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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 18 Sep 2020 at 01:43 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®)

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RevDate: 2020-09-17

Mohon AN, Oberding L, Hundt J, et al (2020)

Optimization and clinical validation of dual-target RT-LAMP for SARS-CoV-2.

Journal of virological methods pii:S0166-0934(20)30224-X [Epub ahead of print].

A novel reverse-transcriptase loop mediated amplification (RT-LAMP) method targeting genes encoding the Spike (S) protein and RNA-dependent RNA polymerase (RdRP) of SARS-CoV-2 has been developed. The LAMP assay achieves a comparable limit of detection (25 copies per reaction) as commonly used RT-PCR protocols using clinical samples quantified by digital droplet PCR. Precision, cross-reactivity, inclusivity, and limit of detection studies were performed according to regulatory standards. Clinical validation of dual-target RT-LAMP (S and RdRP gene) achieved a PPA of 98.48% (95% CI 91.84% to 99.96%) and NPA 100.00% (95% CI 93.84% to 100.00%) based on the E gene and N2 gene reference RT-PCR methods. The method has implications for development of point of care technology using isothermal amplification.

RevDate: 2020-09-17

Broder GB, Lucas JP, Davis J, et al (2020)

Standardized metrics can reveal region-specific opportunities in community engagement to aid recruitment in HIV prevention trials.

PloS one, 15(9):e0239276 pii:PONE-D-20-04045.

Good Participatory Practice (GPP) guidelines support and direct community engagement practices in biomedical HIV prevention trials, however no standardized metrics define the implementation and evaluation of these practices. Collaboratively, the Community Program staff of the HIV Vaccine Trials Network (HVTN) and the HIV Prevention Trials Network (HPTN) created a metric to describe, monitor, and evaluate one component of GPP, recruitment practices, in two HIV monoclonal Antibody Mediated Prevention (AMP) clinical trials, HVTN 703/HPTN 081 and HVTN 704/HPTN 085. Through consultation with community representatives from each clinical research site (hereafter "site(s)"), who made up the study Community Working Groups, recruitment strategy descriptors were developed for both trials to characterize responses to "How did you hear about the AMP study?" The Community Working Groups also helped to define and establish time points that were selected to allow comparisons across sites. Data were collected by 43 of 46 clinical research sites from January 1, 2017 to February 28, 2018. All 43 sites used multiple recruitment strategies successfully, but strategies varied by region. Globally, referrals was the most efficient and effective recruitment strategy as evidenced by the screening: enrollment ratio of 2.2:1 in Africa, and 2.1:1 in the Americas/Switzerland. Print materials were also valuable globally (3:1 Africa, 4.2:1 Americas/Switzerland). In Africa, in-person outreach was also quite effective (2.3:1) and led to the most enrollments (748 of 1186, 63%). In the Americas/Switzerland, outreach was also effective (2.6:1), but internet use resulted in the most screens (1893 of 4275, 44%) and enrollments (677 of 1531, 44%), compared to 12 of 2887 (0.4%) and 2 of 1204 (0.1%) in Africa, respectively. Standardized metrics and data collection aid meaningful comparisons of optimal community engagement methods for trial enrollment. Internet strategies had better success in the Americas/Switzerland than in sub-Saharan African countries. Data are essential in outreach staff efforts to improve screening-to-enrollment ratios. Because the effectiveness of recruitment strategies varies by region, it is critical that clinical research sites tailor community engagement and recruitment strategies to their local environment, and that they are supported with resources enabling use of a range of approaches.

RevDate: 2020-09-17

Zager RA, ACM Johnson (2020)

The NRF2 stimulating agent, tin protoporphyrin, activates protective cytokine pathways in healthy human subjects and in patients with chronic kidney disease.

Physiological reports, 8(18):e14566.

BACKGROUND: Tin protoporphyrin (SnPP), a heme oxygenase 1 (HO-1) inhibitor, triggers adaptive tissue responses that confer potent protection against acute renal- and extra-renal tissue injuries. This effect is mediated, in part, via SnPP-induced activation of the cytoprotective Nrf2 pathway. However, it remains unclear as to whether SnPP can also upregulate humoral cytokine defenses, either in healthy human subjects or in patients with CKD. If so, then systemically derived cytokines could contribute SnPP-induced tissue protection.

METHODS: SnPP (90 mg IV) was administered over 2 hr to six healthy human volunteers (HVs) and 12 subjects with stage 3-4 CKD. Plasma samples were obtained from baseline upto 72 hr post injection. Two representative anti-inflammatory cytokines (IL-10, TGFβ1), and a pro-inflammatory cytokine (TNF-α), were assayed. Because IL-6 has been shown to induce tissue preconditioning, its plasma concentrations were also assessed. In complementary mouse experiments, SnPP effects on renal, splenic, and hepatic IL-10, IL-6, TGFβ1, and TNF-α production (as gauged by their mRNAs) were tested. Tissue HO-1 mRNA served as an Nrf2 activation marker.

RESULTS: SnPP induced marked (~5-7x) increases in plasma IL-10 and IL-6 concentrations within 24-48 hr, and to equal degrees in HVs and CKD patients. SnPP modestly raised plasma TGFβ1 without impacting plasma TNF-α levels. In mouse experiments, SnPP did not affect IL-6, IL-10, TNF-α, or TGFβ1 mRNAs in kidney despite marked renal Nrf2 activation. Conversely, SnPP increased splenic IL-10 and hepatic IL-6/TGFβ1 mRNA levels, suggesting these organs as sites of extra-renal cytokine generation.

CONCLUSIONS: SnPP can trigger cytoprotective cytokine production, most likely in extra-renal tissues. With ready glomerular cytokine filtration, extra-renal/renal "organ cross talk" can result. Thus, humoral factors seemingly can contribute to SnPP's cytoprotective effects.

RevDate: 2020-09-17

Ilozumba MN, Cheng TD, Neuhouser ML, et al (2020)

Associations between Plasma Choline Metabolites and Genetic Polymorphisms in One-Carbon Metabolism in Postmenopausal Women: The Women's Health Initiative Observational Study.

The Journal of nutrition pii:5906633 [Epub ahead of print].

BACKGROUND: Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites.

OBJECTIVES: This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites.

METHODS: We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993-1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined.

RESULTS: The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (-4.00% and -6.75% per variant allele, respectively; both nominal P < 0.05). Another candidate SNP, BHMT2 rs626105 A>G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration.

CONCLUSIONS: Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women.

RevDate: 2020-09-17

Glorioso JC, Cohen JB, Goins WF, et al (2020)

Oncolytic HSV Vectors and Anti-Tumor Immunity.

Current issues in molecular biology, 41:381-468 pii:v41/381 [Epub ahead of print].

The therapeutic promise of oncolytic viruses (OVs) rests on their ability to both selectively kill tumor cells and induce anti-tumor immunity. The potential of tumors to be recognized and eliminated by an effective anti-tumor immune response has been spurred on by the discovery that immune checkpoint inhibition can overcome tumor-specific cytotoxic T cell (CTL) exhaustion and provide durable responses in multiple tumor indications. OV-mediated tumor destruction is now recognized as a powerful means to assist in the development of anti-tumor immunity for two important reasons: (i) OVs, through the elicitation of an anti-viral response and the production of type I interferon, are potent stimulators of inflammation and can be armed with transgenes to further enhance anti-tumor immune responses; and (ii) lytic activity can promote the release of tumor-associated antigens (TAAs) and tumor neoantigens that function as in situ tumor-specific vaccines to elicit adaptive immunity. Oncolytic herpes simplex viruses (oHSVs) are among the most widely studied OVs for the treatment of solid malignancies, and Amgen's oHSV Imlygic® for the treatment of melanoma is the only OV approved in major markets. Here we describe important biological features of HSV that make it an attractive OV, clinical experience with HSV-based vectors, and strategies to increase applicability to cancer treatment.

RevDate: 2020-09-17

Mandrycky C, Hadland B, Y Zheng (2020)

3D curvature-instructed endothelial flow response and tissue vascularization.

Science advances, 6(38): pii:6/38/eabb3629.

Vascularization remains a long-standing challenge in engineering complex tissues. Particularly needed is recapitulating 3D vascular features, including continuous geometries with defined diameter, curvature, and torsion. Here, we developed a spiral microvessel model that allows precise control of curvature and torsion and supports homogeneous tissue perfusion at the centimeter scale. Using this system, we showed proof-of-principle modeling of tumor progression and engineered cardiac tissue vascularization. We demonstrated that 3D curvature induced rotation and mixing under laminar flow, leading to unique phenotypic and transcriptional changes in endothelial cells (ECs). Bulk and single-cell RNA-seq identified specific EC gene clusters in spiral microvessels. These mark a proinflammatory phenotype associated with vascular development and remodeling, and a unique cell cluster expressing genes regulating vascular stability and development. Our results shed light on the role of heterogeneous vascular structures in differential development and pathogenesis and provide previously unavailable tools to potentially improve tissue vascularization and regeneration.

RevDate: 2020-09-16

Joung J, Ladha A, Saito M, et al (2020)

Detection of SARS-CoV-2 with SHERLOCK One-Pot Testing.

RevDate: 2020-09-16

Wei XX, Werner L, Teo MY, et al (2020)

Sequencing of PD-1/L1 Inhibitors and Carboplatin-Based Chemotherapy for Cisplatin-Ineligible Metastatic Urothelial Carcinoma.

The Journal of urology [Epub ahead of print].

PURPOSE: Current first-line treatment options in patients with metastatic urothelial carcinoma (mUC) unfit to receive cisplatin-containing chemotherapy include PD-1/L1 inhibitors and carboplatin-containing chemotherapy. However, the optimal sequencing of these therapies remains unclear.

MATERIAL AND METHODS: We conducted a multicenter retrospective analysis. Consecutive cisplatin-ineligible patients with mUC treated with first-line carboplatin-containing chemotherapy followed sequentially by second-line PD-1/L1 inhibitor, or the reverse order, were included. Patient demographics, objective response, time to treatment failure for first-line (TTF1) and second-line (TTF2) therapy, interval between end of first-line and initiation of second-line treatment (Interval1L-2L), and overall survival (OS) were collected. Multivariate analysis was conducted to examine the association of sequencing on OS.

RESULTS: In this multicenter retrospective study, we identified 146 cisplatin-ineligible patients with mUC treated with first-line (1L) PD-1/L1 inhibitor therapy followed by second-line (2L) carboplatin-containing chemotherapy (Group 1, n=43) or the reverse sequence (Group 2, n=103). In the overall cohort, median age was 72, 76% were men, and 18% had liver metastasis. In both groups, objective response rates were higher with carboplatin-containing chemotherapy (45.6% 1L, 44.2% 2L) compared to PD-1/L1 inhibitors (9.3% 1L, 21.3% 2L). On multivariate analysis, treatment sequence was not associated with overall survival (HR 1.05, p=0.85). Site of metastasis was the only factor significantly associated with overall survival (p=0.002).

CONCLUSIONS: In this biomarker-unselected cohort of cisplatin-ineligible patients with mUC, PD-1/L1 inhibitor followed by carboplatin-containing chemotherapy and the reverse sequence had comparable OS.

RevDate: 2020-09-16

Hall ET, Sridhar D, Singhal S, et al (2020)

Perceptions of time spent pursuing cancer care among patients, caregivers, and oncology professionals.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-020-05763-9 [Epub ahead of print].

PURPOSE: Patients with cancer spend significant time receiving treatment and recovering from side effects. Little is known about how patients and their caregivers perceive time spent receiving cancer treatment and how this impacts health-related quality of life (HRQoL). Our study aims to characterize perceptions of time invested in receiving cancer therapy as experienced by patients, caregivers, and oncology professionals.

METHODS: We conducted semi-structured interviews with patients undergoing treatment for advanced lung cancer and melanoma, their informal caregivers, and oncology professionals (physicians, nurses, social workers, and chaplains). Participants received and provided care at a tertiary cancer center. Interviews were audiorecorded and transcribed verbatim. Transcripts were analyzed qualitatively using predominantly inductive coding to identify themes relating to time perception and cancer care.

RESULTS: We interviewed 29 participants (11 patients, 7 informal caregivers, and 11 oncology professionals) and found they consistently differentiated between time remaining in life ("existential time") and time required to manage cancer treatment and symptoms ("chronological time"). Patients and caregivers reported distress around the mechanics of oncologic care that interrupted their daily lives (hobbies, activities). Participants described the impact of time invested in cancer care on dimensions of quality of life, ranging from minimal to substantial negative impact.

CONCLUSIONS: We found that the time spent undergoing cancer treatment affects well-being and often prevents patients and caregivers from participating in meaningful activities. The investment of personal time undergoing cancer therapy for patients with advanced solid tumors merits further study and can enhance communication between patients, caregivers, and their oncologists.

RevDate: 2020-09-15

Rogers JH, Link AC, McCulloch D, et al (2020)

Characteristics of COVID-19 in Homeless Shelters : A Community-Based Surveillance Study.

Annals of internal medicine [Epub ahead of print].

BACKGROUND: Homeless shelters are a high-risk setting for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission because of crowding and shared hygiene facilities.

OBJECTIVE: To investigate SARS-CoV-2 case counts across several adult and family homeless shelters in a major metropolitan area.

DESIGN: Cross-sectional, community-based surveillance study. (ClinicalTrials.gov: NCT04141917).

SETTING: 14 homeless shelters in King County, Washington.

PARTICIPANTS: A total of 1434 study encounters were done in shelter residents and staff, regardless of symptoms.

INTERVENTION: Two strategies were used for SARS-CoV-2 testing: routine surveillance and contact tracing ("surge testing") events.

MEASUREMENTS: The primary outcome measure was test positivity rate of SARS-CoV-2 infection at shelters, determined by dividing the number of positive cases by the total number of participant encounters, regardless of symptoms. Sociodemographic, clinical, and virologic variables were assessed as correlates of viral positivity.

