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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 05 Jul 2020 at 01:33 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: 2020-07-03

Carlson J, DeWitt WS, K Harris (2020)

Inferring evolutionary dynamics of mutation rates through the lens of mutation spectrum variation.

Current opinion in genetics & development, 62:50-57 pii:S0959-437X(20)30075-7 [Epub ahead of print].

There are many possible failure points in the transmission of genetic information that can produce heritable germline mutations. Once a mutation has been passed from parents to offspring for several generations, it can be difficult or impossible to identify its root cause; however, sometimes the nature of the ancestral and derived DNA sequences can provide mechanistic clues about a genetic change that happened hundreds or thousands of generations ago. Here, we review evidence that the sequence context 'spectrum' of germline mutagenesis has been evolving surprisingly rapidly over the history of humans and other species. We go on to discuss possible causal factors that might underlie rapid mutation spectrum evolution.

RevDate: 2020-07-03

Radich J (2020)

Molecular testing of chronic myeloid leukaemia in low resource areas.

British journal of haematology [Epub ahead of print].

Most cancer cases occur in areas of low resources. The diagnosis, treatment and monitoring of cancers is especially challenging in these locations. Unique partnerships exist between non-profit organisations and pharmaceutical companies to provide free drugs to CML patients throughout the world if the diagnosis can be rigorously and unambiguously established. But there lies the rub: How do you perform molecular diagnostics in areas where even electricity is unreliable? Here we describe the evolution of testing patients from low resource areas, which, when merged with a remarkable effort to bring tyrosine kinase inhibitors to patients across the globe, have led to survival outcomes similar to cases in industrialised countries.

RevDate: 2020-07-02

Rust BJ, Kean LS, Colonna L, et al (2020)

Robust Expansion of HIV CAR T Cells Following Antigen Boosting in ART-Suppressed Nonhuman Primates.

Blood pii:461264 [Epub ahead of print].

CAR T cells targeting CD19+ hematologic malignancies have rapidly emerged as a promising, novel therapy. In contrast, results from the few CAR T-cell studies for infectious diseases such as HIV-1 have been less convincing. These challenges are likely due to the low level of antigen present in ART-suppressed patients in contrast to those with hematologic malignancies. Here we tested in our well-established nonhuman primate model of ART-suppressed HIV-1 infection strategies to overcome these limitations and challenges. We first optimized CAR T cell production to maintain central memory subsets, consistent with current clinical paradigms. We hypothesized that additional exogenous antigen might be required in an ART-suppressed setting to aid expansion and persistence of CAR T cells. Thus, we studied four simian/human immunodeficiency virus (SHIV)-infected, ART-suppressed rhesus macaques infused with virus-specific CD4CAR T cells, followed by supplemental infusion of cell-associated HIV-1 envelope (Env). Env boosting led to significant and unprecedented expansion of virus-specific CAR+ T-cells in vivo; following ART treatment interruption, viral rebound was significantly delayed compared to controls (p=0.014). In two animals with declining CAR T cells, we administered rhesusized anti-PD-1 antibody to reverse PD-1-dependent immune exhaustion. Immune checkpoint blockade triggered expansion of exhausted CAR T cells and concordantly lowered viral loads to undetectable levels. These results demonstrate that supplemental cell-associated antigen enables robust expansion of CAR T-cells in an antigen-sparse environment. To our knowledge, this is the first study to show expansion of virus-specific CAR T cells in infected, suppressed hosts, and delay/control of viral recrudescence.

RevDate: 2020-07-02

Chlebowski RT, Aragaki AK, RL Prentice (2020)

Dietary Moderation and Deaths From Breast Cancer.

RevDate: 2020-07-02

Kazahaya K, Prickett KK, Paulson VA, et al (2020)

Targeted Oncogene Therapy Before Surgery in Pediatric Patients With Advanced Invasive Thyroid Cancer at Initial Presentation: Is It Time for a Paradigm Shift?.

JAMA otolaryngology-- head & neck surgery pii:2767782 [Epub ahead of print].

Importance: Initial data suggest the effectiveness of oncogene-specific targeted therapies in inducing tumor regression of diverse cancers in children and adults, with minimal adverse effects.

Observations: In this review, preliminary data suggest that systemic therapy may be effective in inducing tumor regression in pediatric patients with unresectable invasive thyroid cancer. Although most pediatric patients with thyroid cancer initially present with operable disease, some children have extensive disease that poses substantial surgical challenges and exposes them to higher than usual risk of operative complications. Extensive disease includes thyroid cancer that invades the trachea or esophagus or encases vascular or neural structures. Previous efforts to manage extensive thyroid cancer focused on surgery with near-curative intent. With the recent development of oncogene-specific targeted therapies that are effective in inducing tumor regression, with minimal drug-associated adverse effects, there is an opportunity to consider incorporating these agents as neoadjuvant therapy. In patients with morbidly invasive regional metastasis or with hypoxia associated with extensive pulmonary metastasis, neoadjuvant therapy can be incorporated to induce tumor regression before surgery and radioactive iodine therapy. For patients with widely invasive medullary thyroid cancer, in whom the risk of surgical complications is high and the likelihood of surgical remission is low, these agents may replace surgery depending on the response to therapy and long-term tolerance.

Conclusions and Relevance: With oncogene-specific targeted therapy that is associated with substantial tumor regression and low risk of adverse reactions, there appears to be an opportunity to include children with advanced invasive thyroid cancer in clinical trials exploring neoadjuvant targeted oncogene therapy before or instead of surgery.

RevDate: 2020-07-02

Sheshadri A, Alousi A, Bashoura L, et al (2020)

Feasibility and Reliability of Home-based Spirometry Telemonitoring in Allogeneic Hematopoietic Cell Transplant Recipients.

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

RevDate: 2020-07-02

Sun J, Mathias BJ, Sun W, et al (2020)

Is it Wise to Omit Sentinel Node Biopsy in Elderly Patients with Breast Cancer?.

Annals of surgical oncology pii:10.1245/s10434-020-08759-1 [Epub ahead of print].

BACKGROUND: The Society of Surgical Oncology's Choosing Wisely® guidelines recommend against routine sentinel lymph node biopsy (SLNB) in clinically node-negative (cN0), hormone receptor (HR)-positive breast cancer patients aged ≥ 70 years. We examined the effect of SLNB on treatment and outcomes in this population.

MATERIALS AND METHODS: A single-institution retrospective review of consecutive cN0 women ≥ 70 years of age who received SLNB was performed. We collected clinicopathologic characteristics and treatment data. Patients were compared according to SLN status with subset analysis of HR-positive patients. Outcomes were analyzed using the Kaplan-Meier method and univariable analysis, and were compared using log-rank tests.

RESULTS: Of 500 patients, 345 (69%) were SLN-negative. Median age was 74 years (range 70-96). Most tumors were T1 (72%), N0 (69%), invasive ductal (77%), without lymphovascular invasion (88%), estrogen receptor-positive (88%) and progesterone receptor-positive (75%), and human epidermal growth factor receptor 2 (HER2)-negative (88%) treated with lumpectomy (71%). Median number of SLNs obtained was 2 (range 0-12) and median number of positive SLNs was 0 (range 0-8). Characteristics of the HR-positive subset were similar. In both the overall cohort and the HR-positive subset, SLN status significantly affected the use of adjuvant chemotherapy, although no significant effect on recurrence was observed. SLN-negative patients had better overall survival and less distant recurrence (both p < 0.0001). Adjuvant hormone therapy significantly improved overall survival.

CONCLUSIONS: SLNB can be safely omitted in elderly patients with T1, HR-positive, invasive ductal carcinoma tumors, but may still provide important information affecting treatment. Patients who are candidates for adjuvant systemic chemotherapy should still be considered for SLNB.

RevDate: 2020-07-01

Lurain K, Uldrick TS, Ramaswami R, et al (2020)

Treatment of HIV-associated Primary CNS Lymphoma with Antiretroviral Therapy, Rituximab, and High-Dose Methotrexate.

Blood pii:461242 [Epub ahead of print].

RevDate: 2020-07-01

Blériot C, Li S, Kairi MFBM, et al (2020)

Kupffer Cell Characterization by Mass Cytometry.

Methods in molecular biology (Clifton, N.J.), 2164:87-99.

Kupffer cells are the liver-resident macrophages lining the sinusoids and are mostly known for their role of scavengers, as crucial keepers of organ integrity. But due to the many fundamental functions of the liver notably linked to detoxication, metabolism, protein synthesis, or immunology, Kupffer cells are exposed to a dynamic environment and constantly adapt themselves by modulating their gene and protein expressions. In this context, the characterization of these cells at steady-state and upon challenges may be limited by the classical microscopy or flow cytometry which allow for the use of only few selected markers. On the other end, transcriptomic approach, although being very powerful, can be costly and time-consuming. So mass cytometry offers a good compromise, allowing for the monitoring of a representative set of markers (up to 40) in a simple experiment. Herein, we describe a straightforward experimental and analysis workflow for Kupffer cell characterization by mass cytometry.

RevDate: 2020-06-30

Wartko PD, Weiss NS, Enquobahrie DA, et al (2020)

Maternal Gestational Weight Gain in Relation to Antidepressant Continuation in Pregnancy.

American journal of perinatology [Epub ahead of print].

OBJECTIVE: Both excessive and inadequate gestational weight gain (GWG) are associated with adverse health outcomes for the woman and her child. Antidepressant use in pregnancy could affect GWG, based on evidence in nonpregnant women that some antidepressants may cause weight gain and others weight loss. Previous studies of antidepressant use and GWG were small with limited ability to account for confounding, including by maternal mental health status and severity. We assessed the association of antidepressant continuation in pregnancy with GWG among women using antidepressants before pregnancy.

STUDY DESIGN: Our retrospective cohort study included singleton livebirths from 2001 to 2014 within Kaiser Permanente Washington, an integrated health care system. Data were obtained from electronic health records and linked Washington State birth records. Among women with ≥1 antidepressant fill within 6 months before pregnancy, women who filled an antidepressant during pregnancy were considered "continuers;" women without a fill were "discontinuers." We calculated mean differences in GWG and relative risks (RR) of inadequate and excessive weight gain based on Institute of Medicine guidelines. Using inverse probability of treatment weighting with generalized estimating equations, we addressed differences in maternal characteristics, including mental health conditions.

RESULTS: Among the 2,887 births, 1,689 (59%) were to women who continued antidepressants in pregnancy and 1,198 (42%) were to discontinuers. After accounting for confounding, continuers had similar weight gain to those who discontinued (mean difference: 1.3 lbs, 95% confidence interval [CI]: -0.1 to 2.8 lbs) and similar risks of inadequate and excessive GWG (RR: 0.95, 95% CI: 0.80-1.14 and RR: 1.06, 95% CI: 0.98-1.14, respectively). Findings were comparable for specific antidepressants and trimesters of exposure.

CONCLUSION: We did not find evidence that continuation of antidepressants in pregnancy led to differences in GWG.

KEY POINTS: · Antidepressant use is associated with weight change in nonpregnant populations.. · Prior evidence on whether antidepressant use in pregnancy affects gestational weight gain is sparse.. · We accounted for confounding by characteristics such as mental health conditions and their severity.. · We found no association between pregnancy antidepressant continuation and gestational weight gain..

RevDate: 2020-06-30

Mitchell CM, Reed SD, Diem S, et al (2020)

To the Editor.

Menopause (New York, N.Y.), 27(7):836-837.

RevDate: 2020-06-30

Kornblit B, Storer BE, Andersen NS, et al (2020)

Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen mismatched donors.

Blood pii:461231 [Epub ahead of print].

This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine and mycophenolate mofetil for GVHD prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched Hematopoietic cell transplantation (HCT). Eligible patients had hematological malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2-3 Gy total body irradiation. GVHD prophylaxis was with cyclosporine, mycophenolate mofetil and sirolimus. The primary objective was to determine whether the cumulative incidence of grade II-IV acute GVHD could be reduced to less than 70%, in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. This study was registered with ClinicalTrials.gov, number NCT01251575. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018 of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94). The cumulative incidence of grade 2-4 acute GVHD at day 100 was 36% (95% CI, 25-46) meeting the primary endpoint. The cumulative incidences of nonrelapse morality, relapse/progression and overall survival were 18% (95% CI, 9-27), 30% (IQR, 19-40) and 62% (95% CI, 50-73%) after 4 years. In conclusion the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into a superior overall survival compared to historical results.

RevDate: 2020-06-30

Baldassari AR, Sitlani CM, Highland HM, et al (2020)

Multi-ethnic Genome-wide Association Study of Decomposed Cardioelectric Phenotypes Illustrates Strategies to Identify and Characterize Evidence of Shared Genetic Effects for Complex Traits.

Circulation. Genomic and precision medicine [Epub ahead of print].

Background - We examined how expanding electrocardiographic (ECG) trait genome-wide association studies (GWAS) to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci. Methods - We decomposed 10-second, 12-lead ECGs from 34,668 multiethnic participants (15% African American; 30% Hispanic/Latino) into six contiguous, physiologically-distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and two composite, conventional (PR interval and QT interval) interval-scale traits and conducted multivariable-adjusted, trait-specific univariate GWAS using 1000-G imputed SNPs. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the six continuous ECG traits using the combined phenotype adaptive sum of powered scores test (aSPU). Results - We identified six novel (CD36, PITX2, EMB, ZNF592, YPEL2, and BC043580) and 87 known loci (aSPU p-value<5E-9). Lead SNP rs3211938 at CD36 was common in African Americans (minor allele frequency=10%), near-monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other five novel loci were observed when evaluating the contiguous, but not the composite ECG traits. Combined phenotype testing did not identify novel ECG loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci Conclusions - Despite including one-third as many participants as published ECG trait GWAS, our study identified six novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing GWAS.

RevDate: 2020-06-30

Balkus JE, Hajat A, Rowhani-Rahbar A, et al (2020)

In pursuit of consequential epidemiology: where is diversity and inclusion?.

American journal of epidemiology pii:5864941 [Epub ahead of print].

RevDate: 2020-06-29

Yi JC, Sullivan B, Leisenring WM, et al (2020)

Who enrolls in an online cancer survivorship program? Reach of the INSPIRE randomized controlled trial for hematopoietic cell transplantation survivors.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30371-2 [Epub ahead of print].

BACKGROUND: The internet can be a valuable tool in delivering survivorship care to hematopoietic cell transplantation (HCT) cancer survivors. We describe the reach of INSPIRE, an internet and social media-based randomized controlled trial, to address healthcare and psychosocial needs of HCT survivors.

MATERIALS AND METHODS: All survivors 2-10 years after HCT for hematologic malignancy or myelodysplasia from six transplant centers in the US were approached by mail and follow-up calls. Eligible participants had access to the internet, an email address, and did not have active disease in the past two years. We used logistic regression to determine characteristics of eligible survivors who were more or less likely to enroll.

