly recorded in electronic health records (EHRs), which may contribute to the overall low appropriate utilization of screening.

OBJECTIVES: We sought to assess whether elements commonly extractable from the EHR may be useful as pre-screening tools to identify individuals for formal assessment of eligibility.

METHODS: This is a cross-sectional cohort study of the National Health and Nutrition Examination Survey (NHANES) continuous survey, years 2011-2016. We included all adult participants with complete smoking interview data, weighted to construct a nationally representative cohort. We determined test characteristics for 5 criteria including eligibility age, smoking status (current, former or never) and current smoking intensity to predict lung cancer screening eligibility as defined by the United States Preventive Services Task Force and Centers for Medicare and Medicaid Services.

RESULTS: Almost 9 million individuals, 3.8% of the population, may qualify for screening. Simplified criteria including the appropriate age range (55-77) and smoking status correctly discriminated individuals eligible for screening in most cases (AUC 0.92). When restricting to those of eligible age, smoking status retained fair predictive value (AUC 0.85). Incorporating additional information about current smoking behavior would allow for refinement in approaches to identify specific populations for screening.

CONCLUSIONS: These simplified criteria may be useful in identifying individuals who are eligible for lung cancer screening. Applying these criteria as a pre-screening tool may improve appropriate referral and implementation of screening.

RevDate: 2019-07-12

Wartko PD, Weiss NS, Enquobahrie DA, et al (2019)

Antidepressant continuation in pregnancy and risk of gestational diabetes.

Pharmacoepidemiology and drug safety [Epub ahead of print].

PURPOSE: Previous studies observed modestly higher risk of gestational diabetes (GDM) associated with antidepressant use in pregnancy, potentially due to confounding by indication. We assessed the association of antidepressant continuation in pregnancy with GDM, as well as blood glucose levels, after accounting for confounding.

METHODS: We conducted a retrospective cohort study of singleton live births from 2001 to 2014 to women enrolled in Kaiser Permanente Washington, an integrated health care delivery system, utilizing electronic health data and linked Washington State birth records. We required that women have ≥1 antidepressant prescription fills ≤6 months before pregnancy. Women with an antidepressant fill during pregnancy were categorized as "continuers" (n = 1634); those without a fill were "discontinuers" (n = 1211). We calculated relative risks (RRs) for GDM and mean differences in screening blood glucose levels using generalized estimating equations with inverse probability of treatment weighting to account for baseline characteristics, including mental health conditions and indicators of mental health severity.

RESULTS: Compared with discontinuers, antidepressant continuers had comparable risk of GDM (RR: 1.10; 95% confidence interval [CI], 0.84-1.44) and blood glucose levels (mean difference: 2.3 mg/dL; 95% CI, -1.5 to 6.1 mg/dL). We observed generally similar results for specific antidepressants, with the potential exceptions of risk of GDM associated with sertraline (RR: 1.30; 95% CI, 0.90-1.88) and venlafaxine (RR: 1.52; 95% CI, 0.87-2.68), but neither association was statistically significant.

CONCLUSIONS: Our study suggests that overall, women who continue antidepressants in pregnancy are not at increased risk for GDM or higher blood glucose, although further study may be warranted for sertraline and venlafaxine.

RevDate: 2019-07-12

Darrigo LG, Colturato V, de Souza MP, et al (2019)

Allogeneic Bone Marrow Transplants for Pediatric Severe Aplastic Anemia: Real-world Data comparing Matched Related and Unrelated Donors in a Developing Country. Retrospective study on behalf of the Pediatric Hematopoietic Stem Cell Transplant Working Group of the Brazilian Bone Marrow Transplantation Society (SBTMO) and the Brazil-Seattle Consortium (Gedeco).

Pediatric transplantation [Epub ahead of print].

In this study, we report on major MRD or URD BMT outcomes in pediatric patients with SAA in Brazil. This was a retrospective study, which included 106 patients ≤18 years old who received a first BMT for SAA. All patients received bone marrow as graft source from an MRD (n = 69) or a URD (n = 37). Conditioning regimen was non-myeloablative in 73.6% of cases, and GVHD prophylaxis comprised a calcineurin inhibitor plus methotrexate in 89.6% of patients. After a median follow-up of 4.5 years after BMT, 81 patients are alive, with a 4-year OS of 77% and no statistically significant difference between the MRD and URD groups (82% vs. 69%, respectively; P = .08). Grade III-IV aGVHD at 6 months and cGVHD at 2 years were observed in 8% and 14% of cases, respectively, and were not statistically different between the groups. Twenty-five (23%) patients died at a median of 2.9 months after BMT. Our study showed that 4-year OS after BMT was not statistically different between MRD and URD recipients. This study shows that the outcomes of pediatric patients transplanted for SAA with a URD in Brazil are approaching those of MRD transplants. In contrast, OS after MRD BMT was lower than we would expect based on previous reports. The wide range of preparatory regimens used by the study centers highlights the need for standardized protocols for these children. Our findings provide a benchmark for future studies focused on improving BMT outcomes in this setting in Brazil.

RevDate: 2019-07-12

Lv LJ, Li SH, Li SC, et al (2019)

Early-Onset Preeclampsia Is Associated With Gut Microbial Alterations in Antepartum and Postpartum Women.

Frontiers in cellular and infection microbiology, 9:224.

Background: Imbalances in gut microbiota composition are linked to hypertension, host metabolic abnormalities, systemic inflammation, and other conditions. In the present study, we examined the changes of gut microbiota in women with early-onset preeclampsia (PE) and in normotensive, uncomplicated pregnant women during late pregnancy and at 1 and 6 weeks postpartum. Methods: Gut microbiota profiles of women with PE and healthy pregnant women in the third trimester and at 1 and 6 weeks postpartum were assessed by 16S rRNA gene amplicon sequencing. Plasma levels of interleukin-6 (IL-6), intestinal fatty acid-binding protein (I-FABP), zonulin, and lipopolysaccharide (LPS) were measured in the third trimesters. Results: At the genus level, 8 bacterial genera were significantly enriched in the antepartum samples of PE patients compared to healthy controls, of which Blautia, Ruminococcus2, Bilophila, and Fusobacterium represented the major variances in PE microbiomes. Conversely, 5 genera, including Faecalibacterium, Gemmiger, Akkermansia, Dialister, and Methanobrevibacter, were significantly depleted in antepartum PE samples. Maternal blood pressure and liver enzyme levels were positively correlated to the PE-enriched genera such as Anaerococcus, Ruminococcus2, Oribacterium, and Bilophila, while the fetal features (e.g., Apgar score and newborn birth weight) were positively correlated with PE-depleted genera and negatively correlated with PE-enriched genera. Moreover, maternal blood IL-6 level was positively associated with gut Bilophila and Oribacterium, whereas LPS level was negatively associated with Akkermansia. In terms of postpartum women, both the gut microbial composition and the PE-associated microbial alterations were highly consistent with those of the antepartum women. Conclusion: PE diagnosed in the third trimester of pregnancy is associated with a disrupted gut microbiota composition compared with uncomplicated pregnant women, which are associated with maternal clinical features (blood pressure level and liver dysfunction) and newborn birth weight. Moreover, these antepartum alterations in gut microbiota persisted 6 weeks postpartum.

RevDate: 2019-07-12

de Smith AJ, Walsh KM, Morimoto LM, et al (2019)

Heritable variation at the chromosome 21 gene ERG is associated with acute lymphoblastic leukemia risk in children with and without Down syndrome.

RevDate: 2019-07-12

Kaluza J, Stackelberg O, Harris HR, et al (2019)

Anti-inflammatory diet and risk of abdominal aortic aneurysm in two Swedish cohorts.

Heart (British Cardiac Society) pii:heartjnl-2019-315031 [Epub ahead of print].

OBJECTIVE: The relationship between dietary patterns and development of abdominal aortic aneurysm (AAA) is not well understood. Thus, we prospectively evaluated the association between the anti-inflammatory potential of diet and risk of AAA.

METHODS: The study population included the Cohort of Swedish Men (45 072 men) and the Swedish Mammography Cohort (36 633 women), aged 45-83 years at baseline. The anti-inflammatory potential of diet was estimated using Anti-inflammatory Diet Index (AIDI) based on 11 foods with anti-inflammatory potential and 5 with proinflammatory potential (maximum 16 points) that was validated againsthigh sensitivity C reactive protein (hsCRP). Cox proportional hazard regression models were used to estimate HRs and 95% CIs. During the 14.9 years of follow-up (1 217 263 person-years), 1528 AAA cases (277 (18%) ruptured, 1251 non-ruptured) were ascertained via the Swedish Inpatient Register, the National Cause of Death Register and the Register for Vascular Surgery (Swedvasc).

RESULTS: We observed an inverse association between the AIDI and AAA risk in women and men; HRs between extreme quartiles of the AIDI (≥8 vs ≤5 points) were 0.55 (95% CI 0.36 to 0.83) in women and 0.81 (95% CI 0.68 to 0.98) in men. The AIDI was inversely associated with both ruptured and non-ruptured AAA incidence; the HR of participants in the highest quartile of AIDI compared with those in the lowest quartile was 0.61 (95% CI 0.41 to 0.90) for ruptured AAA and 0.79 (95% CI 0.65 to 0.95) for non-ruptured AAA.

CONCLUSION: Adherence to diet with a high anti-inflammatory potential was associated with a reduced AAA risk, an association that was even more pronounced for AAA rupture.

RevDate: 2019-07-11

Yeary KHK, Alcaraz KI, Ashing KT, et al (2019)

Considering religion and spirituality in precision medicine.

Translational behavioral medicine pii:5531088 [Epub ahead of print].

The emerging era of precision medicine (PM) holds great promise for patient care by considering individual, environmental, and lifestyle factors to optimize treatment. Context is centrally important to PM, yet, to date, little attention has been given to the unique context of religion and spirituality (R/S) and their applicability to PM. R/S can support and reinforce health beliefs and behaviors that affect health outcomes. The purpose of this article is to discuss how R/S can be considered in PM at multiple levels of context and recommend strategies for integrating R/S in PM. We conducted a descriptive, integrative literature review of R/S at the individual, institutional, and societal levels, with the aim of focusing on R/S factors with a high level of salience to PM. We discuss the utility of considering R/S in the suitability and uptake of PM prevention and treatment strategies by providing specific examples of how R/S influences health beliefs and practices at each level. We also propose future directions in research and practice to foster greater understanding and integration of R/S to enhance the acceptability and patient responsiveness of PM research approaches and clinical practices. Elucidating the context of R/S and its value to PM can advance efforts toward a more whole-person and patient-centered approach to improve individual and population health.

RevDate: 2019-07-11

Pardo LM, Voigt AP, Alonzo TA, et al (2019)

Deciphering the Significance of CD56 Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.

Cytometry. Part B, Clinical cytometry [Epub ahead of print].

BACKGROUND: In patients with acute myeloid leukemia (AML), CD56 expression has been associated with adverse clinical outcome. We reported on a phenotype associated with very poor prognosis (RAM) in children enrolled in the Children's Oncology Group trial AAML0531 (Brodersen et al. Leukemia 30 (2016) 2077-2080). RAM is also characterized in part by high-intensity expression of the CD56 antigen. Herein, we investigate underlying biological and clinical differences among CD56-positive AMLs for patients in AAML0531.

METHODS: For 769 newly diagnosed pediatric patients with de novo AML enrolled in AAML0531, bone marrow specimens were submitted for flow cytometric analysis. For each patient, an immunophenotypic expression profile (IEP) was defined by mean fluorescent intensities of assayed surface antigens. Unsupervised hierarchical clustering analysis (HCA) was completed to group patients with similar immunophenotypes. Clusters were then evaluated for CD56 expression. Principal component analysis (PCA) was subsequently applied to determine whether CD56-positive patient groups were nonoverlapping.

RESULTS: HCA of IEPs revealed three unique phenotypic clusters of patients with CD56-positive AML, and PCA showed that these three cohorts are distinct. Cohort 1 (N = 77) showed a prevalence of t(8;21) patients (72%), Cohort 2 (N = 52) a prevalence of 11q23 patients (69%), and Cohort 3 (RAM) (N = 16) a prevalence of patients with co-occurrence of the CBFA2T3-GLIS2 fusion transcript (63%). The 5-year event-free survival (EFS) for Cohorts 1, 2, and 3 were 69, 39, and 19%, respectively.

CONCLUSIONS: When leukemia is considered by its multidimensional immunophenotype and not by the expression of a single antigen, correlations are seen between genotype and there are significant differences in patient outcomes. © 2019 International Clinical Cytometry Society.

RevDate: 2019-07-11

Barlow WE, Beaber EF, Geller BM, et al (2019)

Evaluating screening participation, follow-up and outcomes for breast, cervical and colorectal cancer in the PROSPR consortium.

Journal of the National Cancer Institute pii:5530599 [Epub ahead of print].

BACKGROUND: Cancer screening is a complex process encompassing risk assessment, the initial screening examination, diagnostic evaluation, and treatment of cancer precursors or early cancers. Metrics that enable comparisons across different screening targets are needed. We present population-based screening metrics for breast, cervical, and colorectal cancers for nine sites participating in the PROSPR consortium.

METHODS: We describe how selected metrics map to a trans-organ conceptual model of the screening process. For each cancer type, we calculated calendar year 2013 metrics for the screen-eligible target population (breast: ages 40-74; cervical: ages 21-64; colorectal: ages 50-75). Metrics for screening participation, timely diagnostic evaluation, and diagnosed cancers in the screened and total populations are presented for the total eligible population and stratified by age group and cancer type.

RESULTS: The overall screening eligible populations in 2013 were 305,568 participants for breast, 3,160,128 for cervical, and 2,363,922 for colorectal cancer screening. Being up-to-date for testing was common for all three cancer types: breast (63.5%); cervical (84.6%); and colorectal (77.5%). Percentage of abnormal screens ranged from 10.7% for breast, 4.4% for cervical, and 4.5% for colorectal cancer screening. Abnormal breast screens were followed up diagnostically in almost all (96.8%) cases while cervical and colorectal were similar (76.2% and 76.3%, respectively). Cancer rates per 1,000 screens were 5.66, 0.17, and 1.46, respectively for breast, cervical, and colorectal cancer.

CONCLUSIONS: Comprehensive assessment of metrics by the PROSPR consortium enabled systematic identification of screening process steps in need of improvement. We encourage widespread use of common metrics to allow interventions to be tested across cancer types and healthcare settings.

RevDate: 2019-07-11

Molstad AJ, Hsu L, W Sun (2019)

Gaussian process regression for survival time prediction with genome-wide gene expression.

Biostatistics (Oxford, England) pii:5530981 [Epub ahead of print].

Predicting the survival time of a cancer patient based on his/her genome-wide gene expression remains a challenging problem. For certain types of cancer, the effects of gene expression on survival are both weak and abundant, so identifying non-zero effects with reasonable accuracy is difficult. As an alternative to methods that use variable selection, we propose a Gaussian process accelerated failure time model to predict survival time using genome-wide or pathway-wide gene expression data. Using a Monte Carlo expectation-maximization algorithm, we jointly impute censored log-survival time and estimate model parameters. We demonstrate the performance of our method and its advantage over existing methods in both simulations and real data analysis. The real data that we analyze were collected from 513 patients with kidney renal clear cell carcinoma and include survival time, demographic/clinical variables, and expression of more than 20 000 genes. In addition to the right-censored survival time, our method can also accommodate left-censored or interval-censored outcomes; and it provides a natural way to combine multiple types of high-dimensional -omics data. An R package implementing our method is available in the Supplementary material available at Biostatistics online.

RevDate: 2019-07-11

Wirsching HG, Zhang H, Szulzewsky F, et al (2019)

Arming oHSV with ULBP3 drives abscopal immunity in lymphocyte-depleted glioblastoma.

JCI insight, 4(13): pii:128217.

