tbuckley/cabot-search huggingface dataset:
Chemotherapeutic and targeted agents can modulate the tumor microenvironment and increase the efficacy of immune checkpoint blockades
Authors: Jun-Yan Li, Yu-Pei Chen, Ying-Qin Li, Na Liu, Jun Ma
Journal: Molecular Cancer (2021)

Abstract The development of immune checkpoint blockade (ICB)-based immunotherapy has dramatically changed methods of cancer treatment. This approach triggers a durable treatment response and prolongs patients' survival; however, not all patients can benefit. Accumulating evidence demonstrated that the efficacy of ICB is dependent on a robust antitumor immune response that is usually damaged in most tumors. Conventional chemotherapy and targeted therapy promote the antitumor immune response by increasing the immunogenicity of tumor cells, improving CD8+ T cell infiltration, or inhibiting immunosuppressive cells in the tumor microenvironment. Such immunomodulation provides a convincing rationale for the combination therapy of chemotherapeutics and ICBs, and both preclinical and clinical investigations have shown encouraging results. However, the optimal drug combinations, doses, timing, and sequence of administration, all of which affect the immunomodulatory effect of chemotherapeutics, as well as the benefit of combination therapy, are not yet determined. Future studies should focus on these issues and help to develop the optimal combination regimen for each cancer.
Gastrointestinal carriage of Klebsiella pneumoniae in a general adult population: a cross-sectional study of risk factors and bacterial genomic diversity
Authors: Niclas Raffelsberger, Marit Andrea Klokkhammer Hetland, Kristian Svendsen, Lars Småbrekke, Iren Høyland Löhr, Lotte Leonore Eivindsdatter Andreassen, Sylvain Brisse, Kathryn E. Holt, Arnfinn Sundsfjord, Ørjan Samuelsen, Kirsten Gravningen
Journal: Gut Microbes (2021)

Antibiotic resistant
Biomimetic strategies for tendon/ligament-to-bone interface regeneration
Authors: Tingyun Lei, Tao Zhang, Wei Ju, Xiao Chen, Boon Chin Heng, Weiliang Shen, Zi Yin
Journal: Bioactive Materials (2021)

Tendon/ligament-to-bone healing poses a formidable clinical challenge due to the complex structure, composition, cell population and mechanics of the interface. With rapid advances in tissue engineering, a variety of strategies including advanced biomaterials, bioactive growth factors and multiple stem cell lineages have been developed to facilitate the healing of this tissue interface. Given the important role of structure-function relationship, the review begins with a brief description of enthesis structure and composition. Next, the biomimetic biomaterials including decellularized extracellular matrix scaffolds and synthetic-/natural-origin scaffolds are critically examined. Then, the key roles of the combination, concentration and location of various growth factors in biomimetic application are emphasized. After that, the various stem cell sources and culture systems are described. At last, we discuss unmet needs and existing challenges in the ideal strategies for tendon/ligament-to-bone regeneration and highlight emerging strategies in the field.
Endoplasmic reticulum stress sensor IRE1α propels neutrophil hyperactivity in lupus
Authors: Gautam Sule, Basel H. Abuaita, Paul A. Steffes, Andrew T. Fernandes, Shanea K. Estes, Craig Dobry, Deepika Pandian, Johann E. Gudjonsson, J. Michelle Kahlenberg, Mary X. O’Riordan, Jason S. Knight
Journal: Journal of Clinical Investigation (2021)