RESULTS: Of 2578 eligible HCT survivors, 1065 (41%) enrolled in the study. Mean age of enrollees was 56.3 (SD=12.6; age range 19 to 89 years), 52% were male, and 94% were White. Survivors less likely to enroll included those who were male, age younger than 40, and who received an autologous transplant (all P<.001). Compared with survivors of white race, African Americans were less likely to enroll (P<.001) while Native Americans/Alaska Natives were more likely to join the study (P=.03).

CONCLUSIONS: Reach of the INSPIRE program was broad, including to survivors who traditionally have less access to resources such as Native Americans/Alaskan Natives and rural residents. Strategies are still needed to improve the enrollment of online studies of survivorship resources for males, young adults, African American and autologous HCT survivors, since their use may improve outcomes.

RevDate: 2020-06-29

Scaradavou A, Avecilla ST, Tonon J, et al (2020)

Guidelines for Cord Blood Unit Thaw and Infusion.

RevDate: 2020-06-29

Karabulut AC, Cirz RT, Taylor AF, et al (2020)

Small-molecule sensitization of RecBCD helicase-nuclease to a Chi hotspot-activated state.

Nucleic acids research pii:5864707 [Epub ahead of print].

Coordinating multiple activities of complex enzymes is critical for life, including transcribing, replicating and repairing DNA. Bacterial RecBCD helicase-nuclease must coordinate DNA unwinding and cutting to repair broken DNA. Starting at a DNA end, RecBCD unwinds DNA with its fast RecD helicase on the 5'-ended strand and its slower RecB helicase on the 3'-ended strand. At Chi hotspots (5' GCTGGTGG 3'), RecB's nuclease cuts the 3'-ended strand and loads RecA strand-exchange protein onto it. We report that a small molecule NSAC1003, a sulfanyltriazolobenzimidazole, mimics Chi sites by sensitizing RecBCD to cut DNA at a Chi-independent position a certain percent of the DNA substrate's length. This percent decreases with increasing NSAC1003 concentration. Our data indicate that NSAC1003 slows RecB relative to RecD and sensitizes it to cut DNA when the leading helicase RecD stops at the DNA end. Two previously described RecBCD mutants altered in the RecB ATP-binding site also have this property, but uninhibited wild-type RecBCD lacks it. ATP and NSAC1003 are competitive; computation docks NSAC1003 into RecB's ATP-binding site, suggesting NSAC1003 acts directly on RecB. NSAC1003 will help elucidate molecular mechanisms of RecBCD-Chi regulation and DNA repair. Similar studies could help elucidate other DNA enzymes with activities coordinated at chromosomal sites.

RevDate: 2020-06-30

Klek S, Heald B, Milinovich A, et al (2020)

Genetic Counseling and Germline Testing in the Era of Tumor Sequencing: A Cohort Study.

JNCI cancer spectrum, 4(3):pkaa018.

Background: The clinical impact of addressing potential germline alterations from tumor-only next-generation sequencing (NGS) is not well characterized. Current guidelines for cancer genetic testing may miss clinically actionable germline changes, which may have important implications for cancer screening, treatment, and prevention. We examined whether increasing involvement of the clinical genetics service during somatic tumor-only NGS review at Molecular Tumor Board (MTB) increases the detection of germline findings.

Methods: In a retrospective evaluation of patients who underwent tumor-only NGS and were reviewed at MTB, we quantified genetic counseling (GC) referrals as well as germline testing uptake and results across three cohorts: before (C1) and after (C2) the addition of tumor-only NGS review and after (C3) instituting a formal process to coordinate NGS-based genetics referrals to preexisting oncology appointments. All statistical tests were two-sided.

Results: From 2013 to 2017, 907 tumor-only NGS reports were reviewed at MTB (nC1 = 281, nC2 = 493, nC3 = 133); gastrointestinal (22.5%), lung (19.7%), genitourinary (14.8%), and breast (14.1%) were the most common index cancers. GC visits due to MTB increased with each successive cohort (C1 = 1.1%, C2 = 6.9%, C3 = 13.5%; P for trend [Ptrend] < .001), as did germline testing (C1 = 0.7%, C2 = 3.2%, C3 = 11.3%; Ptrend < .001). Diagnosis of germline pathogenic variants increased with each successive cohort (C1 = 1.4%, C2 = 2.0%, C3 = 7.5%; Ptrend = .003) and with germline pathogenic variants found by MTB review (C1 = 0.4%, C2 = 0.4%, C3 = 2.3%; Ptrend = .12).

Conclusions: Both review of tumor-only NGS by genetics and the institution of a process coordinating GC with oncology appointments increased the discovery of germline pathogenic variants from tumor-only NGS testing. Furthermore, this process identified germline pathogenic variant carriers who would not have otherwise met standard criteria for germline testing.

RevDate: 2020-06-29

Soria JC, DeBraud F, Bahleda R, et al (2015)

Corrections to "Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors".

Annals of oncology : official journal of the European Society for Medical Oncology, 26(2):445.

RevDate: 2020-06-27

Peterson LM, Kurland BF, Yan F, et al (2020)

18F-Fluoroestradiol (18F-FES)-PET imaging in a Phase II trial of vorinostat to restore endocrine sensitivity in ER+/HER2- metastatic breast cancer.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine pii:jnumed.120.244459 [Epub ahead of print].

RATIONALE: Histone deacetylase inhibitors (HDACi) may overcome endocrine resistance in estrogen receptor positive (ER+) metastatic breast cancer. We tested whether 18F-Fluoroestradiol (18F-FES)-PET imaging would elucidate pharmacodynamics of combination HDACi and endocrine therapy. Methods: Patients with ER+/HER2- metastatic breast cancer with prior clinical benefit from endocrine therapy but later progression on aromatase inhibitor (AI) therapy were given vorinostat (400mg daily) sequentially or simultaneously with AI. 18F-FES PET and 18F-Fluorodeoxyglucose (18F-FDG) PET scans were performed at baseline, week 2, and week 8. Results: Eight patients were treated sequentially, then 15 simultaneously. Eight patients had stable disease at week 8 and six of these eight patients had >6 months of stable disease. Higher baseline 18F-FES uptake was associated with longer progression-free survival (PFS). 18F-FES uptake did not systematically increase with vorinostat exposure, indicating no change in regional ER estradiol binding, and 18F-FDG uptake did not show significant decrease, as would have been expected with tumor regression. Conclusion: Simultaneous HDACi and AI dosing in patients with cancers resistant to AI alone showed clinical benefit (6+ months without progression) in 4 of 10 evaluable patients. Higher 18F-FES-PET uptake identified patients likely to benefit from combination therapy, but vorinostat did not change ER expression at the level of detection of 18F-FES-PET.

RevDate: 2020-06-27

Wurmser M, Chaverot N, Madani R, et al (2020)

SIX1 and SIX4 homeoproteins regulate PAX7+ progenitor cell properties during fetal epaxial myogenesis.

Development (Cambridge, England) pii:dev.185975 [Epub ahead of print].

Pax7 expression marks stem cells in developing skeletal muscles and adult satellite cells during homeostasis and muscle regeneration. The genetic determinants that control the entrance into the myogenic program and the appearance of PAX7+ cells during embryogenesis are poorly understood. SIX homeoproteins are encoded by the Sine oculis homeobox related Six1-Six6 genes in vertebrates. Six1, Six2, Six4 and Six5 are expressed in the muscle lineage. Here we tested the hypothesis that Six1 and Six4 could participate in the genesis of myogenic stem cells. We show that fewer PAX7+ cells occupy a satellite cell position between the myofiber and its associated basal lamina in Six1 and Six4 (s1s4KO) at E18. However, PAX7+ cells are detected in remaining muscle masses present in the epaxial region of the double mutant embryos and are able to divide and contribute to muscle growth. To further characterize the properties of s1s4KO PAX7+ cells, we analyzed their transcriptome and tested their properties after transplantation in adult regenerating tibialis anterior (TA) muscle. Mutant stem cells form hypotrophic myofibers that are not innervated but retain the ability to self-renew.

RevDate: 2020-06-26

Holstein SA, Howard A, Avigan D, et al (2020)

Summary of the 2019 BMT CTN Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30366-9 [Epub ahead of print].

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup has organized an annual workshop focused on minimal residual disease (MRD) testing and immune profiling (IP) in multiple myeloma since 2016. In 2019, the workshop took place as an American Society of Hematology (ASH) Friday Scientific Workshop entitled "Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma". This workshop focused on four main topics: the molecular and immunological evolution of plasma cell disorders, the development of new laboratory- and imaging-based MRD assessment approaches, chimeric antigen receptor T-cell therapy research, and the statistical and regulatory issues associated with novel clinical endpoints. In this report, we provide a summary of the workshop and discuss future directions.

RevDate: 2020-06-26

Lévy Y, Lacabaratz C, Ellefsen-Lavoie K, et al (2020)

Optimal priming of poxvirus vector (NYVAC)-based HIV vaccine regimens for T cell responses requires three DNA injections. Results of the randomized multicentre EV03/ANRS VAC20 Phase I/II Trial.

PLoS pathogens, 16(6):e1008522 pii:PPATHOGENS-D-19-01950.

DNA vectors have been widely used as a priming of poxvirus vaccine in prime/boost regimens. Whether the number of DNA impacts qualitatively or quantitatively the immune response is not fully explored. With the aim to reinforce T-cell responses by optimizing the prime-boost regimen, the multicentric EV03/ANRS VAC20 phase I/II trial, randomized 147 HIV-negative volunteers to either 3xDNA plus 1xNYVAC (weeks 0, 4, 8 plus 24; n = 74) or to 2xDNA plus 2xNYVAC (weeks 0, 4 plus 20, 24; n = 73) groups. T-cell responses (IFN-γ ELISPOT) to at least one peptide pool were higher in the 3xDNA than the 2xDNA groups (91% and 80% of vaccinees) (P = 0.049). In the 3xDNA arm, 26 (37%) recipients developed a broader T-cell response (Env plus at least to one of the Gag, Pol, Nef pools) than in the 2xDNA (15; 22%) arms (primary endpoint; P = 0.047) with a higher magnitude against Env (at week 26) (P<0.001). In both groups, vaccine regimens induced HIV-specific polyfunctional CD4 and CD8 T cells and the production of Th1, Th2 and Th17/IL-21 cytokines. Antibody responses were also elicited in up to 81% of vaccines. A higher percentage of IgG responders was noted in the 2xDNA arm compared to the 3xDNA arm, while the 3xDNA group tended to elicit a higher magnitude of IgG3 response against specific Env antigens. We show here that the modulation of the prime strategy, without modifying the route or the dose of administration, or the combination of vectors, may influence the quality of the responses.

RevDate: 2020-06-26

Barnabas RV, van Heerden A, McConnell M, et al (2020)

Lottery incentives have short-term impact on ART initiation among men: results from a randomized pilot study.

Journal of the International AIDS Society, 23 Suppl 2:e25519.

INTRODUCTION: Among people living with HIV in South Africa, viral suppression is lower among men than women. The study aim was to test the impact of lottery incentives, which reward positive health choice (e.g. antiretroviral therapy (ART) linkage) with a chance to win a prize, on strengthening the HIV care continuum including ART initiation and viral suppression for men.

METHODS: We conducted a randomized, prospective trial of lottery incentives in the context of HIV testing and linkage to ART in rural KwaZulu-Natal, South Africa. Men living with HIV were randomly allocated to: lottery incentives and motivational text messages or motivational text messages only. Lottery prize eligibility was conditional on clinic registration, ART initiation, or viral suppression by one, three and six months respectively. After completing each continuum step, participants in the lottery group were notified whether they had won and were encouraged to continue in care. Lottery prizes were either a mobile phone, data or a gift card (valued at R1000/$100). Kaplan-Meier curves were plotted to determine time to ART initiation by study group. The primary outcome was viral suppression at six months.

RESULTS: Between November 2017 and December 2018, we tested 740 men for HIV and enrolled 131 HIV-positive men who reported not being on ART. At baseline, 100 (76%) participants were 30 years and older, 95 (73%) were unemployed and the median CD4 count was 472 cells/μL. At study exit, 84% (110/131) of participants had visited a clinic and 62% (81/131) were virally suppressed. Compared to motivational text messages, lottery incentives decreased the median time to ART initiation from 126 to 66 days (p = 0.0043, age-adjusted Cox regression) among all participants, and, from 134 days to 20 days (p = 0.0077) among participants who were not virally suppressed at baseline. Lottery incentives had an inconclusive effect on clinic registration (RR = 1.21, 95% CI: 0.83 to 1.76) and on viral suppression at six months (RR = 1.13, 95% CI: 0.73 to 1.75) compared to motivational text messages.

CONCLUSIONS: Conditional lottery incentives shortened the time to ART initiation among South African men. Behavioural economics strategies strengthen linkage to ART, but the study power was limited to see an impact on viral suppression.

CLINICAL TRIAL NUMBER: NCT03808194.

RevDate: 2020-06-26

Yin H, Hardikar S, Lindström S, et al (2020)

Telomere maintenance variants and survival after colorectal cancer: Smoking- and sex-specific associations.

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-19-1507 [Epub ahead of print].

BACKGROUND: Telomeres play an important role in colorectal cancer (CRC) prognosis. Variation in telomere maintenance genes may be associated with survival after CRC diagnosis but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors such as smoking and sex also remain to be investigated.

METHODS: We conducted gene-wide analyses of CRC prognosis in 4,896 invasive CRC cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO).1871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and CRC-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P-values were adjusted using Bonferroni correction.

RESULTS: The association between minor allele of rs7200950 (ACD) with CRC-specific survival varied significantly by smoking pack-years (corrected p-value=0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or CRC-specific survival in women but not in men.

CONCLUSIONS: Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose-response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted.

IMPACT: Our study found a gene-smoking and gene-sex interaction on survival after CRC diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on CRC prognosis.

RevDate: 2020-06-26

Lynch RC, AK Gopal (2020)

Phosphatidylinositol-3-Kinase Inhibition in Follicular Lymphoma.

Hematology/oncology clinics of North America, 34(4):727-741.

Chemoimmunotherapy is the standard frontline treatment for symptomatic or high tumor burden follicular lymphoma. Better understanding of the molecular mechanisms of lymphomagenesis has led to the development of drugs targeting these pathways. The phosphatidylinositol-3-kinase pathway is an important signaling pathway in B-cell lymphomas. Three drugs in this class have received FDA approval. We describe the efficacy and toxicities of phosphatidylinositol-3-kinase inhibitors. Response rates in highly refractory disease are high, demonstrate few long-term remissions, and have high long-term toxicity. Early data on dosing and combination strategies are promising and may change how we use these agents in the coming years.

RevDate: 2020-06-25

Niu B, Zeng X, Phan TA, et al (2020)

Mathematical modeling of PDGF-driven glioma reveals the dynamics of immune cells infiltrating into tumors.