Oncolytic viruses induce local tumor destruction and inflammation. Whether virotherapy can also overcome immunosuppression in noninfected tumor areas is under debate. To address this question, we have explored immunologic effects of oncolytic herpes simplex viruses (oHSVs) in a genetically engineered mouse model of isocitrate dehydrogenase (IDH) wild-type glioblastoma, the most common and most malignant primary brain tumor in adults. Our model recapitulates the genomics, the diffuse infiltrative growth pattern, and the extensive macrophage-dominant immunosuppression of human glioblastoma. Infection with an oHSV that was armed with a UL16-binding protein 3 (ULBP3) expression cassette inhibited distant tumor growth in the absence of viral spreading (abscopal effect) and yielded accumulation of activated macrophages and T cells. There was also abscopal synergism of oHSVULBP3 with anti-programmed cell death 1 (anti-PD-1) against distant, uninfected tumor areas; albeit consistent with clinical trials in patients with glioblastoma, monotherapy with anti-PD-1 was ineffective in our model. Arming oHSV with ULBP3 led to upregulation of antigen processing and presentation gene sets in myeloid cells. The cognate ULBP3 receptor NKG2D, however, is not present on myeloid cells, suggesting a noncanonical mechanism of action of ULBP3. Overall, the myeloid-dominant, anti-PD-1-sensitive abscopal effect of oHSVULBP3 warrants further investigation in patients with IDH wild-type glioblastoma.

RevDate: 2019-07-12

Chen YB, Elias N, Heher E, et al (2019)

Haploidentical hematopoietic cell and kidney transplantation for hematological malignancies and end-stage renal failure.

Blood, 134(2):211-215.

At Massachusetts General Hospital, we pioneered simultaneous hematopoietic cell (HCT)/kidney transplantation from HLA-identical related donors for the treatment of hematological malignancies with end-stage renal failure. We have now extended this to HLA-haploidentical donors in a pilot trial. Six recipients, 5 of whom were conditioned with fludarabine, cyclophosphamide, and total-body irradiation, underwent combined HCT/kidney transplantation from haploidentical donors; graft-versus-host disease (GVHD) prophylaxis included post-HCT cyclophosphamide, tacrolimus, and mycophenolate mofetil. One patient died as a result of complications of fludarabine neurological toxicity. No neurological toxicity was observed in subsequent patients who received lower fludarabine doses and more intense postfludarabine dialysis. There were no cases of grade 2 to 4 acute GVHD and 1 case of moderate chronic GVHD by 12 months. One patient experienced relapse of multiple myeloma at 30 months after HCT and died 4 years posttransplantation. Overall, 4 of 6 patients remain alive, without disease relapse and with long-term renal rejection-free survival. This trial was registered at as #NCT01758042.

RevDate: 2019-07-11

Winters BR, De Sarkar N, Arora S, et al (2019)

Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy.

JCI insight, 5: pii:128728.

BACKGROUND: Little is known about the genomic differences between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We compare genomic features of primary and metastatic UTUC and LTUC tumors in a cohort of patients with end stage disease.

METHODS: We performed whole exome sequencing on matched primary and metastatic tumor samples (N=37) from 7 patients with metastatic UC collected via rapid autopsy. Inter- and intra-patient mutational burden, mutational signatures, predicted deleterious mutations, and somatic copy alterations (sCNV) were analyzed.

RESULTS: We investigated 3 patients with UTUC (3 primary samples, 13 metastases) and 4 patients with LTUC (4 primary samples, 17 metastases). We found that sSNV burden was higher in metastatic LTUC compared to UTUC. Moreover, the APOBEC mutational signature was pervasive in metastatic LTUC and less so in UTUC. Despite a lower overall sSNV burden, UTUC displayed greater inter- and intra-individual genomic distances at the copy number level between primary and metastatic tumors than LTUC. Our data also indicate that metastatic UTUC lesions can arise from small clonal populations present in the primary cancer. Importantly, putative druggable mutations were found across patients with the majority shared across all metastases within a patient.

CONCLUSIONS: Metastatic UTUC demonstrated a lower overall mutational burden but greater structural variability compared to LTUC. Our findings suggest that metastatic UTUC displays a greater spectrum of copy number divergence from LTUC. Importantly, we identified druggable lesions shared across metastatic samples, which demonstrate a level of targetable homogeneity within individual patients.

RevDate: 2019-07-10

Dixon SB, Li N, Yasui Y, et al (2019)

Racial and ethnic disparities in neurocognitive, emotional, and quality-of-life outcomes in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Cancer [Epub ahead of print].

BACKGROUND: Survivors of childhood cancer are at risk of neurocognitive impairment, emotional distress, and poor health-related quality of life (HRQOL); however, the effect of race/ethnicity is understudied. The objective of this study was to identify race/ethnicity-based disparities in neurocognitive, emotional, and HRQOL outcomes among survivors of childhood cancer.

METHODS: Self-reported measures of neurocognitive function, emotional distress (the Brief Symptom Inventory-18), and HRQOL (the Medical Outcomes Study Short Form-36 health survey) were compared between minority (Hispanic, n = 821; non-Hispanic black [NHB], n = 600) and non-Hispanic white (NHW) (n = 12,287) survivors from the Childhood Cancer Survivor Study (median age, 30.9 years; range, 16.0-54.1 years). By using a sample of 3055 siblings, the magnitude of same-race/same-ethnicity survivor-sibling differences was compared between racial/ethnic groups, adjusting for demographic and treatment characteristics and current socioeconomic status (SES).

RESULTS: No clear pattern of disparity in neurocognitive outcomes by race/ethnicity was observed. The magnitude of the survivor-sibling difference in the mean score for depression was greater in Hispanics than in NHWs (3.59 vs 1.09; P = .004). NHBs and Hispanics had greater survivor-sibling differences in HRQOL than NHWs for mental health (NHBs: -5.78 vs -0.69; P = .001; Hispanics: -3.87 vs -0.69; P = .03), and social function (NHBs: -7.11 vs -1.47; P < .001; Hispanics: -5.33 vs -1.47; P = .001). NHBs had greater survivor-sibling differences in physical subscale scores for HRQOL than NHWs. In general, the findings were not attenuated by current SES.

CONCLUSIONS: Although no pattern of disparity in neurocognitive outcomes was observed, differences across many HRQOL outcomes among minorities compared with NHWs, not attenuated by current SES, were identified. This suggests that further research into environmental and sociocultural factors during and immediately after treatment is needed.

RevDate: 2019-07-10

Percival MM, EH Estey (2019)

Current treatment strategies for measurable residual disease in patients with acute myeloid leukemia.

Cancer [Epub ahead of print].

Patients with acute myeloid leukemia (AML) who achieve a morphologic complete remission still can have measurable residual disease (MRD) detected by multiparametric flow cytometry, molecular methods, or cytogenetics. Such patients with MRD have a high risk of disease recurrence over a short timeframe, but optimal treatment strategies are unknown. Outcomes with conventional treatment, including allogeneic hematopoietic cell transplantation, are worse than those for patients without MRD. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with MRD.

RevDate: 2019-07-10

Heffner JL, Mull KE, Watson NL, et al (2019)

Long-term smoking cessation outcomes for sexual minority vs. non-minority smokers in a large randomized, controlled trial of two web-based interventions.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco pii:5530422 [Epub ahead of print].

INTRODUCTION: Despite greater smoking prevalence among sexual minority (SM) individuals relative to non-SM individuals, minimal research has examined whether SM smokers have differential success at quitting, and no prior treatment studies have examined differences within SM subgroups. There is also limited knowledge of the psychosocial characteristics of treatment-seeking SM smokers, which could inform targeted treatments. To address these gaps, we compared treatment outcomes and baseline characteristics for SM and non-SM smokers and for bisexual vs. lesbian or gay smokers in a large randomized, controlled trial of two web-based cessation treatments.

METHODS: Trial participants completed a survey to assess baseline characteristics, including self-identification as either SM (n=253; lesbian/gay, n=122; bisexual, n=131) or non-SM (n=2,384). The primary cessation outcome was complete-case self-reported 30-day abstinence at 12 months post-randomization.

RESULTS: Cessation outcomes did not differ significantly for SM vs. non-SM smokers (24% vs. 25%, adjusted OR=0.91, 95% CI=0.65-1.28) or across SM subgroups (24% for bisexual vs. 23% for lesbian/gay, adjusted OR=1.01, 95% CI=0.51-2.00), and there were no interactions with treatment group assignment. At baseline, SM smokers differed from non-SM smokers on most demographics, were more likely to screen positive for all mental health conditions assessed, and had greater exposure to other smokers in the home.

CONCLUSIONS: Substantial differences in baseline characteristics of SM vs. non-SM smokers and bisexual vs. lesbian/gay smokers did not translate into differential treatment outcomes. Nonetheless, SM smokers' willingness or ability to quit smoking could be enhanced by taking their unique psychosocial profile into account when designing targeted interventions.

IMPLICATIONS: The findings of this study, which included the largest sample of sexual minority (SM) smokers in a prospective intervention trial to date, support those of a small extant body of literature showing no differences in treatment-assisted cessation outcomes between sexual minority (SM) and non-SM smokers. Regardless of their quit rates relative to non-SM smokers, SM smokers' willingness or ability to quit smoking could potentially be enhanced by taking their unique psychosocial profile into account in intervention design, including their younger age, lower socioeconomic status, greater likelihood of being racial or ethnic minorities, and greater prevalence of mental health symptoms.

RevDate: 2019-07-10

Sridharan V, Shoda Y, Heffner J, et al (2019)

A Pilot Randomized Controlled Trial of a Web-Based Growth Mindset Intervention to Enhance the Effectiveness of a Smartphone App for Smoking Cessation.

JMIR mHealth and uHealth, 7(7):e14602 pii:v7i7e14602.

BACKGROUND: Although smartphone apps have shown promise for smoking cessation, there is a need to enhance their low engagement rates. This study evaluated the application of the growth mindset theory, which has demonstrated the potential to improve persistence in behavior change in other domains, as a means to improve engagement and cessation.

OBJECTIVE: This study aimed to explore the feasibility, utility, and efficacy of a Web-based growth mindset intervention for addiction when used alongside a smoking cessation app.

METHODS: Daily smokers (N=398) were all recruited on the Web and randomly assigned to receive either a cessation app alone or the app plus a Web-delivered growth mindset intervention. The primary outcome was engagement, that is, the number of log-ins to the smoking cessation app. The secondary outcome was 30-day point prevalence abstinence at 2-month follow-up collected through a Web-based survey.

RESULTS: The 2-month outcome data retention rate was 91.5% (364/398). In addition, 77.9% (310/398) of the participants in the experimental arm viewed at least 1 page of their growth mindset intervention, and 21.1% (84/398) of the group viewed all the growth mindset intervention. The intention-to-treat analysis did not show statistically significant differences between the experimental and comparison arms on log-ins to the app (19.46 vs 21.61; P=.38). The experimental arm had cessation rates, which trended higher than the comparison arm (17% vs 13%; P=.10). The modified intent-to-treat analysis, including only participants who used their assigned intervention at least once (n=115 in experimental group and n=151 in the control group), showed that the experimental arm had a similar number of log-ins (32.31 vs 28.48; P=.55) but significantly higher cessation rates (21% vs 13%; P=.03) than the comparison arm.

CONCLUSIONS: A growth mindset intervention for addiction did not increase engagement rates, although it may increase cessation rates when used alongside a smartphone app for smoking cessation. Future research is required to refine the intervention and assess efficacy with long-term follow-up to evaluate the efficacy of the mindset intervention.


RevDate: 2019-07-10

Burnett-Hartman AN, Chubak J, Hua X, et al (2019)

The association between colorectal sessile serrated adenomas/polyps and subsequent advanced colorectal neoplasia.

Cancer causes & control : CCC pii:10.1007/s10552-019-01205-y [Epub ahead of print].

PURPOSE: Colorectal cancer (CRC) screening guidelines recommend increased surveillance of individuals with sessile serrated adenomas/polyps (SSA/Ps), but there is uncertainty about the risk associated with SSA/Ps. We aimed to determine the association between SSA/Ps and subsequent advanced colorectal neoplasia.

METHODS: This case-control study included Kaiser Permanente Washington (KPWA) members who received an index colonoscopy between 1/1/1998 and 12/31/2007, and had hyperplastic polyps (HPs) or SSA/Ps but no conventional adenomas according to study pathologist histologic review. Subsequent pathology reports and biopsies through 1/1/2013 were reviewed for advanced colorectal neoplasia. We linked to the Seattle-Puget Sound Surveillance Epidemiology and End Results (SEER) registry to identify additional CRC cases. We used generalized estimating equations with a logit link to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for advanced colorectal neoplasia, comparing those with SSA/Ps to those with HPs.

RESULTS: There were 161 individuals with index SSA/Ps, 548 with HPs, and 918 subsequent endoscopies included in analyses. Of those with index SSA/Ps, 19 had subsequent advanced colorectal neoplasia; 39 with HPs had subsequent advanced colorectal neoplasia. Compared to those with HPs, those with SSA/Ps were not statistically significantly more likely to have subsequent advanced colorectal neoplasia (adjusted OR 1.79; CI 0.98-3.28). Polyp size ≥ 10 mm, right colon location, and the presence of multiple serrated polyps were also not associated with advanced colorectal neoplasia.

CONCLUSIONS: Our results suggest that there is not a strong association between SSA/Ps and subsequent advanced colorectal neoplasia during the 5 years following SSA/P removal.

RevDate: 2019-07-10

Vitanza NA, M Monje (2019)

Diffuse Intrinsic Pontine Glioma: From Diagnosis to Next-Generation Clinical Trials.

Current treatment options in neurology, 21(8):37 pii:10.1007/s11940-019-0577-y.

PURPOSE OF REVIEW: This review of diffuse intrinsic pontine glioma (DIPG) provides clinical background, a systematic approach to diagnosis and initial care, and synthesizes historical, modern, and future directions for treatment. We present evidence supporting neurosurgical biopsy, early palliative care involvement, limitation of glucocorticoid use, and the leveraging of preclinical DIPG models as a pipeline to next-generation clinical trials.

RECENT FINDINGS: New molecular understanding of pediatric high-grade gliomas has led to the reclassification of DIPG as one member of a family of diffuse gliomas occurring in the midline of the central nervous system that exhibit pathognomonic mutations in genes encoding histone 3 (H3 K27M). DIPG remains a clinically relevant term, though diagnostically the 80% of DIPG cases that exhibit the H3 K27M mutation have been reclassified as diffuse midline glioma, H3 K27M-mutant. Re-irradiation has been shown to be well-tolerated and of potential benefit. Epigenetic targeting of transcriptional dependencies in preclinical models is fueling molecularly targeted clinical trials. Chimeric antigen receptor T cell immunotherapy has also demonstrated efficacy in preclinical models and provides a promising new clinical strategy. DIPG is a universally fatal, epigenetically driven tumor of the pons that is considered part of a broader class of diffuse midline gliomas sharing H3 K27M mutations. Radiation remains the standard of care, single-agent temozolomide is not recommended, and glucocorticoids should be used only sparingly. A rapid evolution of understanding in the chromatin, signaling, and immunological biology of DIPG may soon result in clinical breakthroughs.

RevDate: 2019-07-10

Woo J, Choi DR, Storer BE, et al (2019)

Impact of clinical, cytogenetic, and molecular profiles on long-term survival after transplantation in patients with chronic myelomonocytic leukemia.

Haematologica pii:haematol.2019.218677 [Epub ahead of print].

