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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 23 May 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: 2019-05-22

Sharon N, Vanderhooft J, Straubhaar J, et al (2019)

Wnt Signaling Separates the Progenitor and Endocrine Compartments during Pancreas Development.

Cell reports, 27(8):2281-2291.e5.

In vitro differentiation of pluripotent cells into β cells is a promising alternative to cadaveric-islet transplantation as a cure for type 1 diabetes (T1D). During the directed differentiation of human embryonic stem cells (hESCS) by exogenous factors, numerous genes that affect the differentiation process are turned on and off autonomously. Manipulating these reactions could increase the efficiency of differentiation and provide a more complete control over the final composition of cell populations. To uncover in vitro autonomous responses, we performed single-cell RNA sequencing on hESCs as they differentiate in spherical clusters. We observed that endocrine cells and their progenitors exist beside one another in separate compartments that activate distinct genetic pathways. WNT pathway inhibition in the endocrine domain of the differentiating clusters reveals a necessary role for the WNT inhibitor APC during islet formation in vivo. Accordingly, WNT inhibition in vitro causes an increase in the proportion of differentiated endocrine cells.

RevDate: 2019-05-22

Wu W, Pierce LA, Zhang Y, et al (2019)

Comparison of prediction models with radiological semantic features and radiomics in lung cancer diagnosis of the pulmonary nodules: a case-control study.

European radiology pii:10.1007/s00330-019-06213-9 [Epub ahead of print].

PURPOSE: To compare the ability of radiological semantic and quantitative texture features in lung cancer diagnosis of pulmonary nodules.

MATERIALS AND METHODS: A total of N = 121 subjects with confirmed non-small-cell lung cancer were matched with 117 controls based on age and gender. Radiological semantic and quantitative texture features were extracted from CT images with or without contrast enhancement. Three different models were compared using LASSO logistic regression: "CS" using clinical and semantic variables, "T" using texture features, and "CST" using clinical, semantic, and texture variables. For each model, we performed 100 trials of fivefold cross-validation and the average receiver operating curve was accessed. The AUC of the cross-validation study (AUCCV) was calculated together with its 95% confidence interval.

RESULTS: The AUCCV (and 95% confidence interval) for models T, CS, and CST was 0.85 (0.71-0.96), 0.88 (0.77-0.96), and 0.88 (0.77-0.97), respectively. After separating the data into two groups with or without contrast enhancement, the AUC (without cross-validation) of the model T was 0.86 both for images with and without contrast enhancement, suggesting that contrast enhancement did not impact the utility of texture analysis.

CONCLUSIONS: The models with semantic and texture features provided cross-validated AUCs of 0.85-0.88 for classification of benign versus cancerous nodules, showing potential in aiding the management of patients.

KEY POINTS: • Pretest probability of cancer can aid and direct the physician in the diagnosis and management of pulmonary nodules in a cost-effective way. • Semantic features (qualitative features reported by radiologists to characterize lung lesions) and radiomic (e.g., texture) features can be extracted from CT images. • Input of these variables into a model can generate a pretest likelihood of cancer to aid clinical decision and management of pulmonary nodules.

RevDate: 2019-05-22

Gilbert PB, Huang Y, Juraska M, et al (2019)

Bridging Efficacy of a Tetravalent Dengue Vaccine from Children/Adolescents to Adults in Highly Endemic Countries Based on Neutralizing Antibody Response.

The American journal of tropical medicine and hygiene [Epub ahead of print].

The CYD-TDV vaccine is licensed in multiple endemic countries based on vaccine efficacy (VE) against symptomatic, virologically confirmed dengue demonstrated in two phase 3 trials (CYD14, 2- to 14-year-olds, Asia; CYD15, 9- to 16-year-olds, Latin America). 50% plaque reduction neutralization test (PRNT50) titers at baseline and month 13 (post-vaccination) were associated with VE and may enable bridging VE to adults. Two phase 2 trials of CYD-TDV measured baseline and month 13 PRNT50 titers: CYD22 (9- to 45-year-olds, Vietnam) and CYD47 (18- to 45-year-olds, India). 50% plaque reduction neutralization test distributions were compared between age cohorts, and four versions of an epidemiological bridging method were used to estimate VE against any serotype (dengue virus [DENV]-Any) and against each serotype over 25 months post first vaccination in a hypothetical CYD14 + CYD15 18- to 45-year-old cohort (bridging population 1) and in the actual CYD47 18- to 45-year-old cohort (bridging population 2). Baseline and month 13 geometric mean PRNT50 titers to each serotype were significantly greater in 18- to 45-year-olds than 9- to 16-year-olds for all comparisons. The four methods estimated VE against DENV-Any at 75.3-86.0% (95% CIs spanning 52.5-100%) for bridging population 1 and 68.4-77.5% (95% CIs spanning 42.3-88.5%) for bridging population 2. The vaccine efficacy against serotype 1, 2, 3, and 4 was estimated at 56.9-76.9%, 68.3-85.8%, 91.4-95.0%, and 93.2-100% (bridging population 1) and 44.5-66.9%, 53.2-69.2%, 79.8-92.0%, and 90.6-95.0% (bridging population 2), respectively; thus, CYD-TDV would likely confer improved efficacy in adults than 9- to 16-year-olds. Using the same methods, we predicted VE against hospitalized DENV-Any over 72 months of follow-up, with estimates 59.1-73.5% (95% CIs spanning 40.9-92.2%) for bridging population 1 and 50.9-65.9% (95% CIs spanning 38.1-82.1%) for bridging population 2.

RevDate: 2019-05-22

Rafiee R, Chauhan L, Alonzo TA, et al (2019)

ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial.

Blood cancer journal, 9(6):51 pii:10.1038/s41408-019-0211-y.

Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC genotype in GO-arm (Event-free survival-EFS: p = 0.022; and risk of relapse-RR, p = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all p > 0.05). Consistent results were obtained when genotype groups were compared by GO and No-GO arms. The in vitro evaluation using HL60-cells further demonstrated consistent impact of rs1045642-T-allele on calicheamicin induced DNA-damage and cell-viability. Our results show the significance of ABCB1 SNPs on GO response in AML and warrants the need to investigate this in other cohorts. Once validated, ABCB1-SNPs in conjunction with CD33-SNPs can open up opportunities to personalize GO-therapy.

RevDate: 2019-05-22

Jackson SS, Van Dyke AL, Zhu B, et al (2019)

Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project.

Cancer research pii:0008-5472.CAN-19-0459 [Epub ahead of print].

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index, waist circumference, hip circumference, waist-to-hip and waist-to-height ratios. Hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in body mass index there were risk increases for GBC (HR: 1.27 [95% CI: 1.19, 1.36]), IHBDC (HR: 1.32 [95% CI: 1.21, 1.45]), and EHBDC (HR: 1.13 [95% CI: 1.03, 1.23]), but not AVC (HR: 0.99 [95% CI: 0.88, 1.11]). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers.

RevDate: 2019-05-21

Limaye AP, Green ML, Edmison BC, et al (2019)

Prospective Assessment of Cytomegalovirus Immunity in High-Risk Donor-Seropositive/Recipient-Seronegative Liver Transplant Recipients Receiving Either Preemptive Therapy or Antiviral Prophylaxis.

The Journal of infectious diseases pii:5480166 [Epub ahead of print].

The differential impact of preemptive therapy (PET) and antiviral prophylaxis (AP) on development of cytomegalovirus (CMV)-specific neutralizing antibody (nAb) and T-cell responses have not previously been directly compared in high-risk donor-seropositive/recipient-seronegative (D+R-) organ transplant recipients. We prospectively assessed T-cell and nAb responses 3 months after transplantation in cohorts of high-risk D+R- liver transplant recipients who received either PET (n = 15) or AP (n = 25) and a control group of CMV-seropositive transplant recipients (R+) (AP; n = 24). CMV phosphoprotein 65 (pp65)- and immediate early protein 1-specific multifunctional T-cell responses were determined by means of intracellular cytokine staining and nAbs against BADrUL131-Y4 CMV in adult retinal pigment epithelial cell line-19 human epithelial cells; nAbs were detected in 8 of 12 (67%) in the PET group, none of 17 in the AP group, and 20 of 22 (91%) in the R+ group. Multifunctional CD8 and CD4 T-cell responses to pp65 were generally similar between PET and R+ groups, and lower for the AP group; multifunctional CD4 responses were similar across all groups. Among D+R- liver transplant recipients, PET was associated with the development of greater nAb and multifunctional CD8 T-cell responses compared with AP, providing a potential mechanism to explain the relative protection against late-onset disease with PET. Future studies are needed to define specific immune parameters predictive of late-onset CMV disease with AP.

RevDate: 2019-05-21

Gulati R, Psutka SP, R Etzioni (2019)

Personalized risks of overdiagnosis for screen-detected prostate cancer incorporating patient comorbidities: Estimation and communication.

The Journal of urology [Epub ahead of print].

PURPOSE: Shared patient-physician decision-making regarding treatment for prostate cancer detected by prostate-specific antigen screening involves a complex calculus weighing the risk of the cancer and patient life expectancy. We investigated quantifying these competing risks using the probability that the cancer was "overdiagnosed"-i.e., would not have been clinically diagnosed (diagnosed without screening) during the patient's remaining lifetime.

MATERIALS AND METHODS: Using an established model of prostate cancer screening and clinical diagnosis, we simulated screen-detected cases and determined whether modeled clinical diagnosis would occur before non-cancer death, which was based on comorbidity-adjusted population lifetables. Logistic regression models were fitted to the simulated data and used to estimate overdiagnosis probabilities given patient age, PSA level, Gleason sum, and comorbidity category. An online calculator was developed to communicate overdiagnosis estimates; face validity and ease of use was assessed by surveying 32 clinical experts.

RESULTS: Estimated probabilities of overdiagnosis ranged 4%-78% across clinicopathologic variables and comorbidity status. Ignoring comorbidity, the estimated probability for a 70-year-old man with PSA 9.4 ng/mL and Gleason 6 is 34%; if he has severe comorbidities, the estimate increases to 51%, a personalization that may help inform the choice between active surveillance and definitive treatment. Based on responses from 20/32 experts, we modified the online calculator's explanation of overdiagnosis and input method for comorbid conditions.

CONCLUSIONS: The probability of overdiagnosis is strongly influenced by comorbidity status in addition to age. Personalized estimates incorporating comorbidity may contribute to shared decision-making between patients and providers regarding personalized treatment selection.

RevDate: 2019-05-21

Little RF, TS Uldrick (2019)

Are There Clues to Oral KSHV Shedding and Kaposi Sarcoma Oncogenesis in the Oral Microbiome?.

The Journal of infectious diseases pii:5491268 [Epub ahead of print].

RevDate: 2019-05-21

Bien SA, U Peters (2019)

Moving from one to many: insights from the growing list of pleiotropic cancer risk genes.

Pleiotropy, a phenomenon in which a single gene affects multiple phenotypes, is becoming very common among different cancer types and cancer-related phenotypes, such as those in hormonal, cardiometabolic and inflammatory/immune conditions. The discovery of pleiotropic associations can improve our understanding of cancer and help to target investigation of genes with greater clinical relevance.

RevDate: 2019-05-21

Goyal L, Shi L, Liu LY, et al (2019)

TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma.

Cancer discovery pii:2159-8290.CD-19-0182 [Epub ahead of print].

ATP-competitive Fibroblast Growth Factor Receptor (FGFR) kinase inhibitors, including BGJ398 and Debio1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor, TAS-120, demonstrated efficacy in four patients with FGFR2-fusion-positive ICC who developed resistance to BGJ398 or Debio1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsies and ctDNA, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC.

RevDate: 2019-05-20

Evans WD, Andrade EL, Barrett N, et al (2019)

Outcomes of the Adelante community social marketing campaign for Latino youth.

Health education research pii:5491515 [Epub ahead of print].

The authors designed and evaluated an innovative, branded campaign called 'Adelante' to promote positive youth development (PYD) and reduce risk behaviors among Latino youth near Washington, DC. Repeated cross-sectional surveys were conducted in the intervention and a comparison community to evaluate campaign exposure and changes in PYD outcomes. The sample consisted of 1549 Latino and immigrant adolescents surveyed at three time points in intervention and comparison communities. A social marketing campaign was implemented using outdoor advertising, Web, video and social media channels to promote PYD and health outcomes over a 1-year period from 2015 to 2016. Measures included media use; self-reported exposure to campaign promotions; Adelante message receptivity; validated PYD scales; substance use, sexual risk taking, violence-related knowledge, attitudes, beliefs, intentions and risk behavior. Outcomes were regressed first on campaign exposure to examine dose-response effects of the Adelante campaign over time. Second, we compared outcomes between the Adelante and comparison communities. We observed a positive effect of self-reported exposure on multiple outcomes, including improvements in pro-violence and sexual risk outcomes and lower pro-violence attitudes and lower risky attitudes toward sex. Adelante was effective in improving youth risk outcomes and offers a promising model for future health promotion with Latino and immigrant populations.

RevDate: 2019-05-20

Kerr KF, Marsh TL, H Janes (2019)

The Importance of Uncertainty and Opt-In v. Opt-Out: Best Practices for Decision Curve Analysis.

Medical decision making : an international journal of the Society for Medical Decision Making [Epub ahead of print].

RevDate: 2019-05-19

Cohen O, Strizich GM, Ramos AR, et al (2019)

Sex Differences in the Association Between Smoking and Sleep Disordered Breathing in the Hispanic Community Health Study/ Study of Latinos.

Chest pii:S0012-3692(19)31054-2 [Epub ahead of print].

BACKGROUND: Previous studies examining associations between cigarette smoking and sleep disordered breathing (SDB) are inconsistent. We therefore investigated this association in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

METHODS: 13,863 US Hispanics/Latinos, 18-76 years old, provided smoking histories and underwent home SDB testing. Logistic regression analyses were conducted to assess the independent association of smoking and SDB with covariate adjustment. Sex and age stratified analyses were done.

RESULTS: The weighted prevalence of moderate-to-severe SDB was 9.7% (95%CI: 9.0, 10.5). No independent and statistically significant association was observed between ever smoking (defined as minimum lifetime cigarette use of 100) and moderate-to-severe SDB (defined as apnea-hypopnea index ≥15) (OR 1.02, 95%CI: 0.85, 1.22; p=0.85). Sex and age were effect modifiers of the aforementioned association. Stratification by age and sex revealed that younger (35-54 years old) female smokers had 83% higher odds of SDB compared to younger female never smokers (OR 1.83, 95%CI: 1.19, 2.81; p=0.01). A significant dose response relationship was noted between smoking intensity and SDB in younger female smokers (p<0.01). Lastly, use of ≥10 cigarettes a day was associated with a nearly 3-fold increase in SDB odds in younger female ever smokers. The above associations were not observed in younger males.

CONCLUSIONS: In the HCHS/SOL, we found no independent and statistically significant association between smoking and SDB. Sex and age stratification revealed a novel statistically significant association between smoking and SDB in younger (35-54 years old) female smokers. Our findings highlight the importance of investigating sex and age specific associations of SDB risk factors.

RevDate: 2019-05-19

Bernstein DI, Flechtner JB, McNeil LK, et al (2019)

Therapeutic HSV-2 vaccine decreases recurrent virus shedding and recurrent genital herpes disease.

Vaccine pii:S0264-410X(19)30621-8 [Epub ahead of print].

BACKGROUND: Genital herpes simplex virus (HSV) type 2 is a common persistent infection that frequently reactivates to cause recurrent lesions and recurrent viral shedding which is incompletely controlled by antiviral therapy. GEN-003 is a candidate therapeutic vaccine containing 2 HSV-2 proteins, gD2 and ICP4, and Matrix-M2 adjuvant (M2).

METHODS: HSV-2 seropositive persons with genital herpes were randomized into three dose cohorts of Gen-003 (60 µg antigen/50 µg M2, 60 µg/75 µg M2 or Placebo). Three intramuscular doses 21 days apart of GEN-003 or placebo were administered. Participants obtained genital area swabs twice-daily for HSV-2 detection and monitored genital lesions for 12 months. The rates of virus shedding and lesion rates before vaccination were compared to 3 defined periods after vaccination; Days 43-71, Month 6 and Month 12.

