tbuckley/cabot-search huggingface dataset:
Patterns and Causes of Signed Linkage Disequilibria in Flies and Plants
Authors: George Sandler, Stephen I Wright, Aneil F Agrawal
Journal: Molecular Biology and Evolution (2021)

Most empirical studies of linkage disequilibrium (LD) study its magnitude, ignoring its sign. Here, we examine patterns of signed LD in two population genomic data sets, one from Capsella grandiflora and one from Drosophila melanogaster. We consider how processes such as drift, admixture, Hill-Robertson interference, and epistasis may contribute to these patterns. We report that most types of mutations exhibit positive LD, particularly, if they are predicted to be less deleterious. We show with simulations that this pattern arises easily in a model of admixture or distance-biased mating, and that genome-wide differences across site types are generally expected due to differences in the strength of purifying selection even in the absence of epistasis. We further explore how signed LD decays on a finer scale, showing that loss of function mutations exhibit particularly positive LD across short distances, a pattern consistent with intragenic antagonistic epistasis. Controlling for genomic distance, signed LD in C. grandiflora decays faster within genes, compared with between genes, likely a by-product of frequent recombination in gene promoters known to occur in plant genomes. Finally, we use information from published biological networks to explore whether there is evidence for negative synergistic epistasis between interacting radical missense mutations. In D. melanogaster networks, we find a modest but significant enrichment of negative LD, consistent with the possibility of intranetwork negative synergistic epistasis.
Aspirin and left ventricular assist devices: rationale and design for the international randomized, placebo‐controlled, non‐inferiority ARIES HM3 trial
Authors: Mandeep R. Mehra, Daniel L. Crandall, Finn Gustafsson, Ulrich P. Jorde, Jason N. Katz, Ivan Netuka, Nir Uriel, Jean M. Connors, Poornima Sood, Gerald Heatley, Francis D. Pagani
Journal: European Journal of Heart Failure (2021)

Abstract Aims Over decades, left ventricular assist device (LVAD) technology has transitioned from less durable bulky pumps to smaller continuous‐flow pumps which have substantially improved long‐term outcomes and quality of life. Contemporary LVAD therapy is beleaguered by haemocompatibility‐related adverse events including thrombosis, stroke and bleeding. A fully magnetically levitated pump, the HeartMate 3 (HM3, Abbott, USA) LVAD, has been shown to be superior to the older HeartMate II (HMII, Abbott, USA) pump by improving haemocompatibility. Experience with the HM3 LVAD suggests near elimination of de‐novo pump thrombosis, a marked reduction in stroke rates, and only a modest decrease in bleeding complications. Since the advent of continuous‐flow LVAD therapy, patients have been prescribed a combination of aspirin and anticoagulation therapy on the presumption that platelet activation and perturbations to the haemostatic axis determine their necessity. Observational studies in patients implanted with the HM3 LVAD who suffer bleeding have suggested a signal of reduced subsequent bleeding events with withdrawal of aspirin. The notion of whether antiplatelet therapy can be avoided in an effort to reduce bleeding complications has now been advanced. Methods To evaluate this hypothesis and its clinical benefits, the Antiplatelet Removal and Hemocompatibility Events with the HeartMate 3 Pump (ARIES HM3) has been introduced as the first‐ever international prospective, randomized, double‐blind and placebo‐controlled, non‐inferiority trial in a patient population implanted with a LVAD. Conclusion This paper reviews the biological and clinical role of aspirin (100 mg) with LVADs and discusses the rationale and design of the ARIES HM3 trial.
The biogenesis and biological function of PIWI-interacting RNA in cancer
Authors: Silu Chen, Shuai Ben, Junyi Xin, Shuwei Li, Rui Zheng, Hao Wang, Lulu Fan, Mulong Du, Zhengdong Zhang, Meilin Wang
Journal: Journal of Hematology & Oncology (2021)