RESULTS: Among 1434 encounters, 29 (2% [95% CI, 1.4% to 2.9%]) cases of SARS-CoV-2 infection were detected across 5 shelters. Most (n = 21 [72.4%]) were detected during surge testing events rather than routine surveillance, and most (n = 21 [72.4% {CI, 52.8% to 87.3%}]) were asymptomatic at the time of sample collection. Persons who were positive for SARS-CoV-2 were more frequently aged 60 years or older than those without SARS-CoV-2 (44.8% vs. 15.9%). Eighty-six percent of persons with positive test results slept in a communal space rather than in a private or shared room.

LIMITATION: Selection bias due to voluntary participation and a relatively small case count.

CONCLUSION: Active surveillance and surge testing were used to detect multiple cases of asymptomatic and symptomatic SARS-CoV-2 infection in homeless shelters. The findings suggest an unmet need for routine viral testing outside of clinical settings for homeless populations.

PRIMARY FUNDING SOURCE: Gates Ventures.

RevDate: 2020-09-15

Vargas CE, Thorpe CS, Dueck AC, et al (2020)

Impact of adjuvant trastuzumab on locoregional failure rates in a randomized clinical trial: North Central Cancer Treatment Group N9831 (alliance) study.

Cancer [Epub ahead of print].

BACKGROUND: The goal of this study was to assess the impact of trastuzumab on locoregional failure.

METHODS: The analysis included 2763 patients with HER2-positive (HER2+) breast cancer who were randomly assigned to adjuvant doxorubicin (A), cyclophosphamide (C), paclitaxel (T) and trastuzumab (H) (arm A, AC→T [n = 922]; arm B, AC→T→H [n = 988]; arm C, AC→T+H→H [n = 853]). Radiotherapy was given after AC→T concurrently with H. Radiotherapy was given after lumpectomy (L) or after mastectomy (M) with ≥4 positive lymph nodes but was optional for 1 to 3 positive lymph nodes. Locoregional failures at 10 years (LFR10) as first events were compared using competing risk analysis.

RESULTS: The median follow-up was 13.0 years. The first site of failure was local-only in 96 cases, locoregional in 16 cases, regional in 32 cases, and not specified in 2 cases; LFR10 was 4.8% (95% CI 4.1%-5.7%). LFR10 was 5.5% (95% CI 4.3%-7.2%), 4.9% (95% CI 3.7%-6.4%), and 2.8% (95% CI 1.9%-4.1%) in arms A, B, and C (B vs A: hazard ratio [HR] 0.91, P = .62; C vs A: HR 0.72, P = .12). For estrogen receptor-positive patients, LFR10 was 3.7% (95% CI 2.8%-4.8%) and for estrogen receptor-negative patients, it was 6.1% (95% CI 5.0%-7.4%; HR 0.61, P = .004). Local treatment included L+RT (n = 1044 [38%]), M+RT (n = 1025 [37%]), and M (n = 694 [25%]). LFR10 was 6.% (95% CI 5.0%-7.8%), 3.0% (95% CI 2.1%-4.3%), and 5.5% (95% CI 4.0%-7.4%) for L+RT, M+RT, and M, respectively (M+RT vs L+RT: HR 0.43, P < .001; M vs L+RT: HR 0.88, P = .57). For 1 to 3 positive lymph nodes, LFR10 was 6.5% (95% CI 4.8%-8.9%), 4.1% (95% CI 2.4%-7.0%), and 4.3% (95% CI 2.9%-6.5%) in L+RT, M+RT, and M, respectively (M vs L+RT: HR 0.68, P = .14; M vs M+RT: HR 1.2, P = .6).

CONCLUSION: Low 10-year LFRs were seen regardless of trastuzumab use. Differences in local therapy in patients with 1 to 3 positive lymph nodes did not appear to improve local control. Local therapy studies for HER2+ and other tumor characteristics are important as the role of local therapies continues to evolve.

RevDate: 2020-09-16

Tenthorey JL, Young C, Sodeinde A, et al (2020)

Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races.

eLife, 9: pii:59988.

Host antiviral proteins engage in evolutionary arms races with viruses, in which both sides rapidly evolve at interaction interfaces to gain or evade immune defense. For example, primate TRIM5α uses its rapidly evolving 'v1' loop to bind retroviral capsids, and single mutations in this loop can dramatically improve retroviral restriction. However, it is unknown whether such gains of viral restriction are rare, or if they incur loss of pre-existing function against other viruses. Using deep mutational scanning, we comprehensively measured how single mutations in the TRIM5α v1 loop affect restriction of divergent retroviruses. Unexpectedly, we found that the majority of mutations increase weak antiviral function. Moreover, most random mutations do not disrupt potent viral restriction, even when it is newly acquired via a single adaptive substitution. Our results indicate that TRIM5α's adaptive landscape is remarkably broad and mutationally resilient, maximizing its chances of success in evolutionary arms races with retroviruses.

RevDate: 2020-09-15

Karunamuni RA, Huynh-Le MP, Fan CC, et al (2020)

African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.

International journal of cancer [Epub ahead of print].

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans. This article is protected by copyright. All rights reserved.

RevDate: 2020-09-15

Kizub DA, Miao J, Schubert MM, et al (2020)

Risk factors for bisphosphonate-associated osteonecrosis of the jaw in the prospective randomized trial of adjuvant bisphosphonates for early-stage breast cancer (SWOG 0307).

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-020-05748-8 [Epub ahead of print].

PURPOSE: Bisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis.

METHODS: SWOG 0307 randomized women with stage I-III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided.

RESULTS: Of 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ.

CONCLUSION: ZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this.

CLINICAL TRIAL NUMBER: NCT00127205 REGISTRATION DATE: July 2005.

RevDate: 2020-09-15

Uy GL, Aldoss I, Foster MC, et al (2020)

Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia.

Blood pii:463757 [Epub ahead of print].

Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after <6 months (early relapse, ER). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART® antibody-based molecule to CD3ε and CD123. This study reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in adults with relapsed/refractory AML. Eighty-eight AML patients were enrolled, 42 in dose-finding and 46 at the recommended phase 2 dose (RP2D) of 500ng/kg/day. Consistent with flotetuzumab's mode of action, the most frequent adverse events were infusion-related reactions (IRR)/cytokine release syndrome (CRS), the majority as grade 1-2. Stepwise dosing during week 1, pre-treatment dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability. Clinical benefit accrued to PIF/ER AML patients, who showed an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the CR/CRh rate was 26.7%, with an overall response rate (CR/CRh/CRi) of 30.0%. In PIF/ER patients who achieved CR/CRh, median OS was 10.2 months (range 1.87-27.27), with 6- and 12-month survival rates of 75% (95%CI, 0.450-1.05) and 50% (95%CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted complete responses to flotetuzumab (AUROC=0.904 versus 0.672 for the ELN risk classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER AML patients. Trial registration number: NCT02152956.

RevDate: 2020-09-15

Czartoski J, Lemos MP, Fong Y, et al (2020)

Rapid Collection of Human Rectal Secretions Using OriCol Devices Is Suitable for Measurement of Mucosal Ig without Blood Contamination.

Journal of immunology (Baltimore, Md. : 1950) pii:jimmunol.2000320 [Epub ahead of print].

Measurements of IgG and IgA in human rectal secretions are used to evaluate the Abs elicited by HIV vaccines or the bioaccumulation following immunoprophylaxis at the sites of HIV exposure. To improve sampling methods and tolerability of the procedure, we optimized a balloon device (OriCol) for rectal microbiome sampling requiring 10 second inflation and compared this method to a 5 minute collection using sponges. Lubrication of the device did not interfere with IgG, IgA, or hemoglobin ELISA. Lubricated OriCols inflated to 30 cc minimized hemoglobin contamination (<4.68 ng/ml) compared with collections with two sponge types (Weck-Cel: 267.2 ng/ml, p < 0.0001; and Merocel: 59.38 ng/ml, p = 0.003). Median human serum albumin for OriCols was 14.9 μg/ml, whereas Merocels and Weck-Cels were 28.57 μg/ml (p = 0.0005) and 106.2 μg/ml (p = 0.0002), respectively. Consistent with reduced systemic contamination, the median IgG measured in OriCol-collected rectal secretions (986 ng) was lower than secretions from sponges (Weck-Cel: 8588 ng, p < 0.0001; Merocel: 2509 ng, p = 0.0389). The median IgA yield of samples using the OriCol method (75,253 ng) was comparable to that using Merocel (71,672 ng; p = 0.6942) but significantly higher than Weck-Cel sponges (16,173 ng, p = 0.0336). Median recovery volumes for OriCols were 800 μl, whereas Merocels and Weck-Cels were 615 μl (p = 0.0010) and 655 μl (p = 0.0113), respectively. The balloon device was acceptable among 23 participants, as 85.1% experiencing their first collection ranked it as "seven: acceptable - a lot" or "six: acceptable - somewhat" in a seven-point Likert scale. Therefore, lubricated OriCols inflated to 30 cc allowed for a rapid, well-tolerated, blood-free collection of human rectal secretions.

RevDate: 2020-09-15

Huang M, O'Shaughnessy J, Zhao J, et al (2020)

Association of Pathological Complete Response with Long-Term Survival Outcomes in Triple-Negative Breast Cancer: A Meta-analysis.

Cancer research pii:0008-5472.CAN-20-1792 [Epub ahead of print].

Pathological complete response (pCR) following neoadjuvant therapy has been associated with improved event-free survival (EFS) and overall survival (OS) in early-stage breast cancer (BC). The magnitude of this association varies by BC subtype, yet further research focusing on subtype-specific populations is limited. Here we provide an updated and comprehensive evaluation of the association between pCR and survival outcomes in triple-negative BC (TNBC). A literature review identified neoadjuvant studies, including clinical trials, real-world cohort studies and studies that pooled multiple trials or cohorts, which reported EFS/OS results by pCR in early-stage TNBC patients. Meta-analyses were performed to evaluate the association between pCR and EFS/OS and to predict long-term survival outcomes based on pCR status. Sensitivity analyses were conducted to assess the impact of cross-study variations. Twenty-five studies with over 4000 TNBC patients were identified. A synthesis of evidence from these studies suggested substantial improvement in EFS and OS for pCR vs. non-pCR (EFS HR [95% confidence interval]: 0.24 [0.20; 0.29]; OS: 0.19 [0.15; 0.24]); consistent results were reported in sensitivity analyses. Collectively, our findings suggest that adjuvant therapy is associated with improved EFS/OS in TNBC patients who received neoadjuvant therapy, regardless of pCR status.

RevDate: 2020-09-15

Mossavar-Rahmani Y, Hua S, Qi Q, et al (2020)

Are sedentary behavior and physical activity independently associated with cardiometabolic benefits? The Hispanic Community Health Study/Study of Latinos.

BMC public health, 20(1):1400 pii:10.1186/s12889-020-09497-5.

BACKGROUND: Whether physical activity can reduce cardiometabolic risk particularly in understudied populations such as US Hispanics/Latinos is of public health interest. We prospectively examined the association of physical activity and cardiometabolic biomarkers in n = 8049 participants of the Hispanic Community Health Study/Study of Latinos, a community-based cohort study of 16,415 adults aged 18-74 yr who self-identified as Hispanic/Latino from four US urban centers.

METHODS: We assessed physical activity using accelerometry in 2008-2011 at visit 1. We assessed cardiometabolic biomarkers twice: once at visit 1 and collected a second measure in 2014-2017 at visit 2. We used survey linear regression models with changes in cardiometabolic markers as the dependent variables and quartiles of sedentary behavior or whether adults met guidelines for moderate-to-vigorous physical activity as the independent variables.

RESULTS: In normoglycemic adults without cardiovascular disease, but not in adults with evidence of cardiometabolic disease, those who were in the lowest quartile for sedentary behavior (< 10.08 h/day) had a significant decline in mean LDL-cholesterol of - 3.94 mg/dL (95% CI: - 6.37, - 1.52) compared to adults in the highest quartile (≥13.0 h/day) who exhibited a significant increase in LDL-cholesterol of 0.14 mg/dL (95% CI, - 2.15,2.42) over the six year period (P < 0.02 in fully adjusted models.) There was also a trend toward lower mean increase in HbA1c comparing the lowest with the highest quartile of sedentary behavior. Overall regardless of glycemic level or evidence of cardiometabolic disease, adults who met guidelines for moderate-to-vigorous physical activity at visit 1, had significantly lower mean increases in level of fasting glucose compared to adults not meeting guidelines in fully adjusted models.

CONCLUSIONS: In this cohort of Hispanics/Latinos, being free of cardiometabolic disease and having low levels of sedentary behavior were associated with health benefits. Among all adults regardless of cardiometabolic disease, meeting guidelines for moderate-to-vigorous physical activity was associated with health benefits. Overall these data suggest that an active lifestyle may blunt the association of advancing age with worsening cardiometabolic risk factors.

RevDate: 2020-09-16

Loes AN, Gentles LE, Greaney AJ, et al (2020)

Attenuated influenza virions expressing the SARS-CoV-2 receptor-binding domain induce neutralizing antibodies in mice.

bioRxiv : the preprint server for biology.

An effective vaccine is essential to controlling the spread of SARS-CoV-2 virus. Here, we describe an influenza-virus-based vaccine for SARS-CoV-2. We incorporated a membrane-anchored form of the SARS-CoV-2 Spike receptor binding domain (RBD) in place of the neuraminidase (NA) coding sequence in an influenza virus also possessing a mutation that reduces the affinity of hemagglutinin for its sialic acid receptor. The resulting ΔNA(RBD)-Flu virus can be generated by reverse genetics and grown to high titers in cell culture. A single-dose intranasal inoculation of mice with ΔNA(RBD)-Flu elicits serum neutralizing antibody titers against SAR-CoV-2 comparable to those observed in humans following natural infection (~1:250). Furthermore, ΔNA(RBD)-Flu itself causes no apparent disease in mice. It might be possible to produce a vaccine similar to ΔNA(RBD)-Flu at scale by leveraging existing platforms for production of influenza vaccines.