Chronic myelomonocytic leukemia is a heterogeneous group of clonal hematopoietic malignancies with variable clinical and molecular features. We analyzed long term results of allogeneic hematopoietic cell transplantation in patients with chronic myelomonocytic leukemia and determined clinical and molecular risk factors associated with outcomes. Data on 129 patients, aged 7-74 (median 55) years, at various stages of the disease and transplanted from related or unrelated donors were analyzed. In 52 patients somatic mutations present pre-hematopoietic cell transplantation were determined using a panel of 75 genes. Progression-free survival at 10 years was 29%. The major cause of death was relapse (32%), which was significantly associated with adverse cytogenetics (hazard ratio 3.77, p = 0.0002), Chronic myelomonocytic leukemia Prognostic Scoring System (hazard ratio 14.3, p = 0.01), and MD Anderson prognostic scores (hazard ratio = 9.4, p=0.005). Mortality was associated with high-risk cytogenetics (hazard ratio 1.88, p = 0.01) and high hematopoietic cell transplantation comorbidity index (score ≥ 4: hazard ratio 1.99, p = 0.01). High overall mutation burden (≥ 10 mutations, hazard ratio = 3.4, p = 0.02), and ≥ 4 mutated epigenetic regulatory genes (hazard ratio 5.4, p=0.003) were linked to relapse. Unsupervised clustering of the correlation matrix revealed distinct high-risk groups with unique associations of mutations and clinical features. Chronic myelomonocytic leukemia with high mutation burden appeared to be distinct from high-risk groups defined by complex cytogenetics. New transplant strategies must be developed that may target specific disease sub-groups, stratified by molecular profiling and clinical risk factors.

RevDate: 2019-07-09

Jarrett OD, Srinivasan S, Richardson BA, et al (2019)

Specific vaginal bacteria are associated with increased risk of Trichomonas vaginalis acquisition in women.

The Journal of infectious diseases pii:5530317 [Epub ahead of print].

BACKGROUND: While bacterial vaginosis has been associated with an increased risk of Trichomonas vaginalis (TV) acquisition, it is unknown if other characteristics of the vaginal microbiota, including the presence of key bacterial species, impact a woman's risk of TV.

METHODS: The pre-TV infection vaginal microbiota of 25 unique episodes of TV were compared to 50 controls who remained uninfected. Trichomonas vaginalis was detected by transcription mediated amplification. Vaginal microbiota were quantified using broad range polymerase chain reaction (PCR) and taxon-specific quantitative PCR of the 16S ribosomal RNA (rRNA) gene.

RESULTS: Trichomonas vaginalis acquisition was significantly associated with the presence of Prevotella amnii (risk ratio [RR] 2.21, 95%CI 1.12-4.38; p=.02) and Sneathia sanguinegens (RR 2.58, 95%CI 1.00-6.62; p=.049). When adjusted for menstrual phase, the association between P. amnii and TV acquisition remained similar (adjusted RR [aRR] 2.11, 95%CI 1.03-4.33; p=.04) but the association between S. sanguinegens and TV was attenuated (aRR 2.31, 95%CI 0.86-6.23; p=.10).

CONCLUSIONS: Key vaginal bacterial species may contribute to susceptibility to TV acquisition. Understanding how these bacterial species increase a woman's risk of TV could help to guide the development of novel strategies to reduce women's risk of TV infection.

RevDate: 2019-07-09

Bastidas A, de la Serna J, El Idrissi M, et al (2019)

Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A Randomized Clinical Trial.

JAMA, 322(2):123-133.

Importance: Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster.

Objective: To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients.

Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT.

Interventions: Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter.

Main Outcomes and Measures: The primary end point was occurrence of confirmed herpes zoster cases.

Results: Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P < .001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P = .02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P = .02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P = .01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points.

Conclusions and Relevance: Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months.

Trial Registration: Identifier: NCT01610414.

RevDate: 2019-07-09

LoPiccolo J, Schollenberger MD, Dakhil S, et al (2019)

Rescue therapy for patients with anti-PD-1-refractory Merkel cell carcinoma: a multicenter, retrospective case series.

Journal for immunotherapy of cancer, 7(1):170 pii:10.1186/s40425-019-0661-6.

Merkel cell carcinoma (MCC) is a rare but clinically aggressive cancer with a high mortality rate. In recent years, antibodies blocking the interactions among PD-1 and its ligands have generated durable tumor regressions in patients with advanced MCC. However, there is a paucity of data regarding effective therapy for patients whose disease is refractory to PD-1 pathway blockade. This retrospective case series describes a heterogeneous group of patients treated with additional immune checkpoint blocking therapy after MCC progression through anti-PD-1. Among 13 patients treated with anti-CTLA-4, alone or in combination with anti-PD-1, objective responses were seen in 4 (31%). Additionally, one patient with MCC refractory to anti-PD-1 and anti-CTLA-4 experienced tumor regression with anti-PD-L1. Our report - the largest case series to date describing this patient population - provides evidence that sequentially-administered salvage immune checkpoint blocking therapy can potentially activate anti-tumor immunity in patients with advanced anti-PD-1-refractory MCC and provides a strong rationale for formally testing these agents in multicenter clinical trials. Additionally, to the best of our knowledge, our report is the first to demonstrate possible anti-tumor activity of second-line treatment with a PD-L1 antibody in a patient with anti-PD-1-refractory disease.

RevDate: 2019-07-09

Donovan KM, Hudgens MG, PB Gilbert (2019)


The annals of applied statistics, 13(2):1147-1165.

An important objective in vaccine studies entails identifying an immune response which is predictive of disease risk. Nonparametric methods are developed for inference on immune response thresholds that are associated with specified levels of disease risk, including where the risk level is zero. This threshold is defined as the minimum immune response value above which disease risk is less than or equal to the desired level. The proposed nonparametric methods are compared to previously developed parametric methods in simulation studies. The methods are extended for use in studies that only measure the immune response in a subset of participants, such as case-cohort or case-control studies, and with right censored time to disease outcomes. Finally, these methods are used to estimate neutralizing antibody thresholds for virologically confirmed dengue risk using data from two recent dengue vaccine trials.

RevDate: 2019-07-08

Ehrhardt MJ, Chen Y, Sandlund JT, et al (2019)

Late Health Outcomes After Contemporary Lymphome Malin de Burkitt Therapy for Mature B-Cell Non-Hodgkin Lymphoma: A Report From the Childhood Cancer Survivor Study.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: The widely used, risk-based Lymphome Malin de Burkitt (LMB) chemotherapy regimen has improved survival rates for children with mature B-cell non-Hodgkin lymphoma (NHL); however, associated late effects remain understudied. We assessed late health outcomes after LMB treatment in the Childhood Cancer Survivor Study.

PATIENTS AND METHODS: Multivariable regression models compared chronic health conditions, health status, and socioeconomic and neurocognitive outcomes between survivors of NHL treated with the LMB regimen (n = 126), survivors of NHL treated with non-LMB regimens (n = 444), and siblings (n = 1,029).

RESULTS: LMB survivors were a median age of 10.2 years (range, 2.5 to 20.5 years) at diagnosis and 24.0 years (range, 10.3 to 35.3 years) at evaluation. Compared with siblings, LMB survivors were at increased risk for adverse health outcomes. However, survivors of NHL treated with LMB and non-LMB regimens did not differ with regard to risk of having any chronic health conditions, impaired health status, neurocognitive deficits, or poorer socioeconomic outcomes. Increased risk for the following specific neurologic conditions was observed in LMB survivors compared with non-LMB survivors: epilepsy (relative risk [RR], 15.2; 95% CI, 3.1 to 73.4); balance problems (RR, 8.9; 95% CI, 2.3 to 34.8); tremors (RR, 7.5; 95% CI, 1.9 to 29.9); weakness in legs (RR, 8.1; 95% CI, 2.5 to 26.4); severe headaches (RR, 3.2; 95% CI, 1.6 to 6.3); and prolonged arm, leg, or back pain (RR, 4.0; 95% CI, 2.2 to 7.1). The survivors from the group C LMB risk group (n = 50) were at the highest risk for these conditions; however, except for worse functional status (odds ratio, 2.7; 95% CI, 1.2 to 5.8), they were not at increased risk for other adverse health status or socioeconomic outcomes compared with non-LMB survivors.

CONCLUSION: Survivors treated with LMB and non-LMB regimens are largely comparable in late health outcomes except for excess neurotoxicity among LMB survivors. These data inform treatment efforts seeking to optimize disease control while minimizing toxicity.

RevDate: 2019-07-08

Ma W, Chen LS, Özbek U, et al (2019)

Integrative proteo-genomic analysis to construct CNA-protein regulatory map in breast and ovarian tumors.

Molecular & cellular proteomics : MCP pii:RA118.001229 [Epub ahead of print].

Recent development in high throughput proteomics and genomics profiling enable one to study regulations of genome alterations on protein activities in a systematic manner. In this paper, we propose a new statistical method, ProMAP, to systematically characterize the regulatory relationships between proteins and DNA copy number alterations (CNA) in breast and ovarian tumors based on proteogenomic data from the CPTAC-TCGA studies. Because of the dynamic nature of mass spectrometry instruments, proteomics data from labelled mass spectrometry experiments usually have non-ignorable batch effects. Moreover, mass spectrometry based proteomic data often possesses high percentages of missing values and non-ignorable missing-data patterns. Thus, we utilize a linear mixed effects model to account for the batch structure and explicitly incorporate the abundance-dependent-missing-data mechanism of proteomic data in ProMAP. In addition, we employ a multivariate regression framework to characterize the multiple-to-multiple regulatory relationships between CNA and proteins. Furthermore, we utilize proper statistical regularization to facilitate the detection of master genetic regulators, which affect the activities of many proteins and often play important roles in genetic regulatory networks. Improved performance of ProMAP over existing methods were illustrated through extensive simulation studies and real data examples. Applying ProMAP to the CPTAC-TCGA breast and ovarian cancer data sets, we identified many genome regions, including a few novel ones, whose CNA were associated with protein and/or phosphoprotein abundances. For example, in breast tumors, a small region in 8p11.21 was recognized as the second biggest hub in the CNA-phosphoprotein regulatory map, and further investigation of the regulatory targets suggests the potential role of 8p11.21 CNA in perturbing oxygen binding and transport activities in tumor cells. This and other findings from our analyses help to characterize the impacts of CNAs on protein activity landscapes, and cast light on the genetic regulation mechanisms underlying these tumors.

RevDate: 2019-07-07

Szmidt MK, Kaluza J, Harris HR, et al (2019)

Long-term dietary fiber intake and risk of chronic obstructive pulmonary disease: a prospective cohort study of women.

European journal of nutrition pii:10.1007/s00394-019-02038-w [Epub ahead of print].

PURPOSE: Until now, only two prospective cohort studies have investigated dietary fiber intake in relation to risk of chronic obstructive pulmonary disease (COPD), but neither examined long-term fiber intake. Both studies reported that total fiber intake was associated with decreased COPD risk; however, results for specific fiber sources were inconsistent. Thus, we prospectively evaluated the association between baseline and long-term intake of dietary fiber and COPD risk in a population-based prospective cohort of 35,339 Swedish women.

METHODS: Dietary fiber intake was assessed in 1987 and 1997 with a food frequency questionnaire. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

RESULTS: During follow-up (2002-2014), 1557 COPD cases were identified via linkage to the Swedish National Patient Register. Long-term high dietary fiber intake (≥ 26.5 vs. < 17.6 g/day) was associated with a 30% (95% CI 17-41%) lower risk of COPD. For specific fiber sources, cereal (≥ 16.3 vs. < 9.4 g/day; HR 0.67, 95% CI 0.55-0.81) and fruit fiber (≥ 7.6 vs. < 2.6 g/day; HR 0.65, 95% CI 0.5-0.81), but not vegetable fiber intake (≥ 5.4 vs. < 2.2 g/day; HR 1.03, 95% CI 0.81-1.28) were associated with lower COPD risk. Current and ex-smokers with low long-term total fiber intake (< 17.6 g/day) compared to never smokers with high intake (≥ 26.5 g/day) had a 33-fold (95% CI 23.6-46.6) and tenfold (95% CI 7.0-16.3), respectively, higher risk of COPD.

CONCLUSIONS: Our findings indicate that high fiber intake is a modifiable lifestyle factor which may decrease COPD risk primarily in current and ex-smokers.

RevDate: 2019-07-06

Rossenkhan R, Rolland M, Labuschagne JPL, et al (2019)

Combining Viral Genetics and Statistical Modeling to Improve HIV-1 Time-of-infection Estimation towards Enhanced Vaccine Efficacy Assessment.

Viruses, 11(7): pii:v11070607.

Knowledge of the time of HIV-1 infection and the multiplicity of viruses that establish HIV-1 infection is crucial for the in-depth analysis of clinical prevention efficacy trial outcomes. Better estimation methods would improve the ability to characterize immunological and genetic sequence correlates of efficacy within preventive efficacy trials of HIV-1 vaccines and monoclonal antibodies. We developed new methods for infection timing and multiplicity estimation using maximum likelihood estimators that shift and scale (calibrate) estimates by fitting true infection times and founder virus multiplicities to a linear regression model with independent variables defined by data on HIV-1 sequences, viral load, diagnostics, and sequence alignment statistics. Using Poisson models of measured mutation counts and phylogenetic trees, we analyzed longitudinal HIV-1 sequence data together with diagnostic and viral load data from the RV217 and CAPRISA 002 acute HIV-1 infection cohort studies. We used leave-one-out cross validation to evaluate the prediction error of these calibrated estimators versus that of existing estimators and found that both infection time and founder multiplicity can be estimated with improved accuracy and precision by calibration. Calibration considerably improved all estimators of time since HIV-1 infection, in terms of reducing bias to near zero and reducing root mean squared error (RMSE) to 5-10 days for sequences collected 1-2 months after infection. The calibration of multiplicity assessments yielded strong improvements with accurate predictions (ROC-AUC above 0.85) in all cases. These results have not yet been validated on external data, and the best-fitting models are likely to be less robust than simpler models to variation in sequencing conditions. For all evaluated models, these results demonstrate the value of calibration for improved estimation of founder multiplicity and of time since HIV-1 infection.

RevDate: 2019-07-05

Lamp K, McGovern S, Fong Y, et al (2019)

Point-of-care CD4 technology invalid result rates in public health care settings across five countries.

PloS one, 14(7):e0219021 pii:PONE-D-19-10541.

BACKGROUND: Since 2010, point-of-care (POC) CD4 testing platforms have been introduced in both urban and rural settings to expand access to testing by bringing diagnostic services closer to patients. We conducted an analysis of routinely collected CD4 testing data to determine the invalid result rates associated with POC CD4 testing.

METHODS: We analyzed 981,152 CD4 testing records collected from Alere Pima Analyzers between January 2011 and December 2016 across five countries in sub-Saharan Africa. Routinely collected data and programmatic records were used to determine the rate of invalid test results per month, by facility type, and by operator based on cumulative usage during the study period. In addition, frequency of invalid test types and utilization of control beads were assessed.

RESULTS: Across the five countries, 75,530 invalid messages were returned, resulting in an overall invalid result rate of 7.7%. The invalid result rate by country ranged from 6.6% to 11.2%. Invalid result rates were consistent across facility types. Invalid result rates were inversely correlated with operator usage: low volume operators (<50 tests over study period) experienced an invalid result rate of 10.2%, while high volume operators (>500 tests over study period) experienced an invalid result rate of 5.5%. Two invalid result types (exposure position control and reagent control) accounted for nearly 50% of invalid results. Routine data showed that control beads were run on 88.3% of days that the device was used.

CONCLUSIONS: Our analysis found that the rate of invalid results was consistent across all types of health facilities, indicating that decentralization of POC CD4 testing to lower level health facilities did not exhibit high invalid result rates or increase cartridge wastage. Additionally, invalid result rates were inversely correlated to operator usage, with high-volume operators experiencing lower invalid result rates than low-volume operators. POC CD4 testing can, therefore, be performed in decentralized national testing programs; however, adequate training, quality assurance, routine monitoring, and ongoing mentorship should also be implemented for success.

