tbuckley/cabot-search huggingface dataset:
SRSF3 and SRSF7 modulate 3′UTR length through suppression or activation of proximal polyadenylation sites and regulation of CFIm levels
Authors: Oliver Daniel Schwich, Nicole Blümel, Mario Keller, Marius Wegener, Samarth Thonta Setty, Melinda Elaine Brunstein, Ina Poser, Igor Ruiz De Los Mozos, Beatrix Suess, Christian Münch, François McNicoll, Kathi Zarnack, Michaela Müller-McNicoll
Journal: Genome biology (2021)

Alternative polyadenylation (APA) refers to the regulated selection of polyadenylation sites (PASs) in transcripts, which determines the length of their 3' untranslated regions (3'UTRs). We have recently shown that SRSF3 and SRSF7, two closely related SR proteins, connect APA with mRNA export. The mechanism underlying APA regulation by SRSF3 and SRSF7 remained unknown.Here we combine iCLIP and 3'-end sequencing and find that SRSF3 and SRSF7 bind upstream of proximal PASs (pPASs), but they exert opposite effects on 3'UTR length. SRSF7 enhances pPAS usage in a concentration-dependent but splicing-independent manner by recruiting the cleavage factor FIP1, generating short 3'UTRs. Protein domains unique to SRSF7, which are absent from SRSF3, contribute to FIP1 recruitment. In contrast, SRSF3 promotes distal PAS (dPAS) usage and hence long 3'UTRs directly by counteracting SRSF7, but also indirectly by maintaining high levels of cleavage factor Im (CFIm) via alternative splicing. Upon SRSF3 depletion, CFIm levels decrease and 3'UTRs are shortened. The indirect SRSF3 targets are particularly sensitive to low CFIm levels, because here CFIm serves a dual function; it enhances dPAS and inhibits pPAS usage by binding immediately downstream and assembling unproductive cleavage complexes, which together promotes long 3'UTRs.We demonstrate that SRSF3 and SRSF7 are direct modulators of pPAS usage and show how small differences in the domain architecture of SR proteins can confer opposite effects on pPAS regulation.
An Interesting Case of Metastatic Papillary Adenocarcinoma
Authors: Menaka Mahendran, Dara Wakefield, Peruvemba Sriram
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"An Interesting Case of Metastatic Papillary Adenocarcinoma." American Journal of Respiratory and Critical Care Medicine, 203(12), pp. e37–e39
Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine
Authors: Maria Prendecki, Candice Clarke, Jonathan Brown, Alison Cox, Sarah Gleeson, Mary Guckian, Paul Randell, Alessia Dalla Pria, Liz Lightstone, Xiao-Ning Xu, Wendy Barclay, Stephen P McAdoo, Peter Kelleher, Michelle Willicombe
Journal: The Lancet (2021)
Barriers and facilitators of germline genetic evaluation for prostate cancer.
Authors: Stacy Loeb, Randall Li, Tatiana Sanchez Nolasco, Nataliya Byrne, Heather H. Cheng, Amy Leader, Veda N. Giri
Journal: Journal of Clinical Oncology (2021)

28 Background: Genetic counseling and germline testing have an increasingly important role for patients with prostate cancer, with the recent approval of precision therapeutic options and implications for cancer screening in families. Although current guidelines recommend germline genetic evaluation for all men with metastatic prostate cancer and some with localized disease, recent data suggests it is underutilized. Our objective was to perform a qualitative study of barriers and facilitators of genetic counseling and germline genetic testing among physicians who manage prostate cancer. Methods: We conducted semi-structured interviews with medical oncologists, radiation oncologists, and urologists from different U.S. practice settings until thematic saturation was achieved at n = 14. The interview guide was based on the Tailored Implementation in Chronic Diseases Framework to identify key determinants of practice. Interview transcripts were independently coded by ≥2 investigators using a constant comparative method. Disagreements were resolved by team discussion. NVivo12 was used for data organization and analysis. Results: The decision to perform or refer for germline genetic evaluation is affected by factors at multiple levels (Table). Although patient factors play a role in some cases (e.g., refusal of testing for specific reasons), the dominant themes in the decision to conduct germline genetic evaluation were primarily at the physician and organizational level. Physician knowledge of prostate cancer genetics, coordination of care between providers, perceptions of the guidelines for genetic testing, and concerns about cost were most frequently discussed as the main factors affecting utilization of germline genetic evaluation. Conclusions: There are currently numerous barriers to the performance of germline genetic evaluation for prostate cancer. Efforts to expand physician education and to facilitate coordination of care surrounding genetic evaluation are important to promote guideline-concordant care. [Table: see text]
Post-hoc analysis of long-term outcomes in patients with CR, PR, or SD to pembrolizumab (pembro) or platinum-based chemotherapy (chemo) as 1L therapy for advanced urothelial carcinoma (UC) in KEYNOTE-361.
