tbuckley/cabot-search huggingface dataset:
Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium
Authors: Miguel Sáinz-Jaspeado, Ross O. Smith, Oscar Plunde, Sven-Christian Pawelzik, Yi Jin, Sofia Nordling, Yindi Ding, Pontus Aspenström, Marie Hedlund, Giulia Bastianello, Flora Ascione, Qingsen Li, Cansaran Saygili Demir, Dinesh Fernando, Geoffrey Daniel, Anders Franco-Cereceda, Jeffrey Kroon, Marco Foiani, Tatiana V. Petrova, Manfred W. Kilimann, Magnus Bäck, Lena Claesson-Welsh
Journal: Circulation (2021)

PALMD (palmdelphin) belongs to the family of paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms in the PALMD locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis and predict severity of the disease.Immunodetection and public database screening showed dominant expression of PALMD in endothelial cells (ECs) in brain and cardiovascular tissues including aortic valves. Mass spectrometry, coimmunoprecipitation, and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in small interferring RNA-treated EC cultures, knockout mice, and human valve samples. RNA sequencing of ECs and transcript arrays on valve samples from an aortic valve study cohort including patients with the single nucleotide polymorphism rs7543130 informed about gene regulatory changes.ECs express the cytosolic PALMD-KKVI splice variant, which associated with RANGAP1 (RAN GTP hydrolyase activating protein 1). RANGAP1 regulates the activity of the GTPase RAN and thereby nucleocytoplasmic shuttling via XPO1 (Exportin1). Reduced PALMD expression resulted in subcellular relocalization of RANGAP1 and XPO1, and nuclear arrest of the XPO1 cargoes p53 and p21. This indicates an important role for PALMD in nucleocytoplasmic transport and consequently in gene regulation because of the effect on localization of transcriptional regulators. Changes in EC responsiveness on loss of PALMD expression included failure to form a perinuclear actin cap when exposed to flow, indicating lack of protection against mechanical stress. Loss of the actin cap correlated with misalignment of the nuclear long axis relative to the cell body, observed in PALMD-deficient ECs, Palmd-/- mouse aorta, and human aortic valve samples derived from patients with calcific aortic valve stenosis. In agreement with these changes in EC behavior, gene ontology analysis showed enrichment of nuclear- and cytoskeleton-related terms in PALMD-silenced ECs.We identify RANGAP1 as a PALMD partner in ECs. Disrupting the PALMD/RANGAP1 complex alters the subcellular localization of RANGAP1 and XPO1, and leads to nuclear arrest of the XPO1 cargoes p53 and p21, accompanied by gene regulatory changes and loss of actin-dependent nuclear resilience. Combined, these consequences of reduced PALMD expression provide a mechanistic underpinning for PALMD's contribution to calcific aortic valve stenosis pathology.
A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
Authors: Aesha I. Ali, Minyu Wang, Bianca von Scheidt, Pilar M. Dominguez, Aaron J. Harrison, Daniela G.M. Tantalo, Jian Kang, Amanda J. Oliver, Jack D. Chan, Xin Du, Yuchen Bai, Belinda Lee, Ricky W. Johnstone, Phillip K. Darcy, Michael H. Kershaw, Clare Y. Slaney
Journal: Clinical Cancer Research (2021)