RevDate: 2019-07-05

Huang JY, Larose TL, Luu HN, et al (2019)

Circulating markers of cellular immune activation in pre-diagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3).

International journal of cancer [Epub ahead of print].

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA), and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared with the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all Ptrend <0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression. This article is protected by copyright. All rights reserved.

RevDate: 2019-07-05

Cohen L, Fiore-Gartland A, Randolph AG, et al (2019)

A Modular Cytokine Analysis Method Reveals Novel Associations With Clinical Phenotypes and Identifies Sets of Co-signaling Cytokines Across Influenza Natural Infection Cohorts and Healthy Controls.

Frontiers in immunology, 10:1338.

Cytokines and chemokines are key signaling molecules of the immune system. Recent technological advances enable measurement of multiplexed cytokine profiles in biological samples. These profiles can then be used to identify potential biomarkers of a variety of clinical phenotypes. However, testing for such associations for each cytokine separately ignores the highly context-dependent covariation in cytokine secretion and decreases statistical power to detect associations due to multiple hypothesis testing. Here we present CytoMod-a novel data-driven approach for analysis of cytokine profiles that uses unsupervised clustering and regression to identify putative functional modules of co-signaling cytokines. Each module represents a biosignature of co-signaling cytokines. We applied this approach to three independent clinical cohorts of subjects naturally infected with influenza in which cytokine profiles and clinical phenotypes were collected. We found that in two out of three cohorts, cytokine modules were significantly associated with clinical phenotypes, and in many cases these associations were stronger than the associations of the individual cytokines within them. By comparing cytokine modules across datasets, we identified cytokine "cores"-specific subsets of co-expressed cytokines that clustered together across the three cohorts. Cytokine cores were also associated with clinical phenotypes. Interestingly, most of these cores were also co-expressed in a cohort of healthy controls, suggesting that in part, patterns of cytokine co-signaling may be generalizable. CytoMod can be readily applied to any cytokine profile dataset regardless of measurement technology, increases the statistical power to detect associations with clinical phenotypes and may help shed light on the complex co-signaling networks of cytokines in both health and infection.

RevDate: 2019-07-05

Sacks JA, Fong Y, Gonzalez MP, et al (2019)

Performance of cepheid GeneXpert HIV-1 viral load plasma assay to accurately detect treatment failure: a clinical meta-analysis.

AIDS (London, England) [Epub ahead of print].

BACKGROUND: Coverage of viral load testing remains low with only half of the patients in need having adequate access. Alternative technologies to high throughput centralized machines can be used to support viral load scale-up; however, clinical performance data are lacking. We conducted a meta-analysis comparing the Cepheid Xpert HIV-1 viral load plasma assay to traditional laboratory-based technologies.

METHODS: Cepheid Xpert HIV-1 and comparator laboratory technology plasma viral load results were provided from 13 of the 19 eligible studies, which accounted for a total of 3790 paired data points. We used random effects models to determine the accuracy and misclassification at various treatment failure thresholds (detectable, 200, 400, 500, 600, 800 and 1000 copies/ml).

RESULTS: Thirty percent of viral load test results were undetectable, while 45% were between detectable and 10 000 copies/ml and the remaining 25% were above 10 000 copies/ml. The median Xpert viral load was 119 copies/ml and the median comparator viral load was 157 copies/ml, while the log10 bias was 0.04 (0.02-0.07). The sensitivity and specificity to detect treatment failure were above 95% at all treatment failure thresholds, except for detectable, at which the sensitivity was 93.33% (95% confidence interval: 88.2-96.3) and specificity was 80.56% (95% CI: 64.6-90.4).

CONCLUSION: The Cepheid Xpert HIV-1 viral load plasma assay results were highly comparable to laboratory-based technologies with limited bias and high sensitivity and specificity to detect treatment failure. Alternative specimen types and technologies that enable decentralized testing services can be considered to expand access to viral load.

RevDate: 2019-07-05

Armstrong AJ, Lin P, Higano CS, et al (2018)

Prognostic Association of Prostate-specific Antigen Decline with Clinical Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide in a Randomized Clinical Trial.

European urology oncology pii:S2588-9311(18)30203-7 [Epub ahead of print].

BACKGROUND: In the PREVAIL study, enzalutamide provided significant improvements versus placebo in clinical outcomes in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC). The association of post-treatment prostate-specific antigen (PSA) decline with clinical outcomes may provide important prognostic information.

OBJECTIVE: To evaluate associations between the magnitude of PSA decline from baseline to month 3 and clinical outcomes among enzalutamide recipients.

This was a post hoc retrospective analysis of PREVAIL, an international, randomized, double-blind, placebo-controlled phase 3 study. Men with mCRPC and no prior chemotherapy from the enzalutamide arm were included (n=872). Patients were grouped by confirmed maximal PSA decline from baseline to month 3 of treatment (n=795 evaluable).

Primary outcomes were overall survival and radiographic progression-free survival. Secondary outcomes included PSA progression-free survival, radiographic response, and degradation of Functional Assessment of Cancer Therapy-Prostate score, which were estimated using the Kaplan-Meier method.

RESULTS AND LIMITATIONS: Following 3mo of enzalutamide treatment, 88% (701/795), 80% (639/795), and 39% (307/795) of patients had postbaseline confirmed maximal PSA declines of ≥30%, ≥50%, and ≥90%, respectively, whereas 12% (94/795) had no confirmed maximal PSA decline or a decline of <30%. Greater degrees of PSA decline within the first 3mo of enzalutamide treatment were increasingly associated with longer overall survival, time to PSA and radiographic progression, higher objective soft-tissue responses, and longer time to quality-of-life deterioration than no PSA decline or declines of <30% from baseline. PSA flares (rise followed by fall) after enzalutamide treatment were rare (<1%).

CONCLUSIONS: The magnitude of PSA decline after 3mo of enzalutamide therapy was strongly associated with better clinical and patient-reported outcomes. This updated prognostic information is of clinical value to this patient population and their health care providers.

PATIENT SUMMARY: We report that decreases in PSA levels are closely linked to better health and survival after 3mo of enzalutamide treatment in men with metastatic prostate cancer. The PREVAIL trial is registered at as NCT01212991.

RevDate: 2019-07-05

Xu C, Furuya-Kanamori L, Liu Y, et al (2019)

Sedentary Behavior, Physical Activity, and All-Cause Mortality: Dose-Response and Intensity Weighted Time-Use Meta-analysis.

Journal of the American Medical Directors Association pii:S1525-8610(19)30400-1 [Epub ahead of print].

OBJECTIVES: Previous studies have placed those with excessive sedentary behavior at increased risk of all-cause mortality. There is evidence of interdependency of sedentary behavior with physical activity, and its elucidation will have implications for guidelines and practice. This study investigated if sedentary behavior-related mortality risk can be offset by moderate- to vigorous-intensity physical activity (MVPA) considered in a time-use fashion.

DESIGN: PubMed was searched (from its inception till May 2018) for studies or meta-analyses that used data harmonized for MVPA. Of the 17 data-custodians located, 7 provided data on sitting time or TV viewing time, or both. A dose-response meta-analysis modeling log relative risks of all-cause mortality against uncompensated sedentary behavior metabolic equivalent hours (USMh) was run using the robust error meta-regression method. (Registration: CRD42017062439) SETTING: Individual subject data held by data custodians on this topic.

PARTICIPANTS: General adults.

MEASUREMENTS: Sedentary time, MVPA.

RESULTS: Five harmonized cohorts of sitting time (258,688 participants) and 4 of TV viewing time (156,593 participants) demonstrated that sedentary behavior was significantly associated with mortality, but this risk was attenuated with increasing energy expenditure through MVPA modeled in a time-use fashion. The average increment in mortality per USMh spent on sitting was 1% [relative risk (RR) 1.01, 95% confidence interval (CI) 1.00, 1.02; P = .01] and that per USMh spent on TV viewing was 7% (RR 1.07, 95% CI 1.04, 1.10; P < .001). The thresholds for risk started at 7 USMh for sitting and 3 USMh for TV viewing.

CONCLUSIONS/IMPLICATIONS: Our findings suggest that overall daily sitting time energy expenditure of 7 MET-hours (or TV viewing of 3 MET-hours) in excess of that expended on MVPA is independently related to all-cause mortality. These findings support the view that sitting is strongly influenced by consideration of concurrent MVPA in its impact on adverse health consequences and that the USMh is a more practical metric of sedentary behavior.

RevDate: 2019-07-05

Ortblad KF, Kearney JE, Mugwanya K, et al (2019)

HIV-1 self-testing to improve the efficiency of pre-exposure prophylaxis delivery: a randomized trial in Kenya.

Trials, 20(1):396 pii:10.1186/s13063-019-3521-2.

BACKGROUND: The introduction of pre-exposure prophylaxis (PrEP) for human immunodeficiency virus-1 (HIV-1) prevention in Africa presents new challenges for health systems that are already overburdened because PrEP delivery requires frequent clinic visits (generally every 3 months) for HIV-1 testing and PrEP refills. HIV-1 self-testing (HIVST) has the potential to improve the efficiency of PrEP delivery by decreasing the number of clinic visits. Here, we describe the rationale and design of a randomized, noninferiority trial designed to test the effectiveness and safety of using HIVST to support PrEP delivery in Kenya.

METHODS: The JiPime-JiPrEP (Kiswahili for 'Test Yourself, PrEP Yourself') study is a three-arm randomized trial taking place in Thika, Kenya. Participants (n = 495) are eligible for enrollment if they are at least 18 years old, HIV-1 seronegative, and have been taking PrEP for 1 month. Three distinct participant types will be enrolled: men (n = 165) and women (n = 165) who are in mutually disclosed HIV-1 serodiscordant relationships, and women (n = 165) who are at HIV-1 risk and not in a known serodiscordant relationship. Participants in each of these subpopulations will be 1:1:1 randomized to: 1) the standard of care, with quarterly clinic visits; 2) oral HIVST, with biannual clinic visits plus oral HIVSTs to use at the quarters between those visits; or 3) blood-based HIVST, with biannual clinic visits plus blood-based HIVSTs. All participants will complete quantitative surveys and provide blood samples for the objective measurement of PrEP adherence at baseline, 6 months, and 12 months. The primary outcomes are PrEP adherence, PrEP continuation, and HIV-1 testing, measured at 6 months and secondarily at 12 months.

DISCUSSION: The findings from this trial can help to understand how HIVST-a new HIV-1 testing technology-can support health systems in sub-Saharan Africa. Additionally, the findings can inform policy aimed at improving the efficiency of PrEP implementation and scale-up in Kenya.

TRIAL REGISTRATION:, NCT03593629 . Retrospectively registered on 20 July 2018.

RevDate: 2019-07-04

Dean NE, Gsell PS, Brookmeyer R, et al (2019)

Design of vaccine efficacy trials during public health emergencies.

Science translational medicine, 11(499):.

Public health emergencies, such as an Ebola disease outbreak, provide a complex and challenging environment for the evaluation of candidate vaccines. Here, we outline the need for flexible and responsive vaccine trial designs to be used in public health emergencies, and we summarize recommendations for their use in this setting.

RevDate: 2019-07-04

Kiani Z, Bruneau J, Geraghty DE, et al (2019)

HLA-F on autologous HIV infected cells activates primary NK cells expressing the activating killer immunoglobulin-like receptor KIR3DS1.

Journal of virology pii:JVI.00933-19 [Epub ahead of print].

HIV-exposed seronegative KIR3DS1 homozygotes have a reduced risk of HIV infection. HLA-F is the ligand for the activating NK cell receptor (NKR) KIR3DS1. HLA-F is expressed on HIV-infected CD4 T cells. Co-culture of sorted, HIV-infected CD4- (siCD4-) T cells with NK cells activated a higher frequency of KIR3DS1+ than KIR3DS1- NK cells from KIR3DS1 homozygotes to elicit anti-HIV functions such as CCL4, IFN-γ and CD107a expression. This was the case whether KIR3DS1+/- NK cells were analyzed inclusively or exclusively by gating out NK cells co-expressing the NKRs, KIR2DL1/L2/L3, 3DL2, KIR2DS1/S2/S3/S5, NKG2A and ILT2. Blocking the interaction of HLA-F on siCD4- cells with KIR3DS1 on exclusively gated KIR3DS1+ NK cells with KIR3DS1-Fc chimeric protein or an HLA-F specific monoclonal antibody, reduced the frequency of activated KIR3DS1+ cells compared to control conditions. KIR3DS1+ NK cell activation by HIV-infected CD4 cells may underlie the reduced risk of KIR3DS1 homozygotes to HIV infection.IMPORTANCE This manuscript investigates a mechanism that may underly epidemiological studies showing that carriage of the KIR3DS1 homozygous genotype is more frequent among HIV exposed seronegative subjects than among HIV susceptible individuals. Carriage of this genotype is associated with a reduced risk of HIV infection. The protective mechanism involves the interaction of HLA-F on CD4 cells infected with replication competent HIV with the activating NK receptor, KIR3DS1. This interaction leads to the activation of KIR3DS1+ NK cells for secretion of cytokines and chemokines with anti-HIV activity. Among these is the secretion of CCL4, which binds and blocks CCR5, the co-receptor for HIV entry of HIV into new target cells. In the setting of an exposure to HIV, incoming HIV-infected cells expressing HLA-F rapidly activate KIR3DS1+ NK cells to elicit anti-HIV activity. Exclusive gating strategies and blocking experiments support the notion that the HLA-F/KIR3DS1 interaction is sufficient to activate NK cell functions.

RevDate: 2019-07-03

Khetan P, Boffetta P, Luce D, et al (2019)

Occupations and the Risk of Head and Neck Cancer: A Pooled Analysis of the International Head and Neck Cancer Epidemiology (INHANCE) Consortium.

Journal of occupational and environmental medicine, 61(5):397-404.

OBJECTIVE: To investigate the associations between head and neck cancer (HNC) risk and occupations.

METHODS: We harmonized data on occupations in a pooled analysis of 8839 HNC cases and 13,730 controls in International Head and Neck Cancer Epidemiology (INHANCE) consortium. Logistic regression was used to estimate odds ratios (ORs) for associations of occupations and HNC risk. Population attributable fraction (PAF) for occupations was calculated using the formula PEC × (OR - 1)/OR.

RESULTS: Trend of increasing HNC risk was found with increasing duration of employment for many occupations, including cooks (OR = 1.36; 95% confidence interval [CI] 1.09 to 1.68), cleaners (OR = 1.38; 95% CI 1.13 to 1.69), painters (OR = 1.82; 95% CI 1.42 to 2.35). The PAF for a priori occupations was 14.5% (95% CI 7.1% to 21.9%) for HNC.

CONCLUSIONS: We found associations between certain occupations and HNC risks, including for subsites, with a duration-response relationship.

RevDate: 2019-07-03

Chen JG, Johnson J, Egner P, et al (2019)

Dose-dependent detoxication of the airborne pollutant benzene in a randomized trial of broccoli sprout beverage in Qidong, China.

The American journal of clinical nutrition pii:5527777 [Epub ahead of print].

BACKGROUND: Airborne pollutants have collectively been classified as a known human carcinogen and, more broadly, affect the health of hundreds of millions of people worldwide. Benzene is a frequent component of air pollution, and strategies to protect individuals against unavoidable exposure to this and other airborne carcinogens could improve the public's health. Earlier clinical trials in Qidong, China, demonstrated efficacy in enhancing the detoxication of benzene using a broccoli sprout beverage.

OBJECTIVES: A randomized, placebo-controlled, multidose trial of a broccoli sprout beverage was designed to determine the lowest effective concentration that enhances benzene detoxication adjudged by enhanced excretion of the urinary biomarker, S-phenylmercapturic acid (SPMA).

