tbuckley/cabot-search huggingface dataset:
Recombination Facilitates Adaptive Evolution in Rhizobial Soil Bacteria
Authors: Maria Izabel A Cavassim, Stig U Andersen, Thomas Bataillon, Mikkel Heide Schierup
Journal: Molecular Biology and Evolution (2021)

Abstract Homologous recombination is expected to increase natural selection efficacy by decoupling the fate of beneficial and deleterious mutations and by readily creating new combinations of beneficial alleles. Here, we investigate how the proportion of amino acid substitutions fixed by adaptive evolution (α) depends on the recombination rate in bacteria. We analyze 3,086 core protein-coding sequences from 196 genomes belonging to five closely related species of the genus Rhizobium. These genes are found in all species and do not display any signs of introgression between species. We estimate α using the site frequency spectrum (SFS) and divergence data for all pairs of species. We evaluate the impact of recombination within each species by dividing genes into three equally sized recombination classes based on their average level of intragenic linkage disequilibrium. We find that α varies from 0.07 to 0.39 across species and is positively correlated with the level of recombination. This is both due to a higher estimated rate of adaptive evolution and a lower estimated rate of nonadaptive evolution, suggesting that recombination both increases the fixation probability of advantageous variants and decreases the probability of fixation of deleterious variants. Our results demonstrate that homologous recombination facilitates adaptive evolution measured by α in the core genome of prokaryote species in agreement with studies in eukaryotes.
Through the Fishbowl
Authors: Disha Dalela
Journal: Annals of Internal Medicine (2021)

Ad LibitumAugust 2021Through the FishbowlDisha Dalela, MBBSDisha Dalela, MBBSUniversity of Massachusetts Shrewsbury, MassachusettsSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-6413 Audio Reading - “Through the Fishbowl” Audio. Virginia L. Hood, MD, a physician from the University of Vermont, reads “Through the Fishbowl” by Disha Dalela, MBBS Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Alas, I am interrupted by the sight of the nurse running in ... Author, Article, and Disclosure InformationAffiliations: University of Massachusetts Shrewsbury, MassachusettsCurrent Author Address: Disha Dalela, MBBS; e-mail, [email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “Through the Fishbowl” Audio. Virginia L. Hood, MD, a physician from the University of Vermont, reads “Through the Fishbowl” by Disha Dalela, MBBS Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics August 2021Volume 174, Issue 8Page: 1072 ePublished: 17 August 2021 Issue Published: August 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Financial Associations Between Authors of Commentaries on Randomized Clinical Trials of Invasive Cardiovascular Interventions and Trial Sponsors
Authors: Irbaz Hameed, Makoto Mori, Adham Ahmed, Nyla Naeem, Christian T. Oakley, Mario Gaudino, Arnar Geirsson
Journal: JAMA Internal Medicine (2021)

This cross-sectional study examines the financial associations between authors of commentaries on randomized clinical trials of invasive cardiovascular interventions and trial sponsors, and whether the financial associations were disclosed.
Genetic in situ engineering of myeloid regulatory cells controls inflammation in autoimmunity
Authors: N.N. Parayath, S. Hao, S.B. Stephan, A.L. Koehne, C.E. Watson, M.T. Stephan
Journal: Journal of Controlled Release (2021)

The ability of myeloid regulatory cells (MRCs) to control immune responses and to promote tolerance has prompted enormous interest in exploiting them therapeutically to treat inflammation, autoimmunity, or to improve outcomes in transplantation. While immunomodulatory small-molecule compounds and antibodies have provided relief for some patients, the dosing entails high systemic drug exposures and thus increased risk of off-target adverse effects. More recently, MRC-based cell-therapy products have entered clinical testing for tolerance induction. However, the elaborate and expensive protocols currently required to manufacture engineered MRCs ex vivo put this approach beyond the reach of many patients who might benefit. A solution could be to directly program MRCs in vivo. Here we describe a targeted nanocarrier that delivers in vitro-transcribed mRNA encoding a key anti-inflammatory mediator. We demonstrate in models of systemic lupus erythematosus that infusions of nanoparticles formulated with mRNA encoding glucocorticoid-induced leucine zipper (GILZ) effectively control the disease. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this new therapy could enable physicians to treat autoimmune disease while avoiding systemic treatments that disrupt immune homeostasis.
Targeting of pancreatic cancer cells and stromal cells using engineered oncolytic Salmonella typhimurium
Authors: Wenzhi Tan, Mai Thi-Quynh Duong, Chaohui Zuo, Yeshan Qin, Ying Zhang, Yanxia Guo, Yeongjin Hong, Jin Hai Zheng, Jung-Joon Min
Journal: Molecular Therapy (2021)

