tbuckley/cabot-search huggingface dataset:
Respiratory Syncytial Virus Infection Promotes Necroptosis and HMGB1 Release by Airway Epithelial Cells
Authors: Jennifer Simpson, Zhixuan Loh, Md Ashik Ullah, Jason P. Lynch, Rhiannon B. Werder, Natasha Collinson, Vivian Zhang, Yves Dondelinger, Mathieu J. M. Bertrand, Mark L. Everard, Christopher C. Blyth, Gunter Hartel, Antoon J. Van Oosterhout, Peter J. Gough, John Bertin, John W. Upham, Kirsten M. Spann, Simon Phipps
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Respiratory syncytial virus (RSV) bronchiolitis causes significant infant mortality. Bronchiolitis is characterized by airway epithelial cell (AEC) death; however, the mode of death remains unknown.Objectives: To determine whether necroptosis contributes to RSV bronchiolitis pathogenesis via HMGB1 (high mobility group box 1) release.Methods: Nasopharyngeal samples were collected from children presenting to the hospital with acute respiratory infection. Primary human AECs and neonatal mice were inoculated with RSV and murine Pneumovirus, respectively. Necroptosis was determined via viability assays and immunohistochemistry for RIPK1 (receptor-interacting protein kinase-1), MLKL (mixed lineage kinase domain-like pseudokinase) protein, and caspase-3. Necroptosis was blocked using pharmacological inhibitors and RIPK1 kinase-dead knockin mice.Measurements and Main Results: HMGB1 levels were elevated in nasopharyngeal samples of children with acute RSV infection. RSV-induced epithelial cell death was associated with increased phosphorylated RIPK1 and phosphorylated MLKL but not active caspase-3 expression. Inhibition of RIPK1 or MLKL attenuated RSV-induced HMGB1 translocation and release, and lowered viral load. MLKL inhibition increased active caspase-3 expression in a caspase-8/9-dependent manner. In susceptible mice, Pneumovirus infection upregulated RIPK1 and MLKL expression in the airway epithelium at 8 to 10 days after infection, coinciding with AEC sloughing, HMGB1 release, and neutrophilic inflammation. Genetic or pharmacological inhibition of RIPK1 or MLKL attenuated these pathologies, lowered viral load, and prevented type 2 inflammation and airway remodeling. Necroptosis inhibition in early life ameliorated asthma progression induced by viral or allergen challenge in later life.Conclusions: Pneumovirus infection induces AEC necroptosis. Inhibition of necroptosis may be a viable strategy to limit the severity of viral bronchiolitis and break its nexus with asthma.
Dynamic Evolution of De Novo DNA Methyltransferases in Rodent and Primate Genomes
Authors: Antoine Molaro, Harmit S Malik, Deborah Bourc’his
Journal: Molecular Biology and Evolution (2020)

Abstract Transcriptional silencing of retrotransposons via DNA methylation is paramount for mammalian fertility and reproductive fitness. During germ cell development, most mammalian species utilize the de novo DNA methyltransferases DNMT3A and DNMT3B to establish DNA methylation patterns. However, many rodent species deploy a third enzyme, DNMT3C, to selectively methylate the promoters of young retrotransposon insertions in their germline. The evolutionary forces that shaped DNMT3C’s unique function are unknown. Using a phylogenomic approach, we confirm here that Dnmt3C arose through a single duplication of Dnmt3B that occurred ∼60 Ma in the last common ancestor of muroid rodents. Importantly, we reveal that DNMT3C is composed of two independently evolving segments: the latter two-thirds have undergone recurrent gene conversion with Dnmt3B, whereas the N-terminus has instead evolved under strong diversifying selection. We hypothesize that positive selection of Dnmt3C is the result of an ongoing evolutionary arms race with young retrotransposon lineages in muroid genomes. Interestingly, although primates lack DNMT3C, we find that the N-terminus of DNMT3A has also evolved under diversifying selection. Thus, the N-termini of two independent de novo methylation enzymes have evolved under diversifying selection in rodents and primates. We hypothesize that repression of young retrotransposons might be driving the recurrent innovation of a functional domain in the N-termini on germline DNMT3s in mammals.
A Sox2:miR-486-5p Axis Regulates Survival of GBM Cells by Inhibiting Tumor Suppressor Networks
Authors: Hernando Lopez-Bertoni, Ivan S. Kotchetkov, Nicole Mihelson, Bachchu Lal, Yuan Rui, Heather Ames, Maria Lugo-Fagundo, Hugo Guerrero-Cazares, Alfredo Quiñones-Hinojosa, Jordan J. Green, John Laterra
Journal: Cancer Research (2020)