METHODS: Following informed consent, 170 subjects were randomly assigned in 5 blocks of 34 each to drink either a placebo beverage (n = 55) or 1 of 3 graded concentrations of a broccoli sprout beverage [full (n = 25), one-half (n = 35), and one-fifth (n = 55)] for 10 consecutive days. Concentrations of SPMA arising through induced benzene conjugation with glutathione were quantified by MS in sequential 12-h overnight urine collections during the intervention.

RESULTS: MS was also used to quantify urinary sulforaphane metabolites in each dosing regimen that resulted in a median 24-h urinary output of 24.6, 10.3, and 4.3 µmol, respectively, confirming a dose-dependent de-escalation of the inducing principle within the beverage. A statistically significant increase in benzene mercapturic acids in urine was found for the high-dose group (+63.2%) during the 10-d period. The one-half dose (+11.3%) and one-fifth dose groups (-6.4%) were not significantly different from placebo controls.

CONCLUSIONS: An intervention with a broccoli sprout beverage enhanced the detoxication of benzene, an important airborne pollutant, when dosed at a concentration evoking a urinary elimination of ∼25 µmol sulforaphane metabolites per day, and it portends a practical and frugal population-based strategy to attenuate associated long-term health risks of air pollution. This trial was registered at as NCT02656420.

RevDate: 2019-07-03

Paunkov A, Chartoumpekis DV, Ziros PG, et al (2019)

Impact of Antioxidant Natural Compounds on the Thyroid Gland and Implication of the Keap1/Nrf2 Signaling Pathway.

Current pharmaceutical design pii:CPD-EPUB-99331 [Epub ahead of print].

BACKGROUND: Natural compounds with potential antioxidant properties have been used in the form of food supplements or extracts with the intent tfor prevention and or treatment of various diseases. Many of these compounds The cytoprotective Nrf2 pathway can be activated the cytoprotective Nrf2 pathwayby many of these compounds. Besides, Ssome of themse compounds are known to impact the thyroid gland, often with potential for side-effects, but in other instances with potential utility for in the treatment of thyroid disorders.

OBJECTIVE: In view of recent data regarding the multiple roles of Nrf2 in the thyroid, this review summarizes the current bibliography on natural compounds that can have an effect on thyroid gland physiology and pathophysiology, and it discusses the respective potential implication of the Nrf2 system in the respective mechanisms.

METHOD & RESULTS: Literature searches for articles from 1950 to 2018 wereas performed in PubMed andor Google Scholar using relevant keywords about phytochemicals, Nrf2 and thyroid. Natural substances were categorized into phenolic compounds, sulfur-containing compounds, quinones, terpenoids, andor under the general category of plant extracts. For individual compounds in each category, respective data were summarized, as derived from in vitro (cell lines), preclinical (animal models) and clinical studies. The Mmain emerging themes were the following: phenolic compounds often showed potential to affect the production of thyroid hormones; sulfur-containing compounds impacted the pathogenesis of goiter and the proliferation of thyroid cancer cells; while quinones and terpenoids modified Nrf 2 signaling in thyroid cell lines.

CONCLUSION: Natural compounds that modify the activity of the Nrf2 pathway should be evaluated carefully, not only for their potential to be used as therapeutic agents for thyroid disorders, but also for their thyroidal safety when used for the prevention and treatment of non-thyroidal diseases.

RevDate: 2019-07-03

Garrison CB, Zhang Y, Navarro SL, et al (2019)

Proteomic analysis of plasma reveals fat mass influences cancer-related pathways in healthy humans fed controlled diets differing in glycemic load.

Cancer prevention research (Philadelphia, Pa.) pii:1940-6207.CAPR-19-0175 [Epub ahead of print].

Increased adiposity and diets high in glycemic load (GL) are associated with increased risk of many chronic diseases including cancer. Using plasma from 80 healthy individuals [40 men/40 women, 29 with DXA-derived low-fat mass (FM) and 51 with high FM] in a randomized crossover-controlled feeding trial and arrays populated with 3504 antibodies, we measured plasma proteins collected at baseline and end of each of two 28-day controlled diets: a low GL diet high in whole grains, legumes, fruits, and vegetables (WG) and a high GL diet high in refined grains and added sugars (RG). Following univariate testing for proteins differing by diet, we evaluated pathway-level involvement. Among all 80 participants, 172 proteins were identified as differing between diets. Stratifying participants by high and low FM identified 221 and 266 proteins respectively as differing between diets (unadjusted p<0.05). These candidate proteins were tested for overrepresentation in Reactome pathways, corresponding to 142 (of 291) pathways in the high FM group and 72 (of 274) pathways in the low FM group. We observed that the cancer-related pathways, DNA Repair, DNA Replication, and Cell Cycle, were overrepresented in the high FM participants while pathways involved in post-translational protein modification were overrepresented in participants with either FM. Although high GL diets are associated with increased risk of some cancers, our study further suggests that biology associated with consumption of GL diets is variable depending on an individual's adiposity and dietary recommendations related to cancer prevention be made with the additional consideration of an individual's FM.

RevDate: 2019-07-02

Zhuang Y, Huang Y, PB Gilbert (2019)

Simultaneous Inference of Treatment Effect Modification by Intermediate Response Endpoint Principal Strata with Application to Vaccine Trials.

The international journal of biostatistics pii:/j/ijb.ahead-of-print/ijb-2018-0058/ijb-2018-0058.xml [Epub ahead of print].

In randomized clinical trials, researchers are often interested in identifying an inexpensive intermediate study endpoint (typically a biomarker) that is a strong effect modifier of the treatment effect on a longer-term clinical endpoint of interest. Motivated by randomized placebo-controlled preventive vaccine efficacy trials, within the principal stratification framework a pseudo-score type estimator has been proposed to estimate disease risks conditional on the counter-factual biomarker of interest under each treatment assignment to vaccine or placebo, yielding an estimator of biomarker conditional vaccine efficacy. This method can be used for trial designs that use baseline predictors of the biomarker and/or designs that vaccinate disease-free placebo recipients at the end of the trial. In this article, we utilize the pseudo-score estimator to estimate the biomarker conditional vaccine efficacy adjusting for baseline covariates. We also propose a perturbation resampling method for making simultaneous inference on conditional vaccine efficacy over the values of the biomarker. We illustrate our method with datasets from two phase 3 dengue vaccine efficacy trials.

RevDate: 2019-07-02

Kachuri L, Helby J, Bojesen SE, et al (2019)

Investigation of Leukocyte Telomere Length and Genetic Variants in Chromosome 5p15.33 as Prognostic Markers in Lung Cancer.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 28(7):1228-1237.

BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus.

METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases.

RESULTS: Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3).

CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration.

IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.

RevDate: 2019-07-02

Bekaii-Saab TS, Ou FS, Ahn DH, et al (2019)

Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study.

The Lancet. Oncology pii:S1470-2045(19)30272-4 [Epub ahead of print].

BACKGROUND: Regorafenib confers an overall survival benefit in patients with refractory metastatic colorectal cancer; however, the adverse event profile of regorafenib has limited its use. Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. This study evaluated the safety and activity of two regorafenib dosing schedules.

METHODS: In this randomised, multicentre, open-label, phase 2 study done in 39 outpatient cancer centres in the USA, adults aged 18 years or older with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy, including EGFR inhibitors if KRAS wild-type, were enrolled. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had no previous treatment with regorafenib. Patients were randomly assigned (1:1:1:1) into four groups with two distinct regorafenib dosing strategies and two clobetasol usage plans, stratified by hospital. Regorafenib dosing strategies were a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib) if no significant drug-related adverse events occurred and a standard-dose strategy (160 mg/day orally) for 21 days of a 28-day cycle. Clobetasol usage plans (0·05% clobetasol cream twice daily applied to palms and soles) were either pre-emptive or reactive. After randomisation to the four preplanned groups, using the Pocock and Simon dynamic allocation procedures stratified by the treating hospitals, we formally tested the interaction between the two interventions, dosing strategy and clobetasol usage. Given the absence of a significant interaction (p=0·74), we decided to pool the data for the pre-emptive and reactive treatment with clobetasol and compared the two dosing strategies (dose escalation vs standard dose). The primary endpoint was the proportion of evaluable patients (defined as those who were eligible, consented, and received any protocol treatment) initiating cycle 3 and was analysed per protocol. Superiority for dose escalation was declared if the one-sided p value with Fisher's exact test was less than 0·2. This trial is registered with, number NCT02368886. This study is fully accrued but remains active.

FINDINGS: Between June 2, 2015, and June 22, 2017, 123 patients were randomly assigned to treatment, of whom 116 (94%) were evaluable. The per-protocol population consisted of 54 patients in the dose-escalation group and 62 in the standard-dose group. At data cutoff on July 24, 2018, median follow-up was 1·18 years (IQR 0·98-1·57). The primary endpoint was met: 23 (43%, 95% CI 29-56) of 54 patients in the dose-escalation group initiated cycle 3 versus 16 (26%, 15-37) of 62 patients in the standard-dose group (one-sided p=0·043). The most common grade 3-4 adverse events were fatigue (seven [13%] patients in the dose-escalation group vs 11 [18%] in the standard-dose group), hand-foot skin reaction (eight [15%] patients vs ten [16%] patients), abdominal pain (nine [17%] patients vs four [6%] patients), and hypertension (four [7%] patients vs nine [15%] patients). 14 patients had at least one drug-related serious adverse event: six patients in the dose-escalation group and eight patients in the standard-dose group. There was one probable treatment-related death in the standard-dose group (myocardial infarction).

INTERPRETATION: The dose-escalation dosing strategy represents an alternative approach for optimising regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data.

FUNDING: Bayer HealthCare Pharmaceuticals.

RevDate: 2019-07-01

Waller EK, Miklos D, Cutler C, et al (2019)

Ibrutinib for Chronic Graft-Versus-Host Disease After Failure of Prior Therapy: 1-Year Update of a Phase 1b/2 Study.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30407-0 [Epub ahead of print].

Chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic stem cell transplantation. In a phase 1b/2, open-label study (PCYC-1129; NCT02195869) involving 42 patients with active cGVHD who were steroid-dependent or -refractory, the activity and safety of ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, was demonstrated. Here, we describe extended follow-up for patients in this study. After a median (range) follow-up of 26 months (0.53‒36.7), best overall response rate (ORR) in the all treated population was 69% (29/42) with 13 (31%) patients who achieved a complete response and 16 (38%) patients who achieved a partial response. Sustained responses of ≥20, ≥32, and ≥44 weeks were seen in 20 (69%), 18 (62%), and 16 (55%) of the 29 responders, respectively. Of 26 patients with ≥2 involved organs, 19 (73%) showed responses in ≥2 organs; 6 of 10 patients (60%) with ≥3 involved organs showed responses in ≥3 organs. A total of 11 of 18 (61%) patients who had sclerosis at baseline showed a sclerotic response (39% complete response, 22% partial response). A total of 27 of 42 (64%) patients reached a corticosteroid dose of <0.15 mg/kg/day during the study; 8 responders discontinued corticosteroid treatment and remained off corticosteroid as of study closure. Safety findings for this updated analysis were consistent with the safety profile seen at the time of original analysis. Common grade ≥3 adverse events (AEs) were pneumonia (n=6), fatigue (n=5), and diarrhea (n=4). The onset of new grade ≥3 AEs decreased from 71% in the first year of treatment to 25% in the second year (n=12). AEs leading to discontinuation occurred in 18 (43%) patients. At a median follow-up of >2 years, ibrutinib continued to produce durable responses in patients with cGVHD that had failed prior systemic therapy. In this pretreated, high-risk population, clinically meaningful benefit and an acceptable safety profile was observed with additional follow-up for ibrutinib. These results demonstrate a substantial advance in the therapeutic management of patients with cGVHD.

RevDate: 2019-07-01

Moskowitz CS, Chou JF, Neglia JP, et al (2019)

Mortality After Breast Cancer Among Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Female survivors of childhood cancer have a high risk of subsequent breast cancer. We describe the ensuing risk for mortality and additional breast cancers.

PATIENTS AND METHODS: Female participants in the Childhood Cancer Survivor Study, a cohort of 5-year survivors of cancer diagnosed between 1970 and 1986 before age 21 years, and subsequently diagnosed with breast cancer (n = 274; median age at breast cancer diagnosis, 38 years; range, 20 to 58 years) were matched to a control group (n = 1,095) with de novo breast cancer. Hazard ratios (HRs) and 95% CIs were estimated from cause-specific proportional hazards models.

RESULTS: Ninety-two childhood cancer survivors died, 49 as a result of breast cancer. Overall survival after breast cancer was 73% by 10 years. Subsequent risk of death as a result of any cause was higher among childhood cancer survivors than among controls (HR, 2.2; 95% CI, 1.7 to 3.0) and remained elevated after adjusting for breast cancer treatment (HR, 2.4; 95% CI, 1.7 to 3.2). Although breast cancer-specific mortality was modestly elevated among childhood cancer survivors (HR, 1.3; 95% CI, 0.9 to 2.0), survivors were five times more likely to die as a result of other health-related causes, including other subsequent malignant neoplasms and cardiovascular or pulmonary disease (HR, 5.5; 95% CI, 3.4 to 9.0). The cumulative incidence of a second asynchronous breast cancer also was elevated significantly compared with controls (P < .001).

CONCLUSION: Mortality after breast cancer was higher in childhood cancer survivors than in women with de novo breast cancer. This increased mortality reflects the burden of comorbidity and highlights the need for risk-reducing interventions.

RevDate: 2019-07-01

Oeffinger KC, Ford JS, Moskowitz CS, et al (2019)

Promoting Breast Cancer Surveillance: The EMPOWER Study, a Randomized Clinical Trial in the Childhood Cancer Survivor Study.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: The aim of the current study was to increase the uptake of screening mammography among high-risk women who were treated for a childhood cancer with chest radiotherapy.

PATIENTS AND METHODS: Two hundred four female survivors in the Childhood Cancer Survivor Study who were treated with chest radiotherapy with 20 Gy or greater, age 25 to 50 years, and without breast imaging in the past 24 months were randomly assigned 2:1 to receive a mailed informational packet followed by a tailored telephone-delivered brief motivational interview (intervention) versus an attention control. Primary outcome was the difference in the proportion of participants who completed a screening mammogram by 12 months as evaluated in an intent-to-treat analysis. Stratum-adjusted relative risk (RR) and 95% CI were estimated using the Cochran-Mantel-Haenszel method. Secondary outcomes included the completion of screening breast magnetic resonance imaging (MRI) and barriers to screening and moderating factors.

RESULTS: Women in the intervention group were significantly more likely than those in the control group to report a mammogram (45 [33.1%] of 136 v 12 [17.6%] of 68; RR, 1.9; 95% CI, 1.1 to 3.3). The intervention was more successful among women age 25 to 39 years (RR, 2.2; 95% CI, 1.1 to 4.7) than among those age 40 to 50 years (RR, 1.4; 95% CI, 0.6 to 3.2). The proportion of women who reported a breast MRI at 12 months was similar between the two groups: 16.2% (intervention) compared with 13.2% (control; RR, 1.2; 95% CI, 0.6 to 2.5). Primary barriers to completing a screening mammogram and/or breast MRI included lack of physician recommendation, deferred action by survivor, cost, and absence of symptoms.

CONCLUSION: Use of mailed materials followed by telephone-delivered counseling increased mammography screening rates in survivors at high risk for breast cancer; however, this approach did not increase the rate of breast MRI. Cost of imaging and physician recommendation were important barriers that should be addressed in future studies.

RevDate: 2019-07-01

Sharma A, McLaughlin RN, Basom RS, et al (2019)

Macaque interferon-induced transmembrane proteins limit replication of SHIV strains in an Envelope-dependent manner.

PLoS pathogens, 15(7):e1007925 pii:PPATHOGENS-D-19-00310 [Epub ahead of print].