Authors: Yohann Loriot, Ajjai Shivaram Alva, Tibor Csőszi, Mustafa Ozguroglu, Nobuaki Matsubara, Lajos Geczi, Susanna Y. Cheng, Yves Fradet, Stephane Oudard, Christof Vulsteke, Rafael Morales-Barrera, Aude Flechon, Seyda Gunduz, Alejo Rodriguez-Vida, Ronac Mamtani, Evan Y. Yu, Chih-Chin Liu, Kentaro Imai, Blanca Homet Moreno, Thomas Powles
Journal: Journal of Clinical Oncology (2021)

435 Background: The phase III KEYNOTE-361 study compared efficacy and safety of 1L pembro + chemo or pembro vs chemo in pts with advanced UC. The trial did not meet its primary endpoints of PFS or OS superiority for pembro + chemo vs chemo; formal testing for OS for pembro vs chemo was not performed. We present a post hoc landmark analysis to examine the durability of CR/PR/SD and long-term survival in pts with CR, PR, or SD to pembro vs chemo at week 9 in KEYNOTE-361 (NCT02853305). Methods: Landmark analyses of OS by CR/PR/SD at 9 weeks after randomization in the ITT population were performed. Pts were included if they had a best response of CR/PR/SD per RECIST v1.1 by blinded independent central review at the landmark date of week 9 (first imaging assessment per study protocol). Duration of CR/PR/SD and OS were estimated by the Kaplan-Meier method. No formal comparisons were performed. Results: 307 pts were randomized to receive pembro and 352 pts to receive chemo in the KEYNOTE-361 study. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 32.5 (22.0-42.4) mo for the pembo arm and 31.4 (22.1-41.6) mo for the chemo arm. In the landmark analysis, fewer pts had CR/PR/SD at week 9 with pembro (n=137 [45%]) than with chemo (n=253 [72%]). Median (range) duration of response for pembro vs chemo was 18.7 (4.4+-35.4+) vs 12.3 (0.0+-29.7+) mo for pts with CR, and 35.0 (1.1-36.1+) vs 6.1 (0.0+-36.3+) mo for pts with PR. Median (range) duration of SD was 4.8 mo (0.0-38.2+) with pembro and 4.6 mo (0.0-16.1+) with chemo. Median OS (95% CI) for pembro vs chemo was not reached (NR) (25.5-NR) vs NR (19.1-NR) for pts with CR; NR (NR-NR) vs 14.8 mo (12.1-21.0) for pts with PR; and 18.5 mo (13.8-28.8) vs 11.1 mo (8.1-14.6) for pts with SD, respectively. Long-term OS rates were higher with pembro vs chemo across all groups (CR/PR/SD) at week 9 (Table). Conclusions: In this post hoc landmark analysis, chemo was associated with more initial responses than pembro, whereas pembro was associated with longer median duration of CR and PR, and generally longer median OS than chemo. Among pts who achieved CR/PR/SD at week 9, the relative OS benefit for pembro vs chemo increased over time. Clinical trial information: NCT02853305. [Table: see text]
Prognostic value of simple blood biomarkers of systemic inflammation for metastatic renal cell carcinoma (mRCC) patients who undergo cytoreductive nephrectomy (CNx).