Small non-coding RNAs (ncRNAs) are vital regulators of biological activities, and aberrant levels of small ncRNAs are commonly found in precancerous lesions and cancer. PIWI-interacting RNAs (piRNAs) are a novel type of small ncRNA initially discovered in germ cells that have a specific length (24-31 nucleotides), bind to PIWI proteins, and show 2'-O-methyl modification at the 3'-end. Numerous studies have revealed that piRNAs can play important roles in tumorigenesis via multiple biological regulatory mechanisms, including silencing transcriptional and posttranscriptional gene processes and accelerating multiprotein interactions. piRNAs are emerging players in the malignant transformation of normal cells and participate in the regulation of cancer hallmarks. Most of the specific cancer hallmarks regulated by piRNAs are involved in sustaining proliferative signaling, resistance to cell death or apoptosis, and activation of invasion and metastasis. Additionally, piRNAs have been used as biomarkers for cancer diagnosis and prognosis and have great potential for clinical utility. However, research on the underlying mechanisms of piRNAs in cancer is limited. Here, we systematically reviewed recent advances in the biogenesis and biological functions of piRNAs and relevant bioinformatics databases with the aim of providing insights into cancer diagnosis and clinical applications. We also focused on some cancer hallmarks rarely reported to be related to piRNAs, which can promote in-depth research of piRNAs in molecular biology and facilitate their clinical translation into cancer treatment.
Existing evidence supports clinical trials on interventions preventing ventricular assist device infection in patients colonized with <scp><i>Staphylococcus aureus</i></scp>. Letter regarding the article ‘Association of preoperative infections, nasal <scp><i>Staphylococcus aureus</i></scp> colonization and gut microbiota with left ventricular assist device outcomes’
Authors: Dennis Nurjadi, Arjang Ruhparwar, Philipp Zanger
Journal: European Journal of Heart Failure (2021)

We read with great interest the work of Yuzefpolskaya et al.1 published in this Journal. However, we would like to bring to the readers' attention that the discussion and conclusions drawn by the authors do not include the results of one prospective cohort study which demonstrated that Staphylococcus aureus nasal colonization prior to left ventricular assist device (LVAD) implantation is associated with about 5-fold increased risk of S. aureus-associated device infection during the first year of follow-up (incidence rate ratio 4.65, 95% confidence interval 1.30–20.65, P = 0.009).2 Besides, that study confirmed the endogenous route of infection by presenting data on matching whole-genomes when comparing colonizing S. aureus cryopreserved prior to LVAD implantation and isolates from LVAD infection post-implantation in a given patient.2 We feel that these findings, which we had published 6 months earlier,2 are of utmost relevance when contextualizing the results by Yuzefpolskaya et al., since they put their findings into a rather ‘confirmatory’ than the originally presented ‘hypothesis generating’ perspective.1 More specifically, based on the combined evidence of both studies,1, 2 it seems doubtful whether there is still equipoise and thus ethical justification for additional research, before we ‘stratify patients' risk for infectious complications after LVAD,’ as concluded by Yuzefpolskaya et al.1 Therefore, we believe that our earlier work2 in conjunction with the observations by Yuzefpolskaya et al.1 form a sound evidence basis for clinical trials on infection prevention in S. aureus-colonized patients that undergo LVAD therapy. Hence, we strongly oppose the call for more confirmatory research on the association of S. aureus colonization and LVAD infection by Yuzefpolskaya et al.1 and ask the research community, based on the existing evidence, to refrain from any further delay in clinical development or adaptation of life-saving decolonization protocols that have proven useful in similar settings.3 Open Access funding enabled and organized by Projekt DEAL.
Biology of Germinal Center B Cells Relating to Lymphomagenesis
Authors: Katia Basso
Journal: HemaSphere (2021)

The germinal center (GC) reaction is a key feature of adaptive humoral immunity. GCs represent the site where mature B cells refine their B-cell receptor (BCR) and are selected based on the newly acquired affinity for the antigen. In the GC, B cells undergo multiple cycles of proliferation, BCR remodeling by immunoglobulin somatic hypermutation (SHM), and affinity-based selection before emerging as effector memory B cells or antibody-secreting plasma cells. At least 2 histologically and functionally distinct compartments are identified in the GC: the dark zone (DZ) and the light zone (LZ). The proliferative burst and immunoglobulin remodeling by SHM occur prevalently in the DZ compartment. In the LZ, GC B cells undergo an affinity-based selection process that requires the interaction with the antigen and accessory cells. GC B cells are also targeted by class switch recombination, an additional mechanism of immunoglobulin remodeling that ensures the expression of diverse isotype classes. These processes are regulated by a complex network of transcription factors, epigenetic modifiers, and signaling pathways that act in concert with mechanisms of intra-GC B-cell trafficking. The same mechanisms underlying the unique ability of GC B cells to generate high affinity antibodies and ensure immunological memory are hijacked during lymphomagenesis and become powerful weapons for malignant transformation. This review will summarize the main processes and transcriptional networks that drive GC B-cell development and are relevant for human B-cell lymphomagenesis.
Health care utilization and outcomes of sepsis in HIV versus non-HIV patients with Burkitt Lymphoma: A nationwide analysis.
Authors: Binav Baral, Muhammad Junaid Tariq, Prasanth Lingamaneni, Anmol Baranwal, Trilok Shrivastava, Muhammad Usman Almani, Shweta Gupta
Journal: Journal of Clinical Oncology (2021)