Abstract Purpose: In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model. Experimental Design: We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T-cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells. A vaccine containing live vaccinia virus coding a gp100 minigene (VV-gp100) was administered to the recipient mice to stimulate CARaMEL cells. The treatment also included the histone deacetylase inhibitor panobinostat (Pano). Results: The combination treatment enabled significant suppression of Her2+ pancreatic cancers leading to the eradication of the majority of the tumors. Besides inducing cancer cell apoptosis, Pano enhanced CAR T-cell gene accessibility and promoted CAR T-cell differentiation into central memory cells. To test the translational potential of this approach, we established a method to transduce human T cells with an anti-Her2 CAR and a gp100-TCR. The exposure of the human T cells to Pano promoted a T-cell central memory phenotype and the combination treatment of human CARaMEL cells and Pano eradicated human pancreatic cancer xenografts in mice. Conclusions: We propose that patients with pancreatic cancer could be treated using a scheme that contains dual-specific CAR T cells, a vaccine that activates the dual-specific CAR T cells through their TCR, and the administration of Pano.
European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus recommendations on patient selection and dose and fractionation for external beam radiotherapy in early breast cancer
Authors: Icro Meattini, Carlotta Becherini, Liesbeth Boersma, Orit Kaidar-Person, Gustavo Nader Marta, Angel Montero, Birgitte Vrou Offersen, Marianne C Aznar, Claus Belka, Adrian Murray Brunt, Samantha Dicuonzo, Pierfrancesco Franco, Mechthild Krause, Mairead MacKenzie, Tanja Marinko, Livia Marrazzo, Ivica Ratosa, Astrid Scholten, Elżbieta Senkus, Hilary Stobart, Philip Poortmans, Charlotte E Coles
Journal: The Lancet Oncology (2021)
Adverse events after antipsychotic discontinuation: an individual participant data meta-analysis
Authors: Lasse Brandt, Johannes Schneider-Thoma, Spyridon Siafis, Orestis Efthimiou, Felix Bermpohl, Luka Loncar, Konrad Neumann, Alkomiet Hasan, Andreas Heinz, Stefan Leucht, Stefan Gutwinski
Journal: The Lancet Psychiatry (2022)
Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing
Authors: Scott Newman, Joy Nakitandwe, Chimene A. Kesserwan, Elizabeth M. Azzato, David A. Wheeler, Michael Rusch, Sheila Shurtleff, Dale J. Hedges, Kayla V. Hamilton, Scott G. Foy, Michael N. Edmonson, Andrew Thrasher, Armita Bahrami, Brent A. Orr, Jeffery M. Klco, Jiali Gu, Lynn W. Harrison, Lu Wang, Michael R. Clay, Annastasia Ouma, Antonina Silkov, Yanling Liu, Zhaojie Zhang, Yu Liu, Samuel W. Brady, Xin Zhou, Ti-Cheng Chang, Manjusha Pande, Eric Davis, Jared Becksfort, Aman Patel, Mark R. Wilkinson, Delaram Rahbarinia, Manish Kubal, Jamie L. Maciaszek, Victor Pastor, Jay Knight, Alexander M. Gout, Jian Wang, Zhaohui Gu, Charles G. Mullighan, Rose B. McGee, Emily A. Quinn, Regina Nuccio, Roya Mostafavi, Elsie L. Gerhardt, Leslie M. Taylor, Jessica M. Valdez, Stacy J. Hines-Dowell, Alberto S. Pappo, Giles Robinson, Liza-Marie Johnson, Ching-Hon Pui, David W. Ellison, James R. Downing, Jinghui Zhang, Kim E. Nichols
Journal: Cancer Discovery (2021)

Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers. This article is highlighted in the In This Issue feature, p. 2945.
Monogenic and Polygenic Contributions to QTc Prolongation in the Population
Authors: Victor Nauffal, Valerie N. Morrill, Sean J. Jurgens, Seung Hoan Choi, Amelia W. Hall, Lu-Chen Weng, Jennifer L. Halford, Christina Austin-Tse, Christopher M. Haggerty, Stephanie L. Harris, Eugene K. Wong, Alvaro Alonso, Dan E. Arking, Emelia J. Benjamin, Eric Boerwinkle, Yuan-I Min, Adolfo Correa, Brandon K. Fornwalt, Susan R. Heckbert, Charles Kooperberg, Henry J. Lin, Ruth J.F. Loos, Kenneth M. Rice, Namrata Gupta, Thomas W. Blackwell, Braxton D. Mitchell, Alanna C. Morrison, Bruce M. Psaty, Wendy S. Post, Susan Redline, Heidi L. Rehm, Stephen S. Rich, Jerome I. Rotter, Elsayed Z. Soliman, Nona Sotoodehnia, Kathryn L. Lunetta, Patrick T. Ellinor, Steven A. Lubitz
Journal: Circulation (2022)