Neoplasia (New York, N.Y.), 22(9):323-332 pii:S1476-5586(20)30122-6 [Epub ahead of print].

BACKGROUND: Tumor-infiltrated immune cells compose a significant component of many cancers. They have been observed to have contradictory impacts on tumors. Although the primary reasons for these observations remain elusive, it is important to understand how immune cells infiltrating into tumors is regulated. Recently our group conducted a series of experimental studies, which showed that muIDH1 gliomas have a significant global reduction of immune cells and suggested that the longer survival time of mice with CIMP gliomas may be due to the IDH mutation and its effect on reducing of the tumor-infiltrated immune cells. However, to comprehend how IDH1 mutants regulate infiltration of immune cells into gliomas and how they affect the aggressiveness of gliomas, it is necessary to integrate our experimental data into a dynamical system to acquire a much deeper understanding of subtle regulation of immune cell infiltration.

METHODS: The method is integration of mathematical modeling and experiments. According to mass conservation laws and assumption that immune cells migrate into the tumor site along a chemotactic gradient field, a mathematical model is formulated. Parameters are estimated from our experiments. Numerical methods are developed to solve the problem. Numerical predictions are compared with experimental results.

RESULTS: Our analysis shows that the net rate of increase of immune cells infiltrated into the tumor is approximately proportional to the 4/5 power of the chemoattractant production rate, and it is an increasing function of time while the percentage of immune cells infiltrated into the tumor is a decreasing function of time. Our model predicts that wtIDH1 mice will survive longer if the immune cells are blocked by reducing chemotactic coefficient. For more aggressive gliomas, our model shows that there is little difference in their survivals between wtIDH1 and muIDH1 tumors, and the percentage of immune cells infiltrated into the tumor is much lower. These predictions are verified by our experimental results. In addition, wtIDH1 and muIDH1 can be quantitatively distinguished by their chemoattractant production rates, and the chemotactic coefficient determines possibilities of immune cells migration along chemoattractant gradient fields.

CONCLUSIONS: The chemoattractant gradient field produced by tumor cells may facilitate immune cells migration to the tumor cite. The chemoattractant production rate may be utilized to classify wtIDH1 and muIDH1 tumors. The dynamics of immune cells infiltrating into tumors is largely determined by tumor cell chemoattractant production rate and chemotactic coefficient.

RevDate: 2020-06-25

Bullock A, Rowan CG, Oestreicher N, et al (2020)

Real-World Assessment of Health Care Costs for Patients with Metastatic Pancreatic Cancer Following Initiation of First-Line Chemotherapy.

Journal of managed care & specialty pharmacy, 26(7):872-878.

BACKGROUND: Management of metastatic pancreatic ductal adenocarcinoma (mPDA) places a significant financial burden on the U.S. health care system because of such factors as treatment with multidrug chemotherapy regimens, management of chemotherapy-related adverse events, and disease- or treatment-related hospitalizations. Depending on functional status, first-line chemotherapy regimens that are guideline recommended include nab-paclitaxel with gemcitabine (AG) and FOLFIRINOX (FFX), the combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin. However, few previous studies have examined overall health care costs associated with mPDA management.

OBJECTIVE: To describe health care costs following initiation of first-line treatment with AG or FFX among patients with mPDA.

METHODS: Retrospective cohorts of first-line AG and FFX initiators were constructed from the MarketScan database (2014-2017). The index date was the date of first-line AG or FFX initiation. Included patients had insurance enrollment for 6 months before the index date. Total cumulative health care costs and costs from outpatient services, inpatient admissions, emergency department visits, chemotherapy administrations, and pharmacy dispensing were assessed within 12 months after the index date (i.e., 0-1, 0-2, …, 0-12 months). Patient-level cost data began accruing from the first paid claim and continued accruing until the censoring date.

RESULTS: A total of 2,199 patients with mPDA initiated first-line AG (n = 1,352) or FFX (n = 847). Compared with AG initiators, FFX patients were younger (mean age 59 vs. 63 years) and had better baseline health status, with fewer having diabetes (43% vs. 57%) or coronary artery disease (12% vs. 22%). Median follow-up was 5.4 and 7.2 months for AG and FFX, respectively. Median first-line treatment duration was 2.1 months with AG and 2.3 months with FFX. Six months following first-line treatment initiation, total cumulative health care costs (median) were $85,714 (95% CI = $79,683-$91,788) and $114,116 (95% CI = $105,816-$119,591) for AG and FFX initiators, respectively. Outpatient services contributed the largest fractional cost for both groups.

CONCLUSIONS: Total health care costs for patients with mPDA who initiated FFX or AG are driven mostly by outpatient rather than inpatient costs. Further research, using comparative methodology, is warranted to fully understand cost drivers and whether higher costs for FFX patients relate primarily to use of FFX or higher underlying use of outpatient care among FFX patients.

DISCLOSURES: This study was funded by Halozyme Therapeutics. Oestreicher and Yeganegi were employees of Halozyme Therapeutics at the time of the study and were involved in study design, data interpretation, and the decision to submit the data for publication. Bullock reports advisory board fees from Eisai, Exelixis, Bayer, and Taiho and consulting fees from Halozyme Therapeutics, outside the submitted work. Rowan reports consulting fees from Halozyme Therapeutics, during the conduct of the study. Chiorean reports grants and consulting fees from Celgene and Halozyme Therapeutics; grants from Lilly, Stemline, Ignyta, Roche, Merck, Boehringer-Ingelheim, Bristol Meyer Squibb, Incyte, Macrogenics, Rafael, and AADi; and consulting fees from Astra Zeneca, Array, Eisai, Ipsen, Five Prime Therapeutics, Seattle Genetics, Vicus, and Legend, outside the submitted work.

RevDate: 2020-06-25

Gupta S, Coronado GD, Argenbright K, et al (2020)

Mailed fecal immunochemical test outreach for colorectal cancer screening: Summary of a Centers for Disease Control and Prevention-sponsored summit.

CA: a cancer journal for clinicians [Epub ahead of print].

Uptake of colorectal cancer screening remains suboptimal. Mailed fecal immunochemical testing (FIT) offers promise for increasing screening rates, but optimal strategies for implementation have not been well synthesized. In June 2019, the Centers for Disease Control and Prevention convened a meeting of subject matter experts and stakeholders to answer key questions regarding mailed FIT implementation in the United States. Points of agreement included: 1) primers, such as texts, telephone calls, and printed mailings before mailed FIT, appear to contribute to effectiveness; 2) invitation letters should be brief and easy to read, and the signatory should be tailored based on setting; 3) instructions for FIT completion should be simple and address challenges that may lead to failed laboratory processing, such as notation of collection date; 4) reminders delivered to initial noncompleters should be used to increase the FIT return rate; 5) data infrastructure should identify eligible patients and track each step in the outreach process, from primer delivery through abnormal FIT follow-up; 6) protocols and procedures such as navigation should be in place to promote colonoscopy after abnormal FIT; 7) a high-quality, 1-sample FIT should be used; 8) sustainability requires a program champion and organizational support for the work, including sufficient funding and external policies (such as quality reporting requirements) to drive commitment to program investment; and 9) the cost effectiveness of mailed FIT has been established. Participants concluded that mailed FIT is an effective and efficient strategy with great potential for increasing colorectal cancer screening in diverse health care settings if more widely implemented.

RevDate: 2020-06-25

Leong J, Jang SH, Bishop SK, et al (2020)

"We understand our community": implementation of the Healthy Eating Healthy Aging program among community-based organizations.

Translational behavioral medicine pii:5862439 [Epub ahead of print].

Cardiovascular disease is the second leading cause of death in the USA among Asian Americans and Pacific Islanders (AAPIs) over the age of 65. Healthy Eating Healthy Aging (HEHA), an evidence-based heart health program, can provide culturally appropriate nutrition education to decrease the risk of cardiovascular disease. Community-based organizations (CBOs) are optimal settings to implement community-based programs. However, there is inadequate research on how evidence-based interventions like HEHA are implemented in CBOs. This study examined processes that facilitated the implementation of HEHA among CBOs serving older AAPIs. Twelve representatives from CBOs that implemented the HEHA program were recruited to participate in a semistructured interview. All the participants were CBO directors or senior managers. A semistructured interview guide was created and informed by the Consolidated Framework for Implementation Research (CFIR) to capture how HEHA played into the five domains of CFIR: (a) intervention characteristics, (b) outer setting, (c) inner setting, (d) characteristics of the individuals, and (e) process. Data analysis captured themes under the CFIR domains. All five CFIR domains emerged from the interviews. Under intervention characteristics, three constructs emerged as facilitating the implementation of HEHA: (a) the participant's beliefs around the quality of the HEHA program and its ability to promote healthy eating, (b) HEHA's adaptability to different AAPI subgroups, and (c) perceptions of how successfully HEHA was bundled and assembled. Under outer setting, the participants described the community's need for healthy eating programs and how the HEHA program meets that need. Four constructs emerged under inner setting: (a) the CBO's structural characteristics and social standing in the community; (b) resources dedicated to the implementation and ongoing operations, including funding, training, education, physical space, and time; (c) the culture of the CBO; and (d) the participant's commitment and involvement in marketing, promotion, and implementation of HEHA. Under characteristics of individuals, participants' described their desire to learn the content of HEHA and deliver them successfully. Under process, participants described strategies to engage relevant individuals to facilitate HEHA implementation. The interviews with CBO representatives provided insights into CFIR domain constructs that facilitated the implementation of HEHA. CBOs are key settings for community health education. Understanding processes that lead to the successful implementation of evidence-based interventions among CBOs is critical for accelerating the dissemination and implementation of best practices.

RevDate: 2020-06-25

Summers C, Sheth VS, M Bleakley (2020)

Minor Histocompatibility Antigen-Specific T Cells.

Frontiers in pediatrics, 8:284.

Minor Histocompatibility (H) antigens are major histocompatibility complex (MHC)/Human Leukocyte Antigen (HLA)-bound peptides that differ between allogeneic hematopoietic stem cell transplantation (HCT) recipients and their donors as a result of genetic polymorphisms. Some minor H antigens can be used as therapeutic T cell targets to augment the graft-vs.-leukemia (GVL) effect in order to prevent or manage leukemia relapse after HCT. Graft engineering and post-HCT immunotherapies are being developed to optimize delivery of T cells specific for selected minor H antigens. These strategies have the potential to reduce relapse risk and thereby permit implementation of HCT approaches that are associated with less toxicity and fewer late effects, which is particularly important in the growing and developing pediatric patient. Most minor H antigens are expressed ubiquitously, including on epithelial tissues, and can be recognized by donor T cells following HCT, leading to graft-vs.-host disease (GVHD) as well as GVL. However, those minor H antigens that are expressed predominantly on hematopoietic cells can be targeted for selective GVL. Once full donor hematopoietic chimerism is achieved after HCT, hematopoietic-restricted minor H antigens are present only on residual recipient malignant hematopoietic cells, and these minor H antigens serve as tumor-specific antigens for donor T cells. Minor H antigen-specific T cells that are delivered as part of the donor hematopoietic stem cell graft at the time of HCT contribute to relapse prevention. However, in some cases the minor H antigen-specific T cells delivered with the graft may be quantitatively insufficient or become functionally impaired over time, leading to leukemia relapse. Following HCT, adoptive T cell immunotherapy can be used to treat or prevent relapse by delivering large numbers of donor T cells targeting hematopoietic-restricted minor H antigens. In this review, we discuss minor H antigens as T cell targets for augmenting the GVL effect in engineered HCT grafts and for post-HCT immunotherapy. We will highlight the importance of these developments for pediatric HCT.

RevDate: 2020-06-25

Malherbe DC, Wibmer CK, Nonyane M, et al (2020)

Rapid Induction of Multifunctional Antibodies in Rabbits and Macaques by Clade C HIV-1 CAP257 Envelopes Circulating During Epitope-Specific Neutralization Breadth Development.

Frontiers in immunology, 11:984.

We report here on HIV-1 immunization results in rabbits and macaques co-immunized with clade C gp160 DNA and gp140 trimeric envelope vaccines, a strategy similar to a recent clinical trial that showed improved speed and magnitude of humoral responses. Clade C envelopes were isolated from CAP257, an individual who developed a unique temporal pattern of neutralization breadth development, comprising three separate "Waves" targeting distinct Env epitopes and different HIV clades. We used phylogeny and neutralization criteria to down-select envelope vaccine candidates, and confirmed antigenicity of our antigens by interaction with well-characterized broadly neutralizing monoclonal antibodies. Using these envelopes, we performed rabbit studies that screened for immunogenicity of CAP257 Envs from timepoints preceding peak neutralization breadth in each Wave. Selected CAP257 envelopes from Waves 1 and 2, during the first 2 years of infection that were highly immunogenic in rabbits were then tested in macaques. We found that in rabbits and macaques, co-immunization of DNA, and protein envelope-based vaccines induced maximum binding and neutralizing antibody titers with three immunizations. No further benefit was obtained with additional immunizations. The vaccine strategies recapitulated the Wave-specific epitope targeting observed in the CAP257 participant, and elicited Tier 1A, 1B, and Tier 2 heterologous neutralization. CAP257 envelope immunogens also induced the development of ADCC and TFH responses in macaques, and these responses positively correlated with heterologous neutralization. Together, the results from two animal models in this study have implications for identifying effective vaccine immunogens. We used a multi-step strategy to (1) select an Env donor with well-characterized neutralization breadth development; (2) study Env phylogeny for potential immunogens circulating near peak breadth timepoints during the first 2 years of infection; (3) test down-selected Envs for antigenicity; (4) screen down-selected Envs in an effective vaccine regimen in rabbits; and (5) advance the most immunogenic Envs to NHP studies. The results were an induction of high titers of HIV-1 envelope-specific antibodies with increasing avidity and cross-clade neutralizing antibodies with effector functions that together may improve the potential for protection in a pre-clinical SHIV model.

RevDate: 2020-06-25

Hurwitz LM, Kulac I, Gumuskaya B, et al (2020)

Use of Aspirin and Statins in Relation to Inflammation in Benign Prostate Tissue in the Placebo Arm of the Prostate Cancer Prevention Trial.

Cancer prevention research (Philadelphia, Pa.) pii:1940-6207.CAPR-19-0450 [Epub ahead of print].

Aspirin and statin use may lower risk of advanced/fatal prostate cancer, possibly by reducing intraprostatic inflammation. To test this hypothesis, we investigated the association of aspirin and statin use with the presence and extent of intraprostatic inflammation, and the abundance of specific immune cell types, in benign prostate tissue from a subset of men from the placebo arm of the Prostate Cancer Prevention Trial. Men were classified as aspirin or statin users if they reported use at baseline or during the seven-year trial. Presence and extent of inflammation were assessed, and markers of specific immune cell types (CD4, CD8, FoxP3, CD68, c-KIT) were scored, in slides from end-of-study prostate biopsies taken irrespective of clinical indication, per trial protocol. Logistic regression was used to estimate associations between medication use and inflammation measures, adjusted for potential confounders. Of 357 men included, 61% reported aspirin use and 32% reported statin use. Prevalence and extent of inflammation were not associated with medication use. However, aspirin users were more likely to have low FoxP3, a T regulatory cell marker (OR: 5.60, 95% CI: 1.16-27.07), and statin users were more likely to have low CD68, a macrophage marker (OR: 1.63, 95% CI: 0.81-3.27). If confirmed, these results suggest that these medications may alter the immune milieu of the prostate, which could potentially mediate effects of these medications on advanced/fatal prostate cancer risk.