e19561 Background: Burkitt lymphoma (BL) is an aggressive AIDS-defining malignancy, the incidence of which has not declined over the last 2 decades despite use of antiretroviral therapy. HIV-BL is more advanced at diagnosis compared to non-HIV-BL with increased risks of immunosuppressive chemotherapy (Lancet Hematology 2020;7(8):e594-e600). We attempted to explore and quantify the prevalence, outcomes and healthcare utilization of HIV-BL vs non-HIV-BL patients admitted with sepsis. Methods: Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (NIS) database was queried to identify all adult HIV and non-HIV admissions with BL between 2016–2018 with a primary diagnosis of sepsis. The groups were compared for demographic differences, inpatient mortality, length of stay (LOS) and hospital charges. Secondary outcomes studied included rates of septic shock (SS), acidosis, acute kidney injury (AKI), tumor lysis syndrome (TLS), pancytopenia, anemia, neutropenia, protein energy malnutrition (PEM) and history of bone-marrow/stem-cell transplant. Statistics were performed using the t-test, z-test and chi-square test. Results: A total of 2310 HIV-BL admissions comprising 205 (8.9%) with sepsis and 11,950 non-HIV-BL admissions with 865 (7.2%) with sepsis (p = 0.006) were identified. Compared to non-HIV cohort, HIV-BL patients were significantly younger (mean age 43.6 versus 55.3 years, p = 0.001) with few over 65 years old (2.4% vs 36%, p = 0.001). Both groups had similar gender ratio, but a higher number of HIV-BL admissions were African American (AA) (51.4% vs 4.9%, p = 0.001), on Medicaid (31.7% vs 15.6%, p &lt; 0.0001), from lowest quartile income zip codes (p &lt; 0.0001) and more likely to be treated at teaching hospitals (73.2% vs 54.9%, p &lt; 0.0001). The overall inpatient mortality was 21.9% in HIV-BL vs 15.6% in non-HIV-BL (p = 0.02). HIV-BL reported increased mean LOS (9 vs 8 days, p = NS) and average $39,599 more in hospital charges for each HIV-BL admission compared to non-HIV-BL with sepsis (amounting to over $8 million over 3 years). The rates of anemia, neutropenia, TLS, AKI, SS, TLS and PEM were similar (p = NS) between the groups. Conclusions: Nationwide, HIV-BL patients had significantly higher rates of sepsis despite being significantly younger. They were also more likely to be AA from lower socioeconomic zip codes and more likely to be on Medicaid. The mean inpatient LOS and hospital charges, although not statistically significant, were higher in HIV-BL compared to their non-HIV counterparts. Also, the difference in total charges for all HIV-BL admissions amounted to over $8 million extra compared to non-HIV-BL in 3 years. These trends need to be evaluated in prospective studies to help identify interventions to improve clinical outcomes and healthcare utilization.
NCT04552223: A phase II study of nivolumab plus BMS-986016 (relatlimab) in patients with metastatic uveal melanoma (UM) (CA224-094).
Authors: Jose Lutzky, Lynn G. Feun, Norma Magallanes, Deukwoo Kwon, J. William Harbour
Journal: Journal of Clinical Oncology (2021)