Authors: Jigi Moudgil-Joshi, Mark Stares, Alex Laird, Steve Leung, Jahangeer Malik, Aravindhan Sundaramurthy, Stefan N. Symeonides
Journal: Journal of Clinical Oncology (2021)

350 Background: The role of cytoreductive nephrectomy (CNx) in patients with metastatic renal cell carcinoma (mRCC) is currently in question. Assessing the benefits and risks of CNx is challenging, with a lack of validated prognostic tools. Biomarkers of the systemic inflammatory response have prognostic utility in mRCC and are included in the IMDC score used to predict survival in patients with mRCC treated with systemic therapy. We sought to investigate their role in patients with mRCC who had undergone CNx. Methods: A cohort of 68 patients, suitable for first-line VEGFR inhibitor (VEGFRi) systemic therapy, who had undergone CNx for mRCC, were identified from a clinical database of patients referred to a regional mRCC service. Inflammatory biomarkers from routine blood tests (haemoglobin, white cell count, neutrophil count, platelets, C-reactive protein (CRP), albumin) and the IMDC score, measured at the time of diagnosis of mRCC, were recorded. The relationship between these and overall survival and time to VEGFRi (tVEGFRi) was examined using Kaplan-Meier and Cox-regression methods. Results: Data were available for 68 patients. Median survival was 33.7 months. On multivariate analysis, albumin ( &lt; 35g g/dL v ≥35 g/dL) and CRP (≤ 10 mg/L v &gt; 10 mg/L) were independently associated with overall survival (p = 0.027 and p = 0.034 respectively). Albumin stratified survival from 24.7 to 87.2 months (p &lt; 0.0001) and CRP from 29.4 to 82.3 months (p = 0.004). 40 (59%) patients subsequently commenced VEGFRi therapy. Median tVEGFRi was 18.1 months, with only 5 (7%) patients commencing treatment within 3 months. 16 (24%) patients yet to receive systemic therapy remain alive after a median 54.0 months follow-up. On multivariate analysis, albumin was also predictive of tVEGFRi (p = 0.037), stratifying tVEGFRi from 6.07 to 45.7 months (p = 0.002). Conclusions: These results highlight that biomarkers of the systemic inflammatory response are strong prognostic factors in mRCC patients who have undergone CNx. Albumin and CRP, but not IMDC, predict survival in this patient group. Significantly, the population investigated here differ from those included in the CARMENA and SURTIME studies, with a majority undergoing surveillance prior to VEGFRi therapy. Our results support a role for CNx in patients where deferred systemic therapy strategies may be employed. Albumin may assist in clinical decision making when considering when to start systemic therapy. We advocate further studies to investigate the prognostic role of these simple, routine clinical tests in patients with mRCC undergoing CNx.
Abstract 13440: Nighttime Hemodynamics Predicts Post-Discharge Outcomes in Patients Hospitalized for Acute Heart Failure
Authors: Hao-Chih Chang, Shih-Hsien Sung, Chen-Huan Chen
Journal: Circulation (2019)

Introduction: Volume overload and perturbations of pulsatile hemodynamics may precipitate acute decompensation of heart failure (AHF). Hypothesis: Nocturnal thoracic volume overload due to rostral ...