Pancreatic cancer is resistant to conventional therapeutic interventions, mainly due to abundant cancer stromal cells and poor immune cell infiltration. Here, we used a targeted cancer therapy approach based on attenuated Salmonella typhimurium engineered to express cytolysin A (ClyA) to target cancer stromal cells and cancer cells and treat pancreatic cancer in mice. Nude mice bearing subcutaneous or orthotopic human pancreatic cancers were treated with engineered S. typhimurium expressing ClyA. The tumor microenvironment was monitored to analyze stromal cell numbers, stromal cell marker expression, and immune cell infiltration. The attenuated bacteria accumulated and proliferated specifically in tumor tissues after intravenous injection. The bacteria secreted ClyA into the tumor microenvironment. A single dose of ClyA-expressing Salmonella markedly inhibited growth of pancreatic cancer both in subcutaneous xenograft- and orthotopic tumor-bearing nude mice. Histological analysis revealed a marked decrease in expression of stromal cell markers and increased immune cell (neutrophils and macrophages) infiltration into tumors after colonization by ClyA-expressing bacteria. ClyA-expressing S. typhimurium destroyed cancer stromal cells and cancer cells in mouse models of human pancreatic cancer. This approach provides a novel strategy for combining anticancer and anti-stromal therapy to treat pancreatic cancer.
Identification of neural oscillations and epileptiform changes in human brain organoids
Authors: Ranmal A. Samarasinghe, Osvaldo A. Miranda, Jessie E. Buth, Simon Mitchell, Isabella Ferando, Momoko Watanabe, Thomas F. Allison, Arinnae Kurdian, Namie N. Fotion, Michael J. Gandal, Peyman Golshani, Kathrin Plath, William E. Lowry, Jack M. Parent, Istvan Mody, Bennett G. Novitch
Journal: Nature Neuroscience (2021)
Activation or exhaustion of CD8+ T cells in patients with COVID-19
Authors: Min-Seok Rha, Eui-Cheol Shin
Journal: Cellular and Molecular Immunology (2021)

Abstract In addition to CD4 + T cells and neutralizing antibodies, CD8 + T cells contribute to protective immune responses against SARS-CoV-2 in patients with coronavirus disease 2019 (COVID-19), an ongoing pandemic disease. In patients with COVID-19, CD8 + T cells exhibiting activated phenotypes are commonly observed, although the absolute number of CD8 + T cells is decreased. In addition, several studies have reported an upregulation of inhibitory immune checkpoint receptors, such as PD-1, and the expression of exhaustion-associated gene signatures in CD8 + T cells from patients with COVID-19. However, whether CD8 + T cells are truly exhausted during COVID-19 has been a controversial issue. In the present review, we summarize the current understanding of CD8 + T-cell exhaustion and describe the available knowledge on the phenotypes and functions of CD8 + T cells in the context of activation and exhaustion. We also summarize recent reports regarding phenotypical and functional analyses of SARS-CoV-2-specific CD8 + T cells and discuss long-term SARS-CoV-2-specific CD8 + T-cell memory.
Genetic blockade of lymphangiogenesis does not impair cardiac function after myocardial infarction
Authors: T.C. Stevenson Keller, Lillian Lim, Swapnil V. Shewale, Kendra McDaid, Íngrid Martí-Pàmies, Alan T. Tang, Carl Wittig, Andrea A. Guerrero, Stephanie Sterling, N. Adrian Leu, Marielle Scherrer-Crosbie, Phyllis A. Gimotty, Mark L. Kahn
Journal: Journal of Clinical Investigation (2021)

In recent decades, treatments for myocardial infarction (MI), such as stem and progenitor cell therapy, have attracted considerable scientific and clinical attention but failed to improve patient outcomes. These efforts indicate that more rigorous mechanistic and functional testing of potential MI therapies is required. Recent studies have suggested that augmenting post-MI lymphatic growth via VEGF-C administration improves cardiac function. However, the mechanisms underlying this proposed therapeutic approach remain vague and untested. To more rigorously test the role of lymphatic vessel growth after MI, we examined the post-MI cardiac function of mice in which lymphangiogenesis had been blocked genetically by pan-endothelial or lymphatic endothelial loss of the lymphangiogenic receptor VEGFR3 or global loss of the VEGF-C and VEGF-D ligands. The results obtained using all 3 genetic approaches were highly concordant and demonstrated that loss of lymphatic vessel growth did not impair left ventricular ejection fraction 2 weeks after MI in mice. We observed a trend toward excess fluid in the infarcted region of the left ventricle, but immune cell infiltration and clearance were unchanged with loss of expanded lymphatics. These studies refute the hypothesis that lymphangiogenesis contributes significantly to cardiac function after MI, and suggest that any effect of exogenous VEGF-C is likely to be mediated by nonlymphangiogenic mechanisms.
Estimating risk of metastatic disease in T1b esophageal adenocarcinoma: incremental progress but gaps remain
Authors: Divyanshoo R. Kohli, Prateek Sharma
Journal: Endoscopy (2021)