RevDate: 2020-06-25

Walter RB (2020)

Expanding Use of CD33-Directed Immunotherapy.

RevDate: 2020-06-24

Dianatinasab M, Wesselius A, Salehi-Abargouei A, et al (2020)

Adherence to a Western dietary pattern and risk of bladder cancer: a pooled analysis of 13 Cohort Studies of the Bladder Cancer Epidemiology and Nutritional Determinants (BLEND) International Study.

International journal of cancer [Epub ahead of print].

Little is known about the association of diet with risk of bladder cancer. This might be due to the fact that the majority of studies have focused on single food items, rather than dietary patterns, which may better capture any influence of diet on bladder cancer risk. We aimed to investigate the association between a measure of Western dietary pattern and bladder cancer risk. Associations between adherence to a Western dietary pattern and risk of developing bladder cancer were assessed by pooling data from 13 prospective cohort studies in the "BLadder cancer Epidemiology and Nutritional Determinants" (BLEND) study and applying Cox regression analysis. Dietary data from 580 768 study participants, including 3401 incident cases, and 577 367 non-cases were analysed. A direct and significant association was observed between higher adherence to a Western dietary pattern and risk of bladder cancer (Hazard Ratio (HR) comparing highest with lowest tertile scores: 1.54, 95% confidence interval (CI): 1.37, 1.72; p-trend = 0.001). This association was observed for men (HR comparing highest with lowest tertile scores: 1.72; 95% CI: 1.51, 1.96; p-trend = 0.001), but not women (p-het = 0.001). Results were consistent with HR above 1.00 after stratification on cancer sub-types (non-muscle invasive and muscle invasive bladder cancer). We found evidence that adherence to a Western dietary pattern is associated with an increased risk of bladder cancer for men but not women. This article is protected by copyright. All rights reserved.

RevDate: 2020-06-24

Hurlburt NK, Wan YH, Stuart AB, et al (2020)

Structural basis for potent neutralization of SARS-CoV-2 and role of antibody affinity maturation.

bioRxiv : the preprint server for biology.

SARS-CoV-2 is a betacoronavirus virus responsible for the COVID-19 pandemic. Here, we determined the X-ray crystal structure of a potent neutralizing monoclonal antibody, CV30, isolated from a patient infected with SARS-CoV-2, in complex with the receptor binding domain (RBD). The structure reveals CV30's epitope overlaps with the human ACE2 receptor binding site thus providing the structural basis for its neutralization by preventing ACE2 binding.

RevDate: 2020-06-24

Navarro SL, Levy L, Curtis KR, et al (2020)

Effect of a Flaxseed Lignan Intervention on Circulating Bile Acids in a Placebo-Controlled Randomized, Crossover Trial.

Nutrients, 12(6): pii:nu12061837.

Plant lignans and their microbial metabolites, e.g., enterolactone (ENL), may affect bile acid (BA) metabolism through interaction with hepatic receptors. We evaluated the effects of a flaxseed lignan extract (50 mg/day secoisolariciresinol diglucoside) compared to a placebo for 60 days each on plasma BA concentrations in 46 healthy men and women (20-45 years) using samples from a completed randomized, crossover intervention. Twenty BA species were measured in fasting plasma using LC-MS. ENL was measured in 24-h urines by GC-MS. We tested for (a) effects of the intervention on BA concentrations overall and stratified by ENL excretion; and (b) cross-sectional associations between plasma BA and ENL. We also explored the overlap in bacterial metabolism at the genus level and conducted in vitro anaerobic incubations of stool with lignan substrate to identify genes that are enriched in response to lignan metabolism. There were no intervention effects, overall or stratified by ENL at FDR < 0.05. In the cross-sectional analysis, irrespective of treatment, five secondary BAs were associated with ENL excretion (FDR < 0.05). In vitro analyses showed positive associations between ENL production and bacterial gene expression of the bile acid-inducible gene cluster and hydroxysteroid dehydrogenases. These data suggest overlap in community bacterial metabolism of secondary BA and ENL.

RevDate: 2020-06-23

Balzora S, Issaka RB, Anyane-Yeboa A, et al (2020)

The impact of COVID-19 on colorectal cancer disparities and the way forward.

Gastrointestinal endoscopy pii:S0016-5107(20)34468-0 [Epub ahead of print].

In response to the COVID-19 pandemic, the United States Surgeon General advised all hospitals and ambulatory care centers to delay nonurgent medical procedures and surgeries. This recommendation, echoed by a multigastroenterology society guideline, led to the suspension of colonoscopies for colorectal cancer (CRC) screening and surveillance. Although this temporary suspension was necessary to contain COVID-19 infections, we as gastroenterologists, patient advocates, and CRC researchers have witnessed the downstream impact of COVID-19 and this recommendation on CRC screening, research, and advocacy. These effects are particularly noticeable in medically underserved communities where CRC morbidity and mortality are highest. COVID-19 related pauses in medical care, as well as shifts in resource allocation and workforce deployment, threaten decades worth of work to improve CRC disparities in medically underserved populations. In this perspective, we present the unique challenges COVID-19 poses to health equity in CRC prevention and provide potential solutions as we navigate these uncharted waters.

RevDate: 2020-06-23

Nicholas TP, Haick AK, Workman TW, et al (2020)

The effects of genotype × phenotype interactions on silver nanoparticle toxicity in organotypic cultures of murine tracheal epithelial cells.

Nanotoxicology [Epub ahead of print].

Silver nanoparticles (AgNP) are used in multiple applications but primarily in the manufacturing of antimicrobial products. Previous studies have identified AgNP toxicity in airway epithelial cells, but no in vitro studies to date have used organotypic cultures as a high-content in vitro model of the conducting airway to characterize the effects of interactions between host genetic and acquired factors, or gene × phenotype interactions (G × P), on AgNP toxicity. In the present study, we derived organotypic cultures from primary murine tracheal epithelial cells (MTEC) to characterize nominal and dosimetric dose-response relationships for AgNPs with a gold core on barrier dysfunction, glutathione (GSH) depletion, reactive oxygen species (ROS) production, lipid peroxidation, and cytotoxicity across two genotypes (A/J and C57BL/6J mice), two phenotypes ('Normal' and 'Type 2 [T2]-Skewed'), and two exposures (an acute exposure of 24 h and a subacute exposure of 4 h, every other day, over 5 days [5 × 4 h]). We characterized the 'T2-Skewed' phenotype as an in vitro model of chronic respiratory diseases, which was marked by increased sensitivity to AgNP-induced barrier dysfunction, GSH depletion, ROS production, lipid peroxidation, and cytotoxicity, suggesting that asthmatics are a sensitive population to AgNP exposures in occupational settings. This also suggests that exposure limits, which should be based upon the most sensitive population, should be derived using in vitro and in vivo models of chronic respiratory diseases. This study highlights the importance of considering dosimetry as well as G × P effects when screening and prioritizing potential respiratory toxicants. Such in vitro studies can be used to inform regulatory policy aimed at special protections for all populations.

RevDate: 2020-06-23

Lou E, Beg MS, Bergsland E, et al (2020)

Reply to S. Boutayeb et al.

RevDate: 2020-06-23

de Blank P, Li N, Fisher MJ, et al (2020)

Late morbidity and mortality in adult survivors of childhood glioma with neurofibromatosis type 1: report from the Childhood Cancer Survivor Study.

Genetics in medicine : official journal of the American College of Medical Genetics pii:10.1038/s41436-020-0873-7 [Epub ahead of print].

PURPOSE: Neurofibromatosis type 1 (NF1) is associated with tumor predisposition and nonmalignant health conditions. Whether survivors of childhood cancer with NF1 are at increased risk for poor long-term health outcomes is unknown.

METHODS: One hundred forty-seven 5+ year survivors of childhood glioma with NF1 from the Childhood Cancer Survivor Study were compared with 2629 non-NF1 glioma survivors and 5051 siblings for late mortality, chronic health conditions, and psychosocial, neurocognitive, and socioeconomic outcomes.

RESULTS: Survivors with NF1 (age at diagnosis: 6.8 ± 4.8 years) had greater cumulative incidence of late mortality 30 years after diagnosis (46.3% [95% confidence interval: 23.9-62.2%]) compared with non-NF1 survivors (18.0% [16.1-20.0%]) and siblings (0.9% [0.6-1.2%]), largely due to subsequent neoplasms. Compared with survivors without NF1, those with NF1 had more severe/life-threatening chronic conditions at cohort entry (46.3% [38.1-54.4%] vs. 30.8% [29.1-32.6%]), but similar rates of new conditions during follow-up (rate ratio: 1.26 [0.90-1.77]). Survivors with NF1 were more likely to report psychosocial impairments, neurocognitive deficits, and socioeconomic difficulties compared with survivors without NF1.

CONCLUSIONS: Late mortality among glioma survivors with NF1 is twice that of other survivors, due largely to subsequent malignancies. Screening, prevention, and early intervention for chronic health conditions and psychosocial and neurocognitive deficits may reduce long-term morbidity in this vulnerable population.

RevDate: 2020-06-22

Song AJ, Shi W, Ellenbogen RG, et al (2020)

Commentary: Stereotactic Radiosurgery for Intracranial Noncavernous Sinus Benign Meningioma: International Stereotactic Radiosurgery Society Systematic Review, Meta-Analysis and Practice Guideline.

Neurosurgery pii:5860969 [Epub ahead of print].

RevDate: 2020-06-22

Serna G, Ruiz-Pace F, Hernando J, et al (2020)

Fusobacterium nucleatum persistence and risk of recurrence after preoperative treatment in locally advanced rectal cancer.

Annals of oncology : official journal of the European Society for Medical Oncology pii:S0923-7534(20)39890-2 [Epub ahead of print].

BACKGROUND: Accumulating evidence has identified Fusobacterium as an important pathogenic gut bacterium associated with colorectal cancer (CRC). Nevertheless, only limited data exist about the role of this bacterium in locally advanced rectal cancer (LARC). In this study, we quantified Fusobacterium nucleatum in untreated and post-neoadjuvant chemo-radiotherapy (nCRT) samples from LARC patients and investigated its association with therapy response and survival.

PATIENTS AND METHODS: A total of 254 samples from 143 patients with rectal adenocarcinomas were analysed for the presence and abundance of F. nucleatum using RNA in situ hybridization and digital image analysis. Assay accuracy was determined using infected cell lines and tumor samples with available qPCR data. We studied the impact of F. nucleatum load on pathological complete response (pCR) and relapse-free survival (RFS). Treatment-induced changes were evaluated in paired pre- and post-nCRT samples (n=71). Finally, tumor microenvironment changes during nCRT were assessed in paired samples (n=45) by immune contexture analysis.

RESULTS: F. nucleatum tissue levels by RNA-ISH strongly correlated with qPCR (r=0.804, P <0.001). F. nucleatum abundance was higher in untreated [median, 7.4; 95% confidence interval (3.7-16.2)] compared to treated [median, 1.6; 95% confidence interval (1.3-2.4)] tumors (P <0.001) with 58% (73/126) and 26% (22/85) positive tumors, respectively (P <0.001). Baseline F. nucleatum levels were not associated with pCR. F. nucleatum positivity after nCRT, but not baseline status, significantly increased risk of relapse [HR=7.5, 95% confidence interval (3.0-19.0); P <0.001]. Tumors that turned F. nucleatum-negative after nCRT had strong increase in CD8+ T cells post-nCRT (P <0.001), while those that persisted F. nucleatum positive after nCRT lacked CD8+ T cells induction in post-nCRT samples as compared to baseline (P =0.69).

CONCLUSION: F. nucleatum persistence post-nCRT is associated with high relapse rates in LARC, potentially linked to suppression of immune cytotoxicity.

RevDate: 2020-06-22

Viskochil R, Gigic B, Lin T, et al (2020)

Associations between physical activity, sedentary behavior and urinary oxidized guanine in colorectal cancer patients: Results from the ColoCare Study.

Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme [Epub ahead of print].

To determine associations between physical activity (PA), sedentary behavior (SB) and oxidative stress in colorectal cancer patients, ColoCare Study participants in Germany wore an accelerometer 6- and/or 12-months post-surgery. Spearman partial correlations were used to assess associations between PA and urinary concentrations of oxidized guanine, a validated marker of oxidative stress. There were no significant associations between PA or SB and oxidized guanine in n=76 measurements (ng/mgcreatinine; r=0.03, p=0.76 for PA, r=-0.05, p=0.69 for SB). Novelty: Objectively-measured physical activity was not associated with a marker of oxidative stress in colorectal cancer patients.

RevDate: 2020-06-22

Clay-Gilmour AI, Hildebrandt MAT, Brown EE, et al (2020)

Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

Blood advances, 4(12):2789-2797.

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.

RevDate: 2020-06-22

Stalter RM, Baeten JM, Donnell D, et al (2020)

Urine Tenofovir Levels Measured by a Novel Immunoassay Predict HIV Protection.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5860911 [Epub ahead of print].

New tools are needed to support PrEP adherence for individuals at risk for HIV, including those that enable provision of real-time feedback. In a large, completed PrEP trial, adequate urine tenofovir levels measured by a novel immunoassay predicted HIV protection and showed good sensitivity and specificity for detectable plasma tenofovir.

RevDate: 2020-06-22

Percival MM, EH Estey (2020)

Truth or consequences: under-reporting of post-accrual changes in clinical trial design.

Leukemia & lymphoma [Epub ahead of print].

RevDate: 2020-06-22

Yang SW, Kernic MA, Mueller BA, et al (2020)

Association of Parental Mental Illness With Child Injury Occurrence, Hospitalization, and Death During Early Childhood.

JAMA pediatrics pii:2766829 [Epub ahead of print].

Importance: Injury is a leading cause of childhood morbidity and mortality worldwide. Serious mental illness (SMI) is a major contributor to the global burden of disease.

Objective: To compare injury event rates in children from birth to 5 years of age among Taiwanese children with and without parents with SMI, including schizophrenia, bipolar disorder, and major depressive disorder.

This population-based, retrospective cohort study of an 11-year Taiwanese birth cohort used data from the Taiwan National Health Insurance Research Database (covering 99% of Taiwanese citizens), the Maternal and Child Health Database, and birth and death certificate databases. The study included 1 999 322 singletons with Taiwanese citizenship born from January 1, 2004, to December 31, 2014, and followed up from birth to their fifth birthday, December 31, 2014, or the date of death, yielding a total of 7 741 026 person-years. Data analysis was performed from April 20, 2017, to September 24, 2019.