Noxious cold stimulation: pro–con perspectives on the hypothermic effect on experimentally evoked cough
Authors: Shuxin Zhong, Liman Fang, Zhe Chen, Chen Zhan, S. Dushinka de Silva, Kefang Lai, Ruchong Chen
Journal: European Respiratory Journal (2021)

We read with great interest in the recent article by Hilton et al. [1] published in the European Respiratory Journal , about the effect of pain conditioning on experimentally evoked cough; the hypothesis and protocol are well thought out. The study showed that noxious cold-water-induced pain significantly reduced capsaicin-evoked cough; however, it was less effective in refractory chronic cough (RCC) patients than healthy volunteers. The results indicated that endogenous inhibitory control mechanisms, especially those activated by noxious stimuli-inducing pain (conditioned pain modulation, CPM), can modulate cough response evoked by capsaicin. Impairment of such mechanisms may contribute to persistent coughing in RCC patients. The cold stimulation effect on the body may have bidirectional influences on cough response in differential exposure temperature and areas <https://bit.ly/38nVohD>
Distinct cytokines predict response to immunotherapy and targeted therapy in metastatic renal cell carcinoma (mRCC).
Authors: Alex Chehrazi-Raffle, Luis A Meza, Marice Alcantara, Nicholas Salgia, Nazli Dizman, Paulo Gustavo Bergerot, Joann Hsu, Marcin Kortylewski, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2021)

352 Background: Previous studies have suggested a link between plasma cytokines and mRCC outcomes with systemic therapy. In a prospective study, we assessed whether plasma cytokines could separately predict outcome with immunotherapy or targeted therapy. Methods: Eligible patients (pts) had histologically proven mRCC with intent to receive a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or an immune checkpoint inhibitor (ICI). Immunologic profiles were evaluated at several time points using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit (CB) was defined as complete response, partial response, or stable disease ≥ 6 months. Results: A total of 56 pts (40:16 M:F) were enrolled; 23 pts and 33 pts received VEGF-TKI and ICI, respectively. The most common VEGF-TKI was cabozantinib; the most common ICI was nivolumab. CB was similar between VEGF-TKI and ICI arms (65% vs 54%). Pts with CB from VEGF-TKIs had lower pretreatment levels of IL-6 (p = 0.02), IL-1RA (p = 0.03), and G-CSF (p = 0.02). Major shifts in plasma cytokines were seen as early as one month; these data will be presented. Conclusions: Distinct plasma cytokines predict benefit with VEGF-TKIs and ICIs. Ongoing work will incorporate analysis of pts receiving VEGF-TKI and ICI combination therapy.
Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis
Authors: Rachel M Glicksman, Ur Metser, Douglass Vines, John Valliant, Zhihui Liu, Peter W Chung, Robert G Bristow, Antonio Finelli, Robert Hamilton, Neil E Fleshner, Nathan Perlis, Alexandre R Zlotta, David Green, Andrew Bayley, Joelle Helou, Srinivas Raman, Girish Kulkarni, Charles Catton, Tony Lam, Rosanna Chan, Padraig Warde, Mary Gospodarowicz, David A Jaffray, Alejandro Berlin
Journal: European Urology (2021)
MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism
Authors: Koki Ueda, Rajni Kumari, Emily Schwenger, Justin C. Wheat, Oliver Bohorquez, Swathi-Rao Narayanagari, Samuel J. Taylor, Luis A. Carvajal, Kith Pradhan, Boris Bartholdy, Tihomira I. Todorova, Hiroki Goto, Daqian Sun, Jiahao Chen, Jidong Shan, Yinghui Song, Cristina Montagna, Shunbin Xiong, Guillermina Lozano, Andrea Pellagatti, Jacqueline Boultwood, Amit Verma, Ulrich Steidl
Journal: Cancer Cell (2021)
COVID-19 in 2021—Continuing Uncertainty
Authors: Carlos del Rio, Preeti Malani
Journal: JAMA (2021)