RevDate: 2020-09-03

Aggarwal RR, Schweizer MT, Nanus DM, et al (2020)

A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-1707 [Epub ahead of print].

PURPOSE: ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).

PATIENTS AND METHODS: Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).

RESULTS: Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post-ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6-12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0-7.8). Median duration of treatment was 3.5 months (range, 0-34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).

CONCLUSIONS: ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.

RevDate: 2020-09-14

Lui GYL, Shaw R, Schaub FX, et al (2020)

BET, SRC, and BCL2 family inhibitors are synergistic drug combinations with PARP inhibitors in ovarian cancer.

EBioMedicine, 60:102988 pii:S2352-3964(20)30364-9 [Epub ahead of print].

BACKGROUND: Homologous recombination deficiencies (HRD) are present in approximately half of epithelial ovarian cancers, for which PARP inhibitors (PARPi) are becoming a preferred treatment option. However, a considerable proportion of these carcinomas acquire resistance or harbour de novo resistance, posing a significant challenge to treatment.

METHODS: To identify new combinatorial therapeutics to overcome resistance to PARPi, we employed high-throughput conditional RNAi and drug screening of patient-derived ovarian cancer cells. To prioritise clinically relevant drug combinations, we integrated empirical validation with analysis of The Cancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets to nominate candidate targets and drugs, reaching three main findings.

FINDINGS: Firstly, we found that the PARPi rucaparib enhanced the effect of BET inhibitors (CPI-203 & CPI-0610) irrespective of clinical subtype or HRD status. Additional drug combination screens identified that dasatinib, a non-receptor tyrosine kinase inhibitor, augmented the effects of rucaparib and BET inhibitors, proposing a potential broadly applicable triple-drug combination for high-grade serous and clear cell ovarian carcinomas. Secondly, rucaparib synergised with the BCL2 family inhibitor navitoclax, with preferential activity in ovarian carcinomas that harbour alterations in BRCA1/2, BARD1, or MSH2/6. Thirdly, we identified potentially antagonistic drug combinations between the PARPi rucaparib and vinca alkaloids, anthracyclines, and antimetabolites, cautioning their use in the clinic.

INTERPRETATION: These findings propose therapeutic strategies to address PARP inhibitor resistance using agents that are already approved or are in clinical development, with the potential for rapid translation to benefit a broad population of ovarian cancer patients.

RevDate: 2020-09-14

Brooks JD, Boice JD, Shore RE, et al (2020)

A case-control study of the joint effect of reproductive factors and radiation treatment for first breast cancer and risk of contralateral breast cancer in the WECARE study.

Breast (Edinburgh, Scotland), 54:62-69 pii:S0960-9776(20)30149-1 [Epub ahead of print].

OBJECTIVE: To examined the impact of reproductive factors on the relationship between radiation treatment (RT) for a first breast cancer and risk of contralateral breast cancer (CBC).

METHODS: The Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based case-control study where cases are women with asynchronous CBC (N = 1521) and controls are women with unilateral breast cancer (N = 2211). Rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression to assess the independent and joint effects of RT (ever/never and location-specific stray radiation dose to the contralateral breast [0, >0-<1Gy, ≥1Gy]) and reproductive factors (e.g., parity).

RESULTS: Nulliparous women treated with RT (≥1Gy dose) were at increased risk of CBC compared with nulliparous women not treated with RT, although this relationship did not reach statistical significance (RR = 1.34, 95% CI 0.87, 2.07). Women treated with RT who had an interval pregnancy (i.e., pregnancy after first diagnosis and before second diagnosis [in cases]/reference date [in controls]) had an increased risk of CBC compared with those who had an interval pregnancy with no RT (RR = 4.60, 95% CI 1.16, 18.28). This was most apparent for women with higher radiation doses to the contralateral breast.

CONCLUSION: Among young female survivors of breast cancer, we found some evidence suggesting that having an interval pregnancy could increase a woman's risk of CBC following RT for a first breast cancer. While sampling variability precludes strong interpretations, these findings suggest a role for pregnancy and hormonal factors in radiation-associated CBC.

RevDate: 2020-09-14

Deeg HJ (2020)

Individuals, Boundaries and GVHD.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30586-3 [Epub ahead of print].

Hematopoietic cell transplantation generates new individuals, transplant chimeras, composed of two genetic partners - the patient and donor-derived cells - no longer restricted by their original genomes. Interactions of donor-derived and recipient cells occur prominently at the boundary of the recipient with a third partner, the microbiome, in particular skin and intestinal tract, leading to disruption of microbiome homeostasis. These interactions of donor and patient cells at the boundary set the stage for the development of graft versus host disease, an expression of the defense of individuality by recipient and donor. Establishment of tolerance and return of homeostasis at the boundary will allow for the survival of the new integrated, physiological individual.

RevDate: 2020-09-14

Ustun C, Morgan EA, Ritz EM, et al (2020)

Core-binding factor acute myeloid leukemia with inv(16): Older age and high white blood cell count are risk factors for treatment failure.

RevDate: 2020-09-14

Cespedes Feliciano EM, Hohensee C, Rosko AE, et al (2020)

Association of Prediagnostic Frailty, Change in Frailty Status, and Mortality After Cancer Diagnosis in the Women's Health Initiative.

JAMA network open, 3(9):e2016747 pii:2770549.

Importance: Understanding changes in frailty in relation to cancer diagnosis can inform optimal selection of cancer treatments and survivorship care.

Objective: To investigate associations of prediagnostic frailty and change in frailty status with mortality after a cancer diagnosis.

This multicenter, prospective cohort study included 7257 community-dwelling, postmenopausal women in the United States who had frailty assessed at the Women's Health Initiative (WHI) enrollment (1993-1998) and the 3-year visit who were subsequently diagnosed as having invasive cancer. The data were analyzed from January 7, 2019, to June, 8, 2020.

Exposure: Frailty scores were defined from validated questionnaire items conceptually aligned with the Fried frailty phenotype, including at least 3 of the following characteristics: self-reported unintentional weight loss, exhaustion, low physical activity, and muscle weakness or impaired walking. Physical function components of the frailty score were updated a median of 10 (range, 1-18) times.

Main Outcomes and Measures: Using multivariable-adjusted Cox proportional hazards models, this study examined associations of prediagnostic frailty (at the 3-year visit, before cancer diagnosis) and prediagnostic changes in frailty (from enrollment to the 3-year visit) with mortality. Women were followed up beginning from cancer diagnosis for mortality outcomes through March 2018. In linear mixed-effects models with frailty scores as a function of time since cancer diagnosis, this study evaluated whether the time slope, ie, the rate of change in frailty score, increased after cancer diagnosis.

Results: This study included 7257 women in the WHI cohort who completed frailty assessments at enrollment and the 3-year WHI visit before cancer diagnosis and subsequently developed cancer. Cancer cases included 2644 breast cancers (36%), 822 lung cancers (11%), 691 colorectal cancers (10%), 445 endometrial cancers (6%), and 286 ovarian cancers (4%). At the 3-year visit, prior to cancer diagnosis, the mean (SD) age was 63 (7) years, and 1161 of 7257 (16%) of participating women met criteria for frailty; 2129 of 7257 (29%) were prefrail, and 3967 of 7257 (55%) were nonfrail. Over a median follow-up of 5.8 years after cancer diagnosis (range, 1 day to 19.9 years), 3056 women died. After multivariable adjustment, women who were frail (vs nonfrail) before cancer diagnosis had an increased risk of mortality after cancer diagnosis (hazard ratio [HR], 1.40; 95% CI, 1.26-1.55; P for trend <.001). Sustained frailty (21% [1537 of 7257] of women) or worsening frailty (22% [1578 of 7257]) vs being consistently nonfrail (45% [3266 of 7257]) before cancer diagnosis increased the risk of mortality after cancer diagnosis (HR, 1.25; 95% CI, 1.14-1.38 and 1.22; 95% CI, 1.11-1.34, respectively; P for trend <.001). In linear mixed-effects models, the rate of increase in physical frailty over time was statistically significantly higher after cancer diagnosis.

Conclusions and Relevance: Sustained and worsening frailty before cancer diagnosis was associated with an increased risk of mortality after cancer diagnosis in postmenopausal women. Furthermore, the rate of decline in physical function accelerated after cancer diagnosis. Frailty assessment could provide valuable information and perhaps prompt interventions to reduce and preempt worsening of physical frailty after cancer diagnosis.

RevDate: 2020-09-14

Dhakal B, Wang T, Kuxhausen M, et al (2020)

Prognostic impact of serum CXC chemokine ligands 4 and 7 on myelodysplastic syndromes post allogeneic hematopoietic cell transplant.

RevDate: 2020-09-14

Sun R, Xu M, Li X, et al (2020)

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Genetic epidemiology [Epub ahead of print].

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

RevDate: 2020-09-14

Labadie JD, Harrison TA, Banbury B, et al (2020)

Postmenopausal Hormone Therapy and Colorectal Cancer Risk by Molecularly Defined Subtypes and Tumor Location.

JNCI cancer spectrum, 4(5):pkaa042 pii:pkaa042.

Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location.

Methods: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided.

Results: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; Phet =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; Phet =.01) tumors.

Conclusions: We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

RevDate: 2020-09-14

Morton LM, Karyadi DM, Hartley SW, et al (2020)

Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

JCO precision oncology, 4: pii:2000141.

PURPOSE: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.

PATIENTS AND METHODS: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based P values using a Bonferroni-corrected significance threshold of P < 8.06 × 10-5.

RESULTS: Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; P = 4.79 × 10-5), most notably but nonsignificantly for FANCM (patient cases, 4.0%; matched controls, 0.6%; P = 9.64 × 10-5). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; P = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with EXO1 variants (patient cases, 1.8%; controls, 0.4%; P = 3.31 × 10-5), another gene implicated in DNA double-strand break repair.

CONCLUSION: In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.

RevDate: 2020-09-14

Steineck A, Krumm N, Sarthy JF, et al (2019)

Response to Pembrolizumab in a Patient With Xeroderma Pigmentosum and Advanced Squamous Cell Carcinoma.

JCO precision oncology, 3: pii:1900028.

RevDate: 2020-09-14

Dasgupta S, Y Huang (2020)

Selecting Biomarkers for building optimal treatment selection rules using Kernel Machines.

Journal of the Royal Statistical Society. Series C, Applied statistics, 69(1):69-88.

Optimal biomarker combinations for treatment-selection can be derived by minimizing total burden to the population caused by the targeted disease and its treatment. However, when multiple biomarkers are present, including all in the model can be expensive and hurt model performance. To remedy this, we consider feature selection in optimization by minimizing an extended total burden that additionally incorporates biomarker costs. Formulating it as a 0-norm penalized weighted-classification, we develop various procedures for estimating linear and nonlinear combinations. Through simulations and a real data example, we demonstrate the importance of incorporating feature-selection and marker cost when deriving treatment-selection rules.

RevDate: 2020-09-14

Halpern AB, Othus M, Howard NP, et al (2020)

Comparison of outpatient care following intensive induction versus post-remission chemotherapy for adults with acute myeloid leukemia and other high-grade myeloid neoplasms.

RevDate: 2020-09-13

Andreatos N, Iyer G, P Grivas (2020)

Emerging biomarkers in urothelial carcinoma: Challenges and opportunities.

Cancer treatment and research communications, 25:100179 pii:S2468-2942(20)30016-2 [Epub ahead of print].

Advanced urothelial carcinoma (UC) is a very important cause of cancer-related morbidity and mortality with, until recently, only a few available therapeutic options. The treatment landscape has dramatically changed in recent years with the introduction of immune checkpoint inhibitors and the development of novel targeted agents, such as erdafitinib, and antibody-drug conjugates, such as enfortumab vedotin. Cost-effective utilization of this rapidly expanding therapeutic armamentarium can be further optimized via the identification and validation of reliable prognostic and predictive biomarkers that inform prognostication and patient selection. In this review, we aim to summarize examples of recent developments in the rapidly expanding field of emerging biomarkers in UC, outlining challenges and opportunities.

RevDate: 2020-09-12

Dong J, Maj C, Tsavachidis S, et al (2020)

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

Gastroenterology pii:S0016-5085(20)35130-1 [Epub ahead of print].

BACKGROUND AND AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored.

METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in three separate studies and then used fixed-effects meta-analysis to provide summary estimates for > 9 million variants for males and females. A series of downstream analyses were conducted separately in males and females to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits.

RESULTS: We included 6,758 male BE/EA cases, 7,489 male controls, 1,670 female BE/EA cases and 6,174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified one variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = 0.039) that was statistically significantly associated with BE/EA risk in males only, and one variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in females only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in males and obesity in females.

CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

RevDate: 2020-09-12

Chiotos K, Hayes M, Kimberlin DW, et al (2020)

Multicenter interim guidance on use of antivirals for children with COVID-19/SARS-CoV-2.

Journal of the Pediatric Infectious Diseases Society pii:5904884 [Epub ahead of print].

BACKGROUND: Although Coronavirus Disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data evaluating agents with potential antiviral activity continue to expand, such that updated guidance is needed regarding use of these agents in children.

METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion.

RESULTS: Given the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for non-invasive or invasive mechanical ventilation or extra-corporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or non-invasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children.

CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.

RevDate: 2020-09-12

Stephens DM, Li H, Schoder H, et al (2020)

Reply to: Interim PET assessment of advanced Hodgkin Lymphoma: is it sufficient?.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine pii:jnumed.120.242685 [Epub ahead of print].

RevDate: 2020-09-12

Yaghootkar H, Zhang Y, Spracklen CN, et al (2020)

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Diabetes pii:db20-0070 [Epub ahead of print].

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14 The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10-16, n=3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

RevDate: 2020-09-12

Oluoch LM, Roxby A, Mugo N, et al (2020)

Does providing laboratory confirmed STI results impact uptake of HIV pre-exposure prophylaxis (PrEP) uptake among Kenyan adolescents girls and young women? A descriptive analysis.