The presence of lymph node metastasis (LNM) is a crucial determinant of long-term prognosis in patients with early esophageal adenocarcinoma (EAC). Presence of nodal disease typically precludes curative endoscopic resection, and requires induction chemoradiotherapy followed by surgical resection [1] [2]. While T1a EAC is associated with a low nodal metastasis rate of 0–2 %, T1b has a much higher rate of 16 %–22 % [2] [3]. Although selective use of endoscopic therapy for superficial disease limited to the upper third of the submucosa has been advocated, many centers perform surgery for all patients with T1b EAC. Hence, there is an unmet clinical need to reliably stratify patients for the most suitable therapy.
Covid-19 booster vaccines: What we know and who’s doing what
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Covid-19 booster vaccines: What we know and who's doing whatThe virulence of the delta variant has prompted many countries to start administering booster vaccines.Elisabeth Mahase looks at what is happening where Elisabeth Mahase Do we need booster doses?How long does immunity after covid-19 vaccination last?It's something everyone would like to know, but it's a question that can't currently be answered with certainty.
Integrated analysis of a phase 2 study of cemiplimab in advanced cutaneous squamous cell carcinoma: extended follow-up of outcomes and quality of life analysis
Authors: Danny Rischin, Nikhil I Khushalani, Chrysalyne D Schmults, Alexander Guminski, Anne Lynn S Chang, Karl D Lewis, Annette M Lim, Leonel Hernandez-Aya, Brett G M Hughes, Dirk Schadendorf, Axel Hauschild, Alesha A Thai, Elizabeth Stankevich, Jocelyn Booth, Suk-Young Yoo, Siyu Li, Zhen Chen, Emmanuel Okoye, Chieh-I Chen, Vera Mastey, Medha Sasane, Israel Lowy, Matthew G Fury, Michael R Migden
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background To provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL). Methods Patients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks). Results Median duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (p&lt;0.0001). Conclusions This is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement. Trial registration number ClinicalTrials.gov Registry ( NCT02760498 ), https://clinicaltrialsgov/ct2/show/NCT02760498 .
Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis
Authors: David Planchard, Benjamin Besse, Harry J.M. Groen, Sayed M.S. Hashemi, Julien Mazieres, Tae Min Kim, Elisabeth Quoix, Pierre-Jean Souquet, Fabrice Barlesi, Christina Baik, Liza C. Villaruz, Ronan J. Kelly, Shirong Zhang, Monique Tan, Eduard Gasal, Libero Santarpia, Bruce E. Johnson
Journal: Journal of Thoracic Oncology (2021)

IntroductionDabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data.MethodsPretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety.ResultsAt data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5–78.5) and 16.3 (range: 0.4–80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8–80.1) and 63.9% (46.2–79.2), median progression-free survival (95% CI) was 10.2 (6.9–16.7) and 10.8 (7.0–14.5) months, and median overall survival (95% CI) was 18.2 (14.3–28.6) and 17.3 (12.3–40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation.ConclusionsDabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment.
Caution in Interpreting Facial Paralysis Data to Understand COVID-19 Vaccination Risks
Authors: Jing Han Ng, Eng King Tan
Journal: JAMA Internal Medicine (2021)

Lucie Renoud; Charles Khouri, PharmD, PhD; Bruno Revol, PharmD, PhD; Marion Lepelley, PharmD; Justine Perez, PharmD; Matthieu Roustit, PharmD, PhD; Jean-Luc Cracowski, MD, PhD
Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease
Authors: Jonathan A. Kirk, Joseph Y. Cheung, Arthur M. Feldman
Journal: Journal of Clinical Investigation (2021)