Abstract Glioblastoma multiforme (GBM) and other solid malignancies are heterogeneous and contain subpopulations of tumor cells that exhibit stem-like features. Our recent findings point to a dedifferentiation mechanism by which reprogramming transcription factors Oct4 and Sox2 drive the stem-like phenotype in glioblastoma, in part, by differentially regulating subsets of miRNAs. Currently, the molecular mechanisms by which reprogramming transcription factors and miRNAs coordinate cancer stem cell tumor-propagating capacity are unclear. In this study, we identified miR-486-5p as a Sox2-induced miRNA that targets the tumor suppressor genes PTEN and FoxO1 and regulates the GBM stem-like cells. miR-486-5p associated with the GBM stem cell phenotype and Sox2 expression and was directly induced by Sox2 in glioma cell lines and patient-derived neurospheres. Forced expression of miR-486-5p enhanced the self-renewal capacity of GBM neurospheres, and inhibition of endogenous miR-486-5p activated PTEN and FoxO1 and induced cell death by upregulating proapoptotic protein BIM via a PTEN-dependent mechanism. Furthermore, delivery of miR-486-5p antagomirs to preestablished orthotopic GBM neurosphere-derived xenografts using advanced nanoparticle formulations reduced tumor sizes in vivo and enhanced the cytotoxic response to ionizing radiation. These results define a previously unrecognized and therapeutically targetable Sox2:miR-486-5p axis that enhances the survival of GBM stem cells by repressing tumor suppressor pathways. Significance: This study identifies a novel axis that links core transcriptional drivers of cancer cell stemness to miR-486-5p–dependent modulation of tumor suppressor genes that feeds back to regulate glioma stem cell survival.
Histologic subtype and response to immune checkpoint inhibitor (ICI) therapy in advanced urothelial cancer (aUC).
Authors: Natalie J. Miller, Ali Raza Khaki, Leonidas Nikolaos Diamantopoulos, Mehmet Asim Bilen, Victor Sacristan Santos, Rafael Morales-Barrera, Michael Edward Devitt, Ariel Ann Nelson, Evan Shreck, Hussein Assi, Alejo Rodriguez-Vida, Mark Lythgoe, Alexandra Drakaki, Monika Joshi, Pedro Isaacsson Velho, Marcus W. Moses, Matt D. Galsky, Guru Sonpavde, Evan Y. Yu, Petros Grivas
Journal: Journal of Clinical Oncology (2020)

495 Background: Urinary tract cancer can be pure urothelial carcinoma (PUC) or variant UC (VUC, defined here as pure non-UC or mixed UC + non-UC); VUC often has a worse prognosis. Little is known about outcomes for patients (pts) with VUC receiving ICI. We hypothesized that VUC does not compromise ICI efficacy in pts with aUC. Methods: We performed a retrospective cohort study across 18 institutions. Demographic, clinicopathologic, treatment and outcomes data was collected for pts with aUC who received ICI. Pts were stratified to PUC vs VUC; VUC was further divided by histologic subtype, i.e. squamous, neuroendocrine (NE), etc. We compared overall response rate (ORR) using logistic regression, progression free survival (PFS) and overall survival (OS) using Kaplan-Meier and Cox proportional hazards; p&lt;0.05 was significant. Results: 519 consecutive pts were identified; 405, 414 and 411 included in ORR, OS and PFS analyses, respectively. Demographics included mean age 69, 27% female, 66% ever smokers, 15% upper tract disease, 54% with extirpative surgery. ORR to ICI between pts with PUC and VUC was comparable (both 28%, p=0.86) without significant differences for individual subtypes vs PUC. Median OS for pts with PUC was 11.0 vs 9.9 mo for VUC (p=0.45), but only 3.7 mo for those with NE features (HR=3.01 [95% CI 1.63-5.57] vs PUC, p&lt;0.001). Median PFS was 4.1 vs 5.2 mo for PUC vs VUC (p=0.46) and 2.8 mo for NE (HR=1.85 [95% CI 0.94-3.61] vs PUC, p=0.07). Conclusions: ORR to ICI and OS were comparable across histologic types; however, OS was shorter for tumors with NE features. VUC should not exclude pts from receiving ICI in routine practice and clinical trials.[Table: see text]
Abstract 11958: Visit-to-visit Blood Pressure Variability is Associated With Cognitive Decline and Incident Dementia: The S.AGES Cohort
Authors: Laure Rouch, Philippe Cestac, Brigitte Sallerin, Linda Benattar-Zibi, Philippe Bertin, Gilles Berrut, Emmanuelle Corruble, Geneviève Derumeaux, Bruno Falissard, Françoise Forette, Florence Pasquier, Michel Pinget, Rissane Ourabah, Nicolas Danchin, Laurent Becquemont, Olivier Hanon, Jean-Sébastien Vidal
Journal: Circulation (2019)