Exposures: Physician-diagnosed parental SMI defined using outpatient and inpatient records from 6 years before the child's birth to 5 years after delivery.

Main Outcome and Measures: Rates of medically attended injury events, injury hospitalization, and injury death retrieved from outpatient records, inpatient records, and death certificates. Generalized estimating equation for log-linear models estimated injury incidence rate ratios (IRRs) comparing parental SMI-exposed children and unexposed children.

Results: The study cohort included 1 999 322 singletons (52.1% males without parental SMI and 52.2% males with parental SMI). Incidence rates of child injury-related outcomes were higher among children exposed to parental SMI (294.8 injury events per 1000 person-years) compared with children who were unexposed (256.1 injury events per 1000 person-years). After adjustment for sociodemographic factors, children with parental SMI had higher rates of injury events (IRR, 1.14; 95% CI, 1.13-1.15), injury hospitalization (IRR, 1.49; 95% CI, 1.42-1.57), and injury death (IRR, 1.82; 95% CI, 1.38-2.39) compared with unexposed children. The results were confirmed in sensitivity analyses. Appendicitis, a negative control outcome, was not associated with parental SMI (IRR, 1.10; 95% CI, 0.94-1.28). In addition, children with and without parental SMI had similar patterns of preventive health care. The mean (SD) number of prenatal visits was 8.09 (2.50) for children with parental SMI and 8.17 (2.47) among unaffected children. The mean (SD) number of well-child visits was 5.70 (2.24) for children with parental SMI and 5.80 (2.21) among unaffected children.

Conclusions and Relevance: In this study, children with parental SMI had increased risk of injury, particularly serious injury. Excess risk may be reduced by providing effective mental health treatment, parenting support, and home safety education to parents with SMI who are raising young children.

RevDate: 2020-06-22

Chow VA, Martin PS, Smith SD, et al (2020)

Addressing the conundrum of male predominance in mantle cell lymphoma using androgen receptor blockade.

RevDate: 2020-06-22

Ramos KJ, Kapnadak SG, Collins BF, et al (2020)

Detection of SARS-CoV-2 by bronchoscopy after negative nasopharyngeal testing: Stay vigilant for COVID-19.

Respiratory medicine case reports, 30:101120 pii:101120.

Purpose: Real-time polymerase chain reaction (RT-PCR) detection of severe acute respiratory syndrome coronavirus (SARS-CoV-2) is required for diagnosis of coronavirus disease 2019 (COVID-19). Sensitivity of RT-PCR nasopharyngeal (NP) testing is presumed to be high, but there is no gold standard against which this has been determined. The objective was to determine whether lower respiratory tract infection (LRTI), detected in bronchoalveolar lavage fluid (BALF), occurs in the absence of upper respiratory tract infection with clinical testing of both specimen types.

Methods: Between March 26, 2020 and April 17, 2020 at the University of Washington Medical Center all patients with BALF specimens clinically tested for SARS-CoV-2 were identified. We assessed the proportion of patients with positive RT-PCR for SARS-CoV-2 in BALF after negative NP testing. We describe 3 cases with positive testing in BALF.

Results: Among 16 patients with BALF samples, 3 cases (19%) had SARS-CoV-2 detected in BALF. In Case 1, negative NP testing occurred early in the infection and respiratory symptoms may have been missed due to neurologic injury. In Case 2, outpatient diagnosis was aspiration pneumonia, but clinical suspicion remained high for COVID-19 at hospitalization based on epidemiological and clinical features. All 3 cases involved older adults (age >65 years), one of whom was immunosuppressed in the setting of lung transplantation (Case 3).

Conclusions: These data demonstrate that SARS-CoV-2 LRTI occurs in the presence of negative NP testing. NP testing may underestimate the prevalence of COVID-19 and has implications for spread of SARS-CoV2 in the community and healthcare setting.

RevDate: 2020-06-21

Zeidan AM, Boddu PC, Patnaik MM, et al (2020)

Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts.

The Lancet. Haematology pii:S2352-3026(20)30205-2 [Epub ahead of print].

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.

RevDate: 2020-06-20

Chan S, Wang X, Jazić I, et al (2020)

Developing and evaluating risk prediction models with panel current status data.

Biometrics [Epub ahead of print].

Panel current status data arise frequently in biomedical studies when the occurrence of a particular clinical condition is only examined at several prescheduled visit times. Existing methods for analyzing current status data have largely focused on regression modeling based on commonly used survival models such as the proportional hazards model and the accelerated failure time model. However, these procedures have the limitations of being difficult to implement and performing sub-optimally in relatively small sample sizes. The performance of these procedures is also unclear under model mis-specification. In addition, no methods currently exist to evaluate the prediction performance of estimated risk models with panel current status data. In this paper, we propose a simple estimator under a general class of non-parametric transformation (NPT) models by fitting a logistic regression working model and demonstrate that our proposed estimator is consistent for the NPT model parameter up to a scale multiplier. Furthermore, we propose non-parametric estimators for evaluating the prediction performance of the risk score derived from model fitting, which is valid regardless of the adequacy of the fitted model. Extensive simulation results suggest that our proposed estimators perform well in finite samples and the regression parameter estimators outperform existing estimators under various scenarios. We illustrate the proposed procedures using data from the Framingham Offspring Study. This article is protected by copyright. All rights reserved.

RevDate: 2020-06-20

Kasturi SP, Rasheed MAU, Havenar-Daughton C, et al (2020)

3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope-specific plasma cells and humoral immunity in nonhuman primates.

Science immunology, 5(48):.

A fundamental challenge in vaccinology is learning how to induce durable antibody responses. Live viral vaccines induce antibody responses that last a lifetime, but those induced with subunit vaccines wane rapidly. Studies in mice and humans have established that long-lived plasma cells (LLPCs) in the bone marrow (BM) are critical mediators of durable antibody responses. Here, we present data that adjuvanting an HIV-1 clade C 1086.C-derived gp140 immunogen (Env) with a novel synthetic Toll-like receptor (TLR)-7/8 agonist named 3M-052 formulated in poly(lactic-co-glycolic)acid or PLGA nanoparticles (NPs) or with alum, either alone or in combination with a TLR-4 agonist GLA, induces notably high and persistent (up to ~1 year) frequencies of Env-specific LLPCs in the BM and serum antibody responses in rhesus macaques. Up to 36 and 18% of Env-specific cells among total IgG-secreting BM-resident plasma cells were detected at peak and termination, respectively. In contrast, adjuvanting Env with alum or GLA in NP induced significantly lower (~<100-fold) LLPC and antibody responses. Immune responses induced by 3M-052 were also significantly higher than those induced by a combination of TLR-7/8 (R848) and TLR-4 (MPL) agonists. Adjuvanting Env with 3M-052 also induced robust activation of blood monocytes, strong plasmablast responses in blood, germinal center B cells, T follicular helper (TFH) cells, and persistent Env-specific plasma cells in draining lymph nodes. Overall, these results demonstrate efficacy of 3M-052 in promoting high magnitude and durability of antibody responses via robust stimulation of innate immunity and BM-resident LLPCs.

RevDate: 2020-06-20

Seydoux E, Homad LJ, MacCamy AJ, et al (2020)

Analysis of a SARS-CoV-2-Infected Individual Reveals Development of Potent Neutralizing Antibodies with Limited Somatic Mutation.

Immunity pii:S1074-7613(20)30231-4 [Epub ahead of print].

Antibody responses develop following SARS-CoV-2 infection, but little is known about their epitope specificities, clonality, binding affinities, epitopes, and neutralizing activity. We isolated B cells specific for the SARS-CoV-2 envelope glycoprotein spike (S) from a COVID-19-infected subject 21 days after the onset of clinical disease. 45 S-specific monoclonal antibodies were generated. They had undergone minimal somatic mutation with limited clonal expansion, and three bound the receptor-binding domain (RBD). Two antibodies neutralized SARS-CoV-2. The most potent antibody bound the RBD and prevented binding to the ACE2 receptor, while the other bound outside the RBD. Thus, most anti-S antibodies that were generated in this patient during the first weeks of COVID-19 infection were non-neutralizing and target epitopes outside the RBD. Antibodies that disrupt the SARS-CoV-2 S-ACE2 interaction can potently neutralize the virus without undergoing extensive maturation. Such antibodies have potential preventive and/or therapeutic potential and can serve as templates for vaccine design.

RevDate: 2020-06-19

Escobar-Hoyos LF, Penson A, Kannan R, et al (2020)

Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer.

Cancer cell pii:S1535-6108(20)30260-9 [Epub ahead of print].

Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here, we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC.

RevDate: 2020-06-21

Shoag JE, Nyame YA, Gulati R, et al (2020)

Reconsidering the Trade-offs of Prostate Cancer Screening.

The New England journal of medicine, 382(25):2465-2468.

RevDate: 2020-06-19

Epperla N, Vaughn JL, Othus M, et al (2020)

Recent survival trends in diffuse large B-cell lymphoma--Have we made any progress beyond rituximab?.

Cancer medicine [Epub ahead of print].

BACKGROUND: Population-based studies previously showed an improvement in overall survival (OS) for patients with diffuse large B-cell lymphoma (DLBCL) who received chemoimmunotherapy with rituximab. However, there is limited data (especially at the population level) that show a similar trend in OS improvement, in the most recent time period. We hypothesized that survival for DLBCL patients diagnosed in the United States has continued to improve in recent years and intended to measure outcome improvements.

METHODS: Using the SEER-18 registries, we compared the incidence and relative survival rates (RSRs) of DLBCL patients between 2002-2007 and 2008-2013 (availability of novel agents, broader use of autologous hematopoietic cell transplantation and improvement in supportive care). Multivariable Cox regression models were used to assess associations between the year of diagnosis and OS while controlling for age, gender, stage, and ethnicity.

RESULTS: There were a total of 53 439 patients with DLBCL who were diagnosed between 2002 and 2013. Of these, 25 810 were diagnosed during time period-1 and 27 629 diagnosed during time period-2. There was a slight decline in incidence of DLBCL (time period-1 vs time period-2), 7.75 (95% CI = 7.66-7.84) vs 7.43 (95% CI = 7.34-7.52) cases per 100 000 persons, respectively (P < .0001). Overall, there was a modest improvement in DLBCL RSRs, with 5-year RSR improving from 61% (time period-1) to 64% (time period-2) and the improvement was noted across all subsets of patients. On multivariable analysis, patients diagnosed in time period-2 had lower mortality relative to time period-1 (HR = 0.87, 95% CI = 0.85-0.89).

CONCLUSIONS: Our study shows an improvement in the outcomes of DLBCL patients beyond the introduction of rituximab, although the magnitude of improvement is small. It will be interesting to see the impact of chimeric antigen receptor-T cell therapy translating to population-level survival in the next 5 years.

RevDate: 2020-06-19

Wang CY, X Song (2020)

Semiparametric regression calibration for general hazard models in survival analysis with covariate measurement error; surprising performance under linear hazard.

Biometrics [Epub ahead of print].

Observational epidemiological studies often confront the problem of estimating exposure-disease relationships when the exposure is not measured exactly. Regression calibration (RC) is a common approach to correct for bias in regression analysis with covariate measurement error. In survival analysis with covariate measurement error, it is well known that the RC estimator may be biased when the hazard is an exponential function of the covariates. In the paper, we investigate the RC estimator with general hazard functions, including exponential and linear functions of the covariates. When the hazard is a linear function of the covariates, we show that a risk set regression calibration (RRC) is consistent and robust to a working model for the calibration function. Under exponential hazard models, there is a trade-off between bias and efficiency when comparing RC and RRC. However, one surprising finding is that the trade-off between bias and efficiency in measurement error research is not seen under linear hazard when the unobserved covariate is from a uniform or normal distribution. Under this situation, the RRC estimator is in general slightly better than the RC estimator in terms of both bias and efficiency. The methods are applied to the Nutritional Biomarkers Study of the Women's Health Initiative. This article is protected by copyright. All rights reserved.

RevDate: 2020-06-19

Crotty EE, Leary SES, Geyer JR, et al (2020)

Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children's Hospital experience.

Journal of neuro-oncology pii:10.1007/s11060-020-03558-w [Epub ahead of print].

INTRODUCTION: Beyond focal radiation, there is no consensus standard therapy for pediatric high-grade glioma (pHGG) and outcomes remain dismal. We describe the largest molecularly-characterized cohort of children with pHGG treated with a 3-drug maintenance regimen of temozolomide, irinotecan, and bevacizumab (TIB) following radiation.

METHODS: We retrospectively reviewed 36 pediatric patients treated with TIB at Seattle Children's Hospital from 2009 to 2018 and analyzed survival using the Kaplan-Meier method. Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated.

RESULTS: Median age at diagnosis was 10.9 years (18 months-18 years). Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (12), H3F3A G34-mutant (2), IDH-mutant (4), and hypermutator profiles (4). Fifteen patients (42%) completed 12 planned cycles of maintenance. Side effects associated with chemotherapy delays or modifications included thrombocytopenia (28%) and nausea/vomiting (19%), with temozolomide dosing most frequently modified. Median event-free survival (EFS) and overall survival (OS) was 16.2 and 20.1 months, with shorter survival seen in DIPG (9.3 and 13.3 months, respectively). Survival at 1, 2, and 5 years was 80%, 10% and 0% for DIPG and 85%, 38%, and 16% for other pHGG.

CONCLUSION: Our single-center experience demonstrates tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide. pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare. Children with pHGG remain excellent candidates for the study of novel therapeutics combined with standard therapy.

RevDate: 2020-06-19

Margres MJ, Ruiz-Aravena M, Hamede R, et al (2020)

Spontaneous Tumor Regression in Tasmanian Devils Associated with RASL11A Activation.

Genetics pii:genetics.120.303428 [Epub ahead of print].

Spontaneous tumor regression has been documented in a small proportion of human cancer patients, but the specific mechanisms underlying tumor regression without treatment are not well-understood. Tasmanian devils are threatened with extinction from a transmissible cancer due to universal susceptibility and a near 100% case fatality rate. In over 10,000 cases, fewer than 20 instances of natural tumor regression have been detected. Previous work in this system has focused on Tasmanian devil genetic variation associated with the regression phenotype. Here, we used comparative and functional genomics to identify tumor genetic variation associated with tumor regression. We show that a single point mutation in the 5' untranslated region of the putative tumor suppressor RASL11A significantly contributes to tumor regression. RASL11A was expressed in regressed tumors but silenced in wild-type, non-regressed tumors, consistent with RASL11A down-regulation in human cancers. Induced RASL11A expression significantly reduced tumor cell proliferation in vitro The RAS pathway is frequently altered in human cancers, and RASL11A activation may provide a therapeutic treatment option for Tasmanian devils as well as a general mechanism for tumor inhibition.