RESULTS: GEN-003 at a dose of 60 µg each antigen/50 µg M2 reduced HSV shedding immediately after dosing with a rate ratio of 0.58, compared to 0.75 for the GEN-003 60 µg/75 µg M2 and 1.06 for placebo. Lesion rates, recurrence rates, and duration of recurrences were also reduced. Reactogenicity was higher with the 75 µg M2 dose than the 50 µg M2 dose, specifically for pain, tenderness, malaise and fatigue. Antibody and cellular immune responses were stimulated by both doses and persisted to 12 months.

CONCLUSIONS: GEN-003 vaccine manufactured with a scalable process gave results similar to those observed in prior clinical trials. GEN-003 had an acceptable safety profile and stimulated both humoral and cellular immune responses. The 60 µg antigen/50 µg M2 provided the maximal effect on virologic and clinical measures and warrants further development. (Funded by Genocea; number NCT02515175).

RevDate: 2019-05-18

Moffett HF, Harms CK, Fitzpatrick KS, et al (2019)

B cells engineered to express pathogen-specific antibodies protect against infection.

Science immunology, 4(35):.

Effective vaccines inducing lifelong protection against many important infections such as respiratory syncytial virus (RSV), HIV, influenza virus, and Epstein-Barr virus (EBV) are not yet available despite decades of research. As an alternative to a protective vaccine, we developed a genetic engineering strategy in which CRISPR-Cas9 was used to replace endogenously encoded antibodies with antibodies targeting RSV, HIV, influenza virus, or EBV in primary human B cells. The engineered antibodies were expressed efficiently in primary B cells under the control of endogenous regulatory elements, which maintained normal antibody expression and secretion. Using engineered mouse B cells, we demonstrated that a single transfer of B cells engineered to express an antibody against RSV resulted in potent and durable protection against RSV infection in RAG1-deficient mice. This approach offers the opportunity to achieve sterilizing immunity against pathogens for which traditional vaccination has failed to induce or maintain protective antibody responses.

RevDate: 2019-05-18

Xi LF, Schiffman M, Hughes JP, et al (2019)

Changes in DNA Level of Oncogenic Human Papillomaviruses Other Than Types 16 and 18 in Relation to Risk of Cervical Intraepithelial Neoplasia Grades 2 and 3.

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-18-0802 [Epub ahead of print].

BACKGROUND: Epidemiologic data addressing clinical relevance of viral load fluctuation of oncogenic types other than human papillomavirus (HPV) types 16 and 18 are limited.

METHODS: A type-stratified set of infections by non-HPV16/18 oncogenic types that were detected at ≥2 visits was randomly selected from women who were enrolled in a clinical trial and followed every 6 months for 2 years for detection of HPV and cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3). Type-specific viral load was measured on both first and last HPV-positive cervical swab samples.

RESULTS: CIN2/3 was initially confirmed at the last HPV-positive visit for 67 of 439 infections. The increase in risk of CIN2/3 was associated with high, relative to low, viral load at both first and last positive visits (OR adjusted=3.67; 95% CI, 1.19-11.32) and marginally associated with a change of viral load from low to high levels (OR adjusted=3.15; 95% CI, 0.96-10.35) for infection by species group alpha-9 non-HPV16 oncogenic types but not species group alpha-5-7 non-HPV18 oncogenic types. Among women with an initial diagnosis of CIN2/3 at the first positive visit, CIN2/3 was more frequently redetected at the last positive visit for infections with, compared to without, high DNA load of species group alpha-9 non-HPV16 oncogenic types at both visits (P exact=0.04).

CONCLUSIONS: In agreement with data on baseline viral load, the viral load change-associated risk of CIN2/3 differs by HPV species groups.

IMPACT: These findings underscore the importance of distinguishing species groups in future studies of clinical relevance of HPV DNA load.

RevDate: 2019-05-17

Corey L, Gray GE, SP Buchbinder (2019)

The aspirational necessity of HIV prevention.

Journal of the International AIDS Society, 22(5):e25289.

RevDate: 2019-05-17

Grivas P, Drakaki A, Friedlander TW, et al (2019)

Conceptual Framework for Therapeutic Development Beyond Anti-PD-1/PD-L1 in Urothelial Cancer.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

Platinum-based chemotherapy has been the standard of care in advanced urothelial cancer, but long-term outcomes have remained poor. Immune checkpoint inhibitors, with their favorable toxicity profiles and noteworthy efficacy, have steered a new era in advanced urothelial cancer, with five agents targeting the PD-1/PD-L1 pathway approved by the U.S. Food and Drug Administration (FDA). However, most patients do not achieve response, whereas immunotherapy-related adverse events may cause morbidity, increased health care use, and-rarely-mortality. Therefore, there is an urgent need for additional therapeutic modalities across the disease spectrum. A plethora of clinical trials are ongoing in various disease settings, including chemotherapy regimens, radiotherapy, antibody-drug conjugates, agents targeting additional immune checkpoint pathways, vaccine, cytokines, adoptive cell therapies, as well as targeted and anti-angiogenic agents. Two agents, enfortumab vedotin and erdafitinib, have breakthrough designation by the FDA but are not approved yet (at the time of this paper's preparation). Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials. Evaluation of new treatments has met with substantial challenges for many reasons, for example, molecular heterogeneity, clonal evolution, and genomic instability. In the era of precision molecular medicine, and because patients do not respond uniformly to current therapies, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. Here, we review current updates and future directions of experimental therapeutics in urothelial cancer, including examples (but not an exhaustive list) of ongoing clinical trials.

RevDate: 2019-05-17

Klepin HD, Estey E, T Kadia (2019)

More Versus Less Therapy for Older Adults With Acute Myeloid Leukemia: New Perspectives on an Old Debate.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

Most patients with newly diagnosed acute myeloid leukemia (AML) are at least age 65 and continue to have short survival, with many patients receiving no specific anti-AML therapy, particularly if they are older than age 75. Although consensus regarding optimal treatment of this growing population is lacking, treatment options are expanding even for the oldest patients. A fundamental question when seeing an older patient with AML is whether to recommend "more intensive" or "less intensive" induction therapy. Existing data can support more intensive treatment strategies for selected older adults, although there is growing evidence to support less intensive therapies as well. Randomized trials to provide clear comparisons between treatment strategies among well-characterized older adult populations are lacking. Reliance on age alone to determine treatment choice is problematic, as "fitness" or "unfitness" varies dramatically among patients of the same chronologic age and remains poorly characterized in existing studies. This article will provide differing perspectives on the "more" versus "less" question, with particular attention to recent drug approvals. Issues relevant to both treatment decision-making in practice and alternative trial design to inform gaps in knowledge will be discussed. Given the heterogeneity, an important conclusion will be that there is unlikely to be a single best approach and that appropriate decision-making requires considerations of many factors specific to individual patients.

RevDate: 2019-05-17

Simonich CA, Doepker L, Ralph D, et al (2019)

Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage.

Nature communications, 10(1):2190 pii:10.1038/s41467-019-09481-7.

HIV-infected infants develop broadly neutralizing plasma responses with more rapid kinetics than adults, suggesting the ontogeny of infant responses could better inform a path to achievable vaccine targets. Here we reconstruct the developmental lineage of BF520.1, an infant-derived HIV-specific broadly neutralizing antibody (bnAb), using computational methods developed specifically for this purpose. We find that the BF520.1 inferred naive precursor binds HIV Env. We also show that heterologous cross-clade neutralizing activity evolved in the infant within six months of infection and that, ultimately, only 2% SHM is needed to achieve the full breadth of the mature antibody. Mutagenesis and structural analyses reveal that, for this infant bnAb, substitutions in the kappa chain were critical for activity, particularly in CDRL1. Overall, the developmental pathway of this infant antibody includes features distinct from adult antibodies, including several that may be amenable to better vaccine responses.

RevDate: 2019-05-17

Johnston CD, Cotton SL, Rittling SR, et al (2019)

Systematic evasion of the restriction-modification barrier in bacteria.

Proceedings of the National Academy of Sciences of the United States of America pii:1820256116 [Epub ahead of print].

Bacteria that are recalcitrant to genetic manipulation using modern in vitro techniques are termed genetically intractable. Genetic intractability is a fundamental barrier to progress that hinders basic, synthetic, and translational microbiology research and development beyond a few model organisms. The most common underlying causes of genetic intractability are restriction-modification (RM) systems, ubiquitous defense mechanisms against xenogeneic DNA that hinder the use of genetic approaches in the vast majority of bacteria and exhibit strain-level variation. Here, we describe a systematic approach to overcome RM systems. Our approach was inspired by a simple hypothesis: if a synthetic piece of DNA lacks the highly specific target recognition motifs for a host's RM systems, then it is invisible to these systems and will not be degraded during artificial transformation. Accordingly, in this process, we determine the genome and methylome of an individual bacterial strain and use this information to define the bacterium's RM target motifs. We then synonymously eliminate RM targets from the nucleotide sequence of a genetic tool in silico, synthesize an RM-silent "SyngenicDNA" tool, and propagate the tool as minicircle plasmids, termed SyMPL (SyngenicDNA Minicircle Plasmid) tools, before transformation. In a proof-of-principle of our approach, we demonstrate a profound improvement (five orders of magnitude) in the transformation of a clinically relevant USA300 strain of Staphylococcus aureus This stealth-by-engineering SyngenicDNA approach is effective, flexible, and we expect in future applications could enable microbial genetics free of the restraints of restriction-modification barriers.

RevDate: 2019-05-17

Dingens AS, Arenz D, Overbaugh J, et al (2019)

Massively Parallel Profiling of HIV-1 Resistance to the Fusion Inhibitor Enfuvirtide.

Viruses, 11(5): pii:v11050439.

Identifying drug resistance mutations is important for the clinical use of antivirals and can help define both a drug's mechanism of action and the mechanistic basis of resistance. Resistance mutations are often identified one-at-a-time by studying viral evolution within treated patients or during viral growth in the presence of a drug in cell culture. Such approaches have previously mapped resistance to enfuvirtide, the only clinically approved HIV-1 fusion inhibitor, to enfuvirtide's binding site in the N-terminal heptad repeat (NHR) of the Envelope (Env) transmembrane domain as well as a limited number of allosteric sites. Here, we sought to better delineate the genotypic determinants of resistance throughout Env. We used deep mutational scanning to quantify the effect of all single-amino-acid mutations to the subtype A BG505 Env on resistance to enfuvirtide. We identified both previously characterized and numerous novel resistance mutations in the NHR. Additional resistance mutations clustered in other regions of Env conformational intermediates, suggesting they may act during different fusion steps by altering fusion kinetics and/or exposure of the enfuvirtide binding site. This complete map of resistance sheds light on the diverse mechanisms of enfuvirtide resistance and highlights the utility of using deep mutational scanning to comprehensively map potential drug resistance mutations.

RevDate: 2019-05-16

Lloyd EC, Haase AM, Foster CE, et al (2019)

A systematic review of studies probing longitudinal associations between anxiety and anorexia nervosa.

Psychiatry research, 276:175-185 pii:S0165-1781(19)30792-9 [Epub ahead of print].

The current study aimed to establish whether anxiety predicts subsequent anorexia nervosa onset and maintenance. A systematic review of longitudinal studies assessing the association between stable anxiety exposures (e.g. trait anxiety/anxiety disorder pathology) and anorexia nervosa development or maintenance was undertaken. Eight studies met inclusion criteria. Seven probed the association between anxiety and anorexia nervosa onset, and one assessed the association between anxiety and anorexia nervosa maintenance. Individuals with anorexia nervosa were more likely to report childhood anxiety compared to healthy individuals, but whether childhood anxiety explains unique variance in anorexia nervosa development is unclear. Current evidence does not support longitudinal associations between specific anxiety disorders (independently of other anxiety disorders) and subsequent anorexia nervosa onset, however anxiety disorder diagnosis in general may predict increased anorexia nervosa risk. The single study probing the association between anxiety and anorexia nervosa maintenance did not find evidence supporting a relationship. The quality of individual studies was fair to high, however the body of evidence was of low quality. Further research that minimises bias, allowing for strong conclusions concerning longitudinal associations between anxiety and subsequent anorexia nervosa outcomes, is required to inform anorexia nervosa aetiology. This in turn may promote improved prevention and treatment.

RevDate: 2019-05-16

Krantz EM, Zier J, Stohs E, et al (2019)

Antibiotic Prescribing and Respiratory Viral Testing for Acute Upper Respiratory Infections Among Adult Patients at an Ambulatory Cancer Center.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5490165 [Epub ahead of print].

BACKGROUND: Outpatient antibiotic prescribing for acute upper respiratory infections (URI) is a high priority target for antimicrobial stewardship that has not been described for cancer patients.

METHODS: We conducted a retrospective cohort study of adult patients at an ambulatory cancer center with ICD-10 diagnosis code consistent with URI from October 1, 2015 to September 30, 2016. We obtained antimicrobial prescribing, respiratory viral testing, and other clinical data at first encounter for the URI through day 14. We used generalized estimating equations to test associations of baseline factors with antibiotic prescribing.

RESULTS: Of 341 charts reviewed, 251 (74%) patients were eligible for analysis. Nearly one-third (32%) of patients were prescribed antibiotics for URI. Respiratory viruses were detected among 85 (75%) of 113 patients tested. Antibiotic prescribing (p=0.001) and viral testing (p<0.001) varied by clinical service. Sputum production or chest congestion was associated with higher risk of antibiotic prescribing (RR=2.3, 95% CI 1.4-3.8, p<0.001). Viral testing on day 0 was associated with lower risk of antibiotic prescribing (RR=0.4, 95% CI 0.2-0.8, p=0.01) though collinearity between viral testing and clinical service limited our ability to separate these effects on prescribing. Antibiotic prescribing was not associated with subsequent URI-related healthcare visits (p=0.89).

CONCLUSIONS: Nearly one-third of hematology-oncology outpatients were prescribed antibiotics for URI, despite viral etiologies identified among 75% of those tested. Antibiotic prescribing was significantly lower among patients receiving an initial respiratory viral test. The role of viral testing in antibiotic prescribing for URI in outpatient oncology settings merits further study.

RevDate: 2019-05-16

Sorror ML, Storer BE, Nyland J, et al (2019)

Revised Acute Myeloid Leukemia Composite Model Using the 2017 European LeukemiaNet Risk Classification.

JAMA oncology pii:2733791 [Epub ahead of print].

RevDate: 2019-05-16

Pescatello LS, Buchner DM, Jakicic JM, et al (2019)

Physical Activity to Prevent and Treat Hypertension: A Systematic Review.

Medicine and science in sports and exercise, 51(6):1314-1323.

PURPOSE: This systematic umbrella review examines and updates the evidence on the relationship between physical activity (PA) and blood pressure (BP) presented in the 2008 Physical Activity Guidelines Advisory Committee Scientific Report.

METHODS: We performed a systematic review to identify systematic reviews and meta-analyses involving adults with normal BP, prehypertension, and hypertension published from 2006 to February 2018.

RESULTS: In total, 17 meta-analyses and one systematic review with 594,129 adults ≥18 yr qualified. Strong evidence demonstrates: 1) an inverse dose-response relationship between PA and incident hypertension among adults with normal BP; 2) PA reduces the risk of cardiovascular disease (CVD) progression among adults with hypertension; 3) PA reduces BP among adults with normal BP, prehypertension, and hypertension; and 4) the magnitude of the BP response to PA varies by resting BP, with greater benefits among adults with prehypertension than normal BP. Moderate evidence indicates the relationship between resting BP and the magnitude of benefit does not vary by PA type among adults with normal BP, prehypertension, and hypertension. Limited evidence suggests the magnitude of the BP response to PA varies by resting BP among adults with hypertension. Insufficient evidence is available to determine if factors such as sex, age, race/ethnicity, socioeconomic status, and weight status or the frequency, intensity, time, and duration of PA influence the associations between PA and BP.

CONCLUSIONS: Future research is needed that adheres to standard BP measurement protocols and classification schemes to better understand the influence of PA on the risk of comorbid conditions, health-related quality of life, and CVD progression and mortality; the interactive effects between PA and antihypertensive medication use; and the immediate BP-lowering benefits of PA.