Objective: To investigate the impact of visit-to-visit systolic, diastolic, mean arterial pressure variability on cognitive decline and incident dementia in non-institutionalized patients aged ≥ 65...
Effects on mental health of a UK welfare reform, Universal Credit: a longitudinal controlled study
Authors: Sophie Wickham, Lee Bentley, Tanith Rose, Margaret Whitehead, David Taylor-Robinson, Ben Barr
Journal: The Lancet Public Health (2020)

Universal Credit, a welfare benefit reform in the UK, began to replace six existing benefit schemes in April, 2013, starting with the income-based Job Seekers Allowance. We aimed to determine the effects on mental health of the introduction of Universal Credit.
Proposal of a new subcategory of the pT3 classification: Effects of tumor location and subclassification of renal pelvic pT3 to predict the prognosis of pelvic carcinoma more accurately than the current TNM classification.
Authors: Tomoyasu Sano, Ryohei Hattori, Shin Yamada, Osamu Kamihira, Hiroaki Kobayashi, Yoshikazu Tsuji, Naoto Sassa, Momokazu Gotoh, Toyonori Tsuzuki
Journal: Journal of Clinical Oncology (2020)

455 Background: Whether pT3 urothelial carcinoma of the renal pelvis (UCRP) and urothelial carcinoma of the ureter (UCU) show the same prognosis or not remains controversial.This study aims to reveal whether the prognosis of pT3 UCRP shows similar to those of pT3 UCU. Methods: We retrospectively evaluated 954 patients who underwent nephroureterectomy between 1983 and 2017 at our institutions.None of the patients received neoadjuvant therapy.All HE slides for each patient were reviewed by a single genitourinary pathologist (TT).pT3 UCRP was subdivided pT3a (urothelial carcinomas that extend only to the renal medulla) and pT3b (urothelial carcinomas that extend to the renal cortex and/or peripelvic adipose tissue) according to the criteria previously we proposed.Fine and Gray model was developed to predict the reccurence-free survival (RFS) and cancer-specific survival (CSS). Results: Overall, 954 patients were eligible for this study, 493 of whom were pT3 with only renal pelvis and 461 of whom were pT3 with only ureter. A total of 202 cases were pT3 UCRP and 146 were pT3 UCU. The pT3 subclassification of UCRP resulted in 79 pT3a and 120 pT3b cases.No significant difference was found in the 5-yr RFS and 5-yr CSS between pT3a UCRP and pT2 UCRP and pT2 UCU. (RFS; pT3a UCRP vs pT2 UCRP: HR = 1.19 p = 0.74; pT3a UCRP vs pT2 UCU HR = 0.88, p = 0.72, CSS;pT3a UCRP vs. pT2 UCRP: HR = 0.69; p = 0.56; pT3a UCRP vs. pT2 UCU: HR = 0.66, p = 0.31) The RFS rate was significantly higher in the pT3a UCRP than that of pT3b, (pT3a vs pT3b: HR = 2.59, p = 0.0038) and so was the CSS rate. (pT3a vs. pT3b: HR = 3.1 p = 0.001) In fine and gray model analysis for RFS, pT stage, lymph node metastasis, WHO/ISUP grade, lymphovascular invasion were independently associated with tumor recurrence, whereas pT stage, lymph node metastasis, operation method, histologic type, lymphovascular invasion, gross type, adjuvant chemotherapy were independently associated with cancer mortality. Conclusions: Subclassifying pT3 UCRP into pT3a and pT3b was useful in determining the prognosis of different patients.The pT3b UCRP showed similar outcome compared to those of UCU.
Association of antiretroviral therapy with anal high-risk human papillomavirus, anal intraepithelial neoplasia, and anal cancer in people living with HIV: a systematic review and meta-analysis
Authors: Helen Kelly, Admire Chikandiwa, Laia Alemany Vilches, Joel M Palefsky, Silvia de Sanjose, Philippe Mayaud
Journal: The Lancet HIV (2020)
Phase II efficacy trial of pazopanib in nonclear cell metastatic renal cell cancer (mRCC): PINCR.
Authors: Brian Addis Costello, Thai Huu Ho, Gabriela Perez Burbano, David W. Hillman, Fernando Quevedo, Henry C. Pitot, Lance C. Pagliaro, Alan Haruo Bryce, Winston Tan, Richard Wayne Joseph, Bradley C. Leibovich, Erik P. Castle, Roxana Stefania Dronca, Manish Kohli
Journal: Journal of Clinical Oncology (2020)

696 Background: A number of treatments for metastatic renal cell carcinoma (RCC) have been FDA approved since December, 2005. Trials evaluating these agents excluded non-clear cell histologies and therefore the efficacy of these treatments remains unclear in patients (pts) with metastatic non-clear cell RCC (mncRCC). Methods: This is a single arm Phase II study designed to determine the efficacy of pazopanib in mncRCC. Treatment was pazopanib 800 mg by mouth daily until progression or intolerability of treatment. Dose reductions were allowed for toxicity with dose level -1 being 600 mg daily and dose level -2, 400 mg daily. Cycles were every 28 days. Main eligibility criteria included: (1) age ³ 18 years old; (2) histologic confirmation of ncRCC; (3) ECOG Performance Status (PS) 0, 1, or 2; (4) up to one prior treatment for mncRCC (5) measurable or non-measurable metastatic disease per RECIST criteria. The primary endpoint was overall survival rate at 12 months. Secondary endpoints were best tumor response rates after two cycles, PFS, OS and toxicity. Results: 38 pts were enrolled between May 16, 2013 and February 1, 2018. 35 pts were evaluable for primary endpoint. Median age 63 years old and 22/35 (62.9%) were male. Most common histology was papillary RCC, 14/35 (40%), and most common number of metastatic sites was 1. 29/35 (82.9%) had prior nephrectomy and 30/35 (85.7%) had no prior systemic therapy. Median number of cycles was 5. 12-month OS was 65.7% (90% CI, 50.5-78.9%). Best response in first 2 cycles: PR 11%, SD 60%, PD 9%, not evaluated 20%. Median PFS was 7.5 months (90% CI, 5.0-11.0); median OS 18.9 months (90% CI, 13.0-NE). Grade 3 / 4 AEs seen in 25 pts with hypertension, transaminitis and abdominal pain being most common (seen in &gt;10%). Conclusions: There are limited data about the efficacy of available therapies for mncRCC. This study shows that pazopanib has similar efficacy compared to historical data in clinical trials using other TKIs in mncRCC. The safety profile of pazopanib in pts with mncRCC was found to be similar to that found in prior clinical trials studying pazopanib. Our findings warrant further investigation into the utility of pazopanib in metastatic ncRCC. Clinical trial information: NCT01767636.
CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma
Authors: Beatriz Salvador-Barbero, Mónica Álvarez-Fernández, Elisabet Zapatero-Solana, Aicha El Bakkali, María del Camino Menéndez, Pedro P. López-Casas, Tomas Di Domenico, Tao Xie, Todd VanArsdale, David J. Shields, Manuel Hidalgo, Marcos Malumbres
Journal: Cancer Cell (2020)