Sexually transmitted infections pii:sextrans-2020-054637 [Epub ahead of print].

RevDate: 2020-09-12

Shental N, Levy S, Wuvshet V, et al (2020)

Efficient high-throughput SARS-CoV-2 testing to detect asymptomatic carriers.

Science advances, 6(37): pii:sciadv.abc5961.

Recent reports suggest that 10 to 30% of severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infected patients are asymptomatic and that viral shedding may occur before symptom onset. Therefore, there is an urgent need to increase diagnostic testing capabilities to prevent disease spread. We developed P-BEST, a method for Pooling-Based Efficient SARS-CoV-2 Testing, which identifies all positive subjects within a set of samples using a single round of testing. Each sample is assigned into multiple pools using a combinatorial pooling strategy based on compressed sensing. We pooled sets of 384 samples into 48 pools, providing both an eightfold increase in testing efficiency and an eightfold reduction in test costs, while identifying up to five positive carriers. We then used P-BEST to screen 1115 health care workers using 144 tests. P- BEST provides an efficient and easy-to-implement solution for increasing testing capacity that can be easily integrated into diagnostic laboratories.

RevDate: 2020-09-12

Liang X, Harris HR, Hendryx M, et al (2020)

Sleep characteristics and risk of ovarian cancer among postmenopausal women.

Cancer prevention research (Philadelphia, Pa.) pii:1940-6207.CAPR-20-0174 [Epub ahead of print].

Several studies have assessed the relationship between sleep duration and ovarian cancer risk, but the results are conflicting. Importantly, no studies addressed the relationship between sleep disturbance or sleep quality and ovarian cancer incidence. Moreover, few studies have examined the relationships between sleep measures and subtypes of ovarian cancer. This study included 109,024 postmenopausal women aged 50-79 from the Women's Health Initiative (WHI) during 1993-1998 and followed through 2018. The Cox proportional hazards model was used to estimate adjusted hazard ratios for the associations between sleep habits and the incidence of ovarian cancer and its subtypes. No association was observed between sleep duration, sleep quality, sleep disturbance, or insomnia and risk of overall ovarian cancer, serous/non-serous or Type I/Type II ovarian cancer subtype. However, compared with women with average sleep quality, women with restful or very restful sleep quality had a significantly lower risk of invasive serous subtype (HR: 0.73, 95% CI: 0.60-0.90) while insomnia was associated with a higher risk of invasive serous subtype (HR: 1.36, 95% CI: 1.12-1.66). Associations with insomnia differed significantly by serous and non-serous subtypes, and Type I and Type II subtypes (Pheterogeneity=0.001 and Pheterogeneity<0.001, respectively). This study provides no evidence on association between sleep habits and overall ovarian cancer risk among postmenopausal women. However, restful or very restful sleep quality was associated with a lower risk of invasive serous ovarian cancer, and insomnia was associated with a higher risk of invasive serous ovarian cancer. Associations with insomnia differed by subtypes.

RevDate: 2020-08-13

Denlinger CS, Sanft T, Moslehi JJ, et al (2020)

NCCN Guidelines Insights: Survivorship, Version 2.2020.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(8):1016-1023.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment, with the goal of helping healthcare professionals who work with survivors, including those in primary care. The guidelines also provide recommendations to help clinicians promote physical activity, weight management, and proper immunizations in survivors and facilitate care coordination to ensure that all of the survivors' needs are addressed. These NCCN Guidelines Insights summarize additions and changes made to the guidelines in 2020 regarding cardiovascular disease risk assessment and screening for subsequent primary malignancies.

RevDate: 2020-09-11

Stephens DS, MJ McElrath (2020)

COVID-19 and the Path to Immunity.

JAMA pii:2770758 [Epub ahead of print].

RevDate: 2020-09-11

Zhou W, Liu G, Hung RJ, et al (2020)

Causal Relationships between Body Mass Index, Smoking, and Lung Cancer: Univariable and Multivariable Mendelian Randomization.

International journal of cancer [Epub ahead of print].

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes, based on an aggregated genome wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 x 10-4). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = 0.011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = 0.008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = 0.036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = 0.746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer. This article is protected by copyright. All rights reserved.

RevDate: 2020-09-11

Chauhan L, Shin M, Wang YC, et al (2019)

CD33_PGx6_Score Predicts Gemtuzumab Ozogamicin Response in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

JCO precision oncology, 3: pii:1800387.

PURPOSE: The US Food and Drug Administration recently announced reapproval of gemtuzumab ozogamicin (GO) for treatment of CD33-positive acute myeloid leukemia (AML), thus opening up opportunities to develop strategies for effective use of GO. In light of our recent report showing prognostic significance of CD33 splicing single nucleotide polymorphisms (SNPs), the objective of this study was to comprehensively evaluate CD33 SNPs for accurate prediction of patients with AML who are more or less likely to respond to GO.

PATIENTS AND METHODS: We investigated the five new CD33 SNPs (rs2455069, rs35112940, rs61736475, rs1803254, and rs201074739) for association with CD33 leukemic cell surface expression and clinical response in pediatric patients with AML enrolled in the Children's Oncology Group AAML0531 trial. We further developed a composite CD33 pharmacogenetics (PGx) score using six CD33 SNPs (CD33_PGx6_score) for association with clinical outcome.

RESULTS: Four CD33 SNPs were associated with cell surface CD33 levels and clinical response in the GO versus no-GO arms. Therefore, the CD33_PGx6_score was built using directional genotype scores for the previously reported splicing SNP and five new SNPs. Patients with a CD33_PGx6_score of 0 or higher had higher CD33 expression levels compared with patients with a score of less than 0 (P < .001). In addition, patients with a score of 0 or higher demonstrated an improved disease-free survival in the GO versus no-GO arms (62.5% ± 7.8% v 46.8% ± 8.3%, respectively; P = .008) and a reduced risk of relapse (28.3% ± 7.2% v 49.9% ± 8.4%, respectively; P < .001). No improvement from GO was observed in patients with a CD33-PGx6_score of less than 0. Consistent results were observed across the risk groups.

CONCLUSION: In this study, we report a composite CD33_PGx6_score using directional genotype scores of CD33 SNPs. Once validated, our findings hold promise for use of the CD33_PGx6_score to guide efficient use of GO in patients with AML. In addition, because the CD33_PGx6_score considers SNPs with varying abundance in different ethnic groups, it has potential for global application.

RevDate: 2020-09-11

Cheng HH, Salipante SJ, Nelson PS, et al (2018)

Polyclonal BRCA2 Reversion Mutations Detected in Circulating Tumor DNA After Platinum Chemotherapy in a Patient With Metastatic Prostate Cancer.

JCO precision oncology, 2: pii:1700169.

RevDate: 2020-09-11

Kuderer NM, Burton KA, Blau S, et al (2017)

Participant Attitudes Toward an Intensive Trial of Multiple Biopsies, Multidimensional Molecular Analysis, and Reporting of Results in Metastatic Triple-Negative Breast Cancer.

JCO precision oncology, 1: pii:1700076.

Purpose: Multidimensional molecular analysis of tumor tissue intensively over space and time can provide insight into how cancers evolve and escape treatment. Attitudes of participants in such trials have not been assessed. We explored patient views regarding an intensive study incorporating multiple biopsies, multidimensional molecular testing, and drug response predictions that are reported to the oncologist and patient.

Patients and Methods: A structured, self-administered survey was conducted among the first 15 patients enrolled in ITOMIC-001 (Intensive Trial of Omics in Cancer). Patients with metastatic triple-negative breast cancer were accrued at two sites in Washington state. Surveys containing 17 items were administered at enrollment and after the return of results. Surveys explored perceptions regarding risks, personal benefits, benefits to others, uncertainties associated with interpreting complex molecular results, concerns regarding multiple biopsies, and potential loss of confidentiality. At follow-up, three additional unique items explored patient coping.

Results: All participants expressed a strong desire for their experiences to benefit others, and all perceived a higher likelihood of deriving benefit than described during detailed consent discussions. Loss of confidentiality ranked lowest among patient concerns. Despite acknowledging uncertainties and risks inherent in complex molecular testing for clinical reporting, participants wanted access to findings in evaluating treatment choices, even if the best available evidence was weak. Follow-up surveys demonstrated relatively little change in attitudes, although concern about study biopsies generally declined. Study participation helped several patients cope better with their disease.

Conclusion: In advanced breast cancer, these findings demonstrate the feasibility of engaging motivated patients in trials that navigate the uncertainties associated with intensive spatial and longitudinal multidimensional molecular testing for the purpose of advancing precision medicine.

RevDate: 2020-09-11

Kaya-Okur HS, Janssens DH, Henikoff JG, et al (2020)

Efficient low-cost chromatin profiling with CUT&Tag.

Nature protocols pii:10.1038/s41596-020-0373-x [Epub ahead of print].

We recently introduced Cleavage Under Targets & Tagmentation (CUT&Tag), an epigenomic profiling strategy in which antibodies are bound to chromatin proteins in situ in permeabilized nuclei. These antibodies are then used to tether the cut-and-paste transposase Tn5. Activation of the transposase simultaneously cleaves DNA and adds adapters ('tagmentation') for paired-end DNA sequencing. Here, we introduce a streamlined CUT&Tag protocol that suppresses DNA accessibility artefacts to ensure high-fidelity mapping of the antibody-targeted protein and improves the signal-to-noise ratio over current chromatin profiling methods. Streamlined CUT&Tag can be performed in a single PCR tube, from cells to amplified libraries, providing low-cost genome-wide chromatin maps. By simplifying library preparation CUT&Tag requires less than a day at the bench, from live cells to sequencing-ready barcoded libraries. As a result of low background levels, barcoded and pooled CUT&Tag libraries can be sequenced for as little as $25 per sample. This enables routine genome-wide profiling of chromatin proteins and modifications and requires no special skills or equipment.

RevDate: 2020-09-11

Bedford T, Greninger AL, Roychoudhury P, et al (2020)

Cryptic transmission of SARS-CoV-2 in Washington state.

Science (New York, N.Y.) pii:science.abc0523 [Epub ahead of print].

Following its emergence in Wuhan, China, in late November or early December 2019, the SARS-CoV-2 virus has rapidly spread globally. Genome sequencing of SARS-CoV-2 allows reconstruction of its transmission history, although this is contingent on sampling. We have analyzed 453 SARS-CoV-2 genomes collected between 20 February and 15 March 2020 from infected patients in Washington State, USA. We find that most SARS-CoV-2 infections sampled during this time derive from a single introduction in late January or early February 2020 which subsequently spread locally before active community surveillance was implemented.

RevDate: 2020-09-11

Gerds AT, Gotlib J, Bose P, et al (2020)

Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(9):1248-1269.

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

RevDate: 2020-09-11

Motzer RJ, Jonasch E, Boyle S, et al (2020)

NCCN Guidelines Insights: Kidney Cancer, Version 1.2021.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(9):1160-1170.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

RevDate: 2020-09-10

Chen GC, Qi Q, Hua S, et al (2020)

Accelerometer-assessed physical activity and incident diabetes in a population covering the adult life span: the Hispanic Community Health Study/Study of Latinos.

The American journal of clinical nutrition pii:5903730 [Epub ahead of print].

BACKGROUND: The association between accelerometer-assessed physical activity and risk of diabetes remains unclear, especially among US Hispanic/Latino adults who have lower levels of physical activity and a higher diabetes burden compared with other racial/ethnical populations in the country.

OBJECTIVES: To examine the association between accelerometer-assessed physical activity and incident diabetes in a US Hispanic/Latino population.

METHODS: We included 7280 participants of the Hispanic Community Health Study/Study of Latinos who aged 18-74 y and free of diabetes at baseline. Data on moderate-to-vigorous physical activity (MVPA) were collected using a 7-d accelerometer measurement. Incident diabetes was assessed after a mean ± SD of 6.0 ± 0.8 y using standard procedures including blood tests. RRs and 95% CIs of diabetes associated with MVPA were estimated using survey Poisson regressions. The associations of MVPA with 6-y changes in adiposity measures were also examined.

RESULTS: A total of 871 incident cases of diabetes were identified. MVPA was inversely and nonlinearly associated with risk of diabetes (P-nonlinearity = 0.006), with benefits accruing rapidly at the lower end of MVPA range (<30 min/d) and leveling off thereafter. The association differed by population age (P-interaction = 0.006). Higher MVPA was associated with lower risk of diabetes among individuals older than 50 y (RRQ4 versus Q1 = 0.50; 95% CI: 0.35, 0.73; P-trend < 0.001) but not among younger individuals (RRQ4 versus Q1 = 0.98; 95% CI: 0.66, 1.47; P-trend = 0.92). An inverse association between MVPA and 6-y gain in waist circumference was also limited to the older group (P-interaction with age < 0.001).

CONCLUSIONS: Among US Hispanic/Latino adults, baseline accelerometer-derived MVPA was inversely associated with incident diabetes only among individuals aged 50 y and older. Further studies are needed to confirm our findings and to clarify potential mechanisms underlying the possible age differences in the MVPA-diabetes association. This study was registered at clinicaltrials.gov as NCT02060344.

RevDate: 2020-09-10

Pollack SM, Redman MW, Baker KK, et al (2020)

Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma: A Phase 1/2 Nonrandomized Clinical Trial.

JAMA oncology pii:2770032 [Epub ahead of print].

Importance: Anthracycline-based therapy is standard first-line treatment for most patients with advanced and metastatic sarcomas. Although multiple trials have attempted to show improved outcomes in patients with soft-tissue sarcoma over doxorubicin monotherapy, each has fallen short of demonstrating improved outcomes.

Objective: To evaluate the safety and efficacy of doxorubicin in combination with pembrolizumab in patients with advanced, anthracycline-naive sarcomas.