RevDate: 2019-05-16

McTiernan A, Friedenreich CM, Katzmarzyk PT, et al (2019)

Physical Activity in Cancer Prevention and Survival: A Systematic Review.

Medicine and science in sports and exercise, 51(6):1252-1261.

PURPOSE: This article reviews and updates the evidence on the associations between physical activity and risk for cancer, and for mortality in persons with cancer, as presented in the 2018 Physical Activity Guidelines Advisory Committee Scientific Report.

METHODS: Systematic reviews of meta-analyses, systematic reviews, and pooled analyses were conducted through December 2016. An updated systematic review of such reports plus original research through February 2018 was conducted. This article also identifies future research needs.

RESULTS: In reviewing 45 reports comprising hundreds of epidemiologic studies with several million study participants, the report found strong evidence for an association between highest versus lowest physical activity levels and reduced risks of bladder, breast, colon, endometrial, esophageal adenocarcinoma, renal, and gastric cancers. Relative risk reductions ranged from approximately 10% to 20%. Based on 18 systematic reviews and meta-analyses, the report also found moderate or limited associations between greater amounts of physical activity and decreased all-cause and cancer-specific mortality in individuals with a diagnosis of breast, colorectal, or prostate cancer, with relative risk reductions ranging almost up to 40% to 50%. The updated search, with five meta-analyses and 25 source articles reviewed, confirmed these findings.

CONCLUSIONS: Levels of physical activity recommended in the 2018 Guidelines are associated with reduced risk and improved survival for several cancers. More research is needed to determine the associations between physical activity and incidence for less common cancers and associations with survival for other cancers. Future studies of cancer incidence and mortality should consider these associations for population subgroups, to determine dose-response relationships between physical activity and cancer risk and prognosis, and to establish mechanisms to explain these associations.

RevDate: 2019-05-16

Lemos MP, Lazarus E, Isaacs A, et al (2019)

Daily Vaginal Swabs and Mobile Phone Sex Report for Assessing HIV Virion Exposure Prospectively Among a Cohort of Young Sexually Active Women in South Africa (HVTN 915).

Journal of acquired immune deficiency syndromes (1999), 81(2):e39-e48.

BACKGROUND: Measurements of HIV exposure could help identify subpopulations at highest risk of acquisition and improve the design of HIV prevention efficacy trials and public health interventions. The HVTN 915 study evaluated the feasibility of self-administered vaginal swabs for detection of HIV virions to assess exposure.

METHODS: Fifty 18- to 25-year-old sexually active HIV-seronegative women using contraception were enrolled in Soweto, South Africa. Participants self-administered daily vaginal swabs and answered sexual behavior questions through mobile phone for 90 days. Clinician-administered vaginal swabs, behavioral questionnaires, HIV diagnostic testing, and counseling were performed at 8 clinic visits. Glycogen concentrations assessed adherence to swabbing. Y-chromosome DNA (Yc-DNA) assessed the accuracy of reported condom use. HIV exposure was measured by virion polymerase chain reaction in swabs from 41 women who reported unprotected vaginal sex during follow-up.

RESULTS: Glycogen was detected in 315/336 (93.8%) participant-collected and in all clinician-collected swabs. Approximately 20/39 daily swabs (51.3%) linked to mobile reports of unprotected sex tested positive for Yc-DNA, whereas 10/187 swabs collected after 3 days of abstinence or protected sex (5.3%) had detectable Yc-DNA. No participant became HIV infected during the study; yet, exposure to HIV was detected by nucleic acids in 2 vaginal swabs from 1 participant, collected less than 1 hour after coitus.

CONCLUSION: There was high adherence to daily vaginal swabbing. Daily mobile surveys had accurate reporting of unprotected sex. Detection of HIV in self-collected vaginal swabs from an uninfected participant demonstrated it was possible to measure HIV exposure, but the detection rate was lower than expected.

RevDate: 2019-05-16

Su Y, Huang J, Wang S, et al (2019)

The Effects of Ganglioside-Monosialic Acid in Taxane-induced Peripheral Neurotoxicity in Patients with Breast Cancer: A Randomized Trial.

Journal of the National Cancer Institute pii:5489913 [Epub ahead of print].

BACKGROUND: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting adverse effect. Ganglioside-monosialic acid (GM1) functions as a neuroprotective factor. We assessed the effects of GM1 on the prevention of TIPN in breast cancer patients.

METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 206 patients with early-stage breast cancer planning to receive taxane-based adjuvant chemotherapy with a follow-up of more than 1 year. Subjects were randomized to receive GM1 (80 mg, Day -1 to Day 2) or placebo. The primary endpoint was the Functional Assessment of Cancer Treatment Neurotoxicity (FACT-Ntx) subscale score after 4-cycles of chemotherapy. Secondary endpoints included neurotoxicity evaluated by CTCAE Version 4.0 and the Eastern Cooperative Oncology Group neuropathy scale (ENS). All statistical tests were two-sided.

RESULTS: In 183 evaluable patients, GM1 group reported better mean FACT-Ntx subscale scores than patients in the placebo group after 4-cycles of chemotherapy (43.27 [95% CI = 43.05 to 43.49] vs 34.34 [95% CI = 33.78 to 34.89]; mean difference = 8.96 [95% CI = 8.38 to 9.54], P < .001). Grade ≥ 1 peripheral neurotoxicity in CTCAE v4.0 scale was statistically significantly lower in GM1 group (14.3% vs 100.0%, P < .001). Additionally, GM1 group reported a statistically significantly lower incidence of grade ≥ 1 neurotoxicity assessed by ENS sensory neuropathy (26.4% vs 97.8%, P < .001) and motor neuropathy subscales (20.9% vs 81.5%, P < .001).

CONCLUSIONS: The treatment with GM1 resulted in a reduction in the severity and incidence of TIPN after 4-cycles of taxane-containing chemotherapy in patients with breast cancer.

RevDate: 2019-05-16

Jiang Y, Girard EJ, Pakiam F, et al (2019)

Calibration of fluorescence imaging for tumor surgical margin delineation: multistep registration of fluorescence and histological images.

Journal of medical imaging (Bellingham, Wash.), 6(2):025005.

Although a greater extent of tumor resection is important for patients' survival, complete tumor removal, especially tumor margins, remains challenging due to the lack of sensitivity and specificity of current surgical guidance techniques at the margins. Intraoperative fluorescence imaging with targeted fluorophores is promising for tumor margin delineation. To verify the tumor margins detected by the fluorescence images, it is necessary to register fluorescence with histological images, which provide the ground truth for tumor regions. However, current registration methods compare fluorescence images to a single-layer histological slide, which is selected subjectively and represents a single plane of the three-dimensional tumor. A multistep pipeline is established to correlate fluorescence images to stacked histological images, including fluorescence calibration and multistep registration. Multiple histological slices are integrated as a two-dimensional (2-D) tumor map using optical attenuation model and average intensity projection. A BLZ-100-labeled medulloblastoma mouse model is used to test the whole framework. On average, the synthesized 2-D tumor map outperforms the selected best slide as ground truth [Dice similarity coefficient (DSC): 0.582 versus 0.398, with significant differences; mean area under the curve (AUC) of the receiver operating characteristic curve: 88% versus 85.5%] and the randomly selected slide as ground truth (DSC: 0.582 versus 0.396 with significant differences; mean AUC: 88% versus 84.1% with significant differences), which indicates our pipeline is reliable and can be applied to investigate targeted fluorescence probes in tumor margin detection. Following this proposed pipeline, BLZ-100 shows enhancement in both tumor cores and tumor margins (mean target-to-background ratio: 8.64 ± 5.76 and 4.82 ± 2.79 , respectively).

RevDate: 2019-05-16

Martins F, Sofiya L, Sykiotis GP, et al (2019)

Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.

Nature reviews. Clinical oncology pii:10.1038/s41571-019-0218-0 [Epub ahead of print].

Immune-checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are arguably the most important development in cancer therapy over the past decade. The indications for these agents continue to expand across malignancies and disease settings, thus reshaping many of the previous standard-of-care approaches and bringing new hope to patients. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), which are often distinctly different from the classical chemotherapy-related toxicities. Owing to the growing use of ICIs in oncology, clinicians will increasingly be confronted with common but also rare irAEs; hence, awareness needs to be raised regarding the clinical presentation, diagnosis and management of these toxicities. In this Review, we provide an overview of the various types of irAEs that have emerged to date. We discuss the epidemiology of these events and their kinetics, risk factors, subtypes and pathophysiology, as well as new insights regarding screening and surveillance strategies. We also highlight the most important aspects of the management of irAEs.

RevDate: 2019-05-16

Kansagra AJ, Frey NV, Bar M, et al (2019)

Clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)-an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT).

Bone marrow transplantation pii:10.1038/s41409-019-0451-2 [Epub ahead of print].

On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

RevDate: 2019-05-15

Sundar H, J Radich (2016)

Optimizing Patient Care in Chronic Phase Chronic Myelogenous Leukemia: A Multidisciplinary Approach.

Journal of the National Comprehensive Cancer Network : JNCCN, 14(14 Suppl 1):S1-S6.

Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome arising from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. This translocation results in the formation of the BCR-ABL fusion gene. The product of this fusion gene, p210, a protein with deregulated tyrosine kinase activity, plays a central role in the pathogenesis of CML. Tyrosine kinase inhibitor (TKI) therapy with small molecule inhibitors of BCR-ABL tyrosine kinase has significantly reduced the annual mortality rate among patients with CML. Although most of these patients respond to first-line TKI therapy, the use of TKIs is complicated by the development of resistance or intolerance in some patients, resulting in a loss of response or discontinuation of treatment. Inadequate response to TKI therapy is associated with poor long-term outcome, and the cases of patients with resistance or intolerance should be carefully evaluated for alternative treatment options. This report discusses the challenges associated with the management of newly diagnosed chronic phase CML in a patient with intolerance to multiple TKI therapies.

RevDate: 2019-05-16

Lipira L, Williams EC, Nevin PE, et al (2019)

Religiosity, Social Support, and Ethnic Identity: Exploring "Resilience Resources" for African-American Women Experiencing HIV-Related Stigma.

Journal of acquired immune deficiency syndromes (1999), 81(2):175-183.

INTRODUCTION: African-American women living with HIV report substantial HIV-related stigma and depression. Resilience resources are strength-based resources that may moderate the effects of HIV-related stigma on poor psychosocial outcomes such as depression.

OBJECTIVE: To evaluate whether religiosity, social support, and ethnic identity moderate the effects of HIV-related stigma on depression among African-American women living with HIV.

METHODS: We used baseline data (May 2013-October 2015) from a randomized controlled trial testing the efficacy of an HIV-related stigma-reduction intervention among African-American women living with HIV in Chicago, IL, and Birmingham, AL, who were older than 18 years and currently receiving HIV services. To assess whether religiosity (7-item Religious Beliefs and Behaviors survey), social support (select subscales from the Medical Outcomes Study Social Support Survey), and ethnic identity (Commitment subscale from the Multigroup Ethnic Identity Measure) modified the relationship between HIV-related stigma (Stigma Scale for Chronic Illness) and depression (8-item Patient Health Questionnaire), we conducted 3 separate moderation analyses using linear regression with interactions between HIV-related stigma and each moderator of interest, adjusted for study site, age, time since diagnosis, and education.

RESULTS: Among 226 African-American women living with HIV, greater levels of HIV-related stigma were associated with greater depression in all 3 models (P < 0.05). Only religiosity modified this association (P = 0.04), with a weaker association among women reporting higher levels of religiosity.

CONCLUSIONS: The protective effects of religiosity may be leveraged in interventions for African-American women living with HIV struggling with HIV-related stigma.

RevDate: 2019-05-15

Goodman PJ, Tangen CM, IM Thompson (Jr) (2019)

More on Long-Term Effects of Finasteride on Prostate Cancer Mortality. Reply.

The New England journal of medicine, 380(20):e38.

RevDate: 2019-05-15

Law PJ, Timofeeva M, Fernandez-Rozadilla C, et al (2019)

Association analyses identify 31 new risk loci for colorectal cancer susceptibility.

Nature communications, 10(1):2154 pii:10.1038/s41467-019-09775-w.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.

RevDate: 2019-05-15

Cheng HH, Sokolova AO, Schaeffer EM, et al (2019)

Germline and Somatic Mutations in Prostate Cancer for the Clinician.

Journal of the National Comprehensive Cancer Network : JNCCN, 17(5):515-521.

It is increasingly important for clinicians involved in the management of prostate cancer to understand the relevance of heritable (germline) mutations that, for select patients, affect prostate cancer risk and cancer biology, and acquired (somatic) mutations that occur in prostate cancer cells. In the advanced disease setting, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials. Similarly, microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors. Germline genetic testing has potential importance in the treatment and assessment of familial risk, and tumor-directed somatic sequencing may guide treatment decision-making. This review provides clinicians with knowledge of basic genetic terminology, awareness of the importance of family history of cancer (not limited to prostate cancer), contrasts between the different but potentially related objectives of germline versus somatic testing of tumor tissue, and indications for genetic counseling. Specific clinical scenarios, objectives of testing, and nature of the assays are reviewed. Germline and somatic mutations of known and potential relevance to prostate cancer are discussed in the context of treatment options, and algorithms to assist clinicians in approaching this area are proposed.

RevDate: 2019-05-15

Heath EI, Nanus DM, Slovin S, et al (2019)

Prostate Cancer National Summit's Call to Action.

Clinical genitourinary cancer pii:S1558-7673(19)30128-4 [Epub ahead of print].

RevDate: 2019-05-15

Graves SS, Gyurkocza B, Stone DM, et al (2019)

Development and characterization of a canine-specific anti-CD94 (KLRD-1) monoclonal antibody.

Veterinary immunology and immunopathology, 211:10-18.

Natural killer (NK) cells are non-T, non-B lymphocytes are part of the innate immune system and function without prior activation. The human NK cell surface determinant, CD94, plays a critical role in regulation of NK cell activity as a heterodimer with NKG2 subclasses. Canine NK cells are not as well defined as the human and murine equivalents, due in part to the paucity of reagents specific to cell surface markers. Canines possess NK/NKT cells that have similar morphological characteristics to those found in humans, yet little is known about their functional characteristics nor of cell surface expression of CD94. Here, we describe the development and function of a monoclonal antibody (mAb) to canine (ca) CD94. Freshly isolated canine CD94+ cells were CD3+/-, CD8+/-, CD4-, CD21-, CD5low, NKp46+, and were cytotoxic against a canine target cell line. Anti-caCD94 mAb proved useful in enriching NK/NKT cells from PBMC for expansion on CTAC feeder cells in the presence of IL-2 and IL-15. The cultured cells were highly cytolytic with co-expression of NKp46 and reduced expression of CD3. Transmission electron microscopy revealed expanded CD94+ lymphocytes were morphologically large granular lymphocytes with large electron dense granules. Anti-caCD94 (mAb) can serve to enrich NK/NKT cells from dog peripheral blood for ex vivo expansion for HCT and is a potentially valuable reagent for studying NK/NKT regulation in the dog.

RevDate: 2019-05-15

Shaw BE, D'Souza A, SJ Lee (2019)

Importance of Assessing Patient-Reported Outcomes With Salvage Autologous Transplantation in Relapsed Multiple Myeloma.

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

RevDate: 2019-05-15

Paudel L, Nagana Gowda GA, D Raftery (2019)

Extractive Ratio Analysis NMR Spectroscopy for Metabolite Identification in Complex Biological Mixtures.

Analytical chemistry [Epub ahead of print].

The complexity of biological mixtures continues to challenge efforts aimed at unknown metabolite identification in the metabolomics field. To address this challenge, we provide a new method to identify related peaks from individual metabolites in complex NMR spectra. Extractive ratio analysis NMR spectroscopy (E-RANSY) builds on our previously described ratio analysis method [ Wei et al. Anal. Chem. 2011 , 83 , 7616 - 7623 ] and exploits the simplified NMR spectra provided by the extraction of metabolites under varied pH conditions. Under such conditions, metabolites from the same biological specimen are extracted differentially, and the resulting NMR spectra exhibit characteristics favorable for unraveling unknown metabolite peaks using ratio analysis. We demonstrate the utility of the E-RANSY method by extracting carboxylic acid containing metabolites from human urine, one of the highly complex biological mixtures encountered in the metabolomics field. E-RANSY performs better than STOCSY and the original RANSY method and offers new avenues to identify unknown metabolites in complex biological mixtures.