Background: Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variations to the QT interval in the population. Methods: We performed a genome-wide association study of the QTc in 84 630 UK Biobank participants and created a polygenic risk score (PRS). Among 26 976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Results: Fifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1 110 494 common variants was significantly associated with the QTc in TOPMed (ΔQTc /decile of PRS =1.4 ms [95% CI, 1.3 to 1.5]; P =1.1×10 -196 ). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc&gt;480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). Conclusions: QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.
Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation
Authors: Rebecca C. Ahrens-Nicklas, Luis Tecedor, Arron F. Hall, Owen Kane, Richard J. Chung, Elena Lysenko, Eric D. Marsh, Colleen S. Stein, Beverly L. Davidson
Journal: Molecular Therapy (2022)

Although neurologic symptoms occur in two-thirds of lysosomal storage disorders (LSDs), for most we do not understand the mechanisms underlying brain dysfunction. A major unanswered question is if the pathogenic hallmark of LSDs, storage accumulation, induces functional defects directly or is a disease bystander. Also, for most LSDs we do not know the impact of loss of function in individual cell types. Understanding these critical questions are essential to therapy development. Here, we determine the impact of genetic rescue in distinct cell types on neural circuit dysfunction in CLN3 disease, the most common pediatric dementia and a paradigmatic neurodegenerative LSD. We restored Cln3 expression via AAV-mediated gene delivery and conditional genetic rescue in a CLN3 disease mouse model. Surprisingly, we found that low-level rescue of Cln3 expression in neurons alone normalized clinically relevant electrophysiologic markers of network dysfunction, despite the presence of substantial residual histopathology, in contrast to restoring expression in astrocytes. Thus, loss of CLN3 function in neurons, not storage accumulation, underlies neurologic dysfunction in CLN3 disease. This impliesies that storage clearance may be an inappropriate target for therapy development and an ineffectual biomarker.
Abstract EP26: Impacts Of Social Isolation During The COVID-19 Pandemic On Congestive Heart Failure Disease Management
Authors: George Tawfellos, Mikhail Torosoff
Journal: Circulation (2022)

Background: We investigated the impact of social isolation associated with the COVID-19 pandemic on the severity and frequency of congestive heart failure (CHF) symptoms and the frequency of hospital admissions. Hypothesis: We assessed the hypothesis that the psychosocial impacts of loneliness, as manifested during the COVID19 pandemic, caused potentially worsened congestive heart failure (CHF) symptom frequency and severity as well as the frequency of hospitalizations. Material and methods: This was a single tertiary center cohort study of inpatients admitted with a primary diagnosis of congestive heart failure. Each patient was asked to rate the extent of isolation related to the pandemic and the extent of changes in the severity and frequency of symptoms on a numeric scale during an in-person interview. The number of admission due to CHF since the start of the pandemic and in the two years before the start of the pandemic was also compared. Results: The study cohort included 40 patients, 52.5% females, 69.7+/-13.3 years old. Of these patients, 47.5% reported near-complete pandemic-related isolation and an additional 32.5% reported mild isolation. Symptom worsening was reported in 55% of all patients, which was more common in socially isolated patients (73.7%), while patients who maintained social contacts more commonly reported no change or improvement in symptoms (61.9%, p=0.024). There was also a strong trend in increased symptom frequency associated with social isolation (63.2% in isolated patients vs. 33.3% in the rest of the cohort, p=0.059). The pandemic period was also associated with a significant overall reduction in CHF-related hospital admissions, from 1.9+/-1.3 to 0.7+/-1.4 times (p=0.001), but no significant differences according to the social isolation status. Conclusions: Our findings suggest that the COVID-19 pandemic resulted in a significant symptom increase in patients who reported social isolation. At the same time and despite this symptom increase, a significant reduction in CHF-related hospital admissions suggests reluctance of patients to be treated in the hospital environment. The effects of interventions aimed at reducing social isolation should be investigated.
Colchicine in Patients With Acute Coronary Syndrome: Two-Year Follow-Up of the Australian COPS Randomized Clinical Trial
Authors: David C. Tong, Jason E. Bloom, Stephen Quinn, Arthur Nasis, Chin Hiew, Philip Roberts-Thomson, Heath Adams, Rumes Sriamareswaran, Nay M. Htun, William Wilson, Dion Stub, William van Gaal, Laurie Howes, Allysha Yeap, Brian Yip, Sam Wu, Padeepa Perera, Nicholas Collins, Andy Yong, Ravinay Bhindi, Robert Whitbourn, Astin Lee, Manuja Premaratne, Kaleab Asrress, Melanie Freeman, John Amerena, Jamie Layland
Journal: Circulation (2021)
A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS
Authors: Maro Ohanian, Martha L. Arellano, Moshe Y. Levy, Kristen O'Dwyer, Hani Babiker, Daruka Mahadevan, Hongying Zhang, Nasrin Rastgoo, Yuying Jin, Jotin Marango, Stephen B Howell, William G Rice, Rafael Bejar
Journal: Blood (2021)
18F-FDG PET Uptake in the Scalp After Platelet-Rich Plasma Therapy
Authors: Sharjeel Usmani, Dalal Al-Turkait, Fareeda Al-Kandari, Najeeb Ahmed
Journal: Clinical Nuclear Medicine (2021)