This nonrandomized clinical trial used a 2-stage phase 2 design and was performed at a single, academic sarcoma specialty center. Patients were adults with good performance status and end-organ function. Patients with all sarcoma subtypes were allowed to enroll with the exception of osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma.

Interventions: Two dose levels of doxorubicin (45 and 75 mg/m2) were tested for safety in combination with pembrolizumab.

Main Outcomes and Measures: Objective response rate (ORR) was the primary end point. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Correlative studies included immunohistochemistry, gene expression, and serum cytokines.

Results: A total of 37 patients (22 men; 15 women) were treated in the combined phase 1/2 trial. The median (range) patient age was 58.4 (25-80) years. The most common histologic subtype was leiomyosarcoma (11 patients). Doxorubicin plus pembrolizumab was well tolerated without significant unexpected toxic effects. The ORR was 13% for phase 2 patients and 19% overall. Median PFS was 8.1 (95% CI, 7.6-10.8) months. Median OS was 27.6 (95% CI, 18.7-not reached) months at the time of this analysis. Two of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses. Tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and associated with inferior PFS (log-rank P = .03). No dose-limiting toxic effects were observed.

Conclusions and Relevance: In this nonrandomized clinical trial, doxorubicin plus pembrolizumab was well tolerated. Although the primary end point for ORR was not reached, the PFS and OS observed compared favorably with prior published studies. Further studies are warranted, especially those focusing on undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.

Trial Registration: ClinicalTrials.gov Identifier: NCT02888665.

RevDate: 2020-09-10

Zhao Y, Feng X, Chen Y, et al (2020)

5-fluorouracil enhances the anti-tumor activity of the glutaminase inhibitor CB-839 against PIK3CA-mutant colorectal cancers.

Cancer research pii:0008-5472.CAN-20-0600 [Epub ahead of print].

PIK3CA encodes the p110α catalytic subunit of PI3 kinase and is frequently mutated in human cancers, including ~30% of colorectal cancer (CRC). Oncogenic mutations in PIK3CA render CRCs more dependent on glutamine. Here we report that the glutaminase inhibitor CB-839 preferentially inhibits xenograft growth of PIK3CA-mutant, but not wild-type (WT), CRCs. Moreover, the combination of CB-839 and 5-fluorouracil (5-FU) induces PIK3CA-mutant tumor regression in xenograft models. CB-839 treatment increased reactive oxygen species and caused nuclear translocation of Nrf2, which in turn up-regulated mRNA expression of uridine phosphorylase 1 (UPP1). UPP1 facilitated the conversion of 5-FU to its active compound, thereby enhancing the inhibition of thymidylate synthase. Consistently, knockout of UPP1 abrogated the tumor inhibitory effect of combined CB-839 and 5-FU administration. A phase I clinical trial showed that the combination of CB-839 and capecitabine, a prodrug of 5-FU, was well tolerated at biologically-active doses. Although not designed to test efficacy, an exploratory analysis of the phase I data showed a trend that PIK3CA-mutant CRC patients might derive greater benefit from this treatment strategy as compared to PIK3CA WT CRC patients. These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA-mutant CRCs and warrants further clinical evaluation.

RevDate: 2020-09-10

Wagner MJ, Chau B, Loggers ET, et al (2020)

Long-term Outcomes for Extraskeletal Myxoid Chondrosarcoma: A SEER Database Analysis.

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-20-0447 [Epub ahead of print].

BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMCS) is a rare tumor that typically has an indolent course but high rate of recurrence. We queried the Surveillance, Epidemiology, and End Results (SEER) database to assess factors associated with metastasis, treatment, and survival.

METHODS: We queried the SEER 1973-2016 database for patients with myxoid chondrosarcoma (ICD-O-3: 9231/3). Kaplan-Meier analyses and Cox proportional hazard models assessed effects on overall survival (OS) of demographics and clinical characteristics. Logistic regression assessed associations between tumor location and distant disease. Primary analysis was a complete case analysis; multiple imputation (MI) was used in a sensitivity analysis.

RESULTS: Locoregional disease (LRD) was found in 373 (85%) of patients. In univariate analysis with LRD, surgery correlated with superior OS [HR = 0.27; 95% confidence interval (CI), 0.16-0.47]; chemotherapy and radiotherapy associated with inferior OS (HR = 1.90; 95% CI, 1.11-3.27 and HR = 1.45; 95% CI, 1.03-2.06, respectively). No treatment modality associated with OS in the adjusted, complete case model. In the adjusted sensitivity analysis, surgery associated with superior outcomes (HR = 0.36; 95% CI, 0.19-0.69). There was no OS difference by primary tumor site. 10-year OS with distant disease was 10% (95% CI, 2%-25%).

CONCLUSIONS: Surgery in LRD associated with improved OS in univariate analysis and adjusted models correcting for missing data. There was no OS benefit with chemotherapy or radiotherapy.

IMPACT: This represents the largest report of EMCS with long-term follow-up. Despite the reputedly indolent nature of EMCS, outcomes with metastatic disease are poor. We provide OS benchmarks and guidance for stratification in future prospective trials.

RevDate: 2020-09-09

Kinsella S, JA Dudakov (2020)

When the Damage Is Done: Injury and Repair in Thymus Function.

Frontiers in immunology, 11:1745.

Even though the thymus is exquisitely sensitive to acute insults like infection, shock, or common cancer therapies such as cytoreductive chemo- or radiation-therapy, it also has a remarkable capacity for repair. This phenomenon of endogenous thymic regeneration has been known for longer even than its primary function to generate T cells, however, the underlying mechanisms controlling the process have been largely unstudied. Although there is likely continual thymic involution and regeneration in response to stress and infection in otherwise healthy people, acute and profound thymic damage such as that caused by common cancer cytoreductive therapies or the conditioning regimes as part of hematopoietic cell transplantation (HCT), leads to prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse. Furthermore, this capacity for regeneration declines with age as a function of thymic involution; which even at steady state leads to reduced capacity to respond to new pathogens, vaccines, and immunotherapy. Consequently, there is a real clinical need for strategies that can boost thymic function and enhance T cell immunity. One approach to the development of such therapies is to exploit the processes of endogenous thymic regeneration into novel pharmacologic strategies to boost T cell reconstitution in clinical settings of immune depletion such as HCT. In this review, we will highlight recent work that has revealed the mechanisms by which the thymus is capable of repairing itself and how this knowledge is being used to develop novel therapies to boost immune function.

RevDate: 2020-09-09

Lam T, VoPham T, Munger KL, et al (2020)

Long-term effects of latitude, ambient temperature, and ultraviolet radiation on the incidence of multiple sclerosis in two cohorts of US women.

Environmental epidemiology (Philadelphia, Pa.), 4(4):e0105.

Background: Differences in multiple sclerosis (MS) risk by latitude have been observed worldwide; however, the exposures driving these associations are unknown. Ultraviolet radiation (UV) has been explored as a risk factor, and ambient temperature has been correlated with disease progression. However, no study has examined the impact of all three exposures. We examined the association between these exposures and incidence of MS within two nationwide prospective cohorts of women, the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII).

Methods: Both cohorts were followed with biennial questionnaires to ascertain new diagnoses and risk factors. Time-varying exposures to latitude, cumulative average July temperature (°C), and cumulative average July erythemal UV (mW/m2) were predicted at each participant's biennially updated residential addresses. Using Cox proportional hazards models adjusted for MS risk factors, we calculated hazard ratios (HR) and 95% confidence intervals (CIs) within each cohort and pooled via meta-analyses.

Results: In multivariable models, there were suggestions that decreasing latitude (meta-analysis multivariable-adjusted HR = 0.72; 95% CI 0.55, 0.94 for women living <35.73° compared with those ≥42.15°, P-for-trend = 0.007) and increasing cumulative average July temperature (meta-analysis multivariable-adjusted HR = 0.81; 95% CI 0.72, 0.91 for each interquartile range increase [3.91°]) were associated with decreasing risk of MS. There was no evidence of heterogeneity between cohorts. We did not observe consistent associations with cumulative average UV.

Conclusion: Our results suggest that adult exposures to decreasing latitude and increasing temperature, but not UV, were associated with reduced MS risk in these two cohorts of women. Studies of MS incidence may want to consider temperature as a risk factor.

RevDate: 2020-09-09

Sarthy JF, Meers MP, Janssens DH, et al (2020)

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones.

eLife, 9: pii:61090 [Epub ahead of print].

Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown how oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNA replication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing cells retain some domains, and only H3.1K27M-bearing cells lack H3K27 trimethylation. Neither oncohistone interferes with PRC2 binding. Using Drosophila as a model, we demonstrate that inhibition of H3K27 trimethylation occurs only when H3K27M oncohistones are deposited into chromatin and only when expressed in cycling cells. We propose that oncohistones inhibit the H3K27 methyltransferase as chromatin patterns are being duplicated in proliferating cells, predisposing them to tumorigenesis.

RevDate: 2020-09-09

Sutherland MW, Ma X, Reboussin BA, et al (2020)

Socioeconomic position is associated with glycemic control in youth and young adults with type 1 diabetes.

Pediatric diabetes [Epub ahead of print].

OBJECTIVE: Health inequities persist in youth and young adults(YYA) with type 1diabetes in achieving optimal glycemic control. The purpose of this study was to assess the contribution of multiple indicators of social needto these inequities.

RESEARCH DESIGN AND METHODS: 222YYAwithtype 1 diabetes enrolled in the SEARCH Food Insecurity Study in South Carolina and Washington between the years 2013-2015 were included. Latent class analysis was used to identify socioeconomic profiles based on household income, parental education, health insurance,household food insecurity, and food assistance. Profileswere evaluated in relation to glycemic control using multivariable linear andlogistic regression, with HbA1c > 9%(75 mmol/mol) defined as high-riskglycemic control.

RESULTS: Twoprofiles were identified: alower socioeconomic profile included YYA whose parents had lower income and/or education,and weremore likely to be uninsured, receive food assistance, and be food insecure.A higher socioeconomic profileincluded YYA whose circumstances were opposite to those in the lower socioeconomic profile.Those with a lower socioeconomic profile were more likely to have high-riskglycemic control relative to thosewith a higher socioeconomic profile (OR = 2.24, 95%CI = 1.16-4.33).

CONCLUSIONS: Lower socioeconomic profilesare associated with high-riskglycemic controlamong YYA with type 1 diabetes. This supports recommendations that care providers of YYA with type 1 diabetes assess individual social needs in tailoring diabetes management plans to the social context of the patient. This article is protected by copyright. All rights reserved.

RevDate: 2020-09-09

Suzuki T, Uruno A, Yumoto A, et al (2020)

Nrf2 contributes to the weight gain of mice during space travel.

Communications biology, 3(1):496 pii:10.1038/s42003-020-01227-2.

Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining homeostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans.

RevDate: 2020-09-09

Loes AN, Gentles LE, Greaney AJ, et al (2020)

Attenuated Influenza Virions Expressing the SARS-CoV-2 Receptor-Binding Domain Induce Neutralizing Antibodies in Mice.

Viruses, 12(9): pii:v12090987.

An effective vaccine is essential for controlling the spread of the SARS-CoV-2 virus. Here, we describe an influenza virus-based vaccine for SARS-CoV-2. We incorporated a membrane-anchored form of the SARS-CoV-2 spike receptor binding domain (RBD) in place of the neuraminidase (NA) coding sequence in an influenza virus also possessing a mutation that reduces the affinity of hemagglutinin for its sialic acid receptor. The resulting ΔNA(RBD)-Flu virus can be generated by reverse genetics and grown to high titers in cell culture. A single-dose intranasal inoculation of mice with ΔNA(RBD)-Flu elicits serum neutralizing antibody titers against SAR-CoV-2 comparable to those observed in humans following natural infection (~1:200). Furthermore, ΔNA(RBD)-Flu itself causes no apparent disease in mice. It might be possible to produce a vaccine similar to ΔNA(RBD)-Flu at scale by leveraging existing platforms for the production of influenza vaccines.

RevDate: 2020-08-13

Huang M, O'Shaughnessy J, Zhao J, et al (2020)

Evaluation of Pathologic Complete Response as a Surrogate for Long-Term Survival Outcomes in Triple-Negative Breast Cancer.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(8):1096-1104.

BACKGROUND: Pathologic complete response (pCR) is a common efficacy endpoint in neoadjuvant therapy trials for triple-negative breast cancer (TNBC). Previous studies have shown that pCR is strongly associated with improved long-term survival outcomes, including event-free survival (EFS) and overall survival (OS). However, the trial-level associations between treatment effect on pCR and long-term survival outcomes are not well established. This study sought to evaluate these associations by incorporating more recent clinical trials in TNBC.

METHODS: A literature review identified published randomized controlled trials (RCTs) of neoadjuvant therapy for TNBC that reported results for both pCR and EFS/OS. Meta-regression models were performed to evaluate the association of treatment effect on pCR and EFS/OS. Sensitivity analyses were conducted to assess the impact of divergent study designs.

RESULTS: Ten comparisons from 8 RCTs (N=2,478 patients) were identified from the literature review. The log (odds ratio) of pCR was a significant predictor of the log (hazard ratio) of EFS (P=.003), with a coefficient of determination of 0.68 (95% CI, 0.41-0.95). There was a weaker association between pCR and OS (P=.18), with a coefficient of determination of 0.24 (95% CI, 0.01-0.77). Consistent results were found in the exploratory analysis and sensitivity analyses.

CONCLUSIONS: This is the first study that has shown a trial-level association between pCR and survival outcomes in TNBC. By incorporating the most up-to-date RCTs, this study showed a significant trial-level association between pCR and EFS. A positive association between pCR and OS was also recorded.

RevDate: 2020-09-08

Samuelson Bannow BT, Warad D, Jones C, et al (2020)

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis.

Blood pii:463714 [Epub ahead of print].