TPS9590 Background: Uveal melanoma (UM) is a rare disease but 50% of patients will eventually develop metastatic disease, for which not effective therapy is available. Liver-directed therapies, immunotherapy, targeted therapy and chemotherapy have limited activity [1]. Lymphocyte activation gene 3(LAG-3) is an immune checkpoint receptor associated with decreased T-cell effector function and tumor escape. Preclinical models have shown that dual inhibition of LAG-3 and PD-1 blockade generates synergistic anti-tumor activity [2]. Recent preclinical data indicates that uveal melanoma CD8+ T cells express the checkpoint receptor LAG3 to a greater extent than PD1 or CTLA4 [3,4]. Therefore, LAG3 is a potential candidate for checkpoint inhibitor immunotherapy in UM. Relatlimab is a human LAG-3-specific antibody isolated from immunized transgenic mice which binds to a defined epitope on LAG-3 with high affinity and specificity and potently blocks the interaction of LAG-3 with its ligand, MHC Class II. Methods: This is an open-label, single arm, single site investigator-initiated phase II study, NCT04552223. Based on Simon two-stage minimax design, 13 patients will be enrolled in Stage 1. If at least one response is noted, the study will proceed to Stage 2 and enroll an additional 14 patients. The null hypothesis will be rejected if 4 or more responses are observed among 27 patients. This design achieves 5% type I error and 80% power when the true ORR is 20%. The trial opened to accrual in December 2020. As of February 15, 2021 four patients had been enrolled the first stage of accrual. Main eligibility criteria include patients with biopsy proven metastatic uveal melanoma, previously untreated with PD-1, CTLA-4 and/or LAG-3 blocking antibodies and in good performance status. Enrolled patients are treated in the outpatient setting. Nivolumab 480 mg is mixed in the same bag with relatlimab 160 mg and administered intravenously over 60 minutes every 4 weeks until disease progression or intolerable toxicity for up to 24 months. The primary endpoint is best objective response rate (ORR). Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), median duration of response (mDOR), and adverse events (AEs). Correlative studies will evaluate pre- and post-treatment characteristics of T cells in the tumor microenvironment and blood. Clinical trial information: NCT04552223.
Matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP signaling axis
Authors: Yaru Guo, Feng Mei, Ying Huang, Siqin Ma, Yan Wei, Xuehui Zhang, Mingming Xu, Ying He, Boon Chin Heng, Lili Chen, Xuliang Deng
Journal: Bioactive Materials (2021)

Endothelial tip cell outgrowth of blood-vessel sprouts marks the initiation of angiogenesis which is critical in physiological and pathophysiological procedures. However, how mechanical characteristics of extracellular matrix (ECM) modulates tip cell formation has been largely neglected. In this study, we found enhanced CD31 expression in the stiffening outer layer of hepatocellular carcinoma than in surrounding soft tissues. Stiffened matrix promoted sprouting from endothelial cell (EC) spheroids and upregulated expressions of tip cell-enriched genes in vitro. Moreover, tip cells showed increased cellular stiffness, more actin cytoskeleton organization and enhanced YAP nuclear transfer than stalk and phalanx ECs. We further uncovered that substrate stiffness regulates FAK and Paxillin phosphorylation in focal adhesion of ECs promoting Rac1 transition from inactive to active state. YAP is subsequently activated and translocated into nucleus, leading to increased tip cell specification. p-Paxillin can also loosen the intercellular connection which also facilitates tip cell specification. Collectively our present study shows that matrix stiffness modulates tip cell formation through p-PXN-Rac1-YAP signaling axis, shedding light on the role of mechanotransduction in tip cell formation. This is of special significance in biomaterial design and treatment of some pathological situations.
Genomic alterations and associated pathway abnormalities in Ewing sarcoma.
Authors: Adam Rock, Warren Allen Chow, An Uche, Sherri Z. Millis
Journal: Journal of Clinical Oncology (2021)