Neutrophils amplify inflammation in lupus through the release of neutrophil extracellular traps (NETs). The endoplasmic reticulum stress sensor inositol-requiring enzyme 1 α (IRE1α) has been implicated as a perpetuator of inflammation in various chronic diseases; however, IRE1α has been little studied in relation to neutrophil function or lupus pathogenesis. Here, we found that neutrophils activated by lupus-derived immune complexes demonstrated markedly increased IRE1α ribonuclease activity. Importantly, in neutrophils isolated from patients with lupus, we also detected heightened IRE1α activity that was correlated with global disease activity. Immune complex–stimulated neutrophils produced both mitochondrial ROS (mitoROS) and the activated form of caspase-2 in an IRE1α-dependent fashion, whereas inhibition of IRE1α mitigated immune complex–mediated NETosis (in both human neutrophils and a mouse model of lupus). Administration of an IRE1α inhibitor to lupus-prone MRL/lpr mice over 8 weeks reduced mitoROS levels in peripheral blood neutrophils, while also restraining plasma cell expansion and autoantibody formation. In summary, these data identify a role for IRE1α in the hyperactivity of lupus neutrophils and show that this pathway is upstream of mitochondrial dysfunction, mitoROS formation, and NETosis. We believe that inhibition of the IRE1α pathway is a novel strategy for neutralizing NETosis in lupus, and potentially other inflammatory conditions.
Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition
Authors: Sergio Crespo-Garcia, Pamela R. Tsuruda, Agnieszka Dejda, Rathi D. Ryan, Frederik Fournier, Shawnta Y. Chaney, Frederique Pilon, Taner Dogan, Gael Cagnone, Priyanka Patel, Manuel Buscarlet, Sonali Dasgupta, Gabrielle Girouard, Surabhi R. Rao, Ariel M. Wilson, Robert O’Brien, Rachel Juneau, Vera Guber, Alexandre Dubrac, Christian Beausejour, Scott Armstrong, Frederick A. Mallette, Christopher B. Yohn, Jean-Sebastien Joyal, Dan Marquess, Pedro J. Beltran, Przemyslaw Sapieha
Journal: Cell Metabolism (2021)
Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Laboratory Reference Ranges and Testing Intervals Work Group
Authors: Alexander I. Spira, Mark D. Stewart, Suzanne Jones, Elaine Chang, Anitra Fielding, Nicole Richie, Laura S. Wood, Michael A. Thompson, Lee Jones, Abhilasha Nair, Brandon A. Mahal, David E. Gerber
Journal: Clinical Cancer Research (2021)

In clinical research, eligibility criteria promote patient safety and optimize the evidence generated from clinical trials. However, overly stringent eligibility criteria, including laboratory requirements, may limit enrollment, resulting in delayed trial completion and potentially limiting applicability of trial results to a general practice population.Starting in 2018, a working group consisting of experts in direct patient care, the FDA, industry, and patient advocacy developed recommendations to guide the optimal use of laboratory reference ranges and testing intervals in clinical trial eligibility criteria and study procedures. The working group evaluated current eligibility criteria across different clinical trial phases and performed a literature review to evaluate the impact of and justification for laboratory test eligibility requirements and testing intervals in clinical trials. Recommendations were developed on the basis of the goals of promoting safety and optimizing the evidence generated, while also expanding eligibility and applicability, and minimizing excess burden of trial participation.In general, we found little variation over time and trial phase in laboratory test requirements, suggesting that these eligibility criteria are not refined according to ongoing clinical experience. We propose recommendations to optimize the use of laboratory tests when considering eligibility criteria.Tailoring the use of laboratory test requirements and testing intervals may increase the number and diversity of patients in clinical trials and provide clinical data that more closely represent the general practice populations.See related commentary by Giantonio, p. 2369.
99mTc-Mebrofenin Hepatobiliary Scintigraphy Combined With SPECT/CT to Assess Liver Function in Heterotopic Segmental Liver Transplantation in the Splenic Fossa
Authors: Matteo Serenari, Diletta Calabrò, Rachele Bonfiglioli, Stefano Fanti, Matteo Ravaioli
Journal: Clinical Nuclear Medicine (2021)

Abstract Recent studies have shown that the inclusion of a noninvasive and low-cost functional test such as hepatobiliary scintigraphy is considered more reliable than volume alone to predict posthepatectomy liver failure especially in light of new liver regeneration techniques. We herein reported the unique case of a 40-year-old man who underwent heterotopic liver transplantation of segments 2 and 3 in the splenic fossa after splenectomy for unresectable colorectal liver metastases. 99m Tc-mebrofenin hepatobiliary scintigraphy combined with SPECT/CT was performed after liver transplantation to monitor graft function and regeneration before removal of the native liver.
Brian M Davies
Authors: Roger Glass
Journal: BMJ (2021)

Brian Davies, Victoria’s first professor of psychiatry, has died at the age of 92. He taught a generation of Melbourne University medical students and postgraduates. He established Melbourne’s first academic department of psychiatry, taking up the Melbourne University Cato chair of psychiatry in 1964.

His quiet, diffident, and, at times, enigmatic nature resulted in a leadership style that enabled department staff to feel free to pursue their research passions while also being gently guided and supported, yet nudged when necessary.

The department that he led quickly gained an enviable reputation for wide ranging quality research, excellent teaching, and state of the art treatment and caring of patients.