HIV-1 does not persistently infect macaques due in part to restriction by several macaque host factors. This has been partially circumvented by generating chimeric SIV/HIV-1 viruses (SHIVs) that encode SIV antagonist of known restriction factors. However, most SHIVs replicate poorly in macaques unless they are further adapted in culture and/or macaques (adapted SHIVs). Therefore, development of SHIVs encoding HIV-1 sequences derived directly from infected humans without adaptation (unadapted SHIVs) has been challenging. In contrast to the adapted SHIVs, the unadapted SHIVs have lower replication kinetics in macaque lymphocytes and are sensitive to type-1 interferon (IFN). The HIV-1 Envelope (Env) in the chimeric virus determines both the reduced replication and the IFN-sensitivity differences. There is limited information on macaque restriction factors that specifically limit replication of the more biologically relevant, unadapted SHIV variants. In order to identify the IFN-induced host factor(s) that could contribute to the inhibition of SHIVs in macaque lymphocytes, we measured IFN-induced gene expression in immortalized pig-tailed macaque (Ptm) lymphocytes using RNA-Seq. We found 147 genes that were significantly upregulated upon IFN treatment in Ptm lymphocytes and 31/147 were identified as genes that encode transmembrane helices and thus are likely present in membranes where interaction with viral Env is plausible. Within this group of upregulated genes with putative membrane-localized proteins, we identified several interferon-induced transmembrane protein (IFITM) genes, including several previously uncharacterized Ptm IFITM3-related genes. An evolutionary genomic analysis of these genes suggests the genes are IFITM3 duplications not found in humans that are both within the IFITM locus and also dispersed elsewhere in the Ptm genome. We observed that Ptm IFITMs are generally packaged at higher levels in unadapted SHIVs when compared to adapted SHIVs. CRISPR/Cas9-mediated knockout of Ptm IFITMs showed that depletion of IFITMs partially rescues the IFN sensitivity of unadapted SHIV. Moreover, we found that the depletion of IFITMs also increased replication of unadapted SHIV in the absence of IFN treatment, suggesting that Ptm IFITMs are likely important host factors that limit replication of unadapted SHIVs. In conclusion, this study shows that Ptm IFITMs selectively restrict replication of unadapted SHIVs. These findings suggest that restriction factors including IFITMs vary in their potency against different SHIV variants and may play a role in selecting for viruses that adapt to species-specific restriction factors.

RevDate: 2019-07-01

Leontiou I, London N, May KM, et al (2019)

The Bub1-TPR Domain Interacts Directly with Mad3 to Generate Robust Spindle Checkpoint Arrest.

Current biology : CB pii:S0960-9822(19)30704-3 [Epub ahead of print].

The spindle checkpoint monitors kinetochore-microtubule interactions and generates a "wait anaphase" delay when any defects are apparent [1-3]. This provides time for cells to correct chromosome attachment errors and ensure high-fidelity chromosome segregation. Checkpoint signals are generated at unattached chromosomes during mitosis. To activate the checkpoint, Mps1Mph1 kinase phosphorylates the kinetochore component KNL1Spc105/Spc7 on conserved MELT motifs to recruit Bub3-Bub1 complexes [4-6] via a direct Bub3 interaction with phospho-MELT motifs [7, 8]. Mps1Mph1 then phosphorylates Bub1, which strengthens its interaction with Mad1-Mad2 complexes to produce a signaling platform [9, 10]. The Bub1-Mad1 platform is thought to recruit Mad3, Cdc20, and Mad2 to produce the mitotic checkpoint complex (MCC), which is the diffusible wait anaphase signal [9, 11, 12]. The MCC binds and inhibits the mitotic E3 ubiquitin ligase, known as Cdc20-anaphase promoting complex/cyclosome (APC/C), and stabilizes securin and cyclin to delay anaphase onset [13-17]. Here we demonstrate, in both budding and fission yeast, that kinetochores and KNL1Spc105/Spc7 can be bypassed; simply inducing heterodimers of Mps1Mph1 kinase and Bub1 is sufficient to trigger metaphase arrest that is dependent on Mad1, Mad2, and Mad3. We use this to dissect the domains of Bub1 necessary for arrest, highlighting the need for Bub1-CD1, which binds Mad1 [9], and Bub1's highly conserved N-terminal tetratricopeptide repeat (TPR) domain [18, 19]. We demonstrate that the Bub1 TPR domain is both necessary and sufficient to bind and recruit Mad3. We propose that this brings Mad3 into close proximity to Mad1-Mad2 and Mps1Mph1 kinase, enabling efficient generation of MCC complexes.

RevDate: 2019-07-01

Preston JA, Bewley MA, Marriott HM, et al (2019)

Alveolar Macrophage Apoptosis-associated Bacterial Killing Helps Prevent Murine Pneumonia.

American journal of respiratory and critical care medicine, 200(1):84-97.

Rationale: Antimicrobial resistance challenges therapy of pneumonia. Enhancing macrophage microbicidal responses would combat this problem but is limited by our understanding of how alveolar macrophages (AMs) kill bacteria. Objectives: To define the role and mechanism of AM apoptosis-associated bacterial killing in the lung. Methods: We generated a unique CD68.hMcl-1 transgenic mouse with macrophage-specific overexpression of the human antiapoptotic Mcl-1 protein, a factor upregulated in AMs from patients at increased risk of community-acquired pneumonia, to address the requirement for apoptosis-associated killing. Measurements and Main Results: Wild-type and transgenic macrophages demonstrated comparable ingestion and initial phagolysosomal killing of bacteria. Continued ingestion (for ≥12 h) overwhelmed initial killing, and a second, late-phase microbicidal response killed viable bacteria in wild-type macrophages, but this response was blunted in CD68.hMcl-1 transgenic macrophages. The late phase of bacterial killing required both caspase-induced generation of mitochondrial reactive oxygen species and nitric oxide, the peak generation of which coincided with the late phase of killing. The CD68.hMcl-1 transgene prevented mitochondrial reactive oxygen species but not nitric oxide generation. Apoptosis-associated killing enhanced pulmonary clearance of Streptococcus pneumoniae and Haemophilus influenzae in wild-type mice but not CD68.hMcl-1 transgenic mice. Bacterial clearance was enhanced in vivo in CD68.hMcl-1 transgenic mice by reconstitution of apoptosis with BH3 mimetics or clodronate-encapsulated liposomes. Apoptosis-associated killing was not activated during Staphylococcus aureus lung infection. Conclusions: Mcl-1 upregulation prevents macrophage apoptosis-associated killing and establishes that apoptosis-associated killing is required to allow AMs to clear ingested bacteria. Engagement of macrophage apoptosis should be investigated as a novel, host-based antimicrobial strategy.

RevDate: 2019-06-30

Richardson AK, Walker LC, Cox B, et al (2019)

Breast cancer and cytomegalovirus.

Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico pii:10.1007/s12094-019-02164-1 [Epub ahead of print].

PURPOSE: To determine whether cytomegalovirus is causally associated with breast cancer and whether cytomegalovirus should be categorised as an oncogenic virus.

METHODS: We undertook a review of published epidemiological and laboratory studies, using established causal criteria: Bradford Hill criteria to determine whether cytomegalovirus is associated with breast cancer; and Evans/Mueller criteria to determine whether cytomegalovirus should be categorised as an oncogenic virus.

RESULTS: Although there are inconsistencies in the findings of published epidemiological and laboratory studies, these may be explained by factors such as: differences in timing of blood samples, differences in selection of cases and controls, or high cytomegalovirus seroprevalence among participants in the epidemiological studies; and, in the laboratory studies, differences in sample preparations, age of sample, whether or not paired breast cancer and normal breast tissue samples were used, differences in the tests, primers and/or antibodies used, differences in histological types of breast cancer studied, and/or features of the virus.

CONCLUSIONS: Overall, the results of published studies of cytomegalovirus and breast cancer suggest cytomegalovirus is a causal factor for at least some types of breast cancer. If the evidence for a link between cytomegalovirus and breast cancer continues to strengthen, further research could lead to: targeted screening; therapy using antiviral drugs; and, perhaps, primary prevention of a significant proportion of breast cancer. Vaccination against viruses has already been shown to be effective in preventing cervix and liver cancer; cytomegalovirus vaccines are already under development.

RevDate: 2019-06-30

Granot N, Storer BE, Cooper JP, et al (2019)

Allogeneic hematopoietic cell transplantation in the outpatient setting.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30409-4 [Epub ahead of print].

Conditioning with fludarabine and low dose total body irradiation before allogeneic hematopoietic stem cell transplantation (HCT) enabled treating older or medically infirm patients with advanced hematologic malignancies in the outpatient setting. Between December 1997 and June 2017, 1037 patients with hematological malignancies received peripheral blood stem cell (PBSC) grafts from HLA-matched or 1 HLA-antigen/ allele mismatched related or unrelated donors. Median age was 58 (range, 18-80) years. Serious comorbidities with HCT-CI scores ≥ 3 were present in 52% of patients. We found that 47% of patients were either never hospitalized, or only had an overnight hospital stay for infusion of late-arriving PBSC while 53% were admitted for a median of 6 days. Main reasons for admission were infection, fever, graft-versus-host disease and regimen-related toxicity. Two thirds of admissions occurred within 3 weeks of HCT. The 5-year risk of non-relapse mortality (NRM) was 26% among hospitalized patients and 13% among non-hospitalized patients. Significant risk factors for hospitalization included unrelated transplants, 1-HLA antigen mismatched transplants, high HCT-CI scores, and diagnosis of non-myeloma malignancies. Significant risk factors for NRM were hospitalization, older age, unrelated transplants and high HCT-CI scores. Ambulatory allogeneic HCT is feasible and safe.

RevDate: 2019-06-29

Scott SR, Smith KE, Dahman C, et al (2019)

Cd isotope fractionation during tobacco combustion produces isotopic variation outside the range measured in dietary sources.

The Science of the total environment, 688:600-608 pii:S0048-9697(19)32842-6 [Epub ahead of print].

Cadmium production has risen 1000-fold in the past 100 years, from under 20 to over 20,000 tons per year, causing anthropogenically-mobilized Cd to overwhelm natural sources in global cycling. Cadmium has no known biological function in humans, yet has biochemical behaviors similar to zinc and manganese, making exposure detrimental to human health. Identifying and quantifying the sources of Cd for human sub-populations is key to reducing exposures. Cadmium stable isotopes may provide a method for tracing Cd sources throughout the environment and the human body, but at present the limited database for high precision Cd isotopic compositions is inadequate to support such an analysis. Here, we provide new Cd isotope data on dietary sources, cigarette smoking components, and environmentally relevant standard reference materials. Results indicated that minor but significant variations are observed in food products (e.g., peanuts, sunflower seeds, spinach, kale, lettuce, cocoa powder; ~0.9‰ at 4 amu) that may be useful for tracing contamination in agricultural soils. In contrast, Cd isotope fractionation during smoking is larger (~6‰ at 4 amu) and has implications for tracing cadmium sources from tobacco combustion in the environment and throughout the human body. The primary inhaled component of cigarette smoke contains highest delta values (δ116/112Cd or δ114/110Cd ~5.2‰), while the second-hand smoke and cigarette ash have the lowest delta values (δ116/112Cd or δ114/110Cd ~-0.9‰). Used cigarette butts have δ114/110Cd ~2.4‰, in between the values measured in ash/s hand smoke and the inhaled smoke components. The high delta values of the inhaled smoke indicate that Cd isotopes may be used to determine the extent of Cd exposure due to smoking in human biological samples. This study provides new data for previously uncharacterized isotopic reservoirs that can be included in future studies of Cd source-exposure tracing.

RevDate: 2019-06-29

Grivas P, EY Yu (2019)

Role of Targeted Therapies in Management of Metastatic Urothelial Cancer in the Era of Immunotherapy.

Current treatment options in oncology, 20(8):67 pii:10.1007/s11864-019-0665-y.

OPINION STATEMENT: Despite significant advances and the approval of immune checkpoint inhibitors, metastatic urothelial carcinoma (mUC) is still very hard to treat and has poor outcomes. Deeper understanding of the molecular underpinnings of mUC has identified potential biomarkers, biologic drivers, and relevant therapy targets. However, targeted therapies in mUC have had significant challenges due to molecular heterogeneity, clonal evolution, and genomic instability, and have not improved outcomes so far. Despite that, recent technological developments, clinical utilization of molecular biology, and discovery of new agents with preclinical and early clinical activity have signaled a new age of experimental therapeutics in mUC. The more frequent use of next-generation sequencing of tumor tissue and cell-free circulating tumor DNA, combined with novel agents tested in clinical trials, provides promise. There is a plethora of agents being tested in mUC, including inhibitors of receptors and signaling pathways (e.g., fibroblast growth factor receptor, human epidermal growth factor receptor, phosphatidylinositol 3-kinase/AKT/mTOR pathway), angiogenesis (e.g., vascular endothelial growth factor and its receptors), poly (ADP-ribose) polymerase (PARP) inhibitors, immuno-oncology agents, cytotoxic agents (e.g., chemotherapy, antibody drug conjugates), and epigenetic modulators, among others. Two agents, enfortumab-vedotin (antibody drug conjugate) and erdafitinib (fibroblast growth factor receptor inhibitor), have breakthrough designation by the FDA, but are not approved as of March 2019. Novel combinations with various modalities and optimal sequencing of active therapies are being investigated in clinical trials. More sophisticated patient selection, discovery and prospective validation of predictive (and prognostic) biomarkers with clinical utility, and relevant clinical trial designs are important parameters in that context. Based on the above, there is high potential for targeted therapies to be added in the growing armamentarium of mUC, and possibly complement chemotherapy and immuno-oncology agents.

RevDate: 2019-06-29

Bien SA, Su YR, Conti DV, et al (2019)

Correction to: Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer.

Every author has erroneously been assigned to the affiliation "62". The affiliation 62 belongs to the author Graham Casey.

RevDate: 2019-06-29

Kim HT, Ahn KW, Hu ZH, et al (2019)

Prognostic score and cytogenetic risk classification for chronic lymphocytic leukemia patients: Center for International Blood and Marrow Transplant Research report.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-18-3988 [Epub ahead of print].

PURPOSE: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT).

EXPERIMENTAL DESIGN: We performed a retrospective analysis of outcomes of 606 CLL patients who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research.

RESULTS: Based on multivariable models, disease status, comorbidity index, lymphocyte count and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low, intermediate, high, and very high risk (4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, p<0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, p<0.0001). We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (p<0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4-year) and OS (75% at 4-year).

CONCLUSIONS: In this large cohort of previously treated CLL patients who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.

RevDate: 2019-06-29

Erba HP, Becker PS, Shami PJ, et al (2019)

Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia.

Blood advances, 3(13):1939-1949.

This open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX, PUMA, P21, and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53-wild-type patients and 0 of 3 (0%) TP53-mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at as #NCT02016729.

RevDate: 2019-06-29

Meers MP, Janssens DH, S Henikoff (2019)

Pioneer Factor-Nucleosome Binding Events during Differentiation Are Motif Encoded.

Molecular cell pii:S1097-2765(19)30397-1 [Epub ahead of print].

Although the in vitro structural and in vivo spatial characteristics of transcription factor (TF) binding are well defined, TF interactions with chromatin and other companion TFs during development are poorly understood. To analyze such interactions in vivo, we profiled several TFs across a time course of human embryonic stem cell differentiation and studied their interactions with nucleosomes and co-occurring TFs by enhanced chromatin occupancy (EChO), a computational strategy for classifying TF interactions with chromatin. EChO shows that multiple individual TFs can employ either direct DNA binding or "pioneer" nucleosome binding at different enhancer targets. Nucleosome binding is not exclusively confined to inaccessible chromatin but rather correlated with local binding of other TFs and degeneracy at key bases in the pioneer factor target motif responsible for direct DNA binding. Our strategy reveals a dynamic exchange of TFs at enhancers across developmental time that is aided by pioneer nucleosome binding.