Heparin-induced thrombocytopenia (HIT) is a life-threatening, pro-thrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays such as the Platelet Factor 4-Heparin ELISAs lack specificity, and the "gold standard" C14-labeled serotonin release assay (SRA) is of limited value for early patient management due to availability only through reference laboratories. Recent studies demonstrate that "pathogenic" HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin Expression Assay (PEA), may provide an option for rapid and conclusive results. Four hundred and nine consecutive adults suspected of HIT were classified as disease-positive, -negative or -indeterminate based upon predefined criteria that combined 4Ts scores and HIT ELISA results. Patients deemed "HIT-indeterminate" were considered disease-negative in the primary analysis and disease-positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (Area under the curve [AUC] of 0.94; 0.87-1.0, 95% CI) and similar to that of SRA (0.91; 0.82-1.0, 95% CI). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (0.78-0.98, 95% CI) and 0.86 (0.77-0.96, 95% CI), respectively. The PEA, a technically simple non-radioactive assay that uses ~20-fold fewer platelets compared to the SRA had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.

RevDate: 2020-09-08

Lieberman NAP, Peddu V, Xie H, et al (2020)

In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age.

PLoS biology, 18(9):e3000849 pii:PBIOLOGY-D-20-01861.

Despite limited genomic diversity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across infection status, viral load, age, and sex among shotgun RNA sequencing profiles of nasopharyngeal (NP) swabs from 430 individuals with PCR-confirmed SARS-CoV-2 and 54 negative controls. SARS-CoV-2 induced a strong antiviral response with up-regulation of antiviral factors such as OAS1-3 and IFIT1-3 and T helper type 1 (Th1) chemokines CXCL9/10/11, as well as a reduction in transcription of ribosomal proteins. SARS-CoV-2 culture in human airway epithelial (HAE) cultures replicated the in vivo antiviral host response 7 days post infection, with no induction of interferon-stimulated genes after 3 days. Patient-matched longitudinal specimens (mean elapsed time = 6.3 days) demonstrated reduction in interferon-induced transcription, recovery of transcription of ribosomal proteins, and initiation of wound healing and humoral immune responses. Expression of interferon-responsive genes, including ACE2, increased as a function of viral load, while transcripts for B cell-specific proteins and neutrophil chemokines were elevated in patients with lower viral load. Older individuals had reduced expression of the Th1 chemokines CXCL9/10/11 and their cognate receptor CXCR3, as well as CD8A and granzyme B, suggesting deficiencies in trafficking and/or function of cytotoxic T cells and natural killer (NK) cells. Relative to females, males had reduced B cell-specific and NK cell-specific transcripts and an increase in inhibitors of nuclear factor kappa-B (NF-κB) signaling, possibly inappropriately throttling antiviral responses. Collectively, our data demonstrate that host responses to SARS-CoV-2 are dependent on viral load and infection time course, with observed differences due to age and sex that may contribute to disease severity.

RevDate: 2020-09-08

Schweizer MT, Cheng HH, Nelson PS, et al (2020)

Two Steps Forward and One Step Back for Precision in Prostate Cancer Treatment.

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

RevDate: 2020-09-08

Thakur J, S Henikoff (2020)

Architectural RNA in chromatin organization.

Biochemical Society transactions pii:226363 [Epub ahead of print].

RNA plays a well-established architectural role in the formation of membraneless interchromatin nuclear bodies. However, a less well-known role of RNA is in organizing chromatin, whereby specific RNAs have been found to recruit chromatin modifier proteins. Whether or not RNA can act as an architectural molecule for chromatin remains unclear, partly because dissecting the architectural role of RNA from its regulatory role remains challenging. Studies that have addressed RNA's architectural role in chromatin organization rely on in situ RNA depletion using Ribonuclease A (RNase A) and suggest that RNA plays a major direct architectural role in chromatin organization. In this review, we will discuss these findings, candidate chromatin architectural long non-coding RNAs and possible mechanisms by which RNA, along with RNA binding proteins might be mediating chromatin organization.

RevDate: 2020-09-08

Moodley J, Naidoo S, Kelly C, et al (2020)

The Impact of Male Partner Circumcision on Women's Health Outcomes.

AIDS education and prevention : official publication of the International Society for AIDS Education, 32(4):356-366.

Medical male circumcision is a proven method of HIV risk reduction in men with no known direct benefit to women. We investigated the benefit of partner circumcision on women's health. We conducted a secondary analysis of 5,029 women enrolled in the Vaginal and Oral Interventions to Control the Epidemic trial across 15 African sites, to look at the impact of partner circumcision status on sexually transmitted infections, pregnancy, frequency of sex, and condom use in women. Of 4,982 participants with a baseline response, 31% had circumcised partners. Women with circumcised partners had a significantly reduced risk of syphilis acquisition, hazard ratio 0.51 (0.26, 1.00), p value = .05. Participants with uncircumcised partners were significantly less likely to have used a condom at the last sex act than the other two groups, adj. relative risk 0.86 (0.80, 0.92), adj. p value < .0001. We found no evidence of sexual risk compensation in women with circumcised partners.

RevDate: 2020-09-08

Yagishita Y, McCallum ML, Kensler TW, et al (2020)

Constitutive activation of Nrf2 in mice expands enterogenesis in small intestine through negative regulation of Math1.

Cellular and molecular gastroenterology and hepatology pii:S2352-345X(20)30137-5 [Epub ahead of print].

BACKGROUND & AIMS: Notch signaling coordinates cell differentiation processes in the intestinal epithelium. The transcription factor Nrf2 orchestrates defense mechanisms by regulating cellular redox homeostasis, which as shown previously in murine liver, can be amplified through signaling crosstalk with the Notch pathway. However, interplay between these two signaling pathways in the gut is unknown.

METHODS: Mice modified genetically to amplify Nrf2 in the intestinal epithelium (Keap1f/f::VilCre) were generated as well as pharmacological activation of Nrf2 and subjected to phenotypic and cell lineage analyses. Cell lines were used for reporter gene assays together with Nrf2 overexpression to study transcriptional regulation of the Notch downstream effector.

RESULTS: Constitutive activation of Nrf2 signaling caused increased intestinal length along with expanded cell number and thickness of enterocytes without any alterations of secretory lineage, outcomes abrogated by concomitant disruption of Nrf2. The Nrf2 and Notch pathways in epithelium showed inverse spatial profiles, where Nrf2 activity in crypts was lower than villi. In progenitor cells of Keap1f/f::VilCre mice, Notch downstream effector Math1, which regulates a differentiation balance of cell lineage through lateral inhibition, showed suppressed expression. In vitro results demonstrated Nrf2 negatively regulated Math1, where six antioxidant response elements located in the regulatory regions contributed to this repression.

CONCLUSIONS: Activation of Nrf2 perturbed the dialog of the Notch cascade though negative regulation of Math1 in progenitor cells, leading to enhanced enterogenesis. The crosstalk between the Nrf2 and Notch pathways could be critical for fine-tuning intestinal homeostasis and point to new approaches for the pharmacological management of absorptive deficiencies.

RevDate: 2020-09-08

Verhoeven D, Allemani C, Kaufman C, et al (2020)

Breast Cancer: global quality care optimizing care delivery with existing financial and personnel resources.

ESMO open, 4(Suppl 2):.

Our vision about breast cancer quality care within a global health framework was recently published by Oxford University Press. The aim of our work was to reflect on the potential to achieve a world-wide improvement in quality care, assessing value for money. The population-based survival estimates from the CONCORD programme and the Breast Health Global Initiative (BHGI) are valuable tools for this global effort. Because cancer care delivery is becoming unsustainable in many countries assessing healthcare value for the cost is becoming increasingly important. Recommendations are made for better global quality care for patients with breast cancer.

RevDate: 2020-09-06

Graves SS, Parker MH, Stone D, et al (2020)

Corrigendum to 'Anti-ICOS Monoclonal Antibody Treatment of Canine Chronic GVHD' [Biology of Blood and Marrow Transplantation 24/1 (2018) 50-54].

RevDate: 2020-09-03

Chou EL, Pettinger M, Haring B, et al (2020)

Lipoprotein(a) levels and risk of abdominal aortic aneurysm in the Women's Health Initiative.

Journal of vascular surgery pii:S0741-5214(20)31908-X [Epub ahead of print].

OBJECTIVE: Few studies have prospectively examined associations of lipoprotein(a) [Lp(a)] levels with risk of abdominal aortic aneurysm (AAA), particularly in women. Accounting for commonly recognized risk factors, we investigated baseline Lp(a) levels with risk of AAA among postmenopausal women participating in the ongoing national Women's Health Initiative (WHI).

METHODS: WHI participants with baseline Lp(a) levels who were beneficiaries of Medicare Parts A&B fee-for-service at study enrollment, or who aged into Medicare at any point, were included. Participants with missing covariate data or known AAA at baseline were excluded. Thoracic aneurysms were excluded due to different pathophysiology. AAA cases and interventions were identified by International Classification of Disease-9/10 codes and Current Procedural Terminology codes from claims data. Hazard ratios were computed using Cox proportional hazard models according to quintiles of Lp(a) (mg/dL).

RESULTS: Among the 6,615 participants included in the analysis, the mean age was 65.3 years. 66.6% were non-Hispanic White, 18.9% Black, 7% Hispanic and 4.7% Asian/Pacific Islander. Compared to participants in the lowest quintile, those in higher quintiles were more likely to be overweight, Black, former or current smokers, hypertensive, hyperlipidemic, to have history of cardiovascular disease, use MHT and use statins. During 65,476 person-years of follow-up, over a median of 10.4 years, 415 women were diagnosed with AAA and 36 required interventions. Over half required intervention for ruptured AAA. We failed to find a statistically significant association between Lp(a) and incident AAA. Additional sensitivity analyses by race, exclusion of statin users, and alternative categorizations of Lp(a) by log-transformed levels, tertiles and a cutoff of >50mg/dL were conducted and did not reveal any significant associations.

CONCLUSIONS: We found no statistically significant association between Lp(a) levels and risk of AAA in a large and well-phenotyped sample of postmenopausal women. Women with high Lp(a) levels were more likely to be overweight, Black, former or current smokers, hypertensive, hyperlipidemic, to have history of cardiovascular disease, or use hormone therapy and statins, compared to those with lower levels. These findings differ from previous prospective, case-control and meta-analysis studies which supported a significant relationship between higher Lp(a) levels and increased risk of AAA. Differences in association may be due to study limitations or sex differences.

RevDate: 2020-09-03

van der Plas E, Qiu W, Nieman BJ, et al (2020)

Sex-specific associations between chemotherapy, chronic conditions and neurocognitive impairment in ALL survivors: A report from the Childhood Cancer Survivor Study.

Journal of the National Cancer Institute pii:5901053 [Epub ahead of print].

BACKGROUND: The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with chemotherapy only.

METHODS: This cross-sectional study included 1,207 ALL survivors (54.0% female; mean age 30.6 years) and 2,273 siblings (56.9% female; mean age 47.6 years), who completed the CCSS Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were two-sided.

RESULTS: Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs. 16.9%; adjusted odds ratio [OR]=1.89, 95% confidence interval [CI]=1.31 to .74; females: 12.5% vs. 17.6%; OR = 1.50, 95% CI = 1.07to2.14), as well as impaired memory (males: 11.6% vs. 19.9%, OR = 1.89, CI = 1.31to2.74; females: 14.78% vs. 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), while impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92).

CONCLUSION: Neurocognitive impairment is associated with methotrexate, dexamethasone and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship.

RevDate: 2020-09-03

Averin A, Silvia A, Lamerato L, et al (2020)

Risk of chemotherapy-induced febrile neutropenia in patients with metastatic cancer not receiving granulocyte colony-stimulating factor prophylaxis in US clinical practice.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-020-05715-3 [Epub ahead of print].

OBJECTIVES: To evaluate the use of granulocyte colony-stimulating factor (G-CSF) prophylaxis in US patients with selected metastatic cancers and chemotherapy-induced febrile neutropenia (FN) incidence and associated outcomes among the subgroup who did not receive prophylaxis.

METHODS: This retrospective cohort study was conducted at four US health systems and included adults with metastatic cancer (breast, colorectal, lung, non-Hodgkin lymphoma [NHL]) who received myelosuppressive chemotherapy (2009-2017). Patients were stratified by FN risk level based on risk factors and chemotherapy (low/unclassified risk, intermediate risk without any risk factors, intermediate risk with ≥ 1 risk factor [IR + 1], high risk [HR]). G-CSF use was evaluated among all patients stratified by FN risk, and FN/FN-related outcomes were evaluated among patients who did not receive first-cycle G-CSF prophylaxis.

RESULTS: Among 1457 metastatic cancer patients, 20.5% and 28.1% were classified as HR and IR + 1, respectively. First-cycle G-CSF prophylaxis use was 48.5% among HR patients and 13.9% among IR + 1 patients. In the subgroup not receiving first-cycle G-CSF prophylaxis, FN incidence in cycle 1 was 7.8% for HR patients and 4.8% for IR + 1 patients; during the course, corresponding values were 16.9% and 15.9%. Most (> 90%) FN episodes required hospitalization, and mortality risk ranged from 7.1 to 26.9% across subgroups.

CONCLUSION: In this retrospective study, the majority of metastatic cancer chemotherapy patients for whom G-CSF prophylaxis is recommended did not receive it; FN incidence in this subgroup was notably high. Patients with elevated FN risk should be carefully identified and managed to ensure appropriate use of supportive care.

RevDate: 2020-09-05

Qin N, Li Y, Wang C, et al (2020)

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.

Frontiers of medicine pii:10.1007/s11684-020-0779-4 [Epub ahead of print].

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

RevDate: 2020-09-05

Vuckovic D, Bao EL, Akbari P, et al (2020)

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Cell, 182(5):1214-1231.e11.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

RevDate: 2020-09-05

Chen MH, Raffield LM, Mousas A, et al (2020)

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Cell, 182(5):1198-1213.e14.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

RevDate: 2020-09-05

Barnabas RV, H van Rooyen (2020)

Data-driven HIV programming to maximise health benefits.

The lancet. HIV pii:S2352-3018(20)30235-6 [Epub ahead of print].