Highlights•CDK4/6 inhibitors should be applied after and not before cytotoxic chemotherapy•CDK4/6 inhibitors prevent DNA repair after mitotic poisons and DNA-damaging agents•Inhibiting CDK4/6 results in an RB1-dependent repression of the DNA-repair machinery•CDK4/6 and PARP inhibitors cooperate in preventing tumor cell proliferationSummaryInhibition of the cell-cycle kinases CDK4 and CDK6 is now part of the standard treatment in advanced breast cancer. CDK4/6 inhibitors, however, are not expected to cooperate with DNA-damaging or antimitotic chemotherapies as the former prevent cell-cycle entry, thus interfering with S-phase- or mitosis-targeting agents. Here, we report that sequential administration of CDK4/6 inhibitors after taxanes cooperates to prevent cellular proliferation in pancreatic ductal adenocarcinoma (PDAC) cells, patient-derived xenografts, and genetically engineered mice with Kras G12V and Cdkn2a-null mutations frequently observed in PDAC. This effect correlates with the repressive activity of CDK4/6 inhibitors on homologous recombination proteins required for the recovery from chromosomal damage. CDK4/6 inhibitors also prevent recovery from multiple DNA-damaging agents, suggesting broad applicability for their sequential administration after available chemotherapeutic agents.Graphical abstract
Patient-reported outcomes on treatment-related side effects in renal cell carcinoma.
Authors: Dena Battle, Wendy Kimryn Rathmell, Eric Jonasch, Pavlos Msaouel, Adam P. Stern, Tian Zhang, Daniel J. George, Michael D. Staehler
Journal: Journal of Clinical Oncology (2020)

654 Background: Effective management of treatment related toxicities is crucial to maximizing patient outcomes and enhancing quality of life in renal cell carcinoma. Little is known about patient perception and reporting of side effects in a real world setting outside clinical trials. We sought to gather independent data from online patient communities to estimate gaps in communication and reporting. Methods: KCCure conducted an anonymous online survey from 07/19 to 09/19 using questions related to side-effect experience and management. Results: 1,136 patients (median age 57 years [range 28-86], 54% male) participated, 411 patients on systemic therapy were asked about side-effects. 47% of patients reported bothersome side effects impacting their daily lives. The most poorly managed side-effect was fatigue (25%), followed by taste alteration (15%) and loss of appetite (15%). Only 50% of patients are confident their medical oncologist will offer help for side effects, and 20% are worried that reporting side effects may result in dose reduction or treatment discontinuation. 6% of patients don’t talk about their side effects. Patients who identified as non-white (Hispanic, African American, Asian/Pacific Islander and Native American) were three times less likely to talk about side effects. 51% indicated the best advice on managing treatment related side effects was provided by their medical oncologist; 40% seek advice from online patient communities and 35% from advocacy organizations. Only 8% used manufacturer support websites. 13% had never had any concomitant medication prescribed to manage side effects. Major unreported side effects are sexual dysfunction, cognitive impairment and vision disturbances. Conclusions: The majority of patients experience treatment related side-effects on a regular basis, but underreporting may be significant due to a variety of factors, including fear of dose-reduction or discontinuation. Sexual side-effects are underreported. Future studies need to explore differences in reporting for minority populations as well as side effect experiences according to the class of agent prescribed, and the setting in which treatment occurs.
The role of lymph node dissection in pT2-3 renal cell carcinoma: Analysis of the National Cancer Database.
Authors: Fady Ghali, Devin Patel, Margaret Meagher, Aaron Bradshaw, Sunil Patel, Raksha Dutt, James Don Murphy, Ithaar Derweesh
Journal: Journal of Clinical Oncology (2020)