UncertaintyMore than a year has passed since the first confirmed case of SARS-CoV-2 infection in the US was reported on January 20, 2020.What followed was an unprecedented year with nearly 30 million documented infections and more than 500 000 excess deaths in the US due to SARS-CoV-2.Alongside this devastation is the successful development and deployment of multiple safe and effective vaccines. 1o date, almost 80 million doses of vaccine have been administered in the US with some experts suggesting that the extent of disease, including the number of deaths, will continue to decline between now and summer.Yet moving to the next phase of the pandemic remains a challenge; clinicians and patients have many questions that may not have clear answers.This Viewpoint summarizes the current best evidence to some of these complex questions.Which Vaccine Is Best and How Should They Be Deployed?Currently,2mRNAvaccines(createdbyPfizer-BioNTech and Moderna) and 1 adenovirus-vectored vaccine (Janssen/Johnson & Johnson) have received Emergency Use Authorization (EUA) by the US Food and Drug Administration (FDA).These vaccines have proven to be safe and highly effective in preventing severe COVID-19 and death and likely also prevent transmission. 1he Janssen vaccine is the first adenovirusvectored vaccine to be evaluated and to receive EUA by the FDA.This vaccine uses a cold virus (Ad26) engineered to carry the genetic code of the SARS-CoV-2 spike protein.As a single-dose vaccine, it offers practical advantages in terms of deployment and scale-up.However, comparing the different vaccines is more difficult with respect to efficacy.The 2 mRNA vaccines have similar efficacy of approximately 95% for the prevention of symptomatic COVID-19 and nearly 100% efficacy in preventing death from COVID-19 after 2 doses. 1 However, neither of these vaccines were tested when more recently identified SARS-CoV-2 variants like B.1.1.7 and B.1.135were the predominant ones in circulation.The Janssen vaccine was 66% protective against moderate to severe COVID-19 although this varied by geographic location: 72% protective in the US while only 57% protective in South Africa, reflecting the various variants in each country. 2 However, the vaccine was 85% protective against severe disease and 100% protective against hospitalization and death from COVID-19 without geographic differences. 2t present, given the differences between the 3 vaccines, which vaccine should individuals receive?Initially the answer is that they should receive whichever vaccine is available when they become eligible.However, as supplies become less of a limitation, it may be that for groups with higher risk of severe disease and complications (eg, older adults, immunocompromised people), the mRNA vaccines would provide an advan-
Adverse pathology as a predictor of distant metastasis and prostate cancer mortality with 20-year follow up.
Authors: Michael Austin Brooks, Lewis Thomas, Cristina Magi-Galluzi, Jianbo Li, Michael Crager, Ruixiao Lu, John Abran, Tamer Aboushwareb, Eric A. Klein
Journal: Journal of Clinical Oncology (2021)

219 Background: Adverse pathology (AP) at radical prostatectomy (RP) is often used as a proxy for long-term prostate cancer outcomes. The goal of this study was to assess the association of AP at RP, defined as high-grade (&gt; Grade Group 3) and/or non-organ confined disease (pT3), with distant metastasis and prostate cancer death. Methods: A stratified cohort sample of 428 patients was used to evaluate the association of adverse pathology with the risk of distant metastases and prostate cancer-specific mortality over 20 years after prostatectomy in 2641 patients treated between 1987-2004. Cox regression of cause-specific hazards was used to estimate the absolute risk of both endpoints, with death from other causes treated as a competing risk. Subgroup analysis in patients with low/intermediate risk disease potentially eligible for active surveillance was performed. Results: Among the 428 patients, 343 had AUA Low or Intermediate risk disease and 85 had High risk disease. Median follow-up time was 15.5 years (IQR 14.6–16.6 years). Using the cohort sampling weights for estimation, at RP 29.8% of patients had high-grade disease, 42.3 % had non-organ confined disease, 19.3% had both, and thus 52.8% had AP. Adverse pathology was highly associated with metastasis and prostate cancer mortality in the overall cohort (HR 12.30, 95% CI 5.30-28.55, and 10.03, 95% CI 3.42-29.47, respectively, both p&lt;0.001), and in the low/intermediate risk subgroup potentially eligible for active surveillance (HR 10.48, 95% CI 4.18-26.28, and 8.60, 95% CI 2.40-30.84, respectively, both p≤0.001). Conclusions: Adverse pathology at radical prostatectomy is highly associated with future development of metastasis and prostate cancer mortality and may be used as a short-term predictor of outcomes. [Table: see text]
Single-cell analysis by mass cytometry reveals metabolic states of early-activated CD8+ T cells during the primary immune response
Authors: Lauren S. Levine, Kamir J. Hiam-Galvez, Diana M. Marquez, Iliana Tenvooren, Matthew Z. Madden, Diana C. Contreras, Debolanle O. Dahunsi, Jonathan M. Irish, Olalekan O. Oluwole, Jeffrey C. Rathmell, Matthew H. Spitzer
Journal: Immunity (2021)
Intestinal and systemic inflammation induced by symptomatic and asymptomatic enterotoxigenic <i>E. coli</i> infection and impact on intestinal colonization and ETEC specific immune responses in an experimental human challenge model
Authors: Jessica Brubaker, Xueyan Zhang, A. Louis Bourgeois, Clayton Harro, David A Sack, Subhra Chakraborty
Journal: Gut Microbes (2021)

Recent studies have gained a better appreciation of the potential impacts of enteric infections beyond symptomatic diarrhea. It is recognized that infections by several enteropathogens could be associated with growth deficits in children and intestinal and systemic inflammation may play an important underlying role. With enterotoxigenic
Safety and Efficacy of B-Cell Depletion with Rituximab for the Treatment of Systemic Sclerosis–associated Pulmonary Arterial Hypertension: A Multicenter, Double-Blind, Randomized, Placebo-controlled Trial
Authors: Roham T. Zamanian, David Badesch, Lorinda Chung, Robyn T. Domsic, Thomas Medsger, Ashley Pinckney, Lynette Keyes-Elstein, Carla D’Aveta, Meagan Spychala, R. James White, Paul M. Hassoun, Fernando Torres, Andrew J. Sweatt, Jerry A. Molitor, Dinesh Khanna, Holden Maecker, Beverly Welch, Ellen Goldmuntz, Mark R. Nicolls
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) is one of the most prevalent and deadly forms of PAH. B cells may contribute to SSc pathogenesis. Objectives: We investigated the safety and efficacy of B-cell depletion for SSc-PAH. Methods: In an NIH-sponsored, multicenter, double-blinded, randomized, placebo-controlled, proof-of-concept trial, 57 patients with SSc-PAH on stable-dose standard medical therapy received two infusions of 1,000 mg rituximab or placebo administered 2 weeks apart. The primary outcome measure was the change in 6-minute-walk distance (6MWD) at 24 weeks. Secondary endpoints included safety and invasive hemodynamics. We applied a machine learning approach to predict drug responsiveness. Measurements and Main Results: We randomized 57 subjects from 2010 to 2018. In the primary analysis, using data through Week 24, the adjusted mean change in 6MWD at 24 weeks favored the treatment arm but did not reach statistical significance (23.6 ± 11.1 m vs. 0.5 ± 9.7 m; P = 0.12). Although a negative study, when data through Week 48 were also considered, the estimated change in 6MWD at Week 24 was 25.5 ± 8.8 m for rituximab and 0.4 ± 7.4 m for placebo (P = 0.03). Rituximab treatment appeared to be safe and well tolerated. Low levels of RF (rheumatoid factor), IL-12, and IL-17 were sensitive and specific as favorable predictors of a rituximab response as measured by an improved 6MWD (receiver operating characteristic area under the curve, 0.88-0.95). Conclusions: B-cell depletion therapy is a potentially effective and safe adjuvant treatment for SSc-PAH. Future studies in these patients can confirm whether the identified biomarkers predict rituximab responsiveness. Clinical trial registered with www.clinicaltrails.gov (NCT01086540).