The son of a Welsh coal miner, he followed his older brother to Cardiff University Medical School. He graduated in 1950, his medical training having included just one lecture in psychiatry. He said: “I wasn’t interested—in those days psychiatry was the last chapter in the medical textbooks. I just wanted to be a physician like my brother.”

Having completed physician training Brian asked senior colleagues for advice regarding what should be his next career step. “Do psychiatry training—psychiatry will be big in four years” was the advice.

Brian was able to …
Fatigue and the prediction of negative health outcomes: A systematic review with meta-analysis
Authors: V. Knoop, B. Cloots, A. Costenoble, A. Debain, R. Vella Azzopardi, S. Vermeiren, B. Jansen, A. Scafoglieri, I. Bautmans, Ivan Bautmans, Dominque Verté, Ingo Beyer, Mirko Petrovic, Liesbeth De Donder, Tinie Kardol, Gina Rossi, Peter Clarys, Aldo Scafoglieri, Erik Cattrysse, Paul de Hert, Bart Jansen
Journal: Ageing Research Reviews (2021)
The association between deaths from infection and mutations of the BRAF, FBXW7, NRAS and XPO1 genes: a report from the LRF CLL4 trial
Authors: Monica Else, Stuart J. Blakemore, Jonathan C. Strefford, Daniel Catovsky
Journal: Leukemia (2021)

Causes of death, in particular deaths due to infection, have not been widely studied in randomised trials in chronic lymphocytic leukaemia. With long-term follow-up (median 13 years) we examined the cause of death in 600/777 patients in the LRF CLL4 trial. Blood samples, taken at randomisation from 499 patients, were available for identifying gene mutations. Infection was a cause of death in 258 patients (43%). Patients dying of infection were more likely than those who died of other causes to have received ≥2 lines of treatment (194/258 [75%] versus 231/342 [68%], P = 0.04) and to have died in the winter months (149/258 [58%] versus 166/342 [49%], P = 0.03), respectively. In patients with mutation data, the factors significantly associated with death from infection versus all other deaths were 11q deletion (47/162 [29%] versus 40/209 [19%], P = 0.03) and mutations of the BRAF, FBXW7, NRAS and XPO1 genes. Death was caused by an infection in 46/67 assessable patients (69%) who had a mutation of one or more of these four genes versus only 129/333 patients (39%) without any of these mutations (odds ratio: 3.46 [95% CI 1.98-6.07] P < 0.0001). Careful management of infection risk, including prophylaxis against infection, may be important in patients who carry these mutations.
Neuropsychiatric disease classification using functional connectomics - results of the connectomics in neuroimaging transfer learning challenge
Authors: Markus D. Schirmer, Archana Venkataraman, Islem Rekik, Minjeong Kim, Stewart H. Mostofsky, Mary Beth Nebel, Keri Rosch, Karen Seymour, Deana Crocetti, Hassna Irzan, Michael Hütel, Sebastien Ourselin, Neil Marlow, Andrew Melbourne, Egor Levchenko, Shuo Zhou, Mwiza Kunda, Haiping Lu, Nicha C. Dvornek, Juntang Zhuang, Gideon Pinto, Sandip Samal, Jennings Zhang, Jorge L. Bernal-Rusiel, Rudolph Pienaar, Ai Wern Chung
Journal: Medical Image Analysis (2021)
Reintervention technique with insertion of an uncovered metal stent by a 5.4-Fr delivery system for an occluded endoscopic ultrasound-guided hepaticogastrostomy stent
Authors: Takeshi Ogura, Atsushi Okuda, Nobu Nishioka, Masanori Yamada, Kazuhide Higuchi
Journal: Endoscopy (2021)

Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is indicated for patients with failed endoscopic retrograde cholangiopancreatography (ERCP) [1]. The clinical benefit of EUS-HGS using a long-length, partially covered, self-expandable metal stent (PCSEMS) to prevent stent migration has been reported [2] [3]. However, reintervention can be challenging in the event of stent obstruction because biliary access through a long-length PCSEMS is often difficult. Biliary access through the mesh of the EUS-HGS stent may be a useful reintervention technique [4] [5]. In this procedure, insertion of the device into the biliary tract is a limiting step because the lumen of the mesh is relatively narrow. A novel uncovered self-expandable metal stent (UCSEMS) has recently become available in Japan (YABUSAME; KANEKA Medical, Osaka, Japan) ([Fig. 1]). As the diameter of the stent delivery system is only 5.4 Fr and the tip is extremely tapered, stent delivery is performed by insertion along a guidewire. Here we describe the technique of reintervention through the mesh of an occluded EUS-HGS stent using the novel UCSEMS ([Video 1]).
Abstract 17744: Arginine-Glycine-Aspartic Acid-Motif Containing Peptides and Integrin Binding Modulate Human Induced Pluripotent Stem-Cell Derived Cardiomyocyte Calcium Cycling
Authors: Brian X Wang, Christopher Kane, Liam Couch, Kenneth T MacLeod, Cesare M Terracciano
Journal: Circulation (2017)

Introduction: Cardiac fibroblasts are key regulators of the extracellular matrix (ECM), which forms the mechanical environment for cardiomyocytes through extensive integrin binding. Arginine-Glycin...
A Randomized Controlled Trial of an Educational Handbook for Caregivers of Children with Atopic Dermatitis
Authors: Jennifer Lebovidge, Corinna Rea, Karol Timmons, Sophia Delano, Kimberly Greco, Frances DeFreitas, Felice Chan, Tiffany Jeong, Melissa Rosen, Lynda Schneider
Journal: Journal of Allergy and Clinical Immunology (2021)
Covid-19: Government wasted millions on poor quality PPE, spending watchdog finds
Authors: Clare Dyer
Journal: BMJ (2021)

The use of antibiotics in acute exacerbations of chronic bronchitis (AECBs) remains the subject of controversy despite considerable medical and socioeconomic implications. First, the contribution of bacterial infection to AECBs is difficult to assess in patients with chronic obstructive pulmonary disease (COPD) who are chronically colonized with respiratory pathogens. In addition, several studies suggest a major role of viral infections in AECBs. Secondly, it is unlikely that all COPD patients will benefit from antibiotics during AECBs. In particular, the benefit in mild COPD remains uncertain. Unfortunately, the number of studies complying with evidence-based medicine requirements is too small for definite recommendations in AECBs to be drawn up. Considering the impact of acute exacerbations of chronic bronchitis on chronic obstructive pulmonary disease patients, as well as the community, and the impact of antibiotic therapy on the development of bacterial resistance, there is an urgent need for the design of appropriate multicentric studies to define the usefulness of this type of treatment in acute exacerbations of chronic bronchitis.
Abstract 11824: Coil Embolization in Aortopulmonary Collateral Arteries Before Fontan Surgery Ameliorates the Postoperative Course
Authors: Hirofumi Saiki, Manabu Takanashi, Seiko Kuwata, Satoshi Masutani, Hideaki Senzaki
Journal: Circulation (2019)

Introduction: Evidence suggested minimal advantage of performing coil embolization in aortopulmonary collateral arteries (APCA) before the Fontan procedure, whereas advanced imaging modality demons...
EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19
Authors: Alessia Alunno, Aurélie Najm, Pedro M Machado, Heidi Bertheussen, Gerd R Burmester, Francesco Carubbi, Gabriele De Marco, Roberto Giacomelli, Olivier Hermine, John D Isaacs, Isabelle Koné-Paut, César Magro-Checa, Iain McInnes, Pier Luigi Meroni, Luca Quartuccio, Athimalaipet V Ramanan, Manuel Ramos-Casals, Javier Rodríguez Carrio, Hendrik Schulze-Koops, Tanja A Stamm, Sander W Tas, Benjamin Terrier, Dennis G McGonagle, Xavier Mariette
Journal: Annals of the Rheumatic Diseases (2021)

Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies.PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting.Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1-6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7-14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates.Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19.
TAS4464, a Novel, Highly Potent NEDD8-Activating Enzyme Inhibitor Shows Antitumor Activity in Ibrutinib-Insensitive Mantle Cell Lymphoma Via Inactivation of the NF-κB Pathway
Authors: Hiromi Muraoka, Chihoko Yoshimura, Shingo Tsuji, Akihiro Hashimoto, Fumio Nakagawa, Takashi Mizutani, Shuichi Ohkubo, Kenichi Matsuo, Teruhiro Utsugi, Yoshikazu Iwasawa
Journal: Blood (2017)
Ablation Versus Drug Therapy for Atrial Fibrillation in Heart Failure
Authors: Douglas L. Packer, Jonathan P. Piccini, Kristi H. Monahan, Hussein R. Al-Khalidi, Adam P. Silverstein, Peter A. Noseworthy, Jeanne E. Poole, Tristram D. Bahnson, Kerry L. Lee, Daniel B. Mark
Journal: Circulation (2021)

In patients with heart failure and atrial fibrillation (AF), several clinical trials have reported improved outcomes, including freedom from AF recurrence, quality of life, and survival, with catheter ablation. This article describes the treatment-related outcomes of the AF patients with heart failure enrolled in the CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation).The CABANA trial randomized 2204 patients with AF who were ≥65 years old or <65 years old with ≥1 risk factor for stroke at 126 sites to ablation with pulmonary vein isolation or drug therapy including rate or rhythm control drugs. Of these, 778 (35%) had New York Heart Association class >II at baseline and form the subject of this article. The CABANA trial's primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest.Of the 778 patients with heart failure enrolled in CABANA, 378 were assigned to ablation and 400 to drug therapy. Ejection fraction at baseline was available for 571 patients (73.0%), and 9.3% of these had an ejection fraction <40%, whereas 11.7% had ejection fractions between 40% and 50%. In the intention-to-treat analysis, the ablation arm had a 36% relative reduction in the primary composite end point (hazard ratio, 0.64 [95% CI, 0.41-0.99]) and a 43% relative reduction in all-cause mortality (hazard ratio, 0.57 [95% CI, 0.33-0.96]) compared with drug therapy alone over a median follow-up of 48.5 months. AF recurrence was decreased with ablation (hazard ratio, 0.56 [95% CI, 0.42-0.74]). The adjusted mean difference for the AFEQT (Atrial Fibrillation Effect on Quality of Life) summary score averaged over the entire 60-month follow-up was 5.0 points, favoring the ablation arm (95% CI, 2.5-7.4 points), and the MAFSI (Mayo Atrial Fibrillation-Specific Symptom Inventory) frequency score difference was -2.0 points, favoring ablation (95% CI, -2.9 to -1.2).In patients with AF enrolled in the CABANA trial who had clinically diagnosed stable heart failure at trial entry, catheter ablation produced clinically important improvements in survival, freedom from AF recurrence, and quality of life relative to drug therapy. These results, obtained in a cohort most of whom had preserved left ventricular function, require independent trial verification. Registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT00911508; Unique identifier: NCT0091150.
Mutations disrupting neuritogenesis genes confer risk for cerebral palsy (vol 52, pg 1046, 2020)
Authors: Sheng Chih Jin, Sara A Lewis, Somayeh Bakhtiari, Xue Zeng, Michael C Sierant, Sheetal Shetty, Sandra M Nordlie, Aureliane Elie, Mark A Corbett, Bethany Y Norton, Clare L van Eyk, Shozeb Haider, Brandon S Guida, Helen Magee, James Liu, Stephen Pastore, John B Vincent, Janice Brunstrom-Hernandez, Antigone Papavasileiou, Michael C Fahey, Jesia G Berry, Kelly Harper, Chongchen Zhou, Junhui Zhang, Boyang Li, Hongyu Zhao, Jennifer Heim, Dani L Webber, Mahalia Sb Frank, Lei Xia, Yiran Xu, Dengna Zhu, Bohao Zhang, Amar H Sheth, James R Knight, Christopher Castaldi, Irina R Tikhonova, Francesc Lopez-Giraldez, Boris Keren, Sandra Whalen, Julien Buratti, Diane Doummar, Megan Cho, Kyle Retterer, Francisca Millan, Yangong Wang, Jeff L Waugh, Lance Rodan, Julie S Cohen, Ali Fatemi, Angela E Lin, John P Phillips, Timothy Feyma, Suzanna C MacLennan, Spencer Vaughan, Kylie E Crompton, Susan M Reid, Dinah S Reddihough, Qing Shang, Chao Gao, Iona Novak, Nadia Badawi, Yana A Wilson, Sarah J McIntyre, Shrikant M Mane, Xiaoyang Wang, David J Amor, Daniela C Zarnescu, Qiongshi Lu, Qinghe Xing, Changlian Zhu, Kaya Bilguvar, Sergio Padilla-Lopez, Richard P Lifton, Jozef Gecz, Alastair H MacLennan, Michael C Kruer
Journal: Nature Genetics (2021)