756 Background: We sought to assess the impact of LND in non metastatic pT2-3 patients utilizing a large population-based dataset. Methods: The National Cancer Database was queried for patients with cN0pT2-3 RCC that underwent radical nephrectomy (RN) +/- LND from 2004-2015. Descriptive analyses and Multivariable cox regression (MVA) were performed to elucidate factors associated with all-cause mortality (ACM) on a per stage basis (pT2 and pT3 RCC). Kaplan-Meier analyses (KMA) were used to determine the impact of LND on ACM. Results: 43,143 patients were analyzed, 9,491 (22.0%) underwent LND, 6.7% were positive (pN+). MVA demonstrated increasing age (HR 1.04, p&lt;0.001), pN+ (HR 2.90, p&lt;0.001), increasing Charlson score (CCI, HR 2.92, p&lt;0.001), and high grade (HR 1.11, p&lt;0.001), were associated with worsened ACM in pT2. MVA in pT3 revealed increasing age (HR 1.03, p&lt;0.001), pN0 with 0-4 nodes removed (HR 1.24, p&lt;0.001), pN+ (HR 3.06, p&lt;0.001), papillary and non-specific histology (HR 1.17 p=0.002, HR 1.14 p&lt;0.001 respectively), increasing CCI (HR 2.09, p&lt;0.001), high grade (HR1.19, p&lt;0.001), black race (HR 1.12, p=0.028), and increasing tumor size (HR 1.00, p&lt;0.001) were associated with worsened ACM. MVA for increased likelihood of pN+ found high grade (HR1.23, p&lt;0.001), Academic facility and integrated network cancer center (HR 2.13 and 1.17, p&lt;0.001 and p=0.013 respectively), &gt;10cm tumor (HR 1.67 p&lt;0.001), clear cell histology (p&lt;0.001), Caucasian race (p&lt;0.001)and male sex (HR 1.06 P=0.026) were associated. KMA of pT2 patients demonstrates no significant difference in 5-year OS for LND compared to no LND (60.8% vs. 55.9%, p=0.21), and worsened OS for pN+ compared to pN0 and pNx (p&lt;0.001). KMA of pT3 patients showed worsened 5-year OS for patients undergoing LND (p&lt;0.001), and pN+ had worsened OS compared to pN0 and pNx (p&lt;0.001). Conclusions: LND conveyed no ACM benefit in cN0 pT2 or pT3 RCC. pN+ was associated with decreased survival, with risk factors including Caucasian race, clear cell histology, high grade disease, tumors &gt;10cm. LND in patients with cN0pT2-T3 disease may identify higher risk cohorts.
Abstract 13093: Predictors for the Favorable Change of Fibrous-cap in Non-culprit Lipid Plaques in Response to Statin Therapy: A Serial Optical Coherence Tomography Study
Authors: Yoshiyasu Minami, Daniel S. Ong, Shiro Uemura, Zhao Wang, Aaron D. Aguirre, Shankha Mukhopadhyay, Tsunenari Soeda, Rocco Vergallo, Lei Gao, Lei Xing, Hang Lee, Bo Yu, Ik-Kyung Jang
Journal: Circulation (2015)

Introduction: Previous studies demonstrated that statins improved fibrous cap thickness (FCT) in patients with coronary artery disease. However, factors affecting the favorable FCT change in response to statin therapy remain unknown. Aim: To identify the clinical factors for favorable FCT change of non-culprit coronary plaques with statin therapy in patients with coronary artery disease. Methods: A total of 152 non-culprit plaques from 90 patients who were treated with statin and had serial optical coherence tomography (OCT) imaging at baseline and follow-up were included. FCT was assessed at the thinnest portion within the entire plaque. Results: The mean FCT was improved from 105.7 ± 52.3 μm to 128.4 ± 60.7 μm (P&lt;0.001) from baseline to follow-up (median 6.38 [6.07-12.5] months). Multivariate liner regression analysis demonstrated that the percent change of FCT was significantly correlated to the eGFR at baseline (B=1.043, 95% confidential interval (CI) [0.321, 1.765], P=0.005) (Table). The percent change of FCT in patients with CKD Stage 1 (eGFR≥90) was significantly greater (42.3% [6.45, 100.0]) than in those with Stage 2 (eGFR: 60-89) (0.0% [-21.6, 58.5], P=0.007) or with Stage≥3 (eGFR&lt;60) (0.0% [-14.3, 54.5], P=0.033) (Figure). Conclusions: Higher eGFR value at baseline was significantly correlated to the greater FCT improvement of non-culprit coronary plaques with statin therapy. Patients with eGFR≥90, in particular, had best response to statin therapy.
You cannot go wrong: choosing digital single-operator cholangioscopy for the diagnosis of biliary strictures
Authors: Udayakumar Navaneethan
Journal: Endoscopy (2020)

Direct endoscopic visualization of the biliary system is difficult. Cholangioscopy provides an opportunity to directly visualize the bile duct in order to diagnose biliary strictures [1]. Three different cholangioscopy techniques are described including "dual-operator" and "single-operator" cholangioscopy, and the "direct" peroral technique [1].