RevDate: 2019-05-14

Foss EJ, Gatbonton-Schwager T, Thiesen AH, et al (2019)

Sir2 suppresses transcription-mediated displacement of Mcm2-7 replicative helicases at the ribosomal DNA repeats.

PLoS genetics, 15(5):e1008138 pii:PGENETICS-D-19-00042 [Epub ahead of print].

Repetitive DNA sequences within eukaryotic heterochromatin are poorly transcribed and replicate late in S-phase. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA arrays (rDNA). Despite the widespread association between transcription and replication, it remains unclear how transcription might impinge on replication, or vice versa. Here we show that, when silencing of an RNA polymerase II (RNA Pol II)-transcribed non-coding RNA at the rDNA is disrupted by SIR2 deletion, RNA polymerase pushes and thereby relocalizes replicative Mcm2-7 helicases away from their loading sites to an adjacent region with low nucleosome occupancy, and this relocalization is associated with increased rDNA origin efficiency. Our results suggest a model in which two of the major defining features of heterochromatin, transcriptional silencing and late replication, are mechanistically linked through suppression of polymerase-mediated displacement of replication initiation complexes.

RevDate: 2019-05-14

Morris MJ, Loriot Y, Sweeney CJ, et al (2019)

Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomised phase 2a trial.

European journal of cancer (Oxford, England : 1990), 114:107-116 pii:S0959-8049(19)30240-0 [Epub ahead of print].

PURPOSE: Radium 223 dichloride (radium-223) is an alpha particle-emitting bone-directed therapy that prolongs overall survival in men with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Docetaxel is an antimicrotubule cytotoxic agent that improves survival in mCRPC. We investigated whether combining these potentially cross-sensitising agents to dually target tumour and bone would be safe and effective.

PATIENTS AND METHODS: Phase 1 was a dose escalation study to define a recommended phase 2 dose (RP2D) of docetaxel and radium-223. In phase 2a, patients were randomised 2:1 to the recommended combination regimen or docetaxel at a dose of 75 mg/m2 every 3 weeks (q3w). Patients with bone-predominant mCRPC were eligible. End-points were safety, efficacy and treatment-related changes in serum and imaging biomarkers.

RESULTS: Twenty patients were enrolled in phase 1; 53 patients were randomised in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m2 q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% vs 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers.

CONCLUSIONS: Radium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced antitumour activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted. number: NCT01106352.

RevDate: 2019-05-12

Vaughn JE, Shankaran V, RB Walter (2019)

Trends in Clinical Benefits and Costs of Novel Therapeutics in AML: at What Price Does Progress Come?.

Current hematologic malignancy reports pii:10.1007/s11899-019-00510-2 [Epub ahead of print].

PURPOSE OF REVIEW: Since 2017, eight novel agents have been approved for the treatment of acute myeloid leukemia (AML) in the USA. Here, we review the clinical benefits and costs associated with these drugs.

RECENT FINDINGS: For some of the newly-approved drugs, clinical benefit has been documented in randomized trials. Others received accelerated approval based on surrogate endpoints in early phase trials. All, however, carry significant costs and toxicities. Cost-effectiveness analyses are so far only available for midostaurin, CPX-351, and gemtuzumab ozogamicin. Recently approved drugs for AML have varying levels of evidence for clinical effectiveness and because of associated high costs may further increase the overall economic burden of AML care. This issue is complex and whether novel AML drugs will cost-effective will depend on multiple factors, including their ability to improve survival and quality of life while simultaneously reducing the costs of healthcare resource utilization.

RevDate: 2019-05-12

Janes H, Donnell D, Gilbert PB, et al (2019)

Taking stock of the present and looking ahead: envisioning challenges in the design of future HIV prevention efficacy trials.

The lancet. HIV pii:S2352-3018(19)30133-X [Epub ahead of print].

Despite the recent success of antiretrovirals for HIV prevention, additional, more effective, or more acceptable biomedical interventions will ultimately be needed to end the HIV epidemic. Designing clinical trials to evaluate the efficacy of new products that reduce HIV infection risk is challenging because of the existence of highly effective interventions to prevent HIV. However, the implementation of these interventions is uneven, and the fact that multiple HIV prevention efficacy trials are currently evaluating new products means the field confronts uncertainty in the emerging standard of prevention. In this Viewpoint, we take stock of the current state of HIV prevention, and subsequently discuss the key challenges in designing future trials to evaluate the next generation of HIV prevention products. We also highlight gaps in the knowledge base that need to be addressed to advance the design of research. Future trials are tenable, even in the context of existing and effective interventions, and should involve careful statistical approaches and multidisciplinary collaborative design.

RevDate: 2019-05-11

Simoni Y, Fehlings M, EW Newell (2019)

Multiplex MHC Class I Tetramer Combined with Intranuclear Staining by Mass Cytometry.

Methods in molecular biology (Clifton, N.J.), 1989:147-158.

Antigen-specific CD8+ T cells play a crucial role in the host protective immune response against viruses, tumors, and other diseases. Major histocompatibility complex (MHC) class I tetramers allow for a direct detection of such antigen-specific CD8+ T cells. Using mass cytometry together with multiplex MHC class I tetramer staining, we are able to screen more than 1000 different antigen candidates simultaneously across tissues in health and disease, while retaining the possibility to deliver an in-depth characterization of antigen-specific CD8+ T cells and associated phenotypes. Here we describe the method for a MHC class I tetramer multiplexing approach together with intracellular antibody staining for a parallel phenotypic cell characterization using mass cytometry in human specimens.

RevDate: 2019-05-11

Garg S, Reyes-Palomares A, He L, et al (2019)

Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML.

Blood pii:blood.2018862383 [Epub ahead of print].

FLT3, DNMT3A, and NPM1 are the most frequently mutated genes in cytogenetically normal acute myeloid leukemia (AML), but little is known about how these mutations synergize upon co-occurrence. Here we show that triple-mutated AML is characterized by high leukemia stem cell (LSC) frequency, an aberrant leukemia specific GPR56highCD34low immunophenotype, and synergistic upregulation of Hepatic Leukemia Factor (HLF). Cell sorting based on the LSC marker GPR56 allowed isolation of triple mutated from DNMT3A/NPM1 double-mutated subclones. Moreover, in DNMT3A R882 mutated patients, CpG hypomethylation at the HLF transcription start site correlated with high HLF mRNA expression, which was itself associated with poor survival. Loss of HLF 3 via CRISPR/Cas9 significantly reduced the CD34+GPR56+ LSC compartment of primary human triple-mutated AML cells in serial xenotransplantation assays. HLF knockout cells were more actively cycling when freshly harvested from mice, but rapidly exhausted when re-introduced in culture. RNA-sequencing (RNA-Seq) of primary human triple-mutated AML cells after shRNA mediated HLF knockdown revealed the NOTCH target Hairy And Enhancer Of Split 1 (HES1) and the cyclin-dependent kinase inhibitor CDKN1C/p57 as novel targets of HLF potentially mediating these effects. Overall our data establish HLF as a novel LSC regulator in this genetically defined high-risk AML subgroup.

RevDate: 2019-05-10

Hwang V, Mendez E, Chow LQM, et al (2019)

Wound Complications in Head and Neck Squamous Cell Carcinomas After Anti-PD-1 Therapy.

Immune checkpoint inhibitors have demonstrated activity in recurrent/metastatic head and neck squamous cell cancer, but less is known regarding their long-term sequelae. We describe four patients who, after complete responses to anti-PD-1 therapy, developed complications requiring surgical intervention. Patient 1 is a 57-year-old female whose marked tumor regression exposed some mandibular hardware. Patient 2 is a 39-year-old male who developed an ulcerated buccal lesion with exposed mandible. Patient 3 is a 66-year-old male with craniofacial osteoradionecrosis. Patient 4 is a 71-year-old male who developed an exposed and fractured mandible. All patients successfully underwent surgical intervention and remain disease free. Laryngoscope, 2019.

RevDate: 2019-05-10

Ustun C, Le-Rademacher J, Wang HL, et al (2019)

Allogeneic hematopoietic cell transplantation compared to chemotherapy consolidation in older acute myeloid leukemia (AML) patients 60-75 years in first complete remission (CR1): an alliance (A151509), SWOG, ECOG-ACRIN, and CIBMTR study.

Leukemia pii:10.1038/s41375-019-0477-x [Epub ahead of print].

The preferred post-remission therapy for older patients with acute myeloid leukemia (AML) in first complete remission (CR1) remains uncertain. In this retrospective, multicenter study, we compared the outcomes for older AML patients (age 60-77 years) receiving allogeneic hematopoietic cell transplantation (alloHCT) (n = 431) with those treated on prospective National Clinical Trials Network induction and nontransplantation chemotherapy (CT) consolidation trials (n = 211). AlloHCT patients were younger (median age: 64.2 versus 67.9 years, p < 0.001), but more frequently had high-risk AML (high WBC, secondary AML, and unfavorable cytogenetics). Overall survival (OS) was worse in alloHCT during the first 9 months after CR1 (HR = 1.52, p = 0.02), but was significantly better thereafter (HR = 0.53, p < 0.0001) relative to CT. Treatment-related mortality (TRM) following HCT was worse in the first 9 months (HR = 2.8, 95% CI: 1.5-5.2, p = 0.0009), while post-HCT relapse was significantly less frequent beyond 9 months (HR = 0.42, 95% CI: 0.29-0.61, p < 0.0001). Despite higher early TRM, alloHCT recipients had superior long-term OS [29% (24-34%) versus CT 13.8% (9-21%) at 5 years]. Although this is a retrospective analysis with potential biases, it indicates that alloHCT led to heightened early risks from TRM, yet reduced relapse and superior long-term survival relative to CT in older AML patients in CR1.

RevDate: 2019-05-10

Panaite L, M Shadman (2019)

Concurrent diagnosis of classical Hodgkin lymphoma and Langerhans cell histiocytosis.

Blood, 133(19):2109.

RevDate: 2019-05-09

Coronato-Nunes B, Calegar DA, Monteiro KJL, et al (2017)

Giardia intestinalis infection associated with malnutrition in children living in northeastern Brazil.

Journal of infection in developing countries, 11(7):563-570.

INTRODUCTION: The present study aimed to determine the prevalence and factors associated with Giardia intestinalis infection, verifying its impact on the nutritional status of children in northeastern Brazil.

METHODOLOGY: A cross-sectional study was conducted to obtain parasitological, sociodemographic, and anthropometric data in two municipalities in the states of Piauí and Ceará, northeastern Brazil.

RESULTS: Prevalence of giardiasis was 55/511 (10.8%). G. intestinalis was more frequent in people living in poverty (30/209 [14.4%], p = 0.041), performing open evacuation (26/173 [15%], p = 0.034), and drinking rainwater stored in cisterns (9/56 [16.1%], p = 0.005). The proportion of stunting and being underweight in children infected with G. intestinalis was significantly higher than that in uninfected children (5/23 [21.7%] vs. 10/179 [5.6%], p = 0.017, OR = 4.69, 95% confidence interval [CI] = 1.44-15.25 and 5/23 [21.7%] vs. 13/179 [7.3%], p = 0.038, OR = 3.54, 95% CI = 1.13-11.09, respectively). Infection with G. intestinalis remained significantly associated with stunting and being underweight after adjustment for poverty, municipality, sex, and age in a logistic regression multivariate model.

CONCLUSIONS: In rural areas in northeastern Brazil, giardiasis has acquired great public health importance in the soil-transmitted helminths control era, impacting the nutritional status of children and requiring new approaches to diagnosis and treatment and translational research that could generate applicable solutions at the community level.

RevDate: 2019-05-09

Kummer K, Jensen PN, Kratz M, et al (2019)

Full-Fat Dairy Food Intake is Associated with a Lower Risk of Incident Diabetes Among American Indians with Low Total Dairy Food Intake.

The Journal of nutrition pii:5478929 [Epub ahead of print].

BACKGROUND: Diet plays a key role in development of diabetes, and there has been recent interest in better understanding the association of dairy food intake with diabetes.

OBJECTIVE: This study examined the associations of full-fat and low-fat dairy food intake with incident diabetes among American Indians-a population with a high burden of diabetes.

METHODS: The study included participants from the Strong Heart Family Study (SHFS), a family-based study of cardiovascular disease in American Indians, free of diabetes at baseline (2001-2003) (n = 1623). Participants were 14-86-y-old at baseline and 60.8% were female. Dairy food intake was assessed using a Block food frequency questionnaire. Incident diabetes was defined using American Diabetes Association criteria. Parametric survival models with a Weibull distribution were used to evaluate the associations of full-fat and low-fat dairy food intake with incident diabetes. Serving sizes were defined as 250 mL for milk and 42.5 g for cheese.

RESULTS: We identified 277 cases of diabetes during a mean follow-up of 11 y. Reported intake of dairy foods was low [median full-fat dairy food intake: 0.11 serving/1000 kcal; median low-fat dairy food intake: 0.03 serving/1000 kcal]. Participants who reported the highest full-fat dairy food intake had a lower risk of diabetes compared to those who reported the lowest full-fat food dairy intake [HR (95% CI): 0.79 (0.59, 1.06); P-trend = 0.03, comparing extreme tertiles, after adjustment for age, sex, site, physical activity, education, smoking, diet quality, and low-fat dairy food intake]. Low-fat dairy food intake was not associated with diabetes.

CONCLUSIONS: American Indians who participated in the SHFS reported low dairy food intake. Participants who reported higher full-fat dairy food intake had a lower risk of diabetes than participants who reported lower intake. These findings may be of interest to populations with low dairy food intake.

RevDate: 2019-05-09

Qin Y, Wu L, Wang J, et al (2019)

A Fluorescence-Activated Single-Droplet Dispenser for High Accuracy Single-Droplet and Single-Cell Sorting and Dispensing.

Analytical chemistry [Epub ahead of print].

The ability to sort and dispense droplets accurately is essential to droplet-based single-cell analysis. Here, we describe a fluorescence-activated single-droplet dispenser (FASD) that is analogous to a conventional fluorescence-activated cell sorter, but sorts droplets containing single cells within an oil emulsion. The FASD system uses cytometric detection and electrohydrodynamic actuation-based single-droplet manipulation, allowing droplet isolation and dispensing with high efficiency and accuracy. The system is compatible with multiwell plates and can be integrated with existing microfluidic devices and large-scale screening systems. By enabling sorting based on single-cell reactions such as PCR, this platform will help expand the basis of cell sorting from mainly protein biomarkers to nucleic acid sequences and secreted biomolecules.

RevDate: 2019-05-08

Tonorezos ES, Ford JS, Wang L, et al (2019)

Impact of exercise on psychological burden in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Cancer [Epub ahead of print].

BACKGROUND: Childhood cancer survivors are at risk for adverse psychological outcomes. Whether exercise can attenuate this risk is unknown.

METHODS: In total, 6199 participants in the Childhood Cancer Survivor Study (median age, 34.3 years [range, 22.0-54.0 years]; median age at diagnosis, 10.0 years [range, 0-21.0 years]) completed a questionnaire assessing vigorous exercise and medical/psychological conditions. Outcomes were evaluated a median of 7.8 years (range, 0.1-10.0 years) later and were defined as: symptom level above the 90th percentile of population norms for depression, anxiety, or somatization on the Brief Symptom Inventory-18; cancer-related pain; cognitive impairment using a validated self-report neurocognitive questionnaire; or poor health-related quality of life. Log-binomial regression estimated associations between exercise (metabolic equivalent [MET]-hours per week-1) and outcomes adjusting for cancer diagnosis, treatment, demographics, and baseline conditions.