RevDate: 2020-06-21

Wu NC, Thompson AJ, Lee JM, et al (2020)

Different genetic barriers for resistance to HA stem antibodies in influenza H3 and H1 viruses.

Science (New York, N.Y.), 368(6497):1335-1340.

The discovery and characterization of broadly neutralizing human antibodies (bnAbs) to the highly conserved stem region of influenza hemagglutinin (HA) have contributed to considerations of a universal influenza vaccine. However, the potential for resistance to stem bnAbs also needs to be more thoroughly evaluated. Using deep mutational scanning, with a focus on epitope residues, we found that the genetic barrier to resistance to stem bnAbs is low for the H3 subtype but substantially higher for the H1 subtype owing to structural differences in the HA stem. Several strong resistance mutations in H3 can be observed in naturally circulating strains and do not reduce in vitro viral fitness and in vivo pathogenicity. This study highlights a potential challenge for development of a truly universal influenza vaccine.

RevDate: 2020-06-19

Dandoy CE, Davies SM, Ahn KW, et al (2020)

Comparison of total body irradiation versus non- total body irradiation containing regimens for de novo acute myeloid leukemia in children.

Haematologica pii:haematol.2020.249458 [Epub ahead of print].

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, p<0.0001) but relapse was lower (23% vs. 37%, p<0.0001) compared to non-TBI regimens. Consequently, overall (62% vs. 60%, p=1.00) and leukemia-free survival (55% vs. 52%, p=0.42) did not differ between treatment groups. Grade II-IV acute GVHD was higher with TBI regimens (56% vs. 27%, p<0.0001) but not chronic GVHD. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%, p<0.001) but there were no differences in late pulmonary, cardiac or renal impairment. In the absence of a survival advantage, the choice of TBI or non-TBI regimen merits careful consideration with the data favoring non-TBI regimens to limit the burden of morbidity associated with endocrine dysfunction.

RevDate: 2020-06-19

Talhouk A, George J, Wang C, et al (2020)

Development and validation of the gene-expression Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE (PrOTYPE).

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-0103 [Epub ahead of print].

PURPOSE: Gene-expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by non-standardized methods which are not applicable in a clinical setting. We sought to generate a clinical-grade minimal gene-set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.

EXPERIMENTAL DESIGN: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene-expression data from 1650 tumors. We applied resulting models to NanoString data on 3829 HGSOCs from the Ovarian Tumor Tissue Analysis Consortium. We further developed, confirmed, and validated a reduced, minimal gene-set predictor, with methods suitable for a single patient setting.

RESULTS: Gene-expression data was used to derive the Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor infiltrating lymphocytes, and outcome. The locked-down clinical-grade PrOTYPE test includes a model with 55 genes that predicted gene-expression subtype with >95% accuracy that was maintained in all analytical and biological validations.

CONCLUSIONS: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical-grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.

RevDate: 2020-06-19

Jazić I, Lee S, S Haneuse (2020)

Estimation and inference for semi-competing risks based on data from a nested case-control study.

Statistical methods in medical research [Epub ahead of print].

In semi-competing risks, the occurrence of some non-terminal event is subject to a terminal event, usually death. While existing methods for semi-competing risks data analysis assume complete information on all relevant covariates, data on at least one covariate are often not readily available in practice. In this setting, for standard univariate time-to-event analyses, researchers may choose from several strategies for sub-sampling patients on whom to collect complete data, including the nested case-control study design. Here, we consider a semi-competing risks analysis through the reuse of data from an existing nested case-control study for which risk sets were formed based on either the non-terminal or the terminal event. Additionally, we introduce the supplemented nested case-control design in which detailed data are collected on additional events of the other type. We propose estimation with respect to a frailty illness-death model through maximum weighted likelihood, specifying the baseline hazard functions either parametrically or semi-parametrically via B-splines. Two standard error estimators are proposed: (i) a computationally simple sandwich estimator and (ii) an estimator based on a perturbation resampling procedure. We derive the asymptotic properties of the proposed methods and evaluate their small-sample properties via simulation. The designs/methods are illustrated with an investigation of risk factors for acute graft-versus-host disease among N = 8838 patients undergoing hematopoietic stem cell transplantation, for which death is a significant competing risk.

RevDate: 2020-06-19

Desai A, Kuderer NM, GH Lyman (2020)

Crowdsourcing in Crisis: Rising to the Occasion.

JCO clinical cancer informatics, 4:551-554.

RevDate: 2020-06-17

Mani NS, Budak JZ, Lan KF, et al (2020)

Prevalence of COVID-19 Infection and Outcomes Among Symptomatic Healthcare Workers in Seattle, Washington.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5858272 [Epub ahead of print].

BACKGROUND: Healthcare workers (HCW) serving on the front lines of the coronavirus disease 2019 (COVID-19) pandemic have been at increased risk for infection due to SARS-CoV-2 in some settings. Healthcare-acquired infection has been reported in similar epidemics, but there are limited data on the prevalence of COVID-19 among HCWs and their associated clinical outcomes in the United States.

METHODS: We established two high-throughput employee testing centers in Seattle, Washington with drive-through and walk-through options for symptomatic employees in the University of Washington Medicine system and its affiliated organizations. Using data from these testing centers, we report the prevalence of SARS-CoV-2 infection among symptomatic employees and describe the clinical characteristics and outcomes among employees with COVID-19.

RESULTS: Between March 12 and April 23, a total of 3,477 symptomatic employees were tested for COVID-19 at two employee testing centers; 185 (5.3%) employees tested positive for COVID-19. The prevalence of SARS-CoV-2 was similar when comparing frontline HCWs (5.2%) to non-frontline staff (5.5%). Among 174 positive employees reached for follow-up at least 14 days after diagnosis, 6 reported COVID-related hospitalization; all recovered.

CONCLUSIONS: During the study period, we observed that the prevalence of positive SARS-CoV-2 tests among symptomatic HCWs was comparable to that of symptomatic non-frontline staff. Reliable and rapid access to testing for employees is essential to preserve the health, safety, and availability of the healthcare workforce during this pandemic and to facilitate the rapid return of SARS-CoV-2 negative employees to work.

RevDate: 2020-06-17

Yang JJ, Yu D, Shu XO, et al (2020)

Quantifying the association of low-intensity and late initiation of tobacco smoking with total and cause-specific mortality in Asia.

Tobacco control pii:tobaccocontrol-2019-055412 [Epub ahead of print].

BACKGROUND: Little is known about the health harms associated with low-intensity smoking in Asians who, on average, smoke fewer cigarettes and start smoking at a later age than their Western counterparts.

METHODS: In this pooled analysis of 738 013 Asians from 16 prospective cohorts, we quantified the associations of low-intensity (<5 cigarettes/day) and late initiation (≥35 years) of smoking with mortality outcomes. HRs and 95% CIs were estimated for each cohort by Cox regression. Cohort-specific HRs were pooled using random-effects meta-analysis.

FINDINGS: During a mean follow-up of 11.3 years, 92 068 deaths were ascertained. Compared with never smokers, current smokers who consumed <5 cigarettes/day or started smoking after age 35 years had a 16%-41% increased risk of all-cause, cardiovascular disease (CVD), respiratory disease mortality and a >twofold risk of lung cancer mortality. Furthermore, current smokers who started smoking after age 35 and smoked <5 cigarettes/day had significantly elevated risks of all-cause (HRs (95% CIs)=1.14 (1.05 to 1.23)), CVD (1.27 (1.08 to 1.49)) and respiratory disease (1.54 (1.17 to 2.01)) mortality. Even smokers who smoked <5 cigarettes/day but quit smoking before the age of 45 years had a 16% elevated risk of all-cause mortality; however, the risk declined further with increasing duration of abstinence.

CONCLUSIONS: Our study showed that smokers who smoked a small number of cigarettes or started smoking later in life also experienced significantly elevated all-cause and major cause-specific mortality but benefited from cessation. There is no safe way to smoke-not smoking is always the best choice.

RevDate: 2020-06-17

Tang H, Jiang L, Stolzenberg-Solomon R, et al (2020)

Genome-wide gene-diabetes and gene-obesity interaction scan in 8,255 cases and 11,900 controls from the PanScan and PanC4 Consortia.

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-20-0275 [Epub ahead of print].

BACKGROUND: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level.

METHODS: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer GWAS datasets (PanScan I-III and PanC4). Obesity (BMI=30 kg/m2) and diabetes (duration = 3 years) were the environmental variables of interest. Approximately 870,000 SNPs were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual-GWAS summary statistics.

RESULTS: No genome-wide significant interactions with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P<1.25E-6) was observed in the meta-analysis (PGxE= 1.2E-6, PJoint= 4.2E-7).

CONCLUSIONS: Our current analyses did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans.

IMPACT: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

RevDate: 2020-06-17

Song H, Dicks EM, Tyrer J, et al (2020)

Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.

Journal of medical genetics pii:jmedgenet-2019-106739 [Epub ahead of print].

PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.

METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.

RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.

CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

RevDate: 2020-06-17

Utzschneider KM, Johnson TN, Breymeyer KL, et al (2020)

Small changes in glucose variability induced by low and high glycemic index diets are not associated with changes in β-cell function in adults with pre-diabetes.

Journal of diabetes and its complications pii:S1056-8727(20)30338-X [Epub ahead of print].

Oscillating glucose levels can increase oxidative stress and may contribute to β-cell dysfunction. We tested the hypothesis that increased glycemic variability contributes to β-cell dysfunction by experimentally altering glucose variability with controlled diets varying in glycemic index (GI). Fifty-two adults with prediabetes received a 2-week moderate GI (GI = 55-58) control diet followed by randomization to a four-week low GI (LGI: GI < 35) or high GI (HGI HI > 70) diet. Those on the HGI diet were randomized to placebo or the antioxidant N-acetylcysteine (NAC). Participants underwent blinded CGMS, fasting oxidative stress markers and an intravenous glucose tolerance test to estimate β-cell function (disposition index: DI). On the control diet, DI was inversely correlated with SD glucose (r = -0.314, p = 0.03), but neither DI nor glucose variability were associated with oxidative stress markers. The LGI diet decreased SD glucose (Control 0.96 ± 0.08 vs. LGI 0.79 ± 0.06, p = 0.02) while the HGI diet increased it (Control 0.88 ± 0.06 vs. HGI 1.06 ± 0.07, p = 0.03). Neither DI nor oxidative stress markers changed after the LGI or HGI diets. NAC had no effect on DI, glucose variability or oxidative stress markers. We conclude small changes in glucose variability induced by dietary GI in adults with pre-diabetes are unlikely to contribute to β-cell dysfunction.

RevDate: 2020-06-16

Fredricks DN (2020)

Evidence in Microbiome Science: Standards for the Field (and Lab).

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5858264 [Epub ahead of print].

RevDate: 2020-06-16

Chua KLM, Fehlings M, Yeo ELL, et al (2020)

High-dimensional Characterization of the Systemic Immune Landscape Informs on Synergism between Radiotherapy and Immune Checkpoint Blockade.

International journal of radiation oncology, biology, physics pii:S0360-3016(20)31248-7 [Epub ahead of print].

BACKGROUND: Improved anti-tumor responses have been observed in patients following combination radiotherapy (RT) and immune checkpoint blockade (ICB). Whether these clinical responses are linked to the host systemic immune system has not been elucidated.

METHODS: In this study, peripheral blood was longitudinally collected from 10 patients with metastatic disease, who had responded to anti-PD-1/ anti-PD-L1 ICB and received radiotherapy (8-50 Gy in 1-5 fractions) upon disease progression, at the following timepoints: Baseline (pre-RT), 1-2 weeks post-RT and post-ICB#1 on re-introduction post-RT, as part of a single institution prospective observational study. To thoroughly characterize the interaction between combined RT-ICB with the host immune system, we performed high-dimensional, mass cytometry-based immunophenotyping of circulating lymphocytes using a 40 marker-panel addressing lineage, differentiation, activation, trafficking, cytotoxicity, co-stimulatory and inhibitory functions. Phenotypic expressions of circulating lymphocytes were compared across patients and timepoints and correlated with post-RT tumour responses.

RESULTS: Foremost, we demonstrated excellent post-treatment clinical responses including 4 local responses with >50% reduction in radiated tumor size, 1 out-of-field response and 4 patients who resumed ICB for >1 year. Baseline and post-RT immune states were highly heterogeneous between patients. Despite this interindividual heterogeneity in baseline immune states, we observed a systemic immune reaction to RT-ICB common across patients, histology and radiation sites; a subset of pre-existing Ki-67+ CD8+ T cells were increased post-RT and further expanded upon re-introduction of ICB post-RT (2.3-fold increase, P = 0.02). Importantly, RT did not alter the phenotypic profile of these Ki-67+ CD8+ T cells, which was characterized by a distinct activated and differentiated effector phenotype.

CONCLUSIONS: Collectively, these findings point towards a sustained reinvigoration of host anti-tumor immunity following RT-ICB, and suggest an expansion in activated Ki-67+ CD8+ T cells as a possible demonstration of this synergy, thereby providing new insights which may support the development of optimal sequencing strategies.

RevDate: 2020-06-20

Carpp LN, Fong Y, Bonaparte M, et al (2020)

Microneutralization assay titer correlates analysis in two phase 3 trials of the CYD-TDV tetravalent dengue vaccine in Asia and Latin America.

PloS one, 15(6):e0234236.

We previously showed that Month 13 50% plaque reduction neutralization test (PRNT50) neutralizing antibody (nAb) titers against dengue virus (DENV) correlated with vaccine efficacy (VE) of CYD-TDV against symptomatic, virologically-confirmed dengue (VCD) in the CYD14 and CYD15 Phase 3 trials. While PRNT is the gold standard nAb assay, it is time-consuming and costly. We developed a next-generation high-throughput microneutralization (MN) assay and assessed its suitability for immune-correlates analyses and immuno-bridging applications. We analyzed MN and PRNT50 titers measured at baseline and Month 13 in a randomly sampled immunogenicity subset, and at Month 13 in nearly all VCD cases through Month 25. For each serotype, MN and PRNT50 titers showed high correlations, at both baseline and Month 13, with MN yielding a higher frequency of baseline-seronegatives. For both assays, Month 13 titer correlated inversely with VCD risk. Like PRNT50, high Month 13 MN titers were associated with high VE, and estimated VE increased with average Month 13 MN titer. We also studied each assay as a valid surrogate endpoint based on the Prentice criteria, which supported each assay as a valid surrogate for DENV-1 but only partially valid for DENV-2, -3, and -4. In addition, we applied Super-Learner to assess how well demographic, Month 13 MN, and/or Month 13 PRNT50 titers could predict Month 13-25 VCD outcome status; prediction was best when using demographic, MN, and PRNT50 information. We conclude that Month 13 MN titer performs comparably to Month 13 PRNT50 titer as a correlate of risk, correlate of vaccine efficacy, and surrogate endpoint. The MN assay could potentially be used to assess nAb titers in immunogenicity studies, immune-correlates studies, and immuno-bridging applications. Additional research would be needed for assessing the utility of MN titer in correlates analyses of other DENV endpoints and over longer follow-up periods.