11532 Background: Ewing Sarcoma (ES) is an aggressive, translocation-associated, bone cancer associated with a poor prognosis in the recurrent or metastatic setting. ES is identified by the canonical balanced reciprocal chromosomal translocation involving EWSR1 and ETS transcription factors. Secondary somatic alterations in ES are rarely described and genomic alterations (GA) affecting various molecular pathways may work synergistically with ETS-FL1 translocations to promote oncogenesis. Alterations in fibroblast growth factor receptor 4 (FGFR4), a receptor tyrosine kinase protein that functions in cellular processes, have been observed to affect carcinogenesis. Moreover, the FGFR4-Gly388Arg (G388R) single nucleotide polymorphism (SNP) is found to increase the risk of cancer with mouse embryonic fibroblasts derived from knock-in strain of homologous Fgfr4 G385R mice exhibiting a transformed phenotype. We sought to further evaluate the frequency of FGFR4 G388R SNP in relation to other identifiable pathway alterations observed with Comprehensive Genomic Profiling (CGP). Methods: Next generation sequencing (NGS) analysis was obtained in the context of clinical care with clinical status, outcomes, and source acquisition (primary tumor, metastasis, or recurrence) unknown to Foundation Medicine. CGP, FoundationOne Heme, evaluated GAs including base substitutions, indels, amplifications, copy number alterations, gene fusions and rearrangements. 189 samples were assayed by hybrid-capture based CGP, including 406 DNA-sequenced genes in addition to 265 RNA-sequenced genes commonly reported to be rearranged in cancer, as previously described. Tumor mutational burden was assessed from a minimum 1.4 Mb sequenced DNA. Microsatellite instability (MSI) status was determined by a novel algorithm analyzing 114 specific loci. Results: The median age of evaluated patients was 20 (range 0-70) with the number of alterations averaging 7 per patient. Pathways noted to be altered in the presence of FGFR388R SNP occurred frequently with the following pathways most observed: MAPK (33%), WNT (32%), NOTCH1 (20%), HRR (19%), Histone/chromatin remodeling (18%). FGFR388R SNP was observed in more than half (51%) of evaluated samples. Most affected pathways irrespective of FGFR388R SNP status included: MAPK (n = 89), HRR (n = 75), and PIK3 (n = 64). All evaluated samples were TMB low ( &lt; 10 mut/mb) and Microsatellite Stable. Conclusions: Secondary GAs affecting major pathways were observed in high frequency, often co-occurring with the FGFR4 G388R SNP. Secondary alteration of known oncogenic pathways may contribute to sarcoma formation in ES potentially informing further therapeutic strategies in the future.
Disparity between the use of postoperative psychosocial and physical services among older adults with head and neck cancer.
Authors: Gabriel T. Raab, Daniel Restifo, Amy L. Tin, Kaveh Zakeri, Armin Shahrokni
Journal: Journal of Clinical Oncology (2021)

e24016 Background: It is unclear whether older adults undergoing head and neck cancer (HNC) surgery have significant functional and mental health impairments perioperatively. We examined postoperative physical, nutritional and psychosocial service use among a cohort of older adults with HNC co-managed by geriatricians and surgeons. Methods: Our sample consisted of older adults who were referred to the Geriatrics Service at MSKCC between 2015-2019 and took a geriatric assessment (GA) prior to undergoing HNC surgery. Physical, nutritional and psychosocial service utilization during the patient’s stay was assessed. Physical services included a physical, occupational or rehabilitation consult. Nutritional services consisted of speech and swallow or nutritional consult. Psychosocial services consisted of a psychiatry, psychology, or social work consult. All patients were comanaged by geriatricians and surgeons. Relationships between each service use, all 12 geriatric deficits, demographic, and surgical characteristics were assessed using chi-squared analysis and t-test for continuous variables. Results: 159 patients (median age 81) were included. The median time in the OR was 342 min and the median length of stay (LOS) was 6 days. The most common GA impairments were major distress (61%), depression (59%), Social Activity Limitation (SAL) (53%) and deficits in Activities of Daily Living (ADL) (44%). Nutritional and physical services were used much more frequently than psychosocial services (79% and 85% vs 31%; p=.01 and p=.003, respectively). Lower ADL, increasing OR time and LOS were statistically associated with utilization of the three services and SAL was associated with a greater proportion of physical and psychosocial consults (Table). No demographic characteristics were associated with any of the services. Only 38% of patients with major distress and 40% of patients with depression had a mental health consult. In comparison, 93% of patients with an abnormal TUG had a physical consult and 92% of patients with weight loss greater than 10 pounds prior to surgery got a nutritional consult. Conclusions: Many older adults with head and neck cancer experience aging-related impairments. Physical impairments are more commonly addressed than psychosocial impairments. Future studies should aim to identify and overcome barriers to addressing psychosocial issues in HNC patients. [Table: see text]