RESULTS: The prevalence of depression at follow-up was 11.4% (95% CI, 10.6%-12.3%), anxiety 7.4% (95% CI, 6.7%-8.2%) and somatization 13.9% (95% CI, 13.0%-14.9%). Vigorous exercise was associated with lower prevalence of depression and somatization. The adjusted prevalence ratio for depression was 0.87 (95% CI, 0.72-1.05) for 3 to 6 MET hours per week-1 , 0.76 (95% CI, 0.62-0.94) for 9 to 12 MET-hours per week-1 , and 0.74 (95% CI, 0.58-0.95) for 15 to 21 MET-hours per week-1 . Compared with 0 MET hours per week-1 , 15 to 21 MET-hours per week-1 were associated with an adjusted prevalence ratio of 0.79 (95% CI, 0.62-1.00) for somatization. Vigorous exercise also was associated with less impairment in the physical functioning, general health and vitality (Ptrend < .001), emotional role limitations (Ptrend = .02), and mental health (Ptrend = .02) domains as well as higher cognitive function in the domains of task completion, organization, and working memory (P < .05 for all), but not in the domain of cancer pain.

CONCLUSIONS: Vigorous exercise is associated with less psychological burden and cognitive impairment in childhood cancer survivors.

RevDate: 2019-05-08

Mascarenhas L, Lyden ER, Breitfeld PP, et al (2019)

Risk-based treatment for patients with first relapse or progression of rhabdomyosarcoma: A report from the Children's Oncology Group.

Cancer [Epub ahead of print].

BACKGROUND: The purpose of this study was to evaluate risk and response-based multi-agent therapy for patients with rhabdomyosarcoma (RMS) at first relapse.

METHODS: Patients with RMS and measurable disease at first relapse with unfavorable-risk (UR) features were randomized to a 6-week phase 2 window with 1 of 2 treatment schedules of irinotecan with vincristine (VI) (previously reported). Those with at least a partial response to VI continued to receive 44 weeks of multi-agent chemotherapy including the assigned VI regimen. UR patients who did not have measurable disease at study entry, did not have a radiographic response after the VI window, or declined VI window therapy received 31 weeks of multi-agent chemotherapy including tirapazamine (TPZ) at weeks 1, 4, 10, 19, and 28. Favorable-risk (FR) patients received 31 weeks of the same multi-agent chemotherapy without VI and TPZ.

RESULTS: One hundred thirty-six eligible patients were enrolled. For 61 patients not responding to VI, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 17% (95% confidence interval [CI], 8%-29%) and 24% (13%-37%), respectively. For 30 UR patients not treated with VI, the 3-year FFS and OS rates were 21% (8%-37%) and 39% (20%-57%), respectively. FR patients had 3-year FFS and OS rates of 79% (47%-93%) and 84% (50%-96%), respectively. There were no unexpected toxicities.

CONCLUSIONS: Patients with UR RMS at first relapse or disease progression have a poor prognosis when they are treated with this multi-agent therapy, whereas FR patients have a higher chance of being cured with second-line therapy.

RevDate: 2019-05-08

Zhou J, Han J, Nutescu EA, et al (2019)

Type 2 diabetes in adults with sickle cell disease: can we dive deeper? Response to Skinner et al.

RevDate: 2019-05-08

Gordon JA, Noble JW, Midha A, et al (2019)

Upregulation of Scavenger receptor B1 is required for steroidogenic and non-steroidogenic cholesterol metabolism in prostate cancer.

Cancer research pii:0008-5472.CAN-18-2529 [Epub ahead of print].

Aberrant cholesterol metabolism is increasingly appreciated to be essential for prostate cancer (PCa) initiation and progression. Transcript expression of the high-density lipoprotein-cholesterol receptor scavenger receptor B1 (SR-B1) is elevated in primary PCa. Hypothesizing that SR-B1 expression may help facilitate malignant transformation, we document increased SR-B1 protein and transcript expression in PCa relative to normal prostate epithelium that persists in lethal castration-resistant prostate cancer (CRPC) metastasis. As intratumoral steroid synthesis from the precursor cholesterol can drive androgen receptor (AR) pathway activity in CRPC, we screened androgenic benign and cancer cell lines for sensitivity to SR-B1 antagonism. Benign cells were insensitive to SR-B1 antagonism, and cancer line sensitivity inversely correlated with expression levels of full-length and splice-variant AR. In androgen-responsive CRPC cell model C4-2, SR-B1 antagonism suppressed cholesterol uptake, de novo steroidogenesis, and AR activity. SR-B1 antagonism also suppressed growth and viability and induced endoplasmic reticulum stress and autophagy. The inability of exogenous steroids to reverse these effects indicates that AR pathway activation is insufficient to overcome cytotoxic stress caused by a decrease in the availability of cholesterol. Furthermore, SR-B1 antagonism decreased cholesterol uptake, growth, and viability of the AR-null CRPC cell model PC-3, and the small molecule SR-BI antagonist Block Lipid Transport-1 decreased xenograft growth rate despite poor pharmacologic properties. Overall, our findings show that SR-B1 is upregulated in primary and castration-resistant disease and is essential for cholesterol uptake needed to drive both steroidogenic and non-steroidogenic biogenic pathways, thus implicating SR-B1 as a novel and potentially actionable target in CRPC.

RevDate: 2019-05-08

Porotto M, Ferren M, Chen YW, et al (2019)

Authentic Modeling of Human Respiratory Virus Infection in Human Pluripotent Stem Cell-Derived Lung Organoids.

mBio, 10(3): pii:mBio.00723-19.

Infectious viruses so precisely fit their hosts that the study of natural viral infection depends on host-specific mechanisms that affect viral infection. For human parainfluenza virus 3, a prevalent cause of lower respiratory tract disease in infants, circulating human viruses are genetically different from viruses grown in standard laboratory conditions; the surface glycoproteins that mediate host cell entry on circulating viruses are suited to the environment of the human lung and differ from those of viruses grown in cultured cells. Polarized human airway epithelium cultures have been used to represent the large, proximal airways of mature adult airways. Here we modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids derived from human pluripotent stem cells contain mesoderm and pulmonary endoderm and develop into branching airway and alveolar structures. Whole-genome sequencing analysis of parainfluenza viruses replicating in the organoids showed maintenance of nucleotide identity, suggesting that no selective pressure is exerted on the virus in this tissue. Infection with parainfluenza virus led to viral shedding without morphological changes, while respiratory syncytial virus infection induced detachment and shedding of infected cells into the lung organoid lumens, reminiscent of parainfluenza and respiratory syncytial virus in human infant lungs. Measles virus infection, in contrast, induced syncytium formation. These human stem cell-derived lung organoids may serve as an authentic model for respiratory viral pathogenesis in the developing or infant lung, recapitulating respiratory viral infection in the host.IMPORTANCE Respiratory viruses are among the first pathogens encountered by young children, and the significant impact of these viral infections on the developing lung is poorly understood. Circulating viruses are suited to the environment of the human lung and are different from those of viruses grown in cultured cells. We modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids, derived from human pluripotent stem cells, develop into branching airway and alveolar structures and provide a tissue environment that maintains the authentic viral genome. The lung organoids can be genetically engineered prior to differentiation, thereby generating tissues bearing or lacking specific features that may be relevant to viral infection, a feature that may have utility for the study of host-pathogen interaction for a range of lung pathogens.

RevDate: 2019-05-07

Prentice RL, Y Huang (2018)


Statistical theory and related fields, 2(1):23-26.

RevDate: 2019-05-07

Deng N, Sun Y, Liu M, et al (2019)

Alpha-momorcharin regulates cytokine expression and induces apoptosis in monocytes.

Immunopharmacology and immunotoxicology [Epub ahead of print].

BACKGROUND AND AIM: Alpha-momorcharin (α-MMC) is a type I ribosome-inactivating protein (RIP) that is purified from Momordica charantia. Despite its strong antitumor activities, α-MMC exerts the undesirable immunotoxicity effects of hypersensitivity or immunosuppression. Since α-MMC is a plant protein, its application in vivo can easily induce hypersensitivity, but its immunosuppressive mechanism is still unclear.

MATERIALS AND METHODS: The toxicity of α-MMC to peripheral blood cells and the cytokine expression in peripheral blood mononuclear cells (PBMCs) and spleen immune cells were measured in rats. For further confirmation, experiments were performed in vitro with the mononuclear cell line THP-1, B lymphocyte cell line WIL2-S and T lymphocyte cell line Jurkat.

RESULTS: High doses of α-MMC (3.0 mg/kg) resulted in weight loss in rats, a decreased percentage of monocytes, and increased percentages of eosinophils and basophils. Both high-dose and low-dose (1.0 mg/kg) α-MMC inhibited cytokine expression in PBMCs and increased cytokine expression in spleen T cells. In in vitro, α-MMC mainly acted on THP-1 cells, with effects including high dose-induced apoptosis and low dose-induced regulation of inhibitory cytokine expression.

CONCLUSIONS: The action of α-MMC on immune cells mainly affects monocytes, thereby eliciting its immunosuppressive effect. Its mode of action is to guide functional immunosuppressive regulation at low doses and induce apoptosis at high doses. As the monocytes would be recruited into tumor tissues and are polarized into tumor-associated macrophages, the selective cytotoxicity and cytokine release regulation of α-MMC in monocytes may be an important mechanism of its antitumor effects.

RevDate: 2019-05-07

Martínez LE, O'Brien VP, Leverich CK, et al (2019)

Non-helical Helicobacter pylori show altered gland colonization and elicit less gastric pathology during chronic infection.

Infection and immunity pii:IAI.00904-18 [Epub ahead of print].

Half of all humans harbor Helicobacter pylori in their stomachs. Helical cell shape is thought to facilitate H. pylori's ability to bore into the protective mucus layer in a corkscrew-like motion, thus enhancing colonization of the stomach. H. pylori cell shape mutants show impaired colonization of the mouse stomach, highlighting the importance of cell shape in infection. To gain a deeper understanding of how helical cell morphology promotes host colonization by H. pylori, we used 3D-confocal microscopy to visualize the clinical isolate PMSS1 and an isogenic straight rod mutant (Δcsd6) within thick longitudinal mouse stomach sections and performed volumetric image analysis to quantify the number of bacteria residing within corpus and antral glands in addition to measuring total colony forming units (CFU). We found that straight rods show attenuation during acute colonization of the stomach (one day or one week post-infection) as measured by total CFU. Our quantitative imaging revealed that wild-type bacteria extensively colonized antral glands at one week post-infection, while csd6 mutants showed variable colonization of the antrum at this timepoint. During chronic infection (one or three months post-infection), total CFU were highly variable, but similar for wild-type and straight rods. Both wild-type and straight rods persisted and expanded in corpus glands during chronic infection. However, the straight rods showed reduced inflammation and disease progression. Thus, helical cell shape contributes to tissue interactions that promote inflammation during chronic infection, in addition to facilitating niche acquisition during acute infection.

RevDate: 2019-05-07

Abida W, Cyrta J, Heller G, et al (2019)

Genomic correlates of clinical outcome in advanced prostate cancer.

Proceedings of the National Academy of Sciences of the United States of America pii:1902651116 [Epub ahead of print].

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.

RevDate: 2019-05-07

Green D, Kharono B, Tordoff DM, et al (2019)

Demographic and risk group heterogeneity across the UNAIDS 90-90-90 targets: a systematic review and meta-analysis protocol.

Systematic reviews, 8(1):110 pii:10.1186/s13643-019-1024-6.

BACKGROUND: Despite policies for universal HIV testing and treatment (UTT) regardless of CD4 count, there are still 1.8 million new HIV infections and 1 million AIDS-related deaths annually. The UNAIDS 90-90-90 goals target suppression of HIV viral load in 73% of all HIV-infected people worldwide by 2030. However, achieving these targets may not lead to expected reductions in HIV incidence if the remaining 27% (persons with unsuppressed viral load) are the drivers of HIV transmission through high-risk behaviors. We aim to conduct a systematic review and meta-analysis to understand the demographics, mobility, geographic distribution, and risk profile of adults who are not virologically suppressed in sub-Saharan Africa in the era of UTT.

METHODS: We will review the published and grey literature for study sources that contain data on demographic and behavioral strata of virologically suppressed and unsuppressed populations since 2014. We will search PubMed and Embase using four sets of search terms tailored to identify characteristics associated with virological suppression (or lack thereof) and each of the individual 90-90-90 goals. Record screening and data abstraction will be done independently and in duplicate. We will use random effects meta-regression analyses to estimate the distribution of demographic and risk features among groups not virologically suppressed and for each individual 90-90-90 goal.

DISCUSSION: The results of our review will help elucidate factors associated with failure to achieve virological suppression in sub-Saharan Africa, as well as factors associated with failure to achieve each of the 90-90-90 goals. These data will help quantify the population-level effects of current HIV treatment interventions to improve strategies for maximizing virological suppression and ending the HIV epidemic.

PROSPERO CRD42018089505 .

RevDate: 2019-05-06

Dropulic LK, Oestreich MC, Pietz HL, et al (2019)

A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study of a Replication-Defective Herpes Simplex Virus 2 Vaccine, HSV529, in Adults With or Without HSV Infection.

The Journal of infectious diseases pii:5486075 [Epub ahead of print].

BACKGROUND: Herpes simplex virus 2 (HSV2) causes genital herpes in over 400 million persons worldwide.

METHODS: We conducted a randomized, double-blind, placebo-controlled trial of a replication-defective HSV2 vaccine, HSV529. Twenty adults each enrolled in three serogroups, HSV1 /HSV2 , HSV1 /HSV2 , and HSV1 /HSV2 , received vaccine or placebo at 0, 1, and 6 months. The primary endpoint was the frequency of solicited local and systemic reactions to vaccination.

RESULTS: Eighty-nine percent of vaccinees experienced mild to moderate solicited injection site reactions compared with 47% of placebo recipients (p = 0.006, 95% CI 0.129, 0.676). Sixty-four percent of vaccinees experienced systemic reactions compared with 53% of placebo recipients (p = 0.44, 95%CI -0.179, 0.402). Seventy-eight percent of HSV1 /HSV2 vaccine recipients had > 4-fold rises in neutralizing antibody titer after three doses of vaccine, whereas none of the participants in the other serogroups had such responses. HSV2-specific CD4+ T-cell responses were detected in 36% 46%, and 27%, of HSV1 /HSV2 , HSV1 /HSV2 , and HSV1 /HSV2 participants, respectively, one month after the third dose of vaccine, and CD8+ T-cell responses were detected in 14%, 8%, and 18% of participants in each group, respectively.

CONCLUSIONS: HSV529 vaccine was safe and elicited neutralizing antibody and modest CD4+ T-cell responses in HSV seronegative vaccinees.Clinical Trials Registration. NCT01915212.

RevDate: 2019-05-06

Goulart BHL, Silgard ET, Baik CS, et al (2019)

Validity of Natural Language Processing for Ascertainment of EGFR and ALK Test Results in SEER Cases of Stage IV Non-Small-Cell Lung Cancer.

JCO clinical cancer informatics, 3:1-15.

PURPOSE: SEER registries do not report results of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutation tests. To facilitate population-based research in molecularly defined subgroups of non-small-cell lung cancer (NSCLC), we assessed the validity of natural language processing (NLP) for the ascertainment of EGFR and ALK testing from electronic pathology (e-path) reports of NSCLC cases included in two SEER registries: the Cancer Surveillance System (CSS) and the Kentucky Cancer Registry (KCR).

METHODS: We obtained 4,278 e-path reports from 1,634 patients who were diagnosed with stage IV nonsquamous NSCLC from September 1, 2011, to December 31, 2013, included in CSS. We used 855 CSS reports to train NLP systems for the ascertainment of EGFR and ALK test status (reported v not reported) and test results (positive v negative). We assessed sensitivity, specificity, and positive and negative predictive values in an internal validation sample of 3,423 CSS e-path reports and repeated the analysis in an external sample of 1,041 e-path reports from 565 KCR patients. Two oncologists manually reviewed all e-path reports to generate gold-standard data sets.

RESULTS: NLP systems yielded internal validity metrics that ranged from 0.95 to 1.00 for EGFR and ALK test status and results in CSS e-path reports. NLP showed high internal accuracy for the ascertainment of EGFR and ALK in CSS patients-F scores of 0.95 and 0.96, respectively. In the external validation analysis, NLP yielded metrics that ranged from 0.02 to 0.96 in KCR reports and F scores of 0.70 and 0.72, respectively, in KCR patients.