RevDate: 2020-06-19

Gray DM, Anyane-Yeboa A, Balzora S, et al (2020)

COVID-19 and the other pandemic: populations made vulnerable by systemic inequity.

Nature reviews. Gastroenterology & hepatology [Epub ahead of print].

RevDate: 2020-06-16

Goldstein D, Von Hoff DD, Chiorean EG, et al (2020)

Nomogram for Estimating Overall Survival in Patients With Metastatic Pancreatic Cancer.

Pancreas [Epub ahead of print].

OBJECTIVES: This analysis investigated nomogram use to evaluate metastatic pancreatic cancer prognosis.

METHODS: Thirty-four baseline factors were examined in the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) (nab-paclitaxel plus gemcitabine vs gemcitabine) data set. Factors significantly (P < 0.1) associated with overall survival (OS) in a univariable model or with known clinical relevance were tested further. In a multivariable model, factors associated with OS (P < 0.1) were selected to generate the primary nomogram, which was internally validated using bootstrapping, a concordance index, and calibration plots.

RESULTS: Using data from 861 patients, 6 factors were retained (multivariable analysis): neutrophil-lymphocyte ratio, albumin level, Karnofsky performance status, sum of longest diameter of target lesions, presence of liver metastases, and previous Whipple procedure. The nomogram distinguished low-, medium-, and high-risk groups (concordance index, 0.67; 95% confidence interval, 0.65-0.69; median OS, 11.7, 8.0, and 3.3 months, respectively).

CONCLUSIONS: This nomogram may guide estimates of the range of OS outcomes and contribute to patient stratification in future prospective metastatic pancreatic cancer trials; however, external validation is required to improve estimate reliability and applicability to a general patient population. Caution should be exercised in interpreting these results for treatment decisions: patient characteristics could differ from those included in the nomogram development.

RevDate: 2020-06-16

Sidahmed S, Abdalla A, Kheiri B, et al (2020)

Anticoagulants for the treatment of venous thromboembolism in patients with cancer: A comprehensive systematic review, pairwise and network meta-analysis.

Critical reviews in oncology/hematology, 152:103005 pii:S1040-8428(20)30143-8 [Epub ahead of print].

Cancer-associated venous thromboembolism (VTE) is associated with high VTE recurrence and bleeding. We included all randomized clinical trials that evaluated the efficacy and safety of various anticoagulants in cancer-associated VTE. Trial-level data were extracted from 13 trials. Aggregate odds ratios (ORs) were calculated using direct and network meta-analysis. The primary outcome was VTE (pulmonary embolism and/or deep vein thrombosis) recurrence. Secondary outcomes were major bleeding and all-cause mortality. We identified 13 trials with 4869 patient-years of follow-up (6595 total patients; mean age 62.4 ± 12.2; 50.4 % female; 17.7 % hematological malignancies). The most common cancer type was colorectal and 48 % had metastatic cancer at baseline. Compared to vitamin-K-antagonists (VKAs), non-vitamin-K-antagonist-oral-anticoagulants (NOACs) were associated with significantly reduced VTE recurrence (OR, 0.58; 95 % CI, 0.40-0.83) and reduced major bleeding risks (OR, 0.56; 95 % CI, 0.35-0.91). However, no differences were observed in the subgroup analysis of patients with active cancer. Although NOACs were associated with reduced VTE recurrence compared with low-molecular-weight-heparin (LMWHs) (OR, 0.46; 95 % CI, 0.25- 0.85), there was a significant increased major bleeding in high-quality trials. LMWHs were associated with significantly reduced VTE recurrence compared with VKAs (OR, 0.52; 95 % CI, 0.39-0.71) and similar bleeding risks. Conclusions: Among patients with cancer-associated VTE, NOACs were associated with significantly reduced VTE recurrence and bleeding compared with VKAs, however, with similar outcomes in the active cancer population. NOACs were associated with reduced VTE recurrence but higher bleeding risks compared with LMWHs. LMWHs were associated with significantly reduced VTE recurrence and similar bleeding compared with VKAs.

RevDate: 2020-06-16

Subbiah V, Baik C, JM Kirkwood (2020)

Clinical Development of BRAF plus MEK Inhibitor Combinations.

Trends in cancer pii:S2405-8033(20)30164-3 [Epub ahead of print].

Genomic profiling shows that many solid tumors are characterized by specific driver aberrations, and this has expanded the therapeutic options for many patients. The mitogen-activated protein kinase (MAPK) pathway is a key cell signaling pathway involved in regulating cellular growth, proliferation, and survival. Driver mutations in the BRAF gene, a key player in the MAPK pathway, are described in multiple tumor types, including subsets of melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC), making BRAF a desirable target for inhibition. BRAF inhibitors have shown efficacy in several cancers; however, most patients eventually develop resistance. To delay or prevent resistance, combination therapy targeting BRAF and MEK, a downstream signaling target of BRAF in the MAPK pathway, was evaluated and demonstrated synergistic benefit. BRAF and MEK inhibitor combinations have been approved for use in various cancers by the US FDA. We review the clinical data for various BRAF plus MEK combination regimens in three cancer types with underlying BRAF driver mutations: melanoma, NSCLC, and ATC. We also discuss practical treatment considerations and management of selected combination therapy toxicities.

RevDate: 2020-06-15

Archambeault SL, Durston DJ, Wan A, et al (2020)

Phosphorus limitation does not drive loss of bony lateral plates in freshwater stickleback (Gasterosteus aculeatus).

Evolution; international journal of organic evolution [Epub ahead of print].

Connecting the selective forces that drive the evolution of phenotypes to their underlying genotypes is key to understanding adaptation, but such connections are rarely tested experimentally. Threespine stickleback (Gasterosteus aculeatus) are a powerful model for such tests because genotypes that underlie putatively adaptive traits have been identified. For example, a regulatory mutation in the Ectodysplasin (Eda) gene causes a reduction in the number of bony armor plates, which occurs rapidly and repeatedly when marine sticklebacks invade freshwater. However, the source of selection on plate loss in freshwater is unknown. Here, we tested whether dietary reduction of phosphorus can account for selection on plate loss due to a growth advantage of low-plated fish in freshwater. We crossed marine fish heterozygous for the 16 kilobase freshwater Eda haplotype and compared the growth of offspring with different genotypes under contrasting levels of dietary phosphorus in both saltwater and freshwater. Eda genotype was not associated with growth differences in any treatment, or with mechanisms that could mitigate the impacts of phosphorus limitation, like differential phosphorus deposition, phosphorus excretion, or intestine length. This study highlights the importance of experimentally testing the putative selective forces acting on phenotypes and their underlying genotypes in the wild. This article is protected by copyright. All rights reserved.

RevDate: 2020-06-16

Perchetti GA, Nalla AK, Huang ML, et al (2020)

Multiplexing primer/probe sets for detection of SARS-CoV-2 by qRT-PCR.

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 129:104499 pii:S1386-6532(20)30241-9 [Epub ahead of print].

BACKGROUND: The novel respiratory virus SARS-CoV-2, responsible for over 380,000 COVID-19 related deaths, has caused significant strain on healthcare infrastructure and clinical laboratories globally. The pandemic's initial challenges include broad diagnostic testing, consistent reagent supply lines, and access to laboratory instruments and equipment. In early 2020, primer/probe sets distributed by the CDC utilized the same fluorophore for molecular detection - requiring multiple assays to be run in parallel - consuming valuable and limited resources.

METHODS: Nasopharyngeal swabs submitted to UW Virology for SARS-CoV-2 clinical testing were extracted, amplified by our laboratory developed test (LDT) - a CDC-based quantitative reverse transcriptase PCR reaction - and analyzed for agreement between the multiplexed assay. Laboratory- confirmed respiratory infection samples were included to evaluate assay cross-reaction specificity.

RESULTS: Triplexing correctly identified SARS-CoV-2 in 98.4% of confirmed positive or inconclusive patient samples by single-plex LDT (n = 183/186). All 170 SARS-CoV-2 negative samples tested by single-plex LDT were negative by triplexing. Other laboratory-confirmed respiratory infections did not amplify for SARS-CoV-2 in the triplex reaction.

CONCLUSIONS: Multiplexing two virus-specific gene targets and an extraction control was found to be comparable to running parallel assays independently, while significantly improving assay throughput.

RevDate: 2020-06-17

Pattwell SS, Arora S, Cimino PJ, et al (2020)

A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways.

Nature communications, 11(1):2977.

Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.

RevDate: 2020-06-20

Haanen J, Ernstoff M, Wang Y, et al (2020)

Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy.

Journal for immunotherapy of cancer, 8(1):.

Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions.

RevDate: 2020-06-17

Liu Y, Kaur S, Huang Y, et al (2020)

Biomarkers and Strategy to Detect Pre-Invasive and Early Pancreatic Cancer: State of the Field and the Impact of the EDRN.

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-20-0161 [Epub ahead of print].

BACKGROUND: Patients afflicted with pancreatic ductal adenocarcinoma (PDAC) face a dismal prognosis, but headway could be made if physicians could identify the disease earlier. A compelling strategy to broaden the use of surveillance for PDAC is to incorporate molecular biomarkers in combination with clinical analysis and imaging tools.

METHODS: This article summarizes the components involved in accomplishing biomarker validation and an analysis of the requirements of molecular biomarkers for disease surveillance.

RESULTS: We highlight the significance of consortia for this research and highlight resources and infrastructure of the Early Detection Research Network (EDRN). The EDRN brings together the multifaceted expertise and resources needed for biomarker validation, such as study design, clinical care, biospecimen collection and handling, molecular technologies, and biostatistical analysis, and studies coming out of the EDRN have yielded biomarkers that are moving forward in validation. We close the article with an overview of the current investigational biomarkers, an analysis of their performance relative to the established benchmarks, and an outlook on the current needs in the field.

CONCLUSIONS: The outlook for improving the early detection of PDAC looks promising, and the infrastructure of the EDRN has yielded biomarkers that are currently progressing in validation.

IMPACT: The pace of further research should be quickened through the resources and expertise of the EDRN and other consortia.

RevDate: 2020-06-13

Lansigan F, Horwitz SM, Pinter-Brown LC, et al (2020)

Outcomes of Patients with Transformed Mycosis Fungoides: Analysis from a Prospective Multicenter US Cohort Study.

Clinical lymphoma, myeloma & leukemia pii:S2152-2650(20)30217-2 [Epub ahead of print].

INTRODUCTION: We examined patient characteristics, treatments, and outcomes of patients with transformed mycosis fungoides (tMF) from COMPLETE: a large, multicenter, prospective cohort study of peripheral T-cell lymphoma patients in the United States.

METHODS: Patients with tMF were enrolled in COMPLETE at the time of transformation. For this analysis, we identified patients with tMF with completed baseline, treatment, and follow-up records. Median survival was assessed using Kaplan-Meier methodology.

RESULTS: Of the 499 patients enrolled in COMPLETE, 17 had tMF. Median age was 61; 53% were male, 9 had elevated lactate dehydrogenase, and 9 had lymph node involvement. Approximately one-quarter of the patients were African American and 47% had CD30+ disease. Median time to transformation was 53 months. All patients received systemic therapy, with 19% receiving concomitant radiotherapy. Most patients (87%) received single agents, including liposomal doxorubicin, pralatrexate, and gemcitabine. Eight patients (50%) had reported responses to therapy. Median survival was 18 months. One- and 2-year survival rates were 56% and 44%, respectively.

CONCLUSIONS: tMF often expresses CD30 and presents with lymph node involvement. Responses have been seen with single agents, but survival remains poor. Novel treatment approaches are urgently needed to improve outcomes.

RevDate: 2020-06-12

Lee Dupuis L, Quinones CM, Ritchie J, et al (2020)

Response to Kawedia et al Letter to Editor in Response to the Article by McCune Et Al "Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement".

RevDate: 2020-06-12

El-Jawahri A, LeBlanc TW, SJ Lee (2020)

Reply to J. Schildmann et al.

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

RevDate: 2020-06-14

Minasian L, Dimond E, Davis M, et al (2019)

The Evolving Design of NIH-Funded Cardio-Oncology Studies to Address Cancer Treatment-Related Cardiovascular Toxicity.

JACC. CardioOncology, 1(1):105-113.

Cardiovascular (CV) toxicity from cancer therapy is a significant and growing concern. Conventional oncology clinical trial designs focused singularly on cancer treatment efficacy have not provided sufficient information on both CV risk factors and outcomes. Similarly, traditional CV trials evaluating standard interventions typically exclude cancer patients, particularly those actively receiving cancer therapy. Neither trial type simultaneously evaluates the balance between CV toxicity and cancer outcomes. However, there is increasing collaboration among oncologists and cardiologists to design new cardio-oncology trials that address this important need. In this review, we detail five ongoing, oncology-based trials with integrated CV endpoints. Key design features include: 1) a careful assessment of baseline risk factors for CV disease; 2) an introduction of cardioprotective interventions at various timepoints in cancer therapy; 3) a balance of the risk of subclinical CV injury with the need for ongoing cancer treatment; and 4) an understanding of the time profile for development of clinically apparent CV toxicity. Additional critical priorities in cardio-oncology clinical research include harmonization of data collection and definitions for all physician- and patient-reported exposures and outcomes.

RevDate: 2020-06-19

Black A, MacCannell DR, Sibley TR, et al (2020)

Ten recommendations for supporting open pathogen genomic analysis in public health.

Nature medicine, 26(6):832-841.

Increasingly, public-health agencies are using pathogen genomic sequence data to support surveillance and epidemiological investigations. As access to whole-genome sequencing has grown, greater amounts of molecular data have helped improve the ability to detect and track outbreaks of diseases such as COVID-19, investigate transmission chains and explore large-scale population dynamics, such as the spread of antibiotic resistance. However, the wide adoption of whole-genome sequencing also poses new challenges for public-health agencies that must adapt to support a new set of expertise, which means that the capacity to perform genomic data assembly and analysis has not expanded as widely as the adoption of sequencing itself. In this Perspective, we make recommendations for developing an accessible, unified informatic ecosystem to support pathogen genomic analysis in public-health agencies across income settings. We hope that the creation of this ecosystem will allow agencies to effectively and efficiently share data, workflows and analyses and thereby increase the reproducibility, accessibility and auditability of pathogen genomic analysis while also supporting agency autonomy.

RevDate: 2020-06-18
CmpDate: 2020-06-17

Ogburn EL, Bierer BE, Brookmeyer R, et al (2020)

Aggregating data from COVID-19 trials.

Science (New York, N.Y.), 368(6496):1198-1199.

RevDate: 2020-06-15

Armstrong AJ, Lin P, Tombal B, et al (2020)

Five-year Survival Prediction and Safety Outcomes with Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer from the PREVAIL Trial.