RevDate: 2020-09-05

Abramson JS, Palomba ML, Gordon LI, et al (2020)

Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.

Lancet (London, England) pii:S0140-6736(20)31366-0 [Epub ahead of print].

BACKGROUND: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas.

METHODS: We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044.

FINDINGS: Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells.

INTERPRETATION: Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies.

FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.

RevDate: 2020-09-05

Casmir E, Daniel AK, Ongolly F, et al (2020)

Correction to: Protection at First Sexual Intercourse Among Adolescent Girls and Young Women in Kenya.

There was an error in this article as originally published.

RevDate: 2020-09-04

Sokolova AO, Shirts BH, Konnick EQ, et al (2020)

Complexities of Next-Generation Sequencing in Solid Tumors: Case Studies.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(9):1150-1155.

With the promise and potential of clinical next-generation sequencing for tumor and germline testing to impact treatment and outcomes of patients with cancer, there are also risks of oversimplification, misinterpretation, and missed opportunities. These issues risk limiting clinical benefit and, at worst, perpetuating false conclusions that could lead to inappropriate treatment selection, avoidable toxicity, and harm to patients. This report presents 5 case studies illustrating challenges and opportunities in clinical next-generation sequencing interpretation and clinical application in solid tumor oncologic care. First is a case that dissects the origin of an ATM mutation as originating from a hematopoietic clone rather than the tumor. Second is a case illustrating the potential for tumor sequencing to suggest germline variants associated with a hereditary cancer syndrome. Third are 2 cases showing the potential for variant reclassification of a germline variant of uncertain significance when considered alongside family history and tumor sequencing results. Finally, we describe a case illustrating challenges with using microsatellite instability for predicting tumor response to immune checkpoint inhibitors. The common theme of the case studies is the importance of examining clinical context alongside expert review and interpretation, which together highlight an expanding role for contextual examination and multidisciplinary expert review through molecular tumor boards.

RevDate: 2020-09-04

Stankiewicz Karita HC, Waterboer T, Magaret A, et al (2020)

Humoral response to HPV16 proteins in persons with anal high-grade squamous intraepithelial lesion or anal cancer.

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-20-0749 [Epub ahead of print].

BACKGROUND: This study was launched to evalute the association of early and late antibodies to human papillomavirus (HPV)16 detection and risk of anal high-grade intraepithelial lesions (HSIL) or cancer.

METHODS: We analyzed data from persons with anal HSIL or cancer and controls from a case-control study in Seattle, Washington. Sera were evaluated for HPV16 early (E1, E2, E4, E6, E7) and late (L1) antibodies by multiplex serology. Logistic regression models were used to assess serologic associations with risk of anal HSIL or cancer.

RESULTS: The study included 67 participants with anal HSIL, 116 with anal cancer, and 830 population-based controls. HPV16 seropositivity to L1 (aOR 13.8, 95% CI 7.4-25.8), E4 (aOR 2.3, 95% CI 1.1-4.5) and E6 (aOR 4.9, 95% CI 1.1-21.2) was associated with HSIL; and detection of all antibodies to HPV16 late and early proteins was associated with increased risk of anal cancer ranging from aOR 1.7 to 32.5 (L1 aOR 12.5 [95% CI 7.3-21.7], E1 aOR 24.9 [95% CI 10.3-59.9], E2 aOR 6.3 [95% CI 3.4-11.7], E4 aOR 2.8 [95% CI 1.6-4.8], E6 aOR 32.5 [95% CI 14.2-74.4] and E7 aOR 1.7 [95% CI 1.0-3.0]).

CONCLUSIONS: HPV serologic markers proved to be specific for identifying anal cancer. HPV16 E6 seropositivity is relatively uncommon in persons without anal cancer.

IMPACT: This large study comprehensively describes the distinct antibody responses to the HPV16 proteins in persons with anal HSIL or anal cancer. Antibodies to HPV16 E6 should be further evaluated as a potential biomarker for anal cancer prevention.

RevDate: 2020-09-03

Lin SH, Sampson JN, Grünewald TGP, et al (2020)

Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.

PloS one, 15(9):e0237792 pii:PONE-D-20-05330.

BACKGROUND: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.

METHODS: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).

RESULTS: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).

CONCLUSIONS: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.

IMPACT: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.

RevDate: 2020-09-03

Seyed Khoei N, Jenab M, Murphy N, et al (2020)

Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses.

BMC medicine, 18(1):229 pii:10.1186/s12916-020-01703-w.

BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.

METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.

RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).

CONCLUSIONS: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

RevDate: 2020-09-02

Huddleston J, Barnes JR, Rowe T, et al (2020)

Integrating genotypes and phenotypes improves long-term forecasts of seasonal influenza A/H3N2 evolution.

eLife, 9: pii:60067 [Epub ahead of print].

Seasonal influenza virus A/H3N2 is a major cause of death globally. Vaccination remains the most effective preventative. Rapid mutation of hemagglutinin allows viruses to escape adaptive immunity. This antigenic drift necessitates regular vaccine updates. Effective vaccine strains need to represent H3N2 populations circulating one year after strain selection. Experts select strains based on experimental measurements of antigenic drift and predictions made by models from hemagglutinin sequences. We developed a novel influenza forecasting framework that integrates phenotypic measures of antigenic drift and functional constraint with previously published sequence-only fitness estimates. Forecasts informed by phenotypic measures of antigenic drift consistently outperformed previous sequence- only estimates, while sequence-only estimates of functional constraint surpassed more comprehensive experimentally-informed estimates. Importantly, the best models integrated estimates of both functional constraint and either antigenic drift phenotypes or recent population growth.

RevDate: 2020-09-02

Weil AA, Newman KL, Ong TD, et al (2020)

Cross-Sectional Prevalence of SARS-CoV-2 Among Skilled Nursing Facility Employees and Residents Across Facilities in Seattle.

Journal of general internal medicine pii:10.1007/s11606-020-06165-7 [Epub ahead of print].

BACKGROUND: Skilled nursing facilities (SNFs) are high-risk settings for SARS-CoV-2 transmission. Infection rates among employees are infrequently described.

OBJECTIVE: To describe SARS-CoV-2 rates among SNF employees and residents during a non-outbreak time period, we measured cross-sectional SARS-CoV-2 prevalence across multiple sites in the Seattle area.

DESIGN: SARS-CoV-2 testing was performed for SNF employees and residents using quantitative real-time reverse transcription polymerase chain reaction. A subset of employees completed a sociodemographic and symptom questionnaire.

PARTICIPANTS: Between March 29 and May 13, 2020, we tested 1583 employees and 1208 residents at 16 SNFs for SARS-CoV-2.

MAIN MEASURE: SARS-CoV-2 testing results and symptom report among employees and residents.

KEY RESULTS: Eleven of the 16 SNFs had one or more resident or employee test positive. Overall, 46 (2.9%) employees had positive or inconclusive testing for SARS-CoV-2, and among those who completed surveys, most were asymptomatic and involved in direct patient care. The majority of employees tested were female (934, 73%), and most employees were Asian (392, 30%), Black (360, 28%), or white (360, 28%). Among the 1208 residents tested, 110 (9.1%) had positive or inconclusive results. There was no association between the presence of positive residents and positive employees within a SNF (p = 0.62, McNemar's test).

CONCLUSIONS: In the largest study of SNFs to date, SARS-CoV-2 infections were detected among both employees and residents. Employees testing positive were often asymptomatic and involved in direct patient care. Surveillance testing is needed for SNF employees and residents during the pandemic response.

RevDate: 2020-09-02

Dingens AS, Crawford KHD, Adler A, et al (2020)

Serological identification of SARS-CoV-2 infections among children visiting a hospital during the initial Seattle outbreak.

Nature communications, 11(1):4378 pii:10.1038/s41467-020-18178-1.

Children are strikingly underrepresented in COVID-19 case counts. In the United States, children represent 22% of the population but only 1.7% of confirmed SARS-CoV-2 cases as of April 2, 2020. One possibility is that symptom-based viral testing is less likely to identify infected children, since they often experience milder disease than adults. Here, to better assess the frequency of pediatric SARS-CoV-2 infection, we serologically screen 1,775 residual samples from Seattle Children's Hospital collected from 1,076 children seeking medical care during March and April of 2020. Only one child was seropositive in March, but seven were seropositive in April for a period seroprevalence of ≈1%. Most seropositive children (6/8) were not suspected of having had COVID-19. The sera of seropositive children have neutralizing activity, including one that neutralized at a dilution > 1:18,000. Therefore, an increasing number of children seeking medical care were infected by SARS-CoV-2 during the early Seattle outbreak despite few positive viral tests.

RevDate: 2020-09-02

Huang D, Abbott RK, Havenar-Daughton C, et al (2020)

B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models.

Proceedings of the National Academy of Sciences of the United States of America pii:2004489117 [Epub ahead of print].

Animal models of human antigen-specific B cell receptors (BCRs) generally depend on "inferred germline" sequences, and thus their relationship to authentic naive human B cell BCR sequences and affinities is unclear. Here, BCR sequences from authentic naive human VRC01-class B cells from healthy human donors were selected for the generation of three BCR knockin mice. The BCRs span the physiological range of affinities found in humans, and use three different light chains (VK3-20, VK1-5, and VK1-33) found among subclasses of naive human VRC01-class B cells and HIV broadly neutralizing antibodies (bnAbs). The germline-targeting HIV immunogen eOD-GT8 60mer is currently in clinical trial as a candidate bnAb vaccine priming immunogen. To attempt to model human immune responses to the eOD-GT8 60mer, we tested each authentic naive human VRC01-class BCR mouse model under rare human physiological B cell precursor frequency conditions. B cells with high (HuGL18HL) or medium (HuGL17HL) affinity BCRs were primed, recruited to germinal centers, and they affinity matured, and formed memory B cells. Precursor frequency and affinity interdependently influenced responses. Taken together, these experiments utilizing authentic naive human VRC01-class BCRs validate a central tenet of germline-targeting vaccine design and extend the overall concept of the reverse vaccinology approach to vaccine development.

RevDate: 2020-09-02

Tannir NM, Signoretti S, Choueiri TK, et al (2020)

Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-Line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-2063 [Epub ahead of print].

PURPOSE: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in patients with sRCC.

PATIENTS AND METHODS: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histological classification per local pathology report. Patients were randomized 1:1 to receive NIVO (3 mg/kg) plus IPI (1 mg/kg) Q3W (four doses) then NIVO 3 mg/kg Q2W, or SUN 50 mg orally QD (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and IMDC intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics.

RESULTS: Of 1096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS (95% CI) favored NIVO+IPI (NR [25.2-NE]; n=74) versus SUN (14.2 months [9.3-22.9]; n=65) (HR 0.45 [95% CI, 0.3-0.7; P=0.0004]); PFS benefits with NIVO+IPI were similarly observed (median 26.5 vs 5.1 months; HR 0.54 [95% CI, 0.33-0.86; P=0.0093]). Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with SUN, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged.

CONCLUSIONS: NIVO+IPI showed unprecedented long-term survival, response and complete response benefits versus SUN in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.

RevDate: 2020-08-27

Addetia A, Crawford KH, Dingens A, et al (2020)

Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate.

medRxiv : the preprint server for health sciences.

The development of vaccines against SARS-CoV-2 would be greatly facilitated by the identification of immunological correlates of protection in humans. However, to date, studies on protective immunity have only been performed in animal models and correlates of protection have not been established in humans. Here, we describe an outbreak of SARS-CoV-2 on a fishing vessel associated with a high attack rate. Predeparture serological and viral RT-PCR testing along with repeat testing after return to shore was available for 120 of the 122 persons on board over a median follow-up of 32.5 days (range 18.8 to 50.5 days). A total of 104 individuals had an RT-PCR positive viral test with Ct <35 or seroconverted during the follow-up period, yielding an attack rate on board of 85.2% (104/122 individuals). Metagenomic sequencing of 39 viral genomes suggested the outbreak originated largely from a single viral clade. Only three crewmembers tested seropositive prior to the boat's departure in initial serological screening and also had neutralizing and spike-reactive antibodies in follow-up assays. None of these crewmembers with neutralizing antibody titers showed evidence of bona fide viral infection or experienced any symptoms during the viral outbreak. Therefore, the presence of neutralizing antibodies from prior infection was significantly associated with protection against re-infection (Fisher's exact test, p=0.002).

RevDate: 2020-09-01

Dearlove B, Lewitus E, Bai H, et al (2020)

A SARS-CoV-2 vaccine candidate would likely match all currently circulating variants.

Proceedings of the National Academy of Sciences of the United States of America pii:2008281117 [Epub ahead of print].

The magnitude of the COVID-19 pandemic underscores the urgency for a safe and effective vaccine. Many vaccine candidates focus on the Spike protein, as it is targeted by neutralizing antibodies and plays a key role in viral entry. Here we investigate the diversity seen in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequences and compare it to the sequence on which most vaccine candidates are based. Using 18,514 sequences, we perform phylogenetic, population genetics, and structural bioinformatics analyses. We find limited diversity across SARS-CoV-2 genomes: Only 11 sites show polymorphisms in >5% of sequences; yet two mutations, including the D614G mutation in Spike, have already become consensus. Because SARS-CoV-2 is being transmitted more rapidly than it evolves, the viral population is becoming more homogeneous, with a median of seven nucleotide substitutions between genomes. There is evidence of purifying selection but little evidence of diversifying selection, with substitution rates comparable across structural versus nonstructural genes. Finally, the Wuhan-Hu-1 reference sequence for the Spike protein, which is the basis for different vaccine candidates, matches optimized vaccine inserts, being identical to an ancestral sequence and one mutation away from the consensus. While the rapid spread of the D614G mutation warrants further study, our results indicate that drift and bottleneck events can explain the minimal diversity found among SARS-CoV-2 sequences. These findings suggest that a single vaccine candidate should be efficacious against currently circulating lineages.