CONCLUSION: NLP is an internally valid method for the ascertainment of EGFR and ALK test information from e-path reports available in SEER registries, but future work is necessary to increase NLP external validity.

RevDate: 2019-05-06

Chow VA, Gopal AK, Maloney DG, et al (2019)

Outcomes of Patients with Large B-Cell Lymphomas and Progressive Disease Following CD19-Specific CAR T-Cell Therapy.

RevDate: 2019-05-06

Ortiz JR, Sugimoto JD, Neuzil KM, et al (2019)

Reply to Skowronski and De Serres.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5485849 [Epub ahead of print].

RevDate: 2019-05-06

Matrajt L, Halloran ME, R Antia (2019)

Successes and failures of the live-attenuated influenza vaccine: can we do better?.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5485903 [Epub ahead of print].

BACKGROUND: The effectiveness of the live attenuated influenza vaccine (LAIV) can vary widely, ranging from 0 - 50%. The reasons for these discrepancies remain largely unclear.

METHODS: We use mathematical models to explore how the efficacy of LAIV is affected by the degree of mismatch with the currently circulating influenza strain and interference with pre-existing immunity. The models incorporate three key antigenic distances: the distances between the vaccine strain, pre-existing immunity, and the challenge strain.

RESULTS: Our models show that a LAIV that is matched with the currently circulating strain is likely to have only modest efficacy. Our results suggest that the efficacy of the vaccine would be increased (optimized) if, rather than being matched to the circulating strain, it is antigenically slightly further from pre-existing immunity compared with the circulating strain. The models also suggest two regimes in which LAIV that is matched to circulating strains may be protective: in children before they have built immunity to circulating strains, and in response to novel strains (such as antigenic shifts) which are at substantial antigenic distance from previously circulating strains. We provide an explanation for the variation in vaccine effectiveness between studies and countries of vaccine effectiveness observed during the 2014-15 influenza season.

CONCLUSIONS: LAIV is offered to children across the world, however, its effectiveness significantly varies between studies. Here, we propose a mechanistic explanation to understand these differences. We further propose a way to select the LAIV strain that would have a higher chance of being protective.

RevDate: 2019-05-06

Guthrie KA, Caan B, Diem S, et al (2019)

Facebook advertising for recruitment of midlife women with bothersome vaginal symptoms: A pilot study.

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

BACKGROUND: The MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) Network recruited into five randomized clinical trials (n = 100-350) through mass mailings. The fifth trial tested two interventions for postmenopausal vulvovaginal symptoms (itching, pain, irritation, dryness, or pain with sex) and thus required a high level of sensitivity to privacy concerns. For this trial, in addition to mass mailings we pilot tested a social media recruitment approach. We aimed to evaluate the feasibility of recruiting healthy midlife women with bothersome vulvovaginal symptoms to participate in the Vaginal Health Trial through Facebook advertising.

METHODS: As part of a larger advertising campaign that enrolled 302 postmenopausal women for the 12-week randomized, double-blind, placebo-controlled Vaginal Health Trial from April 2016 to February 2017, Facebook advertising was used to recruit 25 participants. The target population for recruitment by mailings and by Facebook ads included women aged 50-70 years and living within 20 miles of study sites in Minneapolis, MN and Seattle, WA. Design of recruitment letters and Facebook advertisements was informed by focus group feedback. Facebook ads were displayed in the "newsfeed" of targeted users and included a link to the study website. Response rates and costs are described for both online ads and mailing.

RESULTS: Facebook ads ran in Minneapolis for 28 days and in Seattle for 15 days, with ads posted and removed from the site as needed based on clinic flow and a set budget limit. Our estimated Facebook advertising reach was over 200,000 women; 461 women responded and 25 were enrolled at a cost of US$14,813. The response rate per estimated reach was 0.22%; costs were US$32 per response and US$593 per randomized participant. The social media recruitment results varied by site, showing greater effectiveness in Seattle than in Minneapolis. We mailed 277,000 recruitment letters; 2166 women responded and 277 were randomized at a cost of US$98,682. The response rate per letter sent was 0.78%; costs were US$46 per response and US$356 per randomized participant. Results varied little across sites.

CONCLUSION: Recruitment to a clinical trial testing interventions for postmenopausal vaginal symptoms is feasible through social media advertising. Variability in observed effectiveness and costs may reflect the small sample sizes and limited budget of the pilot recruitment study.

RevDate: 2019-05-05

Swygert SG, T Tsukiyama (2019)

Unraveling quiescence-specific repressive chromatin domains.

Current genetics pii:10.1007/s00294-019-00985-9 [Epub ahead of print].

Quiescence is a highly conserved inactive life stage in which the cell reversibly exits the cell cycle in response to external cues. Quiescence is essential for diverse processes such as the maintenance of adult stem cell stores, stress resistance, and longevity, and its misregulation has been implicated in cancer. Although the non-cycling nature of quiescent cells has made obtaining sufficient quantities of quiescent cells for study difficult, the development of a Saccharomyces cerevisiae model of quiescence has recently enabled detailed investigation into mechanisms underlying the quiescent state. Like their metazoan counterparts, quiescent budding yeast exhibit widespread transcriptional silencing and dramatic chromatin condensation. We have recently found that the structural maintenance of chromosomes (SMC) complex condensin binds throughout the quiescent budding yeast genome and induces the formation of large chromatin loop domains. In the absence of condensin, quiescent cell chromatin is decondensed and transcription is de-repressed. Here, we briefly discuss our findings in the larger context of the genome organization field.

RevDate: 2019-05-04

Niehaus L, Boland I, Liu M, et al (2019)

Microbial coexistence through chemical-mediated interactions.

Nature communications, 10(1):2052 pii:10.1038/s41467-019-10062-x.

Many microbial functions happen within communities of interacting species. Explaining how species with disparate growth rates can coexist is important for applications such as manipulating host-associated microbiota or engineering industrial communities. Here, we ask how microbes interacting through their chemical environment can achieve coexistence in a continuous growth setup (similar to an industrial bioreactor or gut microbiota) where external resources are being supplied. We formulate and experimentally constrain a model in which mediators of interactions (e.g. metabolites or waste-products) are explicitly incorporated. Our model highlights facilitation and self-restraint as interactions that contribute to coexistence, consistent with our intuition. When interactions are strong, we observe that coexistence is determined primarily by the topology of facilitation and inhibition influences not their strengths. Importantly, we show that consumption or degradation of chemical mediators moderates interaction strengths and promotes coexistence. Our results offer insights into how to build or restructure microbial communities of interest.

RevDate: 2019-05-03

Peterson CW, HP Kiem (2019)

Lessons from London and Berlin: Designing A Scalable Gene Therapy Approach for HIV Cure.

Cell stem cell, 24(5):685-687.

Recently in Nature, Gupta et al. (2019) reported that a second patient has achieved HIV-1 remission/functional cure after allogeneic hematopoietic stem cell transplantation from a donor carrying a mutation in the CCR5 coreceptor. We highlight both patients' treatments and summarize efforts to develop a broader, more patient-friendly approach.

RevDate: 2019-05-03

Sabo MC, Richardson BA, Lavreys L, et al (2019)

Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion.

AIDS (London, England), 33(7):1225-1230.

OBJECTIVES: A recent study of HIV serodiscordant couples found that depot medroxyprogesterone acetate (DMPA) and oral contraceptive pills (OCPs) were associated with increased HIV risk in the presence, but not in the absence, of bacterial vaginosis. We assessed whether bacterial vaginosis is an effect modifier of the association between hormonal contraception and HIV seroconversion in female sex workers (FSWs) in Mombasa, Kenya.

DESIGN: Prospective cohort study.

METHODS: Data collected from HIV-negative FSWs from 1993 to 2017 were analyzed. Cox proportional hazards models were used to assess the relationship between HIV seroconversion and use of DMPA, OCPs, or hormonal contraceptive implants (Norplant, Jadelle).

RESULTS: A total of 1985 women contributed 7127 person-years of follow-up; 307 women seroconverted to HIV (4.32/100 person-years). DMPA was significantly associated with elevated risk of HIV seroconversion in women with [aHR 1.56, 95% confidence interval (CI) 1.08-2.25; P = 0.02] and without (aHR 2.08, 95% CI 1.46-2.97; P < 0.001) bacterial vaginosis (interaction P = 0.4). Similarly, OCP use was associated with increased HIV risk both in the presence (aHR 1.50, 95% CI 0.94-2.39; P = 0.09) and absence (aHR 1.61, 95% CI 0.99-2.64; P = 0.06) of bacterial vaginosis (interaction P = 0.9), though neither stratum reached statistical significance. Implants were not associated with HIV seroconversion overall (aHR 0.99, 95% CI 0.40-2.45; P = 0.9), or in women with (aHR 0.65, 95% CI 0.16-2.72; P = 0.6) and without (aHR 1.39, 95% CI 0.43-4.46; P = 0.6) bacterial vaginosis (interaction P = 0.5).

CONCLUSION: Bacterial vaginosis had no effect on the associations between hormonal contraceptives and HIV seroconversion in this cohort. Contraceptive implants were not associated with increased HIV risk compared with no contraception.

RevDate: 2019-05-02

Geer M, Roberts E, Shango M, et al (2019)

Multicentre retrospective study of intravascular large B-cell lymphoma treated at academic institutions within the United States.

British journal of haematology [Epub ahead of print].

Intravascular large B-cell lymphoma (IVLBCL) is a rare entity, with a generally aggressive course that may vary based on geographic presentation. While a United States (US) registry study showed relatively good outcomes with IVLBCL, clinicopathological and treatment data were unavailable. We performed a detailed retrospective review of cases identified at 8 US medical centres, to improve understanding of IVLBCL and inform management. We compiled data retrieved via an Institutional Review Board-approved review of IVLBCL cases identified from 1999 to 2015 at nine academic institutions across the US. We characterized the cohort's clinical status at time of diagnosis, presenting diagnostic and clinical features of the disease, treatment modalities used and overall prognostic data. Our cohort consisted of 54 patients with varying degrees of clinical features. Adjusting for age, better performance status at presentation was associated with increased survival time for the patients diagnosed in vivo (hazard ratio: 2·12, 95% confidence interval 1·28, 3·53). Based on the data we have collected, it would appear that the time interval to diagnosis is a significant contributor to outcomes of patients with IVLBCL.

RevDate: 2019-05-02

Hanson DJ, Tsvetkova O, Rerolle G, et al (2019)

Genome-wide approach to the CD4 T-cell response to HHV-6B.

Journal of virology pii:JVI.00321-19 [Epub ahead of print].

HHV-6 and CMV are population-prevalent betaherpesviruses with intermittent lytic replication that can be pathogenic in immunocompromised hosts. Elucidation of the adaptive immune response is valuable for understanding pathogenesis and designing novel treatments. Knowledge of T-cell antigens has reached the genome-wide level for CMV and other human herpesviruses, but study of HHV-6 is at an earlier stage. Using rare cell enrichment combined with an HLA-agnostic, proteome-wide approach, we queried HHV-6B-specific CD4 T cells from 18 healthy donors with each known HHV-6B protein. We detect low abundance of HHV-6-specific CD4 T cells in blood; however, the within-person CD4 T-cell response is quite broad: the median number of ORF products recognized was nine per person. Overall, the data expands the number of documented HHV-6B CD4 T-cell antigens from approximately 11 to 60. Epitopes in the proteins encoded by U14, U90, and U95 were mapped with synthetic peptides and HLA restriction defined for some responses. Intriguingly, CD4 T-cell antigens newly described in this report are among the most population-prevalent, including U73, U72, U95 and U30. Our results indicate that selection of HHV-6B ORFs for immunotherapy should consider this expanded panel of HHV-6B antigens.IMPORTANCE Human herpesvirus 6 is highly prevalent and maintains chronic infection in immunocompetent individuals with the potential to replicate widely in settings of immunosuppression, leading to clinical disease. Antiviral compounds may be ineffective and/or pose dose-limiting toxicity, and therefore immune-based therapies have garnered increased interest in recent years. Attempts at addressing this unmet medical need begin with understanding the cellular response to HHV-6 at the individual and population level. The current study provides a comprehensive assessment of HHV-6-specific T-cell responses that may inform development of cell-based therapies directed at this virus.

RevDate: 2019-05-02

Veatch JR, Jesernig B, Kargl J, et al (2019)

Endogenous CD4+ T cells recognize neoantigens in lung cancer patients, including recurrent oncogenic KRAS and ERBB2 (Her2) driver mutations.

Cancer immunology research pii:2326-6066.CIR-18-0402 [Epub ahead of print].

T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune checkpoint inhibitor therapy or adoptive cell transfer. Much of the focus has been on identifying epitopes presented to CD8+ T cells by class I MHC. However, CD4+ class II MHC-restricted T cells have been shown to have an important role in antitumor immunity. Unfortunately, the vast majority of neoantigens recognized by CD8+ or CD4+ T cells in cancer patients result from random mutations and are patient-specific. Here, we screened the blood of 5 NSCLC patients for T-cell responses to candidate mutation-encoded neoepitopes. T-cell responses were detected to 8.8% of screened antigens, with 1-7 antigens identified per patient. A majority of responses were to random, patient-specific mutations. However, CD4+ T cells that recognized the recurrent KRASG12V and the ERBB2 (Her2) internal tandem duplication (ITD) oncogenic driver mutations, but not the corresponding wildtype sequences, were identified in two patients. Two different T-cell receptors (TCRs) specific for KRASG12V and one T-cell receptor specific for Her2-ITD were isolated and conferred antigen specificity when transfected into T cells. Deep sequencing identified the Her2-ITD-specific TCR in the tumor but not non-adjacent lung. Our results showed that CD4+ T-cell responses to neoantigens, including recurrent driver mutations, can be derived from the blood of NSCLC patients. These data support the use of adoptive transfer or vaccination to augment CD4+ neoantigen-specific T cells and elucidate their role in human antitumor immunity.

RevDate: 2019-05-02

Hiatt JB, D MacPherson (2019)

Delivering a STINGing Blow to Small Cell Lung Cancer via Synergistic Inhibition of DNA-Damage Response and Immune-Checkpoint Pathways.

Cancer discovery, 9(5):584-586.

Small cell lung cancer (SCLC) has demonstrated modest responses to immune-checkpoint blockade despite harboring a high mutational burden. In this issue, Sen and colleagues show remarkable synergy between inhibition of the DNA-damage response and the PD-1 axis, resulting in striking tumor regressions in SCLC mouse models.See related article by Sen et al., p. 646.

RevDate: 2019-05-01

Higano C (2019)

Enzalutamide, apalutamide, or darolutamide: are apples or bananas best for patients?.

Nature reviews. Urology pii:10.1038/s41585-019-0186-2 [Epub ahead of print].

RevDate: 2019-04-30

Marks DI, Kebriaei P, Stelljes M, et al (2019)

Outcomes of allogeneic stem cell transplantation after inotuzumab ozogamicin treatment for relapsed or refractory acute lymphoblastic leukemia.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30267-8 [Epub ahead of print].

BACKGROUND: Attaining complete remission of acute lymphoblastic leukemia (ALL) before hematopoietic stem cell transplantation (HSCT) correlates with better post-transplant outcomes. Inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, has shown significantly higher rates of remission, minimal residual disease negativity, and HSCT versus standard chemotherapy in treating relapsed/refractory (R/R) ALL. We investigated the role of previous transplant, and proceeding directly to HSCT after remission, as factors in determining post-transplant survival in the setting of InO treatment for R/R ALL.

METHODS: The analyzed population comprised InO-treated patients who proceeded to allogeneic HSCT in two clinical trials (phase 1/2: NCT01363297 and phase 3: NCT01564784). Overall survival (OS) was defined as time from HSCT to death (any cause).