European urology pii:S0302-2838(20)30329-8 [Epub ahead of print].

BACKGROUND: In the PREVAIL study, enzalutamide significantly improved clinical outcomes versus placebo in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC).

OBJECTIVE: To evaluate long-term benefits and risks of enzalutamide in the final prespecified PREVAIL analysis.

We conducted a final 5-yr survival analysis of PREVAIL in men with chemotherapy-naïve mCRPC from the enzalutamide (n = 689) and placebo (n = 693) arms.

Predictors of the primary outcome of overall survival were estimated using the Kaplan-Meier method. Long-term adverse events over time were analyzed.

RESULTS AND LIMITATIONS: At the 5-yr data cutoff, 1382 of 1717 (80%) men had died. Enzalutamide reduced the hazard of death by 17% (hazard ratio 0.83; 95% confidence interval [CI] 0.75-0.93; p < 0.001), despite 65%, 54%, and 43% of placebo-treated patients receiving subsequent docetaxel, abiraterone, and enzalutamide, respectively. Median overall survival was 36 mo (95% CI 34-38) in the enzalutamide arm versus 31 mo (95% CI 29-34) in the placebo arm, with a median follow-up of 69 mo. Prognostic modeling showed 5-yr survival rates of 42%, 24%, and 5% for low-, intermediate-, and high-risk groups, respectively. Greater degrees of confirmed prostate-specific antigen declines (≤3 mo) were associated with greater 5-yr survival. A higher incidence of fatal treatment-emergent adverse events was observed with enzalutamide (6.9% vs 3.8%), with an increase in fatal cardiovascular events (1.6% vs 0.4%).

CONCLUSIONS: With >5 yr of follow-up, enzalutamide continued to demonstrate improved survival in patients with mCRPC despite crossover and multiple subsequent effective therapies, balanced against a slightly higher rate of fatal cardiovascular events. PREVAIL is registered on ClinicalTrials.gov as NCT01212991.

PATIENT SUMMARY: We report a maintained long-term survival benefit with enzalutamide and risks with >5 yr of enzalutamide treatment and follow-up in men with metastatic prostate cancer, and identify groups of men with widely different outcomes based on clinical factors.

RevDate: 2020-06-17
CmpDate: 2020-06-17

Shenoy MK, MA Koch (2020)

Nourishing the Microbiota to Promote Mucosal Immunity.

Cell host & microbe, 27(6):849-851.

Childhood undernutrition is associated with dysbiosis and dampened vaccine responses. Understanding how nutrients influence the microbiota and immunity is critical for vaccine efficacy. In this issue of Cell Host & Microbe, Di Luccia et al. and Huus et al. reveal that nutrition affects IgA responses to the microbiota and oral vaccines.

RevDate: 2020-06-13

Hill GR, M Koyama (2020)

Cytokines and Co-stimulation in Acute Graft-versus-Host Disease.

Blood pii:460895 [Epub ahead of print].

Allogeneic hematopoietic stem cell transplantation (alloSCT) is an important curative therapy for high-risk hematological malignancies, but the development of severe and/or steroid-refractory acute graft-versus-host disease (aGVHD) remains a significant limitation to optimal outcomes. New approaches to prevent and treat aGVHD remain an unmet need that can be best addressed by understanding the complex disease pathophysiology. It is now clear that chemoradiotherapy utilized prior to alloSCT induces the release of endogenous alarmins (e.g. HMGB-1, ATP, IL-1α, IL-33) from recipient tissue. Exogenous pathogen-derived molecules (e.g. LPS, nucleic acids) also translocate from the gastrointestinal tract lumen. Together, these danger signals activate antigen presenting cells (APC) to efficiently present alloantigen to donor T cells whilst releasing cytokines (e.g. IL-12, IL-23, IL-6, IL-27, IL-10, TGFb) that expand and differentiate both pathogenic and regulatory donor T cells. Concurrent co-stimulatory signals at the APC-T cell interface (e.g. CD80/CD86-CD28, CD40-CD40L, OX40L-OX40, CD155/CD112-DNAM-1) and subsequent co-inhibitory signals (e.g. CD80/CD86-CTLA4, PDL1/2-PD1, CD155/CD112-TIGIT) are critical to the acquisition of effector T cell function and ensuing secretion of pathogenic cytokines (e.g. IL-17, IFNg, TNF, GM-CSF) and cytolytic degranulation pathway effectors (e.g. perforin/granzyme). This review focuses on the combination of cytokine and costimulatory networks at the T cell surface that culminates in effector function and subsequent aGVHD in target tissue. Together, these pathways now represent robust and clinically tractable targets for preventing the initiation of deleterious immunity after alloSCT.

RevDate: 2020-06-11

Dawson L, Benbow N, Fletcher FE, et al (2020)

Addressing ethical challenges in US-based HIV phylogenetic research.

The Journal of infectious diseases pii:5856131 [Epub ahead of print].

In recent years, phylogenetic analysis of HIV sequence data has been used in research studies to investigate transmission patterns between individuals and groups, including analysis of data from HIV prevention clinical trials; in molecular epidemiology; and in public health surveillance programs. Phylogenetic analysis can provide valuable information to inform HIV prevention efforts, but it also has risks, including stigma and marginalization of groups, or potential identification of HIV transmission between individuals. In response to these concerns, an interdisciplinary working group was assembled to address ethical challenges in United States-based HIV phylogenetic research. The working group developed recommendations regarding (1) study design; (2) data security, access, and sharing; (3) community engagement; (4) legal issues; and (5) communication and dissemination. The working group also identified areas for future research and scholarship to promote ethical conduct of HIV phylogenetic research.

RevDate: 2020-06-11

Xiao S, Shimura D, Baum R, et al (2020)

Auxiliary trafficking subunit GJA1-20k protects Connexin43 from degradation and limits ventricular arrhythmias.

The Journal of clinical investigation pii:134682 [Epub ahead of print].

Connexin 43 (Cx43) gap junctions provide intercellular coupling which ensures rapid action potential propagation and synchronized heart contraction. Altered Cx43 localization and reduced gap junction coupling occur in failing hearts, contributing to ventricular arrhythmias and sudden cardiac death. Recent reports have found that an internally translated Cx43 isoform, GJA1-20k, is an auxiliary subunit for the trafficking of Cx43 in heterologous expression systems. Here, we have created a mouse model by using CRISPR technology to mutate a single internal translation initiation site in Cx43 (M213L mutation), which generates full length Cx43 but not GJA1-20k. We find that GJA1M213L/M213L mice have severely abnormal electrocardiograms despite preserved contractile function, reduced total Cx43, reduced gap junctions, and die suddenly at two to four weeks of age. Heterozygous GJA1M213L/WT mice survive to adulthood with increased ventricular ectopy. Biochemical experiments indicate that cytoplasmic Cx43 has a half life that is 50% shorter than membrane associated Cx43. Without GJA1-20k, poorly trafficked Cx43 is degraded. The data support that GJA1-20k, an endogenous entity translated independently of Cx43, is critical for Cx43 gap junction trafficking, maintenance of Cx43 protein, and normal electrical function of the mammalian heart.

RevDate: 2020-06-11

Concannon KF, Thayer JH, Wu QV, et al (2020)

Outcomes Among Homeless Patients With Non-Small-Cell Lung Cancer: A County Hospital Experience.

JCO oncology practice [Epub ahead of print].

PURPOSE: Lung cancer remains the leading cause of cancer death in the United States, with outcomes likely worsened by the presence of poorer outcomes among vulnerable populations such as the homeless. We hypothesized that homeless patients experience delays in biopsy, decreased appointment adherence, and increased overall mortality rates.

METHODS: We conducted a retrospective electronic medical record-based review of all patients with non-small-cell lung cancer (NSCLC; N = 133) between September 2012 and September 2018 at an academic county hospital in Seattle, Washington.

RESULTS: Of the 133 patients treated for NSCLC, 22 (17%) were homeless at the time of their treatment. Among homeless patients with localized lung cancer, the mean time from radiographic finding to biopsy was 248 days, compared with 116 days among housed patients (P = .37). Homeless patients with advanced disease missed a mean of 26% of appointments in the year after diagnosis, compared with 16% among housed patients (P = .03). Homeless patients with advanced NSCLC had a median survival of 0.58 years, versus 1.30 years in housed patients (P = .48).

CONCLUSION: To our knowledge, this is the first US study comparing outcomes among homeless and housed patients with NSCLC within the same institution; we found homeless patients had longer delays to biopsy, increased rates of missed appointments, and a trend toward decreased survival. This study shows potential areas where interventions could be implemented to improve lung cancer outcomes in this patient population.

RevDate: 2020-06-16

Magaret AS, Jacob ST, Halloran ME, et al (2020)

Multigroup, Adaptively Randomized Trials Are Advantageous for Comparing Coronavirus Disease 2019 (COVID-19) Interventions.

RevDate: 2020-06-11

Darrigo LG, Loth G, Kuwahara C, et al (2020)

Hematopoietic Cell Transplantation for Diamond Blackfan anemia: A report from the Pediatric Group of the Brazilian Bone Marrow Transplantation Society.

European journal of haematology [Epub ahead of print].

OBJECTIVES: The aim of this study was to analyze the outcomes of children with Diamond-Blackfan anemia (DBA) treated in Brazil with hematopoietic cell transplantation (HCT).

METHODS: We performed a retrospective analysis of 44 pediatrics patients transplanted between 1990 and 2018. The median age of patients was 5 years, and 57% were male. Twenty-five received their first HCT from an HLA-matched sibling donor (MSD) and 12 from a HLA matched unrelated bone marrow donor (MUD 10/10, n=12) and 7 other HLA mismatched donors (MMD).

RESULTS: After a median follow-up of 4 years, estimate 5-year overall survival (OS) for the entire cohort was 70%, 80% for MSD group, 73% for MUD and 29% for MMD. Thirty-eight out of the 44 evaluable patients engrafted successfully. Primary and secondary graft failure was observed in five and three patients, respectively. Rates of grade II-IV and III-IV acute graft-versus-host disease (aGVHD) were 25 % and 18 % respectively. Nine patients developed chronic GVHD (cGVHD).

CONCLUSION: OS rates observed after HLA matched donors transplant for DBA were comparable to those reported from higher income countries and international registries.

RevDate: 2020-06-12

Dibay Moghadam S, Krieger JW, DKN Louden (2020)

A systematic review of the effectiveness of promoting water intake to reduce sugar-sweetened beverage consumption.

Obesity science & practice, 6(3):229-246.

Objective: To examine whether the promotion of water intake could reduce sugar-sweetened beverage (SSB) consumption or purchases independent of interventions that target SSBs.

Methods: Seven databases were systematically searched. Included studies used water promotion as the primary intervention; used a controlled trial, single group pre-post, or prospective cohort study design; included a measure of SSB consumption or purchase; enrolled human participants of any age who lived in high-income or middle-income countries; contained original data; and appeared in a peer-reviewed English-language article published from 1 January 2000 to January 4, 2019. The search yielded 7068 publications, from which 108 were chosen for full-text review. Seventeen were included in this review.

Results: Nine of the 17 studies were randomized controlled trials, six were nonrandomized controlled trials, and 2 were single-group pre-post studies. Participants were primarily children and adolescents. Interventions included water provision, education or promotion activities. Ten of 17 studies were at low or some/moderate risk of bias. Seven studies showed a statistically significant decrease in SSB consumption of which only 2 were at low or some/moderate risk of bias.

Conclusions: This review found limited evidence that interventions aimed solely at increasing water consumption reduce SSB intake. Further research is needed to investigate whether interventions that combine water promotion and SSB reduction strategies could be synergistic for reducing SSB intake.

RevDate: 2020-06-12

Nicolaides T, Nazemi KJ, Crawford J, et al (2020)

Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002).

Oncotarget, 11(21):1942-1952.

Background: BRAFV600E mutation is present in a subset of pediatric brain tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of BRAFV600E kinase. The goal of this multi-center study conducted through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) was to determine the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs) in children < 18 years with recurrent or progressive BRAFV600E mutant brain tumors. Results: Nineteen eligible patients were enrolled. Eleven patients had received three or more prior therapies. Data reported are from the start of treatment for the first patient (April 30 2014) through August 31 2019. The RP2D was defined as 550 mg/m2 twice daily after DLT criteria adjustment for rash. Related grade ≥ 3 adverse events included secondary keratoacanthoma (n = 1); rash (n =16); and fever (n = 5). Subjects received a median of 23 cycles (range 3-63). Four patients remain on treatment. Centrally reviewed best radiographic responses included 1 complete response, 5 partial responses, and 13 stable disease. The steady-state area under the curve (AUC0-∞median) was 604 mg*h/L (range 329-1052). Methods: Vemurafenib was given starting at 550 mg/m2, twice daily which corresponds to the adult RP2D. Adverse events were graded using the NIH Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Central imaging review was performed. Pharmacokinetic sampling was performed. Conclusions: Vemurafenib has promising anti-tumor activity in recurrent BRAF V600E-positive brain tumors with manageable toxicity. A phase 2 study is ongoing (NCT01748149).

RevDate: 2020-06-11

Wong RL, Ketcham M, Irwin T, et al (2020)

Donor-derived acute promyelocytic leukemia presenting as myeloid sarcoma in a transplanted kidney.

Leukemia pii:10.1038/s41375-020-0903-0 [Epub ahead of print].

RevDate: 2020-06-11

Xue A, Chan M, TS Gujral (2020)

Pan-Cancer Analysis of the Developmental Pathways Reveals Non-Canonical Wnt Signaling as a Driver of Mesenchymal-Type Tumors.

Translational research : the journal of laboratory and clinical medicine pii:S1931-5244(20)30140-7 [Epub ahead of print].

The processes of angiogenesis, cell proliferation, invasion, and migration, and the signaling pathways that drive these events, are activated in both cancer and during embryonic development. Here, we systematically assessed how the activity of major developmental signaling pathways, represented by the expression of genes encoding components of the pathways, correlated with patient survival in ∼8000 patients across 17 cancer types. We also compared the expressed genes enriched in developmental pathways with those associated with epithelial-mesenchymal transition (EMT) both in a cancer cohort and in mice during embryonic development. We found that EMT and gene expression profiles consistent with high activity of several developmental pathways, including the TGFβ, Notch, and non-canonical Wnt pathways, significantly correlated with poor patient survival in multiple cancer types. We investigated individual components of these pathways and found that expression of the gene encoding the non-canonical Wnt receptor, frizzled 2 (FZD2), is highly correlated with both poor patient survival and gene expression indicating EMT in the tumors. Further mechanistic studies and pathway analyses revealed that FZD2-regulated genes in cancer cells in culture or FZD2-regulated gene sets from the TCGA data or FZD2-regulated genes involved in mouse organogenesis converged in EMT-associated biological processes, suggesting that FZD2 is a key driver of mesenchymal-like cell state and thus a contributor to cancer progression and metastasis.

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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 )