Bcl2-associated athanogene-3 (BAG3) is expressed ubiquitously in humans, but its levels are highest in the heart, the skeletal muscle, and the central nervous system; it is also elevated in many cancers. BAG3's diverse functions are supported by its multiple protein-protein binding domains, which couple with small and large heat shock proteins, members of the Bcl2 family, other antiapoptotic proteins, and various sarcomere proteins. In the heart, BAG3 inhibits apoptosis, promotes autophagy, couples the β-adrenergic receptor with the L-type Ca2+ channel, and maintains the structure of the sarcomere. In cancer cells, BAG3 binds to and supports an identical array of prosurvival proteins, and it may represent a therapeutic target. However, the development of strategies to block BAG3 function in cancer cells may be challenging, as they are likely to interfere with the essential roles of BAG3 in the heart. In this Review, we present the current knowledge regarding the biology of this complex protein in the heart and in cancer and suggest several therapeutic options.
27629 Malignancy rates through 4 years of follow-up in guselkumab-treated moderate to severe psoriasis patients from the VOYAGE 1 and 2 trials and comparisons to the general United States population
Authors: Kim A. Papp, Kristian Reich, Kenneth B. Gordon, Mark Lebwohl, Michael Song, Megan Miller, Paraneedharan Ramachandran, Yaung-Kaung Shen, Connie B. Lin, Andrew Blauvelt
Journal: Journal of the American Academy of Dermatology (2021)
Germline <i>SUCLG2</i> Variants in Patients With Pheochromocytoma and Paraganglioma
Authors: Katerina Hadrava Vanova, Ying Pang, Linda Krobova, Michal Kraus, Zuzana Nahacka, Stepana Boukalova, Svetlana D Pack, Renata Zobalova, Jun Zhu, Thanh-Truc Huynh, Ivana Jochmanova, Ondrej Uher, Sona Hubackova, Sarka Dvorakova, Timothy J Garrett, Hans K Ghayee, Xiaolin Wu, Bjoern Schuster, Philip E Knapp, Zdenek Frysak, Igor Hartmann, Naris Nilubol, Jiri Cerny, David Taieb, Jakub Rohlena, Jiri Neuzil, Chunzhang Yang, Karel Pacak
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background Pheochromocytoma and paraganglioma (PPGL) are neuroendocrine tumors with frequent mutations in genes linked to the tricarboxylic acid cycle. However, no pathogenic variant has been found to date in succinyl-CoA ligase (SUCL), an enzyme that provides substrate for succinate dehydrogenase (SDH; mitochondrial complex II [CII]), a known tumor suppressor in PPGL. Methods A cohort of 352 patients with apparently sporadic PPGL underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health, including the SUCLG2 subunit of SUCL. Gene deletion, succinate levels, and protein levels were assessed in tumors where possible. To confirm the possible mechanism, we used a progenitor cell line, hPheo1, derived from a human pheochromocytoma, and ablated and re-expressed SUCLG2. Results We describe 8 germline variants in the guanosine triphosphate–binding domain of SUCLG2 in 15 patients (15 of 352, 4.3%) with apparently sporadic PPGL. Analysis of SUCLG2-mutated tumors and SUCLG2-deficient hPheo1 cells revealed absence of SUCLG2 protein, decrease in the level of the SDHB subunit of SDH, and faulty assembly of the complex II, resulting in aberrant respiration and elevated succinate accumulation. Conclusions Our study suggests SUCLG2 as a novel candidate gene in the genetic landscape of PPGL. Large-scale sequencing may uncover additional cases harboring SUCLG2 variants and provide more detailed information about their prevalence and penetrance.
27350 Dupilumab improves Eczema Area and Severity Index regional scores across all anatomical regions in children aged 6–11 years with severe atopic dermatitis (AD)
Authors: Amy S. Paller, Michael J. Cork, Danielle Marcoux, Andreas Wollenberg, Randy Prescilla, Zhen Chen, Ana B. Rossi, Brad Shumel
Journal: Journal of the American Academy of Dermatology (2021)
25992 Long-term efficacy of tildrakizumab 100 mg by PASI 75/90/100 and PGA in a pooled analysis of reSURFACE 1 and reSURFACE 2 through up to 4 years of treatment
Authors: J. Mark Jackson, Andrew Alexis, Kristine Kucera, Alan M. Mendelsohn, Stephen J. Rozzo, Joseph Gorelick
Journal: Journal of the American Academy of Dermatology (2021)
25754 Presence of psoriatic arthritis has no impact on the clinical efficacy and safety of secukinumab in patients with psoriasis: Pooled analysis of the phase 3 CLEAR and CLARITY trials
Authors: Jerry Bagel, Andrew Blauvelt, Stephen Tyring, Manmath Patekar, Xiangyi Meng, Mark Lebwohl
Journal: Journal of the American Academy of Dermatology (2021)
25993 Efficacy of long-term tildrakizumab for plaque psoriasis: PASI 50/75/90/100 and PGA for up to 5 years of treatment in reSURFACE 2
Authors: Heather Roebuck, Aaron S. Farberg, Sameh Hanna, Alan M. Mendelsohn, Stephen J. Rozzo
Journal: Journal of the American Academy of Dermatology (2021)