RESULTS: Of 236 InO-treated patients, 101 (43%) proceeded to allogeneic HSCT and were included in this analysis. Most received InO as first salvage (62%); 85% had no previous HSCT. Median (95% CI) post-transplant OS was 9.2 months (5.1, not estimable) with 2-year survival probability (95% CI) of 41% (32-51%). In first-HSCT patients (n=86), median (95% CI) post-transplant OS was 11.8 months (5.9, not estimable) with 2-year survival probability (95% CI) of 46% (35-56%); some patients relapsed and needed additional treatment before HSCT (n=28). Those who went directly to first HSCT upon remission with no additional salvage/induction treatment (n=73) fared best: median post-transplant OS was not reached with 2-year survival probability (95% CI) of 51% (39-62%).

CONCLUSION: In patients with R/R ALL, InO followed by allogeneic HSCT provided optimal long-term survival benefit among those with no previous HSCT who went directly to transplant after remission.

RevDate: 2019-04-30

Hang D, Joshi AD, He X, et al (2019)

Colorectal cancer susceptibility variants and risk of conventional adenomas and serrated polyps: results from three cohort studies.

International journal of epidemiology pii:5481891 [Epub ahead of print].

BACKGROUND: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown.

METHODS: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis.

RESULTS: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584).

CONCLUSIONS: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.

RevDate: 2019-04-30

Soh YS, Moncla LH, Eguia R, et al (2019)

Comprehensive mapping of adaptation of the avian influenza polymerase protein PB2 to humans.

eLife, 8: pii:45079.

Viruses like influenza are infamous for their ability to adapt to new hosts. Retrospective studies of natural zoonoses and passaging in the lab have identified a modest number of host-adaptive mutations. However, it is unclear if these mutations represent all ways that influenza can adapt to a new host. Here we take a prospective approach to this question by completely mapping amino-acid mutations to the avian influenza virus polymerase protein PB2 that enhance growth in human cells. We identify numerous previously uncharacterized human-adaptive mutations. These mutations cluster on PB2's surface, highlighting potential interfaces with host factors. Some previously uncharacterized adaptive mutations occur in avian-to-human transmission of H7N9 influenza, showing their importance for natural virus evolution. But other adaptive mutations do not occur in nature because they are inaccessible via single-nucleotide mutations. Overall, our work shows how selection at key molecular surfaces combines with evolutionary accessibility to shape viral host adaptation.

RevDate: 2019-04-30

McNabb S, Harrison TA, Albanes D, et al (2019)

Meta-analysis of 16 studies of the association of alcohol with colorectal cancer.

International journal of cancer [Epub ahead of print].

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from five case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (OR: 0.92, 95% CI: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08), and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage. This article is protected by copyright. All rights reserved.

RevDate: 2019-04-30

Roble G, Pullium J, Hester T, et al (2019)

Disaster Planning for Animals in Hazardous Agent Containment Units.

ILAR journal pii:5481801 [Epub ahead of print].

Disaster response planning for laboratory animal facilities is a time- and personnel-intensive undertaking. This article outlines numerous considerations in formulating a plan for disaster response in a high containment animal unit. The planning process is discussed around a set of elements: planning team formation, situational understanding, goal and objective determination, plan development, preparation, and rehearsal or implementation. The importance of an appropriate planning team and personnel development is explored in relationship to exemplary disaster scenarios such as natural disaster and terrorism. Specific risks such as hazardous agent and animal species type serve to delineate goal-setting methods. These goals provide the framework for an institutional disaster plan. The review further uses elements of the planning process to explore the difficulties of euthanasia of animals treated with hazardous agents. Ultimately, the pitfalls of handling media relations following disaster are examined. Proactive measures for preparing to speak to the media and mitigate negative perceptions of research are presented.

RevDate: 2019-04-30

Kaya-Okur HS, Wu SJ, Codomo CA, et al (2019)

CUT&Tag for efficient epigenomic profiling of small samples and single cells.

Nature communications, 10(1):1930 pii:10.1038/s41467-019-09982-5.

Many chromatin features play critical roles in regulating gene expression. A complete understanding of gene regulation will require the mapping of specific chromatin features in small samples of cells at high resolution. Here we describe Cleavage Under Targets and Tagmentation (CUT&Tag), an enzyme-tethering strategy that provides efficient high-resolution sequencing libraries for profiling diverse chromatin components. In CUT&Tag, a chromatin protein is bound in situ by a specific antibody, which then tethers a protein A-Tn5 transposase fusion protein. Activation of the transposase efficiently generates fragment libraries with high resolution and exceptionally low background. All steps from live cells to sequencing-ready libraries can be performed in a single tube on the benchtop or a microwell in a high-throughput pipeline, and the entire procedure can be performed in one day. We demonstrate the utility of CUT&Tag by profiling histone modifications, RNA Polymerase II and transcription factors on low cell numbers and single cells.

RevDate: 2019-04-30

Yang DC, Blair KM, Taylor JA, et al (2019)

A genome-wide Helicobacter pylori morphology screen uncovers a membrane spanning helical cell shape complex.

Journal of bacteriology pii:JB.00724-18 [Epub ahead of print].

Evident in its name, the gastric pathogen Helicobacter pylori has helical cell morphology which facilitates efficient colonization of the human stomach. An improved light focusing strategy allowed us to robustly distinguish even subtle perturbations of H. pylori cell morphology by deviations in light scattering properties measured by flow cytometry. Profiling of an arrayed genome-wide deletion library identified 28 genes that influence different aspects of cell shape including properties of the helix, cell length or width, cell filament formation, cell shape heterogeneity and cell branching. Included in this mutant collection were two that failed to form any helical cells, a soluble lytic transglycosylase and a previously uncharacterized putative multi-pass inner membrane protein HPG27_0728, renamed Csd7. A combination of cell fractionation, mutational and immunoprecipitation experiments show that Csd7 and Csd2 collaborate to stabilize the Csd1 peptidoglycan (PG) endopeptidase. Thus, both csd2 and csd7 mutants show the same enhancement of PG tetra-pentapeptide crosslinking as csd1 mutants. Csd7 also links Csd1 with the bactofilin CcmA via protein-protein interactions. Although Csd1 is stable in ccmA mutants, these mutants show altered PG tetra-pentapeptide crosslinking, suggesting that Csd7 may directly or indirectly activate as well as stabilize Csd1. These data begin to illuminate a highly orchestrated program to regulate PG modifications that promote helical shape, which includes nine non-essential, non-redundant genes required for helical shape and 26 additional genes that further modify H. pylori's cell morphology.ImportanceThe stomach ulcer and cancer-causing pathogen Helicobacter pylori has helical cell shape which facilitates stomach infection. Using light scattering to measure perturbations of cell morphology, we identified 28 genes that influence different aspects of cell shape. A mutant in a previously uncharacterized protein renamed Csd7 failed to form any helical cells. Biochemical analyses showed that Csd7 collaborates with other proteins to stabilize the cell wall degrading enzyme Csd1. Csd7 also links Csd1 with a putative filament forming protein via protein-protein interactions. These data suggest that helical cell shape arises from a a highly orchestrated program to regulate cell wall modifications. Targeting of this helical cell shape promoting program could offer new ways to block infectivity of this important human pathogen.

RevDate: 2019-04-30

Da Costa AS, Graham JB, Swarts JL, et al (2019)

Regulatory T cells limit unconventional memory to preserve the capacity to mount protective CD8 memory responses to pathogens.

Proceedings of the National Academy of Sciences of the United States of America pii:1818327116 [Epub ahead of print].

Immunological memory exists so that following infection an expanded population of pathogen-specific lymphocytes can rapidly and efficiently control infection in the case of reexposure. However, in the case of CD8+ T lymphocytes, a population of unconventional CD44+CD122+ virtual memory T cells (TVM) has been described that possesses many, though not all, features of "true memory" T cells, without the requirement of first encountering cognate antigen. Here, we demonstrate a role for regulatory T cell-mediated restraint of TVM at least in part through limiting IL-15 trans-presentation by CD11b+ dendritic cells. Further, we show that keeping TVM in check ensures development of functional, antigen-specific "true" memory phenotype CD8+ T cells that can assist in pathogen control upon reexposure.

RevDate: 2019-04-29

Bellettiere J, LaMonte MJ, Evenson KR, et al (2019)

Sedentary behavior and cardiovascular disease in older women: The Objective Physical Activity and Cardiovascular Health (OPACH) Study.

Circulation, 139(8):1036-1046.

Background: Evidence that higher sedentary time is associated with higher risk for cardiovascular disease (CVD) is based mainly on self-reported measures. Few studies have examined whether patterns of sedentary time are associated with higher risk for CVD.

Methods: Women from the Objective Physical Activity and Cardiovascular Health (OPACH) Study (n=5638, aged 63-97, mean age=79±7) with no history of myocardial infarction (MI) or stroke wore accelerometers for 4-to-7 days and were followed for up to 4.9 years for CVD events. Average daily sedentary time and mean sedentary bout duration were the exposures of interest. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CVD using models adjusted for covariates and subsequently adjusted for potential mediators (body mass index (BMI), diabetes, hypertension, and CVD-risk biomarkers [fasting glucose, high-density lipoprotein, triglycerides, and systolic blood pressure]). Restricted cubic spline regression characterized dose-response relationships.

Results: There were 545 CVD events during 19,350 person-years. Adjusting for covariates, women in the highest (≥ ~11 hr/day) vs. the lowest (≤ ~9 hr/day) quartile of sedentary time had higher risk for CVD (HR=1.62; CI=1.21-2.17; p-trend <0.001). Further adjustment for potential mediators attenuated but did not eliminate significance of these associations (p-trend<.05, each). Longer vs. shorter mean bout duration was associated with higher risks for CVD (HR=1.54; CI=1.27-2.02; p-trend=0.003) after adjustment for covariates. Additional adjustment for CVD-risk biomarkers attenuated associations resulting in a quartile 4 vs. quartile 1 HR=1.36; CI=1.01-1.83; p-trend=0.10). Dose-response associations of sedentary time and bout duration with CVD were linear (P-nonlinear >0.05, each). Women jointly classified as having high sedentary time and long bout durations had significantly higher risk for CVD (HR=1.34; CI=1.08-1.65) than women with both low sedentary time and short bout duration. All analyses were repeated for incident coronary heart disease (MI or CVD death) and associations were similar with notably stronger hazard ratios.

Conclusions: Both high sedentary time and long mean bout durations were associated in a dose-response manner with increased CVD risk in older women, suggesting that efforts to reduce CVD burden may benefit from addressing either or both component(s) of sedentary behavior.

RevDate: 2019-04-28

Mathewson AW, Berman D, CB Moens (2019)

Microtubules are required for the maintenance of planar cell polarity in monociliated floorplate cells.

Developmental biology pii:S0012-1606(18)30742-5 [Epub ahead of print].

The asymmetric localization of planar cell polarity (PCP) proteins is essential for the establishment of many planar polarized cellular processes, but the mechanisms that maintain these asymmetric distributions remain poorly understood. A body of evidence has tied oriented subapical microtubules (MTs) to the establishment of PCP protein polarity, yet recent studies have suggested that the MT cytoskeleton is later dispensable for the maintenance of this asymmetry. As MTs underlie the vesicular trafficking of membrane-bound proteins within cells, the requirement for MTs in the maintenance of PCP merited further investigation. We investigated the complex interactions between PCP proteins and the MT cytoskeleton in the polarized context of the floorplate of the zebrafish neural tube. We demonstrated that the progressive posterior polarization of the primary cilia of floorplate cells requires not only Vangl2 but also Fzd3a. We determined that GFP-Vangl2 asymmetrically localizes to anterior membranes whereas Fzd3a-GFP does not polarize on anterior or posterior membranes but maintains a cytosolic enrichment at the base of the primary cilium. Vesicular Fzd3a-GFP is rapidly trafficked along MTs primarily toward the apical membrane during a period of PCP maintenance, whereas vesicular GFP-Vangl2 is less frequently observed. Nocodazole-induced loss of MT polymerization disrupts basal body positioning as well as GFP-Vangl2 localization and reduces cytosolic Fzd3a-GFP movements. Removal of nocodazole after MT disruption restores MT polymerization but does not restore basal body polarity. Interestingly, GFP-Vangl2 repolarizes to anterior membranes and vesicular Fzd3a-GFP dynamics recover after multiple hours of recovery, even in the context of unpolarized basal bodies. Together our findings challenge previous work by revealing an ongoing role for MT-dependent transport of PCP proteins in maintaining both cellular and PCP protein asymmetry during development.

RevDate: 2019-04-28

Sherr K, Ásbjörnsdóttir K, Crocker J, et al (2019)

Scaling-up the Systems Analysis and Improvement Approach for prevention of mother-to-child HIV transmission in Mozambique (SAIA-SCALE): a stepped-wedge cluster randomized trial.

Implementation science : IS, 14(1):41 pii:10.1186/s13012-019-0889-z.

BACKGROUND: The introduction of option B+-rapid initiation of lifelong antiretroviral therapy regardless of disease status for HIV-infected pregnant and breastfeeding women-can dramatically reduce HIV transmission during pregnancy, birth, and breastfeeding. Despite significant investments to scale-up Option B+, results have been mixed, with high rates of loss to follow-up, sub-optimal viral suppression, continued pediatric HIV transmission, and HIV-associated maternal morbidity. The Systems Analysis and Improvement Approach (SAIA) cluster randomized trial demonstrated that a package of systems engineering tools improved flow through the prevention of mother-to-child HIV transmission (PMTCT) cascade. This five-step, facility-level intervention is designed to improve understanding of gaps (cascade analysis), guide identification and prioritization of low-cost workflow modifications (process mapping), and iteratively test and redesign these modifications (continuous quality improvement). This protocol describes a novel model for SAIA delivery (SAIA-SCALE) led by district nurse supervisors (rather than research nurses), and evaluation procedures, to serve as a foundation for national scale-up.

METHODS: The SAIA-SCALE stepped wedge trial includes three implementation waves, each 12 months in duration. Districts are the unit of assignment, with four districts randomly assigned per wave, covering all 12 districts in Manica province, Mozambique. In each district, the three highest volume health facilities will receive the SAIA-SCALE intervention (totaling 36 intervention facilities). The RE-AIM framework will guide SAIA-SCALE's evaluation. Reach describes the proportion of clinics and population in Manica province reached, and sub-groups not reached. Effectiveness assesses impact on PMTCT process measures and patient-level outcomes. Adoption describes the proportion of districts/clinics adopting SAIA-SCALE, and determinants of adoption using the Organizational Readiness for Implementing Change (ORIC) tool. Implementation will identify SAIA-SCALE core elements and determinants of successful implementation using the Consolidated Framework for Implementation Research (CFIR). Maintenance describes the proportion of districts sustaining the intervention. We will also estimate the budget and program impact from the payer perspective for national scale-up.

DISCUSSION: SAIA packages user-friendly systems engineering tools to guide decision-making by frontline health workers, and to identify low-cost, contextually appropriate PMTCT improvement strategies. By integrating SAIA delivery into routine management structures, this pragmatic trial is designed to test a model for national intervention scale-up.

TRIAL REGISTRATION: NCT03425136 (registered 02/06/2018).

RevDate: 2019-04-27

Stromnes IM, Burrack AL, Hulbert A, et al (2019)

Differential effects of depleting versus programming tumor-associated macrophages on engineered T cells in pancreatic ductal adenocarcinoma.

Cancer immunology research pii:2326-6066.CIR-18-0448 [Epub ahead of print].

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to therapies, including immune checkpoint blockade. We investigated two distinct strategies to modulate tumor-associated macrophages (TAMs) to enhance cellular therapy targeting mesothelin in an autochthonous PDA mouse model. Administration of an antibody to colony-stimulating factor (anti-Csf1R) depleted Ly6Clow pro-tumorigenic TAMs and significantly enhanced endogenous T-cell intratumoral accumulation. Despite increasing the number of endogenous T cells at the tumor site, as previously reported, TAM depletion had only minimal impact on intratumoral accumulation and persistence of T cells engineered to express a murine mesothelin-specific T-cell receptor (TCR). TAM depletion interfered with the antitumor activity of the infused T cells in PDA, evidenced by reduced tumor cell apoptosis. In contrast, TAM programming with agonistic anti-CD40 increased both Ly6Chigh TAMs and the intratumoral accumulation and longevity of TCR-engineered T cells. Anti-CD40 significantly increased the frequency and number of proliferating and granzyme B+ engineered T cells, and increased tumor cell apoptosis. However, anti-CD40 failed to rescue intratumoral engineered T-cell IFNγ production. Thus, although functional modulation, rather than TAM depletion, enhanced the longevity of engineered T cells and increased tumor cell apoptosis, ultimately, anti-CD40 modulation was insufficient to rescue key effector defects in tumor-reactive T cells. This study highlights critical distinctions between how endogenous T cells that evolve in vivo, and engineered T cells with previously acquired effector activity, respond to modifications of the tumor microenvironment.

RevDate: 2019-04-26

Dimitrov D, Wood D, Ulrich A, et al (2019)

Projected effectiveness of HIV detection during early infection and rapid ART initiation among MSM and transgender women in Peru: A modeling study.

Infectious Disease Modelling, 4:73-82 pii:S2468-0427(18)30050-2.

Background: The Sabes study, a treatment as prevention intervention in Peru, tested the hypothesis that initiating antiretroviral therapy (ART) early in HIV infection when viral load is high, would markedly reduce onward HIV transmission among high-risk men who have sex with men (MSM) and transgender women (TW). We investigated the potential population-level benefits of detection of HIV early after acquisition and rapid initiation of ART.

Methods: We designed a transmission dynamic model to simulate the HIV epidemic among MSM and TW in Peru, calibrated to data on HIV prevalence and ART coverage from 2004 to 2011. We assessed the impact of an intervention starting in 2018 in which up to 50% of the new infections were diagnosed within three months of acquisition and initiated on ART within 1 month of diagnosis. We estimated the impact of the intervention over 20 years using the cumulative prevented fraction of new HIV infections compared to scenarios without intervention.

Findings: Our model suggests that only 19% of the infected MSM and TW are virally suppressed in 2018 and 35%-40% of the new HIV infections are transmitted from contacts with acutely-infected partners. An intervention reaching 10% of all acutely infected MSM and TW is projected to prevent 13.3% [Uncertainty interval: 11.9%-14.3%] of the new infections over 20 years and reduce HIV incidence in 2038 by 24%. Reaching 50% of all acutely infected MSM and TW will increase the prevalence of viral suppression in 2038 to 59% and prevent 41% of expected infections over 20 years. Reaching 50% of the high-risk MSM and TW in acute phase would reduce HIV incidence in 2038 by 60% and prevent 36% of new infections between 2018 and 2038.

Conclusions: Early detection of HIV infections and rapid initiation of ART among MSM is desirable as it would increase the effectiveness of the HIV prevention program in Peru. Targeting high-risk MSM and TW will be highly efficient.

RevDate: 2019-04-26

Luedtke AR, Carone M, MJ van der Laan (2019)

An omnibus non-parametric test of equality in distribution for unknown functions.

Journal of the Royal Statistical Society. Series B, Statistical methodology, 81(1):75-99.

We present a novel family of nonparametric omnibus tests of the hypothesis that two unknown but estimable functions are equal in distribution when applied to the observed data structure. We developed these tests, which represent a generalization of the maximum mean discrepancy tests described in Gretton et al. [2006], using recent developments from the higher-order pathwise differentiability literature. Despite their complex derivation, the associated test statistics can be expressed rather simply as U-statistics. We study the asymptotic behavior of the proposed tests under the null hypothesis and under both fixed and local alternatives. We provide examples to which our tests can be applied and show that they perform well in a simulation study. As an important special case, our proposed tests can be used to determine whether an unknown function, such as the conditional average treatment effect, is equal to zero almost surely.

RevDate: 2019-04-27

Hom N, Gentles L, Bloom JD, et al (2019)

Deep mutational scan of the highly conserved influenza A M1 matrix protein reveals substantial intrinsic mutational tolerance.

Journal of virology pii:JVI.00161-19 [Epub ahead of print].

Influenza A virus matrix protein M1 is involved in multiple stages of the viral infectious cycle. Despite its functional importance, our present understanding of this essential viral protein is limited. The roles of a small subset of specific amino acids have been reported, but a more comprehensive understanding of the relationship between M1 sequence, structure, and virus fitness remains elusive. Here, we use deep mutational scanning to measure the effect of every amino-acid substitution in M1 on viral replication in cell culture. The map of amino-acid mutational tolerance we have generated allows us to identify sites that are functionally constrained in cell-culture as well as sites that are less constrained. Several sites that exhibit low tolerance to mutation have been found to be critical for M1 function and production of viable virions. Surprisingly, significant portions of the M1 sequence, especially in the C-terminal domain whose structure is undetermined, were found to be highly tolerant of amino acid variation, despite having extremely low levels of sequence diversity among natural influenza strains. This unexpected discrepancy indicates that not all sites in M1 that exhibit high sequence conservation in nature are under strong constraint during selection for viral replication in cell culture.IMPORTANCE The M1 matrix protein is critical for many stages of the influenza infection cycle. Currently, we have an incomplete understanding of this highly conserved protein's function and structure. Key regions of M1, particularly in the C-terminus of the protein, remain poorly characterized. Here we used deep mutational scanning to determine the extent of M1's tolerance to mutation. Surprisingly, nearly two-thirds of the M1 sequence exhibits a high tolerance for substitutions, contrary to the extremely low sequence diversity observed across naturally occurring M1 isolates. Sites with low mutational tolerance were also identified, suggesting that they likely play critical functional roles and are under selective pressure. These results reveal the intrinsic mutational tolerance throughout M1, and shape future inquiries probing the function of this essential influenza A virus protein.

RevDate: 2019-04-25

Godavarthy PS, Kumar R, Herkt SC, et al (2019)

The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1 - CD44 axis.

Haematologica pii:haematol.2018.212365 [Epub ahead of print].

The endosteal bone marrow niche and vascular endothelial cells provide sanctuaries to leukemic cells. In murine chronic myeloid leukemia CD44 on leukemia cells and E-selectin on bone marrow endothelium are essential mediators for the engraftment of leukemic stem cells. We hypothesized that non-adhesion of chronic myeloid leukemia-initiating cells to E-selectin on the bone marrow endothelium may lead to superior eradication of leukemic stem cells in chronic myeloid leukemia after treatment with imatinib than imatinib alone. Indeed, here we show that treatment with the E-selectin inhibitor GMI-1271 in combination with imatinib prolongs survival of mice with chronic myeloid leukemia via decreased contact time of leukemia cells with bone marrow endothelium. Non-adhesion of BCR-ABL1+ cells leads to an increase of cell cycle progression and an increase of expression of the hematopoietic transcription factor and protooncogene Scl/Tal1 in leukemia-initiating cells. We implicate SCL/TAL1 as indirect phosphorylation target of BCR-ABL1 and as a negative transcriptional regulator of CD44 expression. We show that increased SCL/TAL1 expression is associated with improved outcome in human chronic myeloid leukemia. These data demonstrate the BCR-ABL1-specific, cell-intrinsic pathways leading to altered interactions with the vascular niche via the modulation of adhesion molecules - a strategy therapeutically exploitable in future.

RevDate: 2019-04-25

Ligibel J, Dillon DA, Giobbie-Hurder A, et al (2019)

Impact of a pre-operative exercise intervention on breast cancer proliferation and gene expression: Results from the Pre-Operative Health and Body (PreHAB) Study.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-18-3143 [Epub ahead of print].

PURPOSE: Exercise after breast cancer diagnosis is associated with lower cancer-specific mortality, but the biological mechanisms through which exercise impacts breast cancer are not fully understood. The Pre-Operative Health and Body (PreHAB) Study was a randomized window of opportunity trial designed to test the impact of exercise on Ki-67, gene expression, and other biomarkers in women with breast cancer.

EXPERIMENTAL DESIGN: Inactive women with newly diagnosed breast cancer were randomized to an exercise intervention or mind-body control group, and participated in the study between enrollment and surgery (mean 29.3 days). Tumor and serum were collected at baseline and surgery.

RESULTS: Forty-nine women were randomized (27 exercise, 22 control). At baseline, mean age was 52.6, body mass index was 30.2kg/m2 and exercise was 49 min/wk. Exercise participants significantly increased exercise vs. controls (203 vs. 23 min/week, p<0.0001). There were no differences in changes of expression of Ki-67, insulin receptor, and cleaved caspase-3 in exercise participants vs controls. KEGG pathway analysis demonstrated significant upregulation of 18 unique pathways between the baseline biopsy and surgical excision in exercise participants and none in control participants (q<0.1). Top ranked pathways included several implicated in immunity and inflammation. Exploratory analysis of tumor immune infiltrates demonstrated a trend toward a decrease in FOXP3+ cells in exercise vs control participants over the intervention period (p=0.08).

CONCLUSIONS: A window of opportunity exercise intervention did not impact proliferation but led to alterations in gene expression in breast tumors, suggesting that exercise may have a direct effect on breast cancer.

RevDate: 2019-04-26

Bellettiere J, Zhang Y, Berardi V, et al (2019)

Parameterizing and validating existing algorithms for identifying out-of-bed time using hip-worn accelerometer data from older women.

Physiological measurement [Epub ahead of print].

OBJECTIVE: To parameterize and validate two existing algorithms for identifying out-of-bed time using 24-hour hip-worn accelerometer data from older women.

APPROACH: Overall, 628 women (80±6 years old) wore ActiGraph GT3X+ accelerometers 24 hours/day for up to 7 days and concurrently completed sleep-logs. Trained staff used a validated visual analysis protocol to measure in-bed periods on accelerometer tracings (criterion). The Tracy and McVeigh algorithms were adapted for optimal use in older adults. A training set of 314 women was used to choose two key thresholds by maximizing the sum of sensitivity and specificity for each algorithm and data (vertical axis, VA, and vector magnitude, VM) combination. Data from the remaining 314 women were then used to test agreement in waking wear time (i.e., out-of-bed time while wearing the accelerometer) by computing sensitivity, specificity, and kappa comparing the algorithm output with the criterion. Waking wear time-adjusted means of sedentary time, light-intensity physical activity (light PA) and moderate-to-vigorous-intensity physical activity (MVPA) were then estimated and compared.

MAIN RESULTS: Waking wear time agreement with the criterion was high for Tracy_VA, Tracy_VM, McVeigh_VA, and highest for McVeigh_VM. Compared to the criterion, McVeigh_VM had mean sensitivity=0.92, specificity=0.87, kappa=0.80, and overall mean difference (±SD) of -0.04±2.5 hours/day. Minutes of sedentary time, light PA, and MVPA adjusted for waking wear time using the criterion measure and McVeigh_VM were not statistically different (p >0.43 | all).

SIGNIFICANCE: The McVeigh algorithm with optimal parameters using VM performed best compared to criterion sleep-log assisted visual analysis and is suitable for automated identification of waking wear time in older women when visual analysis is not feasible.

RevDate: 2019-04-24

Seilie AM, Chang M, Hanron AE, et al (2019)

Beyond Blood Smears-Qualification of the Plasmodium 18S rRNA as a Biomarker for Controlled Human Malaria Infections.

The American journal of tropical medicine and hygiene [Epub ahead of print].

18S rRNA is a biomarker that provides an alternative to thick blood smears in controlled human malaria infection (CHMI) trials. We reviewed data from CHMI trials at non-endemic sites that used blood smears and Plasmodium 18S rRNA/rDNA biomarker nucleic acid tests (NATs) for time to positivity. We validated a multiplex quantitative reverse transcription-PCR (qRT-PCR) for Plasmodium 18S rRNA, prospectively compared blood smears and qRT-PCR for three trials, and modeled treatment effects at different biomarker-defined parasite densities to assess the impact on infection detection, symptom reduction, and measured intervention efficacy. Literature review demonstrated accelerated NAT-based infection detection compared with blood smears (mean acceleration: 3.2-3.6 days). For prospectively tested trials, the validated Plasmodium 18S rRNA qRT-PCR positivity was earlier (7.6 days; 95% CI: 7.1-8.1 days) than blood smears (11.0 days; 95% CI: 10.3-11.8 days) and significantly preceded the onset of grade 2 malaria-related symptoms (12.2 days; 95% CI: 10.6-13.3 days). Discrepant analysis showed that the risk of a blood smear-positive, biomarker-negative result was negligible. Data modeling predicted that treatment triggered by specific biomarker-defined thresholds can differentiate complete, partial, and non-protective outcomes and eliminate many grade 2 and most grade 3 malaria-related symptoms post-CHMI. Plasmodium 18S rRNA is a sensitive and specific biomarker that can justifiably replace blood smears for infection detection in CHMI trials in non-endemic settings. This study led to biomarker qualification through the U.S. Food and Drug Administration for use in CHMI studies at non-endemic sites, which will facilitate biomarker use for the qualified context of use in drug and vaccine trials.

RevDate: 2019-04-24

Casto AM, Roychoudhury P, Xie H, et al (2019)

Large, stable, contemporary interspecies recombination events in circulating human herpes simplex viruses.

The Journal of infectious diseases pii:5477434 [Epub ahead of print].

The ubiquitous human pathogens, HSV-1 and HSV-2, are distinct viral species that diverged about six million years ago. At least four small, ancient HSV-1 x HSV-2 interspecies recombination events have affected the HSV-2 genome, with recombinants and non-recombinants at each locus circulating today. However, it is unknown if interspecies recombination can affect other loci and if new recombinants continue to be generated. Using 255 newly sequenced and 230 existing HSV genome sequences, we comprehensively assessed interspecies recombination in HSV. Our findings show that the sizes and locations of interspecies recombination events in HSV-2 are significantly more variable than previously appreciated and that they can impact species-specific T-cell recognition of HSV. We describe two large (>5kb) recombination events, one of which arose in its current host, demonstrating that interspecies recombination continues to occur today. These results raise concerns about the use of live attenuated HSV-2 vaccines in high HSV-1 prevalence areas.

RevDate: 2019-04-24

Chan YH, Teo TH, Utt A, et al (2019)

Mutating chikungunya virus non-structural protein produces potent live-attenuated vaccine candidate.

EMBO molecular medicine pii:emmm.201810092 [Epub ahead of print].

Currently, there are no commercially available live-attenuated vaccines against chikungunya virus (CHIKV). Here, CHIKVs with mutations in non-structural proteins (nsPs) were investigated for their suitability as attenuated CHIKV vaccines. R532H mutation in nsP1 caused reduced infectivity in mouse tail fibroblasts but an enhanced type-I IFN response compared to WT-CHIKV Adult mice infected with this nsP-mutant exhibited a mild joint phenotype with low-level viremia that rapidly cleared. Mechanistically, ingenuity pathway analyses revealed a tilt in the anti-inflammatory IL-10 versus pro-inflammatory IL-1β and IL-18 balance during CHIKV nsP-mutant infection that modified acute antiviral and cell signaling canonical pathways. Challenging CHIKV nsP-mutant-infected mice with WT-CHIKV or the closely related O'nyong-nyong virus resulted in no detectable viremia, observable joint inflammation, or damage. Challenged mice showed high antibody titers with efficient neutralizing capacity, indicative of immunological memory. Manipulating molecular processes that govern CHIKV replication could lead to plausible vaccine candidates against alphavirus infection.

RevDate: 2019-04-24

Bezerra ED, Flowers ME, Onstad LE, et al (2019)

A phase 2 study of alpha interferon for molecularly measurable residual disease in chronic myeloid leukemia after allogeneic hematopoietic cell transplantation.

Leukemia & lymphoma [Epub ahead of print].

CML therapy has improved dramatically with the development of tyrosine kinase inhibitors (TKIs). Prior to the TKI era, we conducted two trials of alpha-interferon (IFN) for post-transplant hematologic and cytogenetic relapse. The complete cytogenetic response rate was 33% and 57% respectively. This report describes a third trial in which 40 patients with molecular relapse between 6 and 12 months post-transplant were treated with IFN. The projected cytogenetic relapse at 4.5 years was 12.6% compared with 42% in the historical control group. Although this data may not apply to most patients with CML today due to the availability of multiple TKIs, the effectiveness of short term IFN in post-transplant molecular relapse is supported by long-term treatment-free-survival in 75% of patients after a median follow-up of 15.6 years. This report suggests that alpha-interferon is potentially useful in the rare patient who has post-transplant molecular relapse who does not tolerate, or is resistant to TKIs.


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 )