RevDate: 2019-06-29

Emwas AH, Roy R, McKay RT, et al (2019)

NMR Spectroscopy for Metabolomics Research.

Metabolites, 9(7): pii:metabo9070123.

Over the past two decades, nuclear magnetic resonance (NMR) has emerged as one of the three principal analytical techniques used in metabolomics (the other two being gas chromatography coupled to mass spectrometry (GC-MS) and liquid chromatography coupled with single-stage mass spectrometry (LC-MS)). The relative ease of sample preparation, the ability to quantify metabolite levels, the high level of experimental reproducibility, and the inherently nondestructive nature of NMR spectroscopy have made it the preferred platform for long-term or large-scale clinical metabolomic studies. These advantages, however, are often outweighed by the fact that most other analytical techniques, including both LC-MS and GC-MS, are inherently more sensitive than NMR, with lower limits of detection typically being 10 to 100 times better. This review is intended to introduce readers to the field of NMR-based metabolomics and to highlight both the advantages and disadvantages of NMR spectroscopy for metabolomic studies. It will also explore some of the unique strengths of NMR-based metabolomics, particularly with regard to isotope selection/detection, mixture deconvolution via 2D spectroscopy, automation, and the ability to noninvasively analyze native tissue specimens. Finally, this review will highlight a number of emerging NMR techniques and technologies that are being used to strengthen its utility and overcome its inherent limitations in metabolomic applications.

RevDate: 2019-06-28

Swenson BR, Louie T, Lin HJ, et al (2019)

GWAS of QRS duration identifies new loci specific to Hispanic/Latino populations.

PloS one, 14(6):e0217796 pii:PONE-D-19-02985.

BACKGROUND: The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.

METHODS: We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.

RESULTS: We identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 (P = 1.19x10-24) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.

CONCLUSIONS: Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

RevDate: 2019-06-28

Steuten L, Garmo V, Phatak H, et al (2019)

Treatment Patterns, Overall Survival, and Total Healthcare Costs of Advanced Merkel Cell Carcinoma in the USA.

Applied health economics and health policy pii:10.1007/s40258-019-00492-5 [Epub ahead of print].

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive type of cancer with poor outcomes.

OBJECTIVE: To describe treatment patterns, overall survival, and healthcare costs associated with advanced MCC (aMCC) using data from Medicare enrollees who received an aMCC diagnosis in the USA States between 2006 and 2013.

METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2006 to 2013 were used to describe treatment patterns, 1- and 5-year overall survival, and total healthcare costs for the periods 12 months before aMCC diagnosis and 4-12 months afterward in patients aged ≥ 65 years.

RESULTS: We identified 257 patients with an aMCC diagnosis, of whom 51% had stage IIIb disease and 49% had stage IV. Within 4 months after diagnosis, 84% of patients (n = 216) received treatment; 45% (n = 115) received surgery, 48% (n = 124) radiation therapy, and 31% (n = 80) chemotherapy. Second-line chemotherapy was administered in 33% of patients (n = 26) receiving first-line chemotherapy. Median overall survival was 27 months in patients whose aMCC was diagnosed at stage IIIb and 12 months in patients whose aMCC was diagnosed at stage IV. Median total 12-month direct healthcare costs were US$48,006 (25th-75th percentile range = US$30,594-US$69,797) per patient. Total costs were highest in patients receiving chemotherapy, either alone or combined with radiation and/or surgery (US$52,854; 25th-75th percentile range = US$34,473-US$71,987).

CONCLUSION: Most patients with aMCC received initial treatment, including surgery, radiation, and/or chemotherapy, and approximately one-third of those receiving chemotherapy received second-line chemotherapy. Total 12-month direct healthcare costs were highest in patients who received chemotherapy alone or combined with radiation and/or surgery. These poor survival results and high treatment costs highlight the need for effective new aMCC therapies.

RevDate: 2019-06-28

Sandmaier BM, Kornblit B, Storer BE, et al (2019)

Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial.

The Lancet. Haematology pii:S2352-3026(19)30088-2 [Epub ahead of print].

BACKGROUND: Acute graft-versus-host-disease (GVHD) after non-myeloablative human leucocyte antigen (HLA)-matched, unrelated donor, allogeneic haemopoietic stem cell transplantation (HSCT) is associated with considerable morbidity and mortality. This trial aimed to evaluate the efficacy of adding sirolimus to the standard cyclosporine and mycophenolate mofetil prophylaxis therapy for preventing acute GVHD in this setting.

METHODS: This multicentre, randomised, phase 3 trial took place at nine HSCT centres based in the USA, Denmark, and Germany. Eligible patients were diagnosed with advanced haematological malignancies treatable by allogeneic HSCT, had a Karnofsky score greater than or equal to 60, were aged older than 50 years, or if they were aged 50 years or younger, were considered at high risk of regimen-related toxicity associated with a high-dose pre-transplantation conditioning regimen. Patients were randomly allocated by an adaptive randomisation scheme stratified by transplantation centre to receive either the standard GVHD prophylaxis regimen (cyclosporine and mycophenolate mofetil) or the triple-drug combination regimen (cyclosporine, mycophenolate mofetil, and sirolimus). Patients and physicians were not masked to treatment. All patients were prepared for HSCT with fludarabine (30 mg/m2 per day) 4, 3, and 2 days before receiving 2 or 3 Gy total body irradiation on the day of HSCT (day 0). In both study groups, 5·0 mg/kg of cyclosporine was administered orally twice daily starting 3 days before HSCT, and (in the absence of GVHD) tapered from day 96 through to day 150. In the standard GVHD prophylaxis group, 15 mg/kg of mycophenolate mofetil was given orally three times daily from day 0 until day 30, then twice daily until day 150, and (in the absence of GVHD) tapered off by day 180. In the triple-drug group, mycophenolate mofetil doses were the same as in the standard group, but the drug was discontinued on day 40. Sirolimus was started 3 days before HSCT, taken orally at 2 mg once daily and adjusted to maintain trough concentrations between 3-12 ng/mL through to day 150, and (in the absence of GVHD) tapered off by day 180. The primary endpoint was the cumulative incidence of grade 2-4 acute GVHD at day 100 post-transplantation. Secondary endpoints were non-relapse mortality, overall survival, progression-free survival, cumulative incidence of grade 3-4 acute GVHD, and cumulative incidence of chronic GVHD. Efficacy and safety analyses were per protocol, including all patients who received conditioning treatment and underwent transplantation. Toxic effects were measured according to the Common Terminology Criteria for Adverse Events (CTCAE). The current study was closed prematurely by recommendation of the Data and Safety Monitoring Board on July 27, 2016, after 168 patients received the allocated intervention, based on the results of a prespecified interim analysis for futility. This study is registered with, number NCT01231412.

FINDINGS: Participants were recruited between Nov 1, 2010, and July 27, 2016. Of 180 patients enrolled in the study, 167 received the complete study intervention and were included in safety and efficacy analyses: 77 patients in the standard GVHD prophylaxis group and 90 in the triple-drug group. At the time of analysis, median follow-up was 48 months (IQR 31-60). The cumulative incidence of grade 2-4 acute GVHD at day 100 was lower in the triple-drug group compared with the standard GVHD prophylaxis group (26% [95% CI 17-35] in the triple-drug group vs 52% [41-63] in the standard group; HR 0·45 [95% CI 0·28-0·73]; p=0·0013). After 1 and 4 years, non-relapse mortality increased to 4% (95% CI 0-9) and 16% (8-24) in the triple-drug group and 16% (8-24) and 32% (21-43) in the standard group (HR 0·48 [0·26-0·90]; p=0·021). Overall survival at 1 year was 86% (95% CI 78-93) in the triple-drug group and 70% in the standard group (60-80) and at 4 years it was 64% in the triple-drug group (54-75) and 46% in the standard group (34-57%; HR 0·62 [0·40-0·97]; p=0·035). Progression-free survival at 1 year was 77% (95% CI 68-85) in the triple-drug group and 64% (53-74) in the standard drug group, and at 4 years it was 59% in the triple-drug group (49-70) and 41% in the standard group (30-53%; HR 0·64 [0·42-0·99]; p=0·045). We observed no difference in the cumulative incidence of grade 3-4 acute GVHD (2% [0-5] in the triple-drug group vs 8% [2-14] in the standard group; HR 0·55 [0·16-1·96]; p=0·36) and chronic GVHD (49% [39-59] in triple-drug group vs 50% [39-61] in the standard group; HR 0·94 [0·62-1·40]; p=0·74). In both groups the most common CTCAE grade 4 or higher toxic effects were pulmonary.

INTERPRETATION: Adding sirolimus to cyclosporine and mycophenolate mofetil resulted in a significantly lower proportion of patients developing acute GVHD compared with patients treated with cyclosporine and mycophenolate mofetil alone. Based on these results, the combination of cyclosporine, mycophenolate mofetil, and sirolimus has become the new standard GVHD prophylaxis regimen for patients treated with non-myeloablative conditioning and HLA-matched unrelated HSCT at the Fred Hutchinson Cancer Research Center.

FUNDING: National Institutes of Health.

RevDate: 2019-06-28

Vaughan TL, Onstad L, JY Dai (2019)

Interactive decision support for esophageal adenocarcinoma screening and surveillance.

BMC gastroenterology, 19(1):109 pii:10.1186/s12876-019-1022-0.

BACKGROUND: A key barrier to controlling esophageal adenocarcinoma (EAC) is identifying those most likely to benefit from screening and surveillance. We aimed to develop an online educational tool, termed IC-RISC™, for providers and patients to estimate more precisely their absolute risk of developing EAC, interpret this estimate in the context of risk of dying from other causes, and aid in decision-making.

RESULTS: U.S. incidence and mortality data and published relative risk estimates from observational studies and clinical trials were used to calculate absolute risk of EAC over 10 years adjusting for competing risks. These input parameters varied depending on presence of the key precursor, Barrett's esophagus. The open source application works across common devices to gather risk factor data and graphically illustrate estimated risk on a single page. Changes to input data are immediately reflected in the colored graphs. We used the calculator to compare the risk distribution between EAC cases and controls from six population-based studies to gain insight into the discrimination metrics of current practice guidelines for screening, observing that current guidelines sacrifice a significant amount of specificity to identify 78-86% of eventual cases in the US population.

CONCLUSIONS: This educational tool provides a simple and rapid means to graphically communicate risk of EAC in the context of other health risks, facilitates "what-if" scenarios regarding potential preventative actions, and can inform discussions regarding screening, surveillance and treatment options. Its generic architecture lends itself to being easily extended to other cancers with distinct pathways and/or intermediate stages, such as hepatocellular cancer. IC-RISC™ extends current qualitative clinical practice guidelines into a quantitative assessment, which brings the possibility of preventative actions being offered to persons not currently targeted for screening and, conversely, reducing unnecessary procedures in those at low risk. Prospective validation and application to existing well-characterized cohort studies are needed.

RevDate: 2019-06-29

Russell AB, Elshina E, Kowalsky JR, et al (2019)

Single-Cell Virus Sequencing of Influenza Infections That Trigger Innate Immunity.

Journal of virology, 93(14): pii:JVI.00500-19.

Influenza virus-infected cells vary widely in their expression of viral genes and only occasionally activate innate immunity. Here, we develop a new method to assess how the genetic variation in viral populations contributes to this heterogeneity. We do this by determining the transcriptome and full-length sequences of all viral genes in single cells infected with a nominally "pure" stock of influenza virus. Most cells are infected by virions with defects, some of which increase the frequency of innate-immune activation. These immunostimulatory defects are diverse and include mutations that perturb the function of the viral polymerase protein PB1, large internal deletions in viral genes, and failure to express the virus's interferon antagonist NS1. However, immune activation remains stochastic in cells infected by virions with these defects and occasionally is triggered even by virions that express unmutated copies of all genes. Our work shows that the diverse spectrum of defects in influenza virus populations contributes to-but does not completely explain-the heterogeneity in viral gene expression and immune activation in single infected cells.IMPORTANCE Because influenza virus has a high mutation rate, many cells are infected by mutated virions. But so far, it has been impossible to fully characterize the sequence of the virion infecting any given cell, since conventional techniques such as flow cytometry and single-cell transcriptome sequencing (scRNA-seq) only detect if a protein or transcript is present, not its sequence. Here we develop a new approach that uses long-read PacBio sequencing to determine the sequences of virions infecting single cells. We show that viral genetic variation explains some but not all of the cell-to-cell variability in viral gene expression and innate immune induction. Overall, our study provides the first complete picture of how viral mutations affect the course of infection in single cells.

RevDate: 2019-06-27

Zhu P, Gafken PR, Mehl RA, et al (2019)

A Highly Versatile Expression System for the Production of Multiply Phosphorylated Proteins.

ACS chemical biology [Epub ahead of print].

Genetic Code Expansion (GCE) can use TAG stop codons to guide site-specific incorporation of phosphoserine (pSer) into proteins. To eliminate prematurely truncated peptides, improve yields, and enhance the production of multiphosphorylated proteins, Release Factor 1 (RF1)-deficient expression hosts were developed, yet these grew slowly and their use was associated with extensive misincorporation of natural amino acids instead of pSer. Here, we merge a healthy RF1-deficient E. coli cell line with a high-efficiency pSer GCE translation system to produce a versatile pSer GCE platform in which only trace misincorporation of natural amino acids is detected even when five phosphoserines were introduced into one protein. Approximately 400 and 200 mg of singly and doubly phosphorylated GFP per liter of culture were obtained. Importantly, the lack of truncated protein permits expression of oligomeric proteins and the use of N-terminal solubility-enhancing proteins to aid phospho-protein expression and purification. To illustrate the enhanced utility of this system, we produce doubly phosphorylated STING (Stimulator of Interferon Genes), as well as triply phosphorylated BAD (Bcl2-associated agonist of cell death) complexed with 14-3-3, in quantity, purity, and homogeneity sufficient for structural biology applications. We anticipate that the facile access to phosphoproteins enabled by this system, which we call pSer-3.1G, will expand studies of the phospho-proteome.

RevDate: 2019-06-26

Walsh C, Jang Y, Currin-McCulloch J, et al (2019)

Pilot Use of Selected Measures from the Patient-Reported Outcomes Measurement Information System Social and Mental Health Domains with Young Adult Cancer Patients During the Transition to Survivorship Care.

Journal of adolescent and young adult oncology [Epub ahead of print].

Social reintegration is an important part of young adult cancer patients' transition to survivorship care. As part of a mixed methods study exploring the social functioning of young adult cancer patients during this transition process, participants (N = 13) completed four selected measures from the Patient-Reported Outcomes Measurement Information System (PROMIS) social and mental health domains within ∼6 months of completion of active treatment and 3 months later. The majority of participants (n = 10) had T-scores within normal limits on all measures. Three participants had T-scores in the mild or moderate impairment range across time points. No significant differences were found between groups at Time 1 and Time 2 on any of the four measures.

RevDate: 2019-06-26

Steuten L, Goulart B, Meropol NJ, et al (2019)

Cost Effectiveness of Multigene Panel Sequencing for Patients With Advanced Non-Small-Cell Lung Cancer.

JCO clinical cancer informatics.

PURPOSE: Compared with single-marker genetic testing (SMGT), multigene panel sequencing (MGPS) has the potential to identify more patients with cancer who could benefit from targeted therapies, but the effects on outcome and total cost of care are uncertain. Our goal was to estimate the clinical and cost effectiveness of MGPS versus SMGT among patients with advanced non-small-cell lung cancer (aNSCLC).

METHODS: Patients with aNSCLC-stage IIIB or metastatic-who were diagnosed between 2011 and 2016 were identified from the Flatiron Health database. After stratifying patients into MGPS or SMGT cohorts, we analyzed the percentage of patients who received targeted treatment, survival, and total costs of care. SMGT included epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase testing. MGPS also allowed for the detection of BRAF, RET, ROS1, HER2, and MET mutations. Cost data sources were the Centers for Medicare & Medicaid Services Fee Schedule and 2017 average sales price drug cost. We estimated the incremental cost-effectiveness ratio from a US payer perspective over a lifetime horizon using a decision model.

RESULTS: We identified 5,688 patients with aNSCLC who received MGPS (n = 875) or SMGT (n = 4,813), of which 22% tested positive for epidermal growth factor receptor (18.5% MGPS; 17.3% SMGT) or anaplastic lymphoma kinase (3.59% MGPS; 3.78% SMGT). Among MGPS-tested patients, an additional 8% were found to have BRAF, RET, ROS1, HER2, or MET mutations. Of MGPS-tested patients, 21% received treatments that were targeted to the specific mutations versus 19% with SMGT. Expected survival was 1.14 life years (LYs) in SMGT versus 1.20 LYs in MGPS. Lifetime total costs were $8,814 higher per patient for MGPS. The incremental cost-effectiveness ratio of MGPS versus SMGT was $148,478 per LY gained.

CONCLUSION: On the basis of data from a nationwide oncology patient database, MGPS is shown to have moderate cost effectiveness compared with SMGT in patients with aNSCLC.

RevDate: 2019-06-26

Hedden L, Pollock P, Stirling B, et al (2019)

Patterns and predictors of registration and participation at a supportive care program for prostate cancer survivors.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-019-04927-6 [Epub ahead of print].

PURPOSE: To examine registration rates, and the timing/intensity of follow-up with a prostate cancer supportive care (PCSC) program, and to explore clinical and sociodemographic factors associated with participation and non-participation.

METHODS: We used electronic medical records for a cohort of men diagnosed with prostate cancer (PC) who attended a PC-related appointment at the Vancouver Prostate Centre, January 2013-December 2016. We used multivariate logistic regression to quantify the effect of diagnostic treatment and sociodemographic characteristic PCSC program registration and subsequent attendance. We produced Kaplan-Meier estimators to assess the probability of program attendance over the disease trajectory for those who registered.

RESULTS: Almost 15% of the men who registered for the program did not end up using any services. An additional 23% attended only one session/clinical appointment. Surgical and radiation treatments increased the odds and intensity of participation. Long travel distance decreased the odds of registering and participating. Low income decreased the odds of registration but not subsequent participation.

CONCLUSIONS: While the use of supportive care services can help address the detrimental effects of prostate cancer diagnosis and treatment, one in six men who register for supportive care do not end up using any. Offering these services at no cost and alongside treatment appears to be insufficient to ensuring access for all patients. Additional research is needed to understand barriers and facilitators of accessing supportive care in this population.

RevDate: 2019-06-26

Hu WF, Krieger KL, Lagundžin D, et al (2019)

CTDP1 regulates breast cancer survival and DNA repair through BRCT-specific interactions with FANCI.

Cell death discovery, 5:105 pii:185.

BRCA1 C-terminal domains are found in a specialized group of 23 proteins that function in the DNA damage response to protect genomic integrity. C-terminal domain phosphatase 1 (CTDP1) is the only phosphatase with a BRCA1 C-terminal domain in the human proteome, yet direct participation in the DNA damage response has not been reported. Examination of the CTDP1 BRCA1 C-terminal domain-specific protein interaction network revealed 103 high confidence interactions enriched in DNA damage response proteins, including FANCA and FANCI that are central to the Fanconi anemia DNA repair pathway necessary for the resolution of DNA interstrand crosslink damage. CTDP1 expression promotes DNA damage-induced FANCA and FANCD2 foci formation and enhances homologous recombination repair efficiency. CTDP1 was found to regulate multiple aspects of FANCI activity, including chromatin localization, interaction with γ-H2AX, and SQ motif phosphorylations. Knockdown of CTDP1 increases MCF-10A sensitivity to DNA interstrand crosslinks and double-strand breaks, but not ultraviolet radiation. In addition, CTDP1 knockdown impairs in vitro and in vivo growth of breast cancer cell lines. These results elucidate the molecular functions of CTDP1 in Fanconi anemia interstrand crosslink repair and identify this protein as a potential target for breast cancer therapy.

RevDate: 2019-06-26

Sanseviero E, O'Brien EM, Karras JR, et al (2019)

Anti-CTLA4 activates intratumoral NK cells and combined with IL15/IL15R-alpha complexes enhances tumor control.

Cancer immunology research pii:2326-6066.CIR-18-0386 [Epub ahead of print].

Antibodies targeting CTLA-4 induce durable responses in some patients with melanoma and are being tested in a variety of human cancers. However, these therapies are ineffective for a majority of patients across tumor types. Further understanding the immune alterations induced by these therapies may enable the development of novel strategies to enhance tumor control and biomarkers to identify patients most likely to respond. In several murine models, including colon26, MC38, CT26, and B16 tumors co-treated with GVAX, anti-CTLA-4 efficacy depends on interactions between the Fc region of CTLA-4 antibodies and Fc receptors (FcRs). Anti-CTLA-4 binding to FcRs has been linked to depletion of intratumoral T regulatory cells (Tregs). In agreement with previous studies, we found that Tregs infiltrating CT26, B16-F1, and autochthonous BrafV600EPten-/- melanoma tumors had higher expression of surface CTLA-4 (sCTLA-4) than other T cell subsets, and anti-CTLA-4 treatment led to Fc/FcR-dependent depletion of Tregs infiltrating CT26 tumors. This Treg depletion coincided with activation and degranulation of intratumoral NK cells. Similarly, in NSCLC and melanoma patient-derived tumor tissue Tregs had higher sCTLA-4 expression than other intratumoral T cell subsets, and Tregs infiltrating NSCLC expressed more sCTLA-4 than circulating Tregs. Cutaneous melanoma patients who benefited from Ipilimumab, a monoclonal antibody targeting CTLA-4, had higher intratumoral CD56 expression, compared with patients who received little to no benefit from this therapy. Furthermore, using the murine CT26 model we found that combination therapy with anti-CTLA-4 plus IL15/IL15R-alpha complexes enhanced tumor control compared to either monotherapy.

RevDate: 2019-06-26

Bethancourt HJ, Kratz M, K O'Connor (2019)

Spiritually-motivated restrictions on animal products have a limited impact on consumption of healthy plant-based foods.

The British journal of nutrition pii:S0007114519001533 [Epub ahead of print].

ABSTRACTPlant-based diets are considered healthier than many omnivorous diets. However, it is unclear that restriction of animal products necessarily motivates increased consumption of nutrient- and fiber-rich plant-based foods as opposed to energy-dense but nutrient-poor plant-based foods containing refined grains and added sugars and fats. This study examined food frequency questionnaire and food record data from 99 individuals in the United States with varying degrees of adherence to the Orthodox Christian tradition of restricting meat, dairy, and egg (MDE) products for 48 days prior to Easter to investigate whether restricting MDE products in the absence of explicit nutritional guidance would lead to increased consumption of healthy plant-based foods and greater likelihood of meeting dietary recommendations. Multiple linear regression models assessed changes in major food groups, energy, and nutrients in relation to the degree of reduction in MDE consumption. Logistic regression analyses tested the odds of meeting 2015-2020 Dietary Guidelines for Americans on plant-based foods in relation to MDE restriction. Each serving reduction in MDE products was associated with small (~0.1-0.7 serving) increases in legumes, soy products, and nuts/seeds (all p-values<0.005). MDE restriction was not associated with higher odds of meeting recommendations on vegetable, fruit, or whole grain intake. Consumption of refined grains and added sugars did not change in relation to MDE restriction but remained above recommended thresholds, on average. These findings demonstrate that a reduction of MDE products for spiritual purposes may result in increases in some nutrient-rich plant-based foods but may not uniformly lead to a healthier dietary composition.

RevDate: 2019-06-25

Xie L, Yuan AE, W Shou (2019)

Simulations reveal challenges to artificial community selection and possible strategies for success.

PLoS biology, 17(6):e3000295 pii:PBIOLOGY-D-18-01429 [Epub ahead of print].

Multispecies microbial communities often display "community functions" arising from interactions of member species. Interactions are often difficult to decipher, making it challenging to design communities with desired functions. Alternatively, similar to artificial selection for individuals in agriculture and industry, one could repeatedly choose communities with the highest community functions to reproduce by randomly partitioning each into multiple "Newborn" communities for the next cycle. However, previous efforts in selecting complex communities have generated mixed outcomes that are difficult to interpret. To understand how to effectively enact community selection, we simulated community selection to improve a community function that requires 2 species and imposes a fitness cost on one or both species. Our simulations predict that improvement could be easily stalled unless various aspects of selection were carefully considered. These aspects include promoting species coexistence, suppressing noncontributors, choosing additional communities besides the highest functioning ones to reproduce, and reducing stochastic fluctuations in the biomass of each member species in Newborn communities. These considerations can be addressed experimentally. When executed effectively, community selection is predicted to improve costly community function, and may even force species to evolve slow growth to achieve species coexistence. Our conclusions hold under various alternative model assumptions and are therefore applicable to a variety of communities.

RevDate: 2019-06-25

Smith AG, Pereira S, Jaramillo A, et al (2019)

Comparison of SSOP versus NGS for HLA-A, B, C, DRB1, DRB3/B4/B5, DQA1, DQB1, DPA1, and DPB1 typing: toward single pass high resolution HLA typing in support of solid organ and hematopoietic cell transplant programs.

HLA [Epub ahead of print].

Many clinical laboratories supporting solid organ transplant programs employ multiple HLA genotyping technologies, depending on individual laboratory needs. Sequence specific primers and quantitative PCR serve the rapid turnaround necessary for deceased donor workup, while sequence specific oligonucleotide probe (SSOP) technology is widely employed for higher volumes. When clinical need mandates high resolution data, Sanger sequencing-based typing (SBT) has been the "gold standard". However, all those methods commonly yield ambiguous typing results that utilize valuable laboratory resources when resolution is required. In solid organ transplantation, high resolution typing may provide critical information for highly sensitized patients with donor specific anti-HLA antibodies (DSA), particularly when DSA involve HLA alleles not discriminated by SSOP typing. Arguments against routine use of SBT include assay complexity, long turnaround times (TAT) and increased costs. Here we compare a next generation sequencing (NGS) technology with SSOP for accuracy, effort, turnaround time and level of resolution for genotyping of 11 HLA loci among 289 specimens from five clinical laboratories. Results were concordant except for SSOP mis-assignments in 8 specimens and 21 novel sequences uniquely identified by NGS. With few exceptions, SSOP generated ambiguous results while NGS provided unambiguous 3-field allele assignments. For complete HLA genotyping of up to 24 samples by either SSOP or NGS, bench work was completed on day 1 and typing results were available on day 2. This study provides compelling evidence that, although not viable for STAT typing of deceased donors, a single pass NGS HLA typing method has direct application for solid organ transplantation. This article is protected by copyright. All rights reserved.

RevDate: 2019-06-25

Chapuis AG, Egan DN, Bar M, et al (2019)

T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant.

Nature medicine pii:10.1038/s41591-019-0472-9 [Epub ahead of print].

Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) entering HCT with poor-risk features1-3. When HCT does produce prolonged relapse-free survival, it commonly reflects graft-versus-leukemia effects mediated by donor T cells reactive with antigens on leukemic cells4. As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many normal host tissues, graft-versus-leukemia effects are often accompanied by morbidity and mortality from graft-versus-host disease5. Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens6. We therefore isolated a high-affinity Wilms' Tumor Antigen 1-specific TCR (TCRC4) from HLA-A2+ normal donor repertoires, inserted TCRC4 into Epstein-Bar virus-specific donor CD8+ T cells (TTCR-C4) to minimize graft-versus-host disease risk and enhance transferred T cell survival7,8, and infused these cells prophylactically post-HCT into 12 patients (NCT01640301). Relapse-free survival was 100% at a median of 44 months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54% relapse-free survival (P = 0.002). TTCR-C4 maintained TCRC4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.

RevDate: 2019-06-25

Crane MM, Sands B, Battaglia C, et al (2019)

In vivo measurements reveal a single 5'-intron is sufficient to increase protein expression level in Caenorhabditis elegans.

Scientific reports, 9(1):9192 pii:10.1038/s41598-019-45517-0.

Introns can increase gene expression levels using a variety of mechanisms collectively referred to as Intron Mediated Enhancement (IME). IME has been measured in cell culture and plant models by quantifying expression of intronless and intron-bearing reporter genes in vitro. We developed hardware and software to implement microfluidic chip-based gene expression quantification in vivo. We altered position, number and sequence of introns in reporter genes controlled by the hsp-90 promoter. Consistent with plant and mammalian studies, we determined a single, natural or synthetic, 5'-intron is sufficient for the full IME effect conferred by three synthetic introns, while a 3'-intron is not. We found coding sequence can affect IME; the same three synthetic introns that increase mcherry protein concentration by approximately 50%, increase mEGFP by 80%. We determined IME effect size is not greatly affected by the stronger vit-2 promoter. Our microfluidic imaging approach should facilitate screens for factors affecting IME and other intron-dependent processes.

RevDate: 2019-06-25

Potter JD (2019)

Rising rates of colorectal cancer in younger adults.

BMJ (Clinical research ed.), 365:l4280.

RevDate: 2019-06-24

Kessler RC, Bossarte RM, Luedtke A, et al (2019)

Machine learning methods for developing precision treatment rules with observational data.

Behaviour research and therapy, 120:103412 pii:S0005-7967(19)30098-1 [Epub ahead of print].

Clinical trials have identified a variety of predictor variables for use in precision treatment protocols, ranging from clinical biomarkers and symptom profiles to self-report measures of various sorts. Although such variables are informative collectively, none has proven sufficiently powerful to guide optimal treatment selection individually. This has prompted growing interest in the development of composite precision treatment rules (PTRs) that are constructed by combining information across a range of predictors. But this work has been hampered by the generally small samples in randomized clinical trials and the use of suboptimal analysis methods to analyze the resulting data. In this paper, we propose to address the sample size problem by: working with large observational electronic medical record databases rather than controlled clinical trials to develop preliminary PTRs; validating these preliminary PTRs in subsequent pragmatic trials; and using ensemble machine learning methods rather than individual algorithms to carry out statistical analyses to develop the PTRs. The major challenges in this proposed approach are that treatment are not randomly assigned in observational databases and that these databases often lack measures of key prescriptive predictors and mental disorder treatment outcomes. We proposed a tiered case-cohort design approach that uses innovative methods for measuring and balancing baseline covariates and estimating PTRs to address these challenges.

RevDate: 2019-06-24

Ramsey SD, Shankaran V, SD Sullivan (2019)

Basket Cases: How Real-World Testing for Drugs Approved Based on Basket Trials Might Lead to False Diagnoses, Patient Risks, and Squandered Resources.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

RevDate: 2019-06-24

Meers MP, Bryson TD, Henikoff JG, et al (2019)

Improved CUT&RUN chromatin profiling tools.

eLife, 8: pii:46314 [Epub ahead of print].

Previously we described a novel alternative to Chromatin Immunoprecipitation, CUT&RUN, in which unfixed permeabilized cells are incubated with antibody, followed by binding of a Protein A-Micrococcal Nuclease (pA/MNase) fusion protein (Skene and Henikoff, 2017). Here we introduce three enhancements to CUT&RUN: A hybrid Protein A-Protein G-MNase construct that expands antibody compatibility and simplifies purification, a modified digestion protocol that inhibits premature release of the nuclease-bound complex, and a calibration strategy based on carry-over of E. coli DNA introduced with the fusion protein. These new features, coupled with the previously described low-cost, high efficiency, high reproducibility and high-throughput capability of CUT&RUN make it the method of choice for routine epigenomic profiling.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.


Order from Amazon

Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

Electronic Scholarly Publishing
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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).


ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.


Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )