tbuckley/cabot-search huggingface dataset:
GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors
Authors: David G DeNardo, Anna Galkin, Jakob Dupont, Lei Zhou, Johanna Bendell
Journal: Journal for ImmunoTherapy of Cancer (2021)

Resistance to immune checkpoint inhibitors (ICI) and other anticancer therapies is often associated with the accumulation of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Therefore, targeting MDSC recruitment or function is of significant interest as a strategy to treat patients with ICI-resistant cancer. The migration and recruitment of MDSCs to the TME is mediated in part by the CD11b/CD18 integrin heterodimer (Mac-1; α M β 2 ), expressed on both MDSCs and TAMs. However, inhibition or blockade of CD11b/CD18 has had limited success in clinical trials to date, likely since saturation of CD11b requires doses that are not clinically tolerable with the agents tested so far. Interestingly, activation of CD11b with leukadherin-1 was found to reduce macrophage and neutrophil migration in animal models of inflammatory conditions. Preclinical studies with GB1275, a salt form of leukadherin-1, demonstrated that activation of CD11b improves the antitumor immune response and enhances the response to immunotherapy in mouse models of pancreatic adenocarcinoma, breast cancer and lung cancer. Based on the promising results from preclinical studies, a phase 1/2 clinical study ( NCT04060342 ) of GB1275 in patients with advanced solid tumor types known to be resistant or less likely responsive to immuno-oncology therapies, including pancreatic, breast, prostate, and microsatellite-stable colorectal cancer, is ongoing. In this review, we examine targeting MDSCs as a therapeutic approach in cancer therapy, with a special focus on GB1275 preclinical studies laying the rationale for the phase 1/2 clinical study.
Reply to Wei Liu, Katherine Zukotynski, and Glenn Bauman’s Letter to the Editor re: Rachel M. Glicksman, Ur Metser, Douglass Vines, et al. Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis. Eur Urol 2021;80:374–82
Authors: Rachel M Glicksman, Alejandro Berlin
Journal: European Urology (2021)
Stanniocalcin-1 in the female reproductive system and pregnancy
Authors: Alexa Bishop, Judith E Cartwright, Guy S Whitley
Journal: Human Reproduction Update (2021)

Stanniocalcin-1 (STC-1) is a widely expressed glycoprotein hormone involved in a diverse spectrum of physiological and pathophysiological processes including angiogenesis, mineral homeostasis, cell proliferation, inflammation and apoptosis. Over the last 20 years, numerous studies have reported STC-1 expression within female reproductive tissues including the uterus, ovaries and placenta and implicated STC-1 in processes such as ovarian follicular development, blastocyst implantation, vascular remodelling in early pregnancy and placental development. Notably, dysregulation of STC-1 within reproductive tissues has been linked to the onset of severe reproductive disorders including endometriosis, polycystic ovary syndrome, poor trophoblast invasion and placental perfusion in early pregnancy. Furthermore, significant changes in tissue expression and in maternal systemic concentration take place throughout pregnancy and further substantiate the vital role of this protein in reproductive health and disease.Our aim is to provide a comprehensive overview of the existing literature, to summarise the expression profile and roles of STC-1 within the female reproductive system and its associated pathologies. We highlight the gaps in the current knowledge and suggest potential avenues for future research.Relevant studies were identified through searching the PubMed database using the following search terms: 'stanniocalcin-1', 'placenta', 'ovary', 'endometrium', 'pregnancy', 'reproduction', 'early gestation'. Only English language papers published between 1995 and 2020 were included.This review provides compelling evidence of the vital function that STC-1 plays within the female reproductive system. The literature presented summarise the wide expression profile of STC-1 within female reproductive organs, as well as highlighting the putative roles of STC-1 in various functions in the reproductive system. Moreover, the observed link between altered STC-1 expression and the onset of various reproductive pathologies is presented, including those in pregnancy whose aetiology occurs in the first trimester. This summary emphasises the requirement for further studies on the mechanisms underlying the regulation of STC-1 expression and function.STC-1 is a pleiotropic hormone involved in the regulation of a number of important biological functions needed to maintain female reproductive health. There is also growing evidence that dysregulation of STC-1 is implicated in common reproductive and obstetric disorders. Greater understanding of the physiology and biochemistry of STC-1 within the field may therefore identify possible targets for therapeutic intervention and/or diagnosis.
The Microbiome Colorectal Cancer Puzzle: Initiator, Propagator, and Avenue for Treatment and Research
Authors: Reece J. Knippel, Cynthia L. Sears
Journal: Journal of the National Comprehensive Cancer Network (2021)

The human gut microbiome has an ever-increasing role in the instigation and progression of colorectal cancer (CRC). Recent investigations have focused on identifying the key causative bacterial species and the composition and structure of the microbiome as a whole that ultimately lead to tumorigenesis in the colon. Understanding the bacterial mechanisms that promote CRC provides a rich area for the development of new screening modalities and therapeutics that may improve patient outcomes. This article reviews the various mechanisms that bacteria in the gut use to induce and/or promote tumor formation, discusses the application of the microbiome in the prevention and therapy of CRC, and provides directions for future research endeavors aiming to develop a more complete understanding of this complex phenomenon.
Self‐reported nasal hyperreactivity is common in all chronic upper airway inflammatory phenotypes and not related to general well‐being
Authors: Wout Backaert, Brecht Steelant, Mark Jorissen, Lukas Van Oudenhove, Karel Talavera, Peter W. Hellings, Laura Van Gerven
Journal: Allergy (2021)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Immunotherapy in Patients With Locally Advanced Esophageal Carcinoma: ASCO Treatment of Locally Advanced Esophageal Carcinoma Guideline Rapid Recommendation Update
Authors: Manish A. Shah, Wayne L. Hofstetter, Erin B. Kennedy
Journal: Journal of Clinical Oncology (2021)

ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options.
26304 Efficacy and safety of crisaborole in patients with mild-to-moderate atopic dermatitis with and without comorbid allergies or asthma
Authors: Peter A. Lio, Jonathan M. Spergel, Michael J. Cork, Michael S. Blaiss, Aharon Kessel, Wendy C. Cantrell, John L. Werth, Michael A. O’Connell, Chuanbo Zang, Liza Takiya
Journal: Journal of the American Academy of Dermatology (2021)
Herpetic oesophagitis in an immunocompetent infant with gastroesophageal reflux
Authors: Esther J E Peeters, Pauline De Bruyne, Marjolein Van Waas, Johanna C Escher, Michael Doukas, Danielle M Hendriks, Caroline E Veldhuis-Hogen Esch
Journal: The Lancet Infectious Diseases (2021)
Seeing the Light: CAR T-cell Targeting of Lambda-restricted B-cell Lymphomas
Authors: Michael D. Jain, Frederick L. Locke
Journal: Clinical Cancer Research (2021)

Abstract CD19-targeted chimeric antigen receptor T cells eliminate both malignant and normal B cells. Targeting immunoglobulin light chains instead of CD19 could preserve half of the normal B cells and provide an alternative target. See related article by Ranganathan et al., p. 5951
Prevalence of Central Sensitization in Patients With Hidradenitis Suppurativa
Authors: Pim Aarts, Jessie J. Aitken, Kelsey R. van Straalen
Journal: JAMA Dermatology (2021)

Chronic pain is one of the most prominent symptoms of hidradenitis suppurativa (HS) and an independent domain in the core outcome set for HS. Previously, the chronic, recurrent, inflammatory nature of HS was hypothesized to induce central sensitization (CS; alteration and amplification of pain perception). However, evidence for this hypothesis is currently lacking.To determine the prevalence of CS in patients with HS compared with sex- and age-matched controls.This was a cross-sectional, survey-based, case-control study conducted from February to November 2020 that included all consecutive adult patients with HS attending the outpatient clinic of the Department of Dermatology of the Erasmus University Medical Center Rotterdam, in Rotterdam, the Netherlands. Age- and sex-matched controls without chronic inflammatory dermatologic diseases were recruited from the same department.The main outcome was the Central Sensitization Inventory (CSI) score (ranging from 0-100) as a screening tool for presence of CS. Based on current literature, a score of 40 or higher was deemed to indicate the presence of CS.Overall, 100 patients with HS (median [IQR] age, 34.5 [27.3-47.0] years; 71 [71%] female) and 100 controls (median [IQR] age, 33.5 [27.0-48.8] years; 71 [71%] female) were included, of which 36% and 12%, respectively, had a CSI score of 40 or higher (P < .001). Multivariate logistic regression showed that patients with HS had 4.46 (95% CI, 1.89-10.52; P = .001) times the odds of having a positive CSI compared with controls. In addition, CS was significantly associated with previously diagnosed depression (odds ratio, 6.16; 95% CI, 2.81-13.54; P < .001). No association between CSI score and disease severity was found.In this cross-sectional, case-control study, patients with HS had more than 4 times the odds of having CS, indicated by a positive CSI, compared with age- and sex-matched controls. This new insight in the presence of CS in patients with HS raises the question of whether we are adequately measuring and treating HS-associated pain. Active screening for CS and depressive symptoms in patients with a discrepant pain experience is recommended.
Abstract 13986: Feasibility of Meditation as Therapy for Improved Clinical Outcomes in Patients With Implantable Defibrillators
Authors: Pankaj Malhotra, Dali Fan, Nayereh Pezeshkian, Uma Srivatsa
Journal: Circulation (2019)

Introduction: Sympathetic activation is correlated with increased mortality and arrhythmias in patients with congestive heart failure (CHF). Meditation reduces sympathetic activation. It is current...
Psychological Targets for Lung Cancer Screening Uptake: A Prospective Longitudinal Cohort Study
Authors: Samantha L. Quaife, Jo Waller, Jennifer L. Dickson, Kate E. Brain, Clara Kurtidu, John McCabe, Allan Hackshaw, Stephen W. Duffy, Samuel M. Janes
Journal: Journal of Thoracic Oncology (2021)

Low uptake of low-dose computed tomography lung cancer screening by high-risk groups compromises its effectiveness and equity as a population-level early detection strategy. Numerous psychological factors are implicated qualitatively or retrospectively, but prospective data are needed to validate their associations with uptake behavior and specify psychological targets for intervention.
Brentuximab vedotin-containing escalated BEACOPP variants for newly diagnosed advanced-stage classical Hodgkin lymphoma: follow-up analysis of a randomized phase II study from the German Hodgkin Study Group
Authors: Carla Damaschin, Helen Goergen, Stefanie Kreissl, Annette Plütschow, Frank Breywisch, Stephan Mathas, Julia Meissner, Martin Sökler, Max S. Topp, Vladan Vucinic, Andreas Zimmermann, Bastian von Tresckow, Michael Fuchs, Andreas Engert, Peter Borchmann, Dennis A. Eichenauer
Journal: Leukemia (2021)

Patients with advanced-stage Hodgkin lymphoma (HL) receiving intensive treatment with escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) (eBEACOPP) have excellent outcomes [1,2].However, late effects such as second primary malignancies (SPM) and infertility represent ongoing concerns [3,4].Novel approaches using an eBEACOPP backbone, therefore, aim at reducing toxicity without compromising efficacy.The BrECAPP (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone) and BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) protocols were investigated in a randomized phase II study including patients with newly diagnosed advanced-stage classical HL (cHL).Both regimens combine eBEACOPP-based chemotherapy with the CD30-directed antibody-drug conjugate brentuximab vedotin (BV).Response rates were similar to standard eBEACOPP and especially the BrECADD protocol was associated with reduced acute toxicity [5].The major objectives of the present follow-up analysis of the study were progression-free survival (PFS) and overall survival (OS) at 3 years.Patterns of cHL recurrence, the occurrence of SPM, and causes of death were also evaluated.PFS and OS were analyzed using the Kaplan-Meier method.PFS was defined as the time between randomization and progression or relapse of cHL or death from any cause and was censored at the date of last information on the disease status.OS was defined as the time between randomization and death from any cause and was censored at the date of last information for surviving patients.
Hobit identifies tissue-resident memory T cell precursors that are regulated by Eomes
Authors: Loreto Parga-Vidal, Felix M. Behr, Natasja A. M. Kragten, Benjamin Nota, Thomas H. Wesselink, Inga Kavazović, Laura E. Covill, Margo B. P. Schuller, Yenan T. Bryceson, Felix M. Wensveen, Rene A. W. van Lier, Teunis J. P. van Dam, Regina Stark, Klaas P. J. M. van Gisbergen
Journal: Science Immunology (2021)

Hobit-expressing effector CD8 + T cells are T RM precursors, whose formation is regulated by the T-box transcription factor Eomes.
25240 Cosentyx (secukinumab) for the treatment of adult onset pityriasis rubra pilaris: A single arm, open-label exploratory study
Authors: Jason C. Sluzevich, Meera H. Patel, Thais P. Pincelli, Caitlin M. Brumfiel, Mark R. Pittelkow, Aaron Mangold
Journal: Journal of the American Academy of Dermatology (2021)
BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia
Authors: Weimin Kong, Alexander Dimitri, Wenliang Wang, In-Young Jung, Christopher J. Ott, Maria Fasolino, Yan Wang, Irina Kulikovskaya, Minnal Gupta, Todd Yoder, Jamie E. DeNizio, John K. Everett, Erik F. Williams, Jun Xu, John Scholler, Tyler J. Reich, Vijay G. Bhoj, Kathleen M. Haines, Marcela V. Maus, J. Joseph Melenhorst, Regina M. Young, Julie K. Jadlowsky, Katherine T. Marcucci, James E. Bradner, Bruce L. Levine, David L. Porter, Frederic D. Bushman, Rahul M. Kohli, Carl H. June, Megan M. Davis, Simon F. Lacey, Golnaz Vahedi, Joseph A. Fraietta
Journal: Journal of Clinical Investigation (2021)

Chimeric antigen receptor (CAR) T cells have induced remarkable antitumor responses in B cell malignancies. Some patients do not respond because of T cell deficiencies that hamper the expansion, persistence, and effector function of these cells. We used longitudinal immune profiling to identify phenotypic and pharmacodynamic changes in CD19-directed CAR T cells in patients with chronic lymphocytic leukemia (CLL). CAR expression maintenance was also investigated because this can affect response durability. CAR T cell failure was accompanied by preexisting T cell-intrinsic defects or dysfunction acquired after infusion. In a small subset of patients, CAR silencing was observed coincident with leukemia relapse. Using a small molecule inhibitor, we demonstrated that the bromodomain and extra-terminal (BET) family of chromatin adapters plays a role in downregulating CAR expression. BET protein blockade also ameliorated CAR T cell exhaustion as manifested by inhibitory receptor reduction, enhanced metabolic fitness, increased proliferative capacity, and enriched transcriptomic signatures of T cell reinvigoration. BET inhibition decreased levels of the TET2 methylcytosine dioxygenase, and forced expression of the TET2 catalytic domain eliminated the potency-enhancing effects of BET protein targeting in CAR T cells, providing a mechanism linking BET proteins and T cell dysfunction. Thus, modulating BET epigenetic readers may improve the efficacy of cell-based immunotherapies.
Novel Phenotypes for Acute Kidney Transplant Rejection Using Semi-Supervised Clustering
Authors: Arthur J. Matas, Roslyn B. Mannon, David Rush, Erika Helgeson
Journal: Journal of the American Society of Nephrology (2021)

We note that Vaulet et al. [1][1] confirmed the Deterioration of Kidney Allograft Function (DeKAF) studies that ( 1 ) identified Banff histologic clusters with differing postbiopsy graft survival; and ( 2 ) showed that markers of antibody-mediated rejection affect graft survival, even after
27528 Safety and durability of collagenase Clostridium histolyticum-aaes treatment of cellulite in women: 6-month results of a 5-year phase 3b open-label extension study
Authors: Michael H. Gold, Michael P. McLane, Saji Vijayan, Qinfang Xiang, Joely Kaufman-Janette
Journal: Journal of the American Academy of Dermatology (2021)
27038 Efficacy of guselkumab using composite endpoints in patients with active psoriatic arthritis: Domain-specific efficacy from DISCOVER-1 and DISCOVER-2 phase 3 trials
Authors: Laura C. Coates, Christopher T. Ritchlin, Laure Gossec, Philip S. Helliwell, Proton Rahman, Alexa P. Kollmeier, Chetan Karyekar, Shihong Sheng, Prasheen Agarwal, Philip J. Mease
Journal: Journal of the American Academy of Dermatology (2021)
Polarisation, incivility, and scientific debate during covid-19—an essay by Agnes Arnold-Forster
Authors: Agnes Arnold-Forster
Journal: BMJ (2021)

Over the course of the covid-19 pandemic, scientific debate has become increasingly polarised and politicised. Rather than being a new cultural moment, <b>Agnes Arnold-Forster</b> argues that anger, incivility, and unprofessional conduct have always played a part in topical scientific debates
Lymphatic contractile function: a comprehensive review of drug effects and potential clinical application
Authors: Peter S Russell, Jiwon Hong, Natalie L Trevaskis, John A Windsor, Niels D Martin, Anthony R J Phillips
Journal: Cardiovascular Research (2021)

The lymphatic system and the cardiovascular (CV) system work together to maintain body fluid homeostasis. Despite that, the lymphatic system has been relatively neglected as a potential drug target and a source of adverse effects from CV drugs. Like the heart, the lymphatic vessels undergo phasic contractions to promote lymph flow against a pressure gradient. Dysfunction or failure of the lymphatic pump results in fluid imbalance and tissue oedema. While this can be due to drug effects, it is also a feature of breast cancer-associated lymphoedema, chronic venous insufficiency, congestive heart failure, and acute systemic inflammation. There are currently no specific drug treatments for lymphatic pump dysfunction in clinical use despite the wealth of data from pre-clinical studies. The aim of this study was to identify (i) drugs with direct effects on lymphatic tonic and phasic contractions with potential for clinical application, and (ii) drugs in current clinical use that have a positive or negative side effect on lymphatic function. We comprehensively reviewed all studies that tested the direct effect of a drug on the contractile function of lymphatic vessels. Of the 208 drugs identified from 193 studies, about a quarter had only stimulatory effects on lymphatic tone, contraction frequency, and/or contraction amplitude. Of Food and Drug Administration-approved drugs, there were 14 that increased lymphatic phasic contractile function. The most frequently used class of drugs with inhibitory effects on lymphatic pump function were the calcium channels blockers. This review highlights the opportunity for specific drug treatments of lymphatic dysfunction in various disease states and for avoiding adverse drug effects on lymphatic contractile function.
Comparison of Teleintegrated Care and Telereferral Care for Treating Complex Psychiatric Disorders in Primary Care
Authors: John C. Fortney, Amy M. Bauer, Joseph M. Cerimele, Jeffrey M. Pyne, Paul Pfeiffer, Patrick J. Heagerty, Matt Hawrilenko, Melissa J. Zielinski, Debra Kaysen, Deborah J. Bowen, Danna L. Moore, Lori Ferro, Karla Metzger, Stephanie Shushan, Erin Hafer, John Paul Nolan, Gregory W. Dalack, Jürgen Unützer
Journal: JAMA Psychiatry (2021)

Only one-third of patients with complex psychiatric disorders engage in specialty mental health care, and only one-tenth receive adequate treatment in primary care. Scalable approaches are critically needed to improve access to effective mental health treatments in underserved primary care settings.
Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lupus erythematosus in Japanese
Authors: Yoshihiko Tomofuji, Yuichi Maeda, Eri Oguro-Igashira, Toshihiro Kishikawa, Kenichi Yamamoto, Kyuto Sonehara, Daisuke Motooka, Yuki Matsumoto, Hidetoshi Matsuoka, Maiko Yoshimura, Mayu Yagita, Takuro Nii, Shiro Ohshima, Shota Nakamura, Hidenori Inohara, Kiyoshi Takeda, Atsushi Kumanogoh, Yukinori Okada
Journal: Annals of the Rheumatic Diseases (2021)

Objective Alteration of the gut microbiome has been linked to the pathogenesis of systemic lupus erythematosus (SLE). However, a comprehensive view of the gut microbiome in SLE and its interaction with the host remains to be revealed. This study aimed to reveal SLE-associated changes in the gut microbiome and its interaction with the host by a comprehensive metagenome-wide association study (MWAS) followed by integrative analysis. Methods We performed a MWAS of SLE based on shotgun sequencing of the gut microbial DNA from Japanese individuals ( N case =47, N control =203). We integrated the result of the MWAS with the genome-wide association study (GWAS) data and plasma metabolite data. Results Via species level phylogenetic analysis, we identified and validated increases of Streptococcus intermedius and Streptococcus anginosus in the patients with SLE. Microbial gene analysis revealed increases of Streptococcus -derived genes including one involved in redox reaction. Additionally, microbial pathways related to sulfur metabolism and flagella assembly were altered in the patients with SLE. We identified an overlap in the enriched biological pathways between the metagenome and the germline genome by comparing the result of the MWAS and the GWAS of SLE (ie, MWAS-GWAS interaction). α-diversity and β-diversity analyses provided evidence of dysbiosis in the metagenome of the patients with SLE. Microbiome-metabolome association analysis identified positive dosage correlation of acylcarnitine with Streptococcus intermedius , an SLE-associated taxon. Conclusion Our MWAS followed by integrative analysis revealed SLE-associated changes in the gut microbiome and its interaction with the host, which contribute to our understanding of the relationship between the microbiome and SLE.