RevDate: 2020-09-01

Zhao LP, Papadopoulos GK, Kwok WW, et al (2020)

Next Generation HLA Sequence Analysis Uncovers Seven HLA-DQ Amino Acid Residues and Six Motifs Resistant to Childhood Type 1 Diabetes.

Diabetes pii:db20-0374 [Epub ahead of print].

HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (αa1, α157, α196, β9, β30, β57, β70) that are resistant to T1D among subjects with DQ4, 5, 6 and 7 resistant DQ haplotypes. These seven residues form 13 common motifs; six motifs are significantly resistant, six motifs have modest or no associations (p-values>0.05), and one motif has 7 copies observed among controls only. The motif "DAAFYDG", "DAAYHDG" and "DAAYYDR" have significant resistance to T1D (OR = 0.03, 0.25 and 0.18, p-value = 6.11*10-24, 3.54*10-15 and 1.03*10-21, respectively). Remarkably, a change of a single residue from the motif "DAAYH D G" to "DAAYH S G" (D to S at β57) alters the resistance potential, from resistant motif (OR = 0.15, p-value = 3.54*10-15) to a neutral motif (p-value = 0.183), the change of which was significant (Fisher's p-value = 0.0065). The extended set of linked residues associated with T1D resistance and unique to each cluster of HLA-DQ haplotypes represents facets of all known features and functions of these molecules: antigenic peptide binding, pMHCII complex stability, β167-169 RGD loop, TCR binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identifications of these residues is a novel understanding of resistant DQ associations with T1D. Our analyses endow potential molecular approaches to identify immunological mechanisms that control disease susceptibility or resistance to provide novel targets for immunotherapeutic strategies.

RevDate: 2020-08-31

Mani NS, Lan KF, Jain R, et al (2020)

Post-Prescription Review with Threat of Infectious Disease Consultation and Sustained Reduction in Meropenem Use Over Four Years.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5899791 [Epub ahead of print].

BACKGROUND: Following a meropenem shortage, we implemented a post-prescription review with feedback (PPRF) in November 2015 with mandatory infectious disease (ID) consultation for all meropenem and imipenem courses > 72 hours. Providers were made aware of the policy via an electronic alert at the time of ordering.

METHODS: A retrospective study was conducted at the University of Washington Medical Center (UWMC) and Harborview Medical Center (HMC) to evaluate the impact of the policy on antimicrobial consumption and clinical outcomes pre- and post-intervention during a 6-year period. Antimicrobial use was tracked using days of therapy (DOT) per 1,000 patient-days, and data were analyzed by an interrupted time series.

RESULTS: There were 4,066 and 2,552 patients in the pre- and post-intervention periods, respectively. Meropenem and imipenem use remained steady until the intervention, when a marked reduction in DOT/1,000 patient-days occurred at both hospitals (UWMC: percentage change -72.1%, (95% CI -76.6, -66.9), P & 0.001; HMC: percentage change -43.6%, (95% CI -59.9, -20.7), P = 0.001). Notably, although the intervention did not address antibiotic use until 72 hours after initiation, there was a significant decline in meropenem and imipenem initiation ("first starts") in the post-intervention period, with a 64.9% reduction (95% CI 58.7, 70.2; P &0.001) at UWMC and 44.7% reduction (95% CI 28.1, 57.4; P & 0.001) at HMC.

CONCLUSIONS: Mandatory ID consultation and PPRF for meropenem and imipenem beyond 72 hours resulted in a significant and sustained reduction in the use of these antibiotics and notably impacted their up-front usage.

RevDate: 2020-08-31

Grant SJ, B Lipe (2020)

Management of Frail Older Adults with Newly Diagnosed Multiple Myeloma - Moving Toward a Personalized Approach.

Clinical lymphoma, myeloma & leukemia, 20 Suppl 1:S76-S80.

CASE VIGNETTE: A 75-year-old male undergoes an evaluation for progressively worsening fatigue with associated shortness of breath. He also reports back pain worse at night, which does not resolve with acetaminophen. He is retired, but over the past 2 months he is unable to garden or perform household chores. Due to his pain and fatigue, he has limited his activity. He currently takes 9 prescription medications for chronic medical conditions, which include diabetes mellitus with neuropathy, hypertension, hyperlipidemia, and COPD. Initial evaluation reveals anemia (Hgb 9.0 g/dl last known normal was 2 years ago, Hgb 13.5 g/dl), renal impairment (serum creatinine 2.5 mg/dL), hypercalcemia (11.5 g/dl). Plain X-rays reveal compression fractures involving T3 and T4. Multiple myeloma is suspected, further labs confirm the diagnosis of IgG kappa multiple myeloma. LDH is elevated, beta-2-microglobulin is elevated at 6.1 mg/L and albumin < 3.5 mg/dl. Bone marrow aspiration and biopsy reveal plasmacytosis of 55% and on fluorescence in situ hybridization testing, del 17p/TP53 mutation in 85% of cells is detected. PET/CT confirms diffuse bone disease involving the axial and appendicular skeleton. His Karnofsky performance status (KPS) is 70%. He is widowed and lives alone but has 2 adult children who currently live out of state. This abstract will discuss how assessments of fitness/frailty may be used to develop personalized care tailored to the unique needs of older frail adults with multiple myeloma.

RevDate: 2020-08-30

Vitanza NA, Khalatbari H, Ermoian R, et al (2020)

Molecularly Targeted Treatments for NF1-Mutant Diffuse Intrinsic Pontine Glioma.

The journal of applied laboratory medicine pii:5899256 [Epub ahead of print].

RevDate: 2020-08-30

Necchi A, Madison R, Pal SK, et al (2020)

Comprehensive Genomic Profiling of Upper-tract and Bladder Urothelial Carcinoma.

European urology focus pii:S2405-4569(20)30214-5 [Epub ahead of print].

BACKGROUND: Characterization of the different genomic alterations (GAs) in urothelial carcinoma (UC), by site of origin, may identify contrasting therapeutic opportunities and inform distinct putative pathogenetic mechanisms.

OBJECTIVE: To describe the genomic landscape of UC based on the anatomic site of the primary tumor.

In total, 479 upper tract UC (UTUC) and 1984 bladder UC (BUC) patients underwent comprehensive genomic profiling (CGP) to evaluate all classes of GAs, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Targetable GAs and signatures were assessed according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT).

INTERVENTION: Hybrid-capture-based CGP.

Descriptive analyses and differences between anatomic subgroups were reported.

RESULTS AND LIMITATIONS: In total, 39% of patients with UC harbored one or more tier 1-2 GAs, suggesting potential benefit from approved or investigational therapies. UTUC cases were enriched in FGFR3 short variant (SV) GA (20% vs 13%) and HRAS SV GA (7.3% vs 3%), the latter attributed specifically to enrichment in renal pelvis UC (9.5%) versus ureteral UC (1.8%, p=0.002). RB1 GAs were more frequent in BUC than in UTUC (21% vs 7.8% p<0.001). Non-FGFR3 kinase fusions were observed in 1% of patients, including BRAF/RAF1 fusions in 0.5%. BRAF mutations/fusions were observed in 2% of cases and were mutually exclusive with FGFR3 GA (p=0.002). There were no differences of TMB high/MSI high for primary tumor and metastatic sites, but UTUC was enriched for MSI high (3.4%) relative to BUC (0.8%, p<0.001).

CONCLUSIONS: Differences in the genomic landscapes of UTUC and BUC were modest; however, patients with UTUC were enriched for FGFR3 and HRAS SV relative to BUC. Further investigation on UC, stratified by the site of origin, is warranted. In addition, these results suggest an opportunity for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC.

PATIENT SUMMARY: Genomic profiling of advanced urothelial carcinoma can inform several therapeutic opportunities for patients, particularly those with upper tract urothelial carcinoma, an infrequent and generally aggressive tumor entity with nonoverlapping clinical features compared with its bladder counterpart, which is often treated based on the data extrapolated from bladder cancer.

RevDate: 2020-08-30

Shehata MN, Rahbar H, Flanagan MR, et al (2020)

Risk for Malignant Upgrade After Breast Core Needle Biopsy Diagnosis of Lobular Neoplasia: A Systematic Review and Meta-Analysis.

Journal of the American College of Radiology : JACR pii:S1546-1440(20)30841-3 [Epub ahead of print].

PURPOSE: Lobular neoplasia (LN) detected on breast core needle biopsy is frequently managed with surgical excision because of concern for undersampled malignancy. The authors performed a systematic review and meta-analysis to estimate the risk for upgrade to malignancy in the setting of imaging-concordant, classic LN diagnosed on core biopsy.

METHODS: PubMed and Embase were searched for original articles published from 1998 to 2020 reporting rates of upgrade to malignancy for classic LN, including atypical lobular hyperplasia (ALH) and classic lobular carcinoma in situ (LCIS). Two reviewers extracted study data and assessed the following quality criteria: exclusion of variant LCIS, exclusion of imaging-discordant lesions, and outcome reporting for ≥70% of lesions. For studies meeting all criteria, pooled risks for upgrade to any malignancy (invasive carcinoma or ductal carcinoma in situ) and invasive malignancy for all LN, ALH, and LCIS were estimated using random-effects models.

RESULTS: For 65 full-text articles included in the review, the risk for upgrade to any malignancy ranged from 0% to 45%. Among the 16 studies that met all quality criteria for the meta-analysis, pooled risks for upgrade to any malignancy were 3.1% (95% confidence interval [CI], 1.8%-5.2%) for all LN, 2.3% (95% CI, 1.6%-3.9%) for ALH, and 5.8% (95% CI, 2.9%-11.3%) for LCIS. Risks for upgrade to invasive malignancy were 1.3% (95% CI, 0.7%-2.4%) for all LN, 0.4% (95% CI, 0.0%-4.2%) for ALH, and 3.5% (95% CI, 2.0%-5.9%) for LCIS.

CONCLUSIONS: The risk for upgrade to malignancy for LN found on breast biopsy is low. Imaging surveillance can likely be offered as an alternative to surgical management for LN, particularly for ALH.

RevDate: 2020-08-30

Gauthier J, DG Maloney (2020)

Allogeneic Transplantation and Chimeric Antigen Receptor-Engineered T-Cell Therapy for Relapsed or Refractory Mantle Cell Lymphoma.

Hematology/oncology clinics of North America, 34(5):957-970.

Mantle cell lymphoma (MCL) accounts for fewer than 10% of non-Hodgkin lymphoma. There is a high initial response rate to chemotherapy and rituximab, but a nearly universal risk of relapse. Allogeneic hematopoietic cell transplantation (allo-HCT) provides one of the only curative options. We review the role of allo-HCT for relapsed and refractory (R/R) MCL and discuss a novel promising approach using autologous chimeric antigen receptor-engineered T (CAR-T) cells. We review preliminary safety and efficacy data of 2 pivotal trials investigating the use of CD19-targeted CAR-T cells for R/R MCL after ibrutinib failure and discuss potential timing of these approaches.

RevDate: 2020-08-24

Di Credico G, Polesel J, Dal Maso L, et al (2020)

Alcohol drinking and head and neck cancer risk: the joint effect of intensity and duration.

British journal of cancer pii:10.1038/s41416-020-01031-z [Epub ahead of print].

BACKGROUND: Alcohol is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk.

METHODS: Data from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 controls, 4085 oral cavity, 3359 oropharyngeal, 983 hypopharyngeal and 3340 laryngeal cancers). The dose-response relationship between the risk and the joint exposure to drinking intensity and duration was investigated through bivariate regression spline models, adjusting for potential confounders, including tobacco smoking.

RESULTS: For all subsites, cancer risk steeply increased with increasing drinks/day, with no appreciable threshold effect at lower intensities. For each intensity level, the risk of oral cavity, hypopharyngeal and laryngeal cancers did not vary according to years of drinking, suggesting no effect of duration. For oropharyngeal cancer, the risk increased with durations up to 28 years, flattening thereafter. The risk peaked at the higher levels of intensity and duration for all subsites (odds ratio = 7.95 for oral cavity, 12.86 for oropharynx, 24.96 for hypopharynx and 6.60 for larynx).

CONCLUSIONS: Present results further encourage the reduction of alcohol intensity to mitigate HNC risk.

RevDate: 2020-08-29

Oda SK, Anderson KG, Ravikumar P, et al (2020)

A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy.

The Journal of experimental medicine, 217(12):.

Adoptive T cell therapy (ACT) with genetically modified T cells has shown impressive results against some hematologic cancers, but efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs). For example, Fas ligand is commonly overexpressed in TMEs and induces apoptosis in tumor-infiltrating, Fas receptor-positive lymphocytes. We engineered immunomodulatory fusion proteins (IFPs) to enhance ACT efficacy, combining an inhibitory receptor ectodomain with a costimulatory endodomain to convert negative into positive signals. We developed a Fas-4-1BB IFP that replaces the Fas intracellular tail with costimulatory 4-1BB. Fas-4-1BB IFP-engineered murine T cells exhibited increased pro-survival signaling, proliferation, antitumor function, and altered metabolism in vitro. In vivo, Fas-4-1BB ACT eradicated leukemia and significantly improved survival in the aggressive KPC pancreatic cancer model. Fas-4-1BB IFP expression also enhanced primary human T cell function in vitro. Thus, Fas-4-1BB IFP expression is a novel strategy to improve multiple T cell functions and enhance ACT against solid tumors and hematologic malignancies.

RevDate: 2020-08-29

Marsh RA, Leiding JW, Logan BR, et al (2020)

Correction: Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT.

The original version of this article unfortunately contained the missing author, Caridad Martinez. The authors would like to correct the list. We apologize for any inconvenience that this may have caused. The correct author list is shown above.

RevDate: 2020-08-29

He X, Yin X, Wu J, et al (2020)

Visualization of human T lymphocyte-mediated eradication of cancer cells in vivo.

Proceedings of the National Academy of Sciences of the United States of America pii:2009092117 [Epub ahead of print].

Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.

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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.

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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

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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).

Timelines

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

Biographies

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 )