tbuckley/cabot-search huggingface dataset:
Inhibition of relaxin autocrine signaling confers therapeutic vulnerability in ovarian cancer
Authors: Helen E. Burston, Oliver A. Kent, Laudine Communal, Molly L. Udaskin, Ren X. Sun, Kevin R. Brown, Euihye Jung, Kyle E. Francis, Jose La Rose, Joshua Lowitz, Ronny Drapkin, Anne-Marie Mes-Masson, Robert Rottapel
Journal: Journal of Clinical Investigation (2021)

Ovarian cancer (OC) is the most deadly gynecological malignancy, with unmet clinical need for new therapeutic approaches. The relaxin peptide is a pleiotropic hormone with reproductive functions in the ovary. Relaxin induces cell growth in several types of cancer, but the role of relaxin in OC is poorly understood. Here, using cell lines and xenograft models, we demonstrate that relaxin and its associated GPCR RXFP1 form an autocrine signaling loop essential for OC in vivo tumorigenesis, cell proliferation, and viability. We determined that relaxin signaling activates expression of prooncogenic pathways, including RHO, MAPK, Wnt, and Notch. We found that relaxin is detectable in patient-derived OC tumors, ascites, and serum. Further, inflammatory cytokines IL-6 and TNF-α activated transcription of relaxin via recruitment of STAT3 and NF-κB to the proximal promoter, initiating an autocrine feedback loop that potentiated expression. Inhibition of RXFP1 or relaxin increased cisplatin sensitivity of OC cell lines and abrogated in vivo tumor formation. Finally, we demonstrate that a relaxin-neutralizing antibody reduced OC cell viability and sensitized cells to cisplatin. Collectively, these data identify the relaxin/RXFP1 autocrine loop as a therapeutic vulnerability in OC.
Early and sustained Lactobacillus plantarum probiotic therapy in critical illness: the randomised, placebo-controlled, restoration of gut microflora in critical illness trial (ROCIT)
Authors: Edward Litton, Matt Anstey, David Broadhurst, Andy Chapman, Andrew Currie, Janet Ferrier, Joel Gummer, Alisa Higgins, Jolene Lim, Laurens Manning, Erina Myers, Katrina Orr, Anne-Marie Palermo, Andrea Paparini, Susan Pellicano, Edward Raby, Anu Rammohan, Adrian Regli, Bernhard Richter, Sam Salman, Tobias Strunk, Sharon Waterson, David Weight, Bradley Wibrow, Fiona Wood
Journal: Intensive Care Medicine (2021)
Genetic polymorphisms, vitamin D binding protein and vitamin D deficiency in COVID-19
Authors: Marijn M. Speeckaert, Reinhart Speeckaert, Joris R. Delanghe
Journal: European Respiratory Journal (2021)

With interest, we read the paper of Faniyi et al . [1], which investigated the relationship between vitamin D status and seroconversion for coronavirus disease 2019 (COVID-19) in UK healthcare workers. More specifically, vitamin D deficiency was an independent risk factor for the development of COVID-19 seroconversion, with the biggest differences seen in the Black, Asian and minority ethnic (BAME) male group. Although several comorbidities were taken into account, we would like to highlight the importance of vitamin D binding protein (DBP) and its polymorphism in the interpretation of low 25-hydroxyvitamin D (25(OH)D) levels in the BAME population with COVID-19. Besides adiposity and skin pigmentation, different DBP polymorphisms could also partly influence the low 25(OH)D concentrations in the BAME group with COVID-19 <https://bit.ly/3bIQRsm>
Assessment of Food and Drug Administration– and European Medicines Agency–Approved Systemic Oncology Therapies and Clinically Meaningful Improvements in Quality of Life
Authors: Vanessa Arciero, Seanthel Delos Santos, Liza Koshy, Amanda Rahmadian, Ronak Saluja, Louis Everest, Ambica Parmar, Kelvin K. W. Chan
Journal: JAMA Network Open (2021)

<h3>Importance</h3> For patients with cancer treated with palliative intent, quality of life (QOL) is a critical aspect of treatment decision-making, alongside survival. However, regulatory approval can be based solely on survival measures or antitumor activities, without QOL evidence. <h3>Objective</h3> To investigate whether recently approved oncology therapies demonstrate clinically meaningful improvements in QOL. <h3>Evidence Review</h3> This systematic review study identified oncology drug indications approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) from January 2006 to December 2017 and supporting clinical trials (QOL publications identified to October 2019). Indications were evaluated for the presence of published QOL evidence; QOL benefits according to the American Society of Clinical Oncology Value Framework version 2.0 (ASCO-VF) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) QOL bonus criteria; and clinically meaningful improvements in QOL beyond minimal clinically important differences. Hematology trials were not evaluated by ESMO-MCBS. Associations between QOL evidence and approval year were examined using logistic regression models. <h3>Findings</h3> In total, 214 FDA-approved (77 [36%] hematological) and 170 EMA-approved (52 [31%] hematological) indications were included. QOL evidence was published for 40% and 58% of FDA- and EMA-approved indications, respectively. QOL bonus criterion for ASCO-VF and ESMO-MCBS was met in 13% and 17% of FDA-approved and 21% and 24% of EMA-approved indications, respectively. Clinically meaningful improvements in QOL beyond minimal clinically important differences were noted in 6% and 11% of FDA- and EMA-approved indications, respectively. Availability of published QOL evidence at the time of approval increased over time for EMA (odds ratio [OR], 1.13;<i>P</i> = .03), however not for FDA (OR, 1.10;<i>P</i> = .12). Over time, no increase in awarded QOL bonuses or clinically meaningful improvements in QOL were found. <h3>Conclusions and Relevance</h3> The findings of this systematic review suggest that approved systemic oncology therapies often do not have published evidence to suggest QOL improvement, despite its recognized importance. Of indications with evidence of statistical improvement, few have demonstrated clinically meaningful improvements.
Prostaglandin I2 signaling licenses Treg suppressive function and prevents pathogenic reprogramming
Authors: Allison E. Norlander, Melissa H. Bloodworth, Shinji Toki, Jian Zhang, Weisong Zhou, Kelli Boyd, Vasiliy V. Polosukhin, Jacqueline-Yvonne Cephus, Zachary J. Ceneviva, Vivek D. Gandhi, Nowrin U. Chowdhury, Louis-Marie Charbonnier, Lisa M. Rogers, Janey Wang, David M. Aronoff, Lisa Bastarache, Dawn C. Newcomb, Talal A. Chatila, R. Stokes Peebles
Journal: Journal of Clinical Investigation (2021)

Tregs restrain both the innate and adaptive immune systems to maintain homeostasis. Allergic airway inflammation, characterized by a Th2 response that results from a breakdown of tolerance to innocuous environmental antigens, is negatively regulated by Tregs. We previously reported that prostaglandin I2 (PGI2) promoted immune tolerance in models of allergic inflammation; however, the effect of PGI2 on Treg function was not investigated. Tregs from mice deficient in the