Abstract 18 F-FDG PET/CT has been found useful for the detection of the source of infection/inflammation in the body. Platelet-rich plasma is a new treatment modality in which plasma is injected subdermally or intradermally for potential hair regrowth into the scalp. We report a case of 43-year-old woman with right breast cancer who underwent surgery, chemotherapy, and radiotherapy 2 years ago and is currently on hormonal therapy. 18 F-FDG PET/CT demonstrate incidental findings of increased FDG avidity in the scalp after platelet-rich plasma therapy.
62P Impact of the pretreatment prognostic nutritional index on the survival after first-line immunotherapy in non-small cell lung cancer patients
Authors: S. Takamori, Y. Oku, G. Toyokawa, S. Wakasu, F. Kinoshita, K. Watanabe, N. Haratake, T. Nagano, K. Kosai, Y. Shiraishi, T. Yamashita, M. Shimokawa, F. Shoji, K. Yamazaki, T. Okamoto, T. Seto, S. Takeo, N. Nakashima, I. Okamoto, T. Takenaka
Journal: Annals of Oncology (2022)
Effect of Esophageal Pressure–guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial
Authors: Todd Sarge, Elias Baedorf-Kassis, Valerie Banner-Goodspeed, Victor Novack, Stephen H. Loring, Michelle N. Gong, Deborah Cook, Daniel Talmor, Jeremy R. Beitler, Emily Fish, Sayuri Jinadasa, Ray Ritz, Joseph Previtera, Lawrence Lee, France Clarke, Tom Piraino, Joseph Levitt, Rosemary Vojnik, Pauline Park, Kristin Brierley, Carl Haas, Andrew Weirauch, Eddy Fan, Andrea Matte, R. Scott Harris, Mamary Kone, Stephen Heard, Karen Longtine, François Lellouche, Pierre-Alexandre Bouchard, Lewis Rubinson, Jennifer Titus McGrain, Donald E. G. Griesdale, Denise Foster, Richard Oeckler, Amy Amsbaugh, Edgar Jimenez, Valerie Danesh, Arthur S. Slutsky, Jesse Hall, Rolf D. Hubmayr, Gordon Rubenfeld, David Schoenfeld
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: In acute respiratory distress syndrome (ARDS), the effect of positive end-expiratory pressure (PEEP) may depend on the extent to which multiorgan dysfunction contributes to risk of death, and the precision with which PEEP is titrated to attenuate atelectrauma without exacerbating overdistension. Objectives: To evaluate whether multiorgan dysfunction and lung mechanics modified treatment effect in the EPVent-2 (Esophageal Pressure-guided Ventilation 2) trial, a multicenter trial of esophageal pressure (Pes)-guided PEEP versus empirical high PEEP in moderate to severe ARDS. Methods: This post hoc reanalysis of the EPVent-2 trial evaluated for heterogeneity of treatment effect on mortality by baseline multiorgan dysfunction, determined via Acute Physiology and Chronic Health Evaluation II (APACHE-II). It also evaluated whether PEEP titrated to end-expiratory transpulmonary pressure near 0 cm H2O was associated with survival. Measurements and Main Results: All 200 trial participants were included. Treatment effect on 60-day mortality differed by multiorgan dysfunction severity (P = 0.03 for interaction). Pes-guided PEEP was associated with lower mortality among patients with APACHE-II less than the median value (hazard ratio, 0.43; 95% confidence interval, 0.20–0.92) and may have had the opposite effect in patients with higher APACHE-II (hazard ratio, 1.69; 95% confidence interval, 0.93–3.05). Independent of treatment group or multiorgan dysfunction severity, mortality was lowest when PEEP titration achieved end-expiratory transpulmonary pressure near 0 cm H2O. Conclusions: The effect on survival of Pes-guided PEEP, compared with empirical high PEEP, differed by multiorgan dysfunction severity. Independent of multiorgan dysfunction, PEEP titrated to end-expiratory transpulmonary pressure closer to 0 cm H2O was associated with greater survival than more positive or negative values. These findings warrant prospective testing in a future trial.
Abstract P157: Racial Differences In Atrial Natriuretic Peptide And Insulin
Authors: Catharine Couch, Vibhu Parcha, Pankaj Arora, Barbara Gower
Journal: Circulation (2022)

Low circulating concentrations of the natriuretic peptides (NPs) have been associated with greater risk for Type 2 diabetes (T2D). As a group, African Americans (AA) have lower NP levels and are disproportionately burdened by T2D. Insulin, which is higher in AA, has been shown to regulate NP concentration by increasing the NP clearance receptor. This secondary analysis tests the hypothesis that higher insulin in AA will be associated with lower levels of plasma N-terminal pro-atrial natriuretic peptide (NT-proANP). Participants were 120 AA and European American (EA) men and women ages 19-45 years. Measures of insulin, including fasting insulin and insulin total and incremental area under the curve (AUC and iAUC, respectively, at 30 and 120 m), were derived from an oral glucose tolerance test (OGTT). Insulin sensitivity (SI Clamp ) was assessed using the euglycemic glucose clamp. NT-proANP was measured from fasting samples obtained during the OGTT. Differences in NT-proANP by race was evaluated with analysis of covariance while adjusting for age, sex, and BMI. Linear regression models were used to examine associations between NT-proANP and insulin measures while adjusting for age, sex, race, and BMI. Relative to EA, AA had higher insulin concentrations, lower insulin sensitivity, and lower NT-proANP levels (p&lt;0.05). Fasting insulin and 30 m insulin AUC were inversely associated with NT-proANP (p=0.02, p=0.02, and p=0.04, respectively). These results suggest that the lower NT-proANP observed in AA is related to higher insulin. Future research is needed to investigate the relationship between insulin, ANP, and the NP clearance receptor, particularly in populations at risk for chronic disease.
Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer
Authors: Marie Malier, Khaldoun Gharzeddine, Marie-Hélène Laverriere, Sabrina Marsili, Fabienne Thomas, Magali Court, Thomas Decaens, Gael Roth, Arnaud Millet
Journal: Cancer Research (2021)

Colorectal adenocarcinoma is a leading cause of death worldwide, and immune infiltration in colorectal tumors has been recognized recently as an important pathophysiologic event. In this context, tumor-associated macrophages (TAM) have been related to chemoresistance to 5-fluorouracil (5-FU), the first-line chemotherapeutic agent used in treating colorectal cancers. Nevertheless, the details of this chemoresistance mechanism are still poorly elucidated. In the current study, we report that macrophages specifically overexpress dihydropyrimidine dehydrogenase (DPD) in hypoxia, leading to macrophage-induced chemoresistance to 5-FU via inactivation of the drug. Hypoxia-induced macrophage DPD expression was controlled by HIF2α. TAMs constituted the main contributors to DPD activity in human colorectal primary or secondary tumors, while cancer cells did not express significant levels of DPD. In addition, contrary to humans, macrophages in mice do not express DPD. Together, these findings shed light on the role of TAMs in promoting chemoresistance in colorectal cancers and identify potential new therapeutic targets. SIGNIFICANCE: Hypoxia induces HIF2α-mediated overexpression of dihydropyrimidine dehydrogenase in TAMs, leading to chemoresistance to 5-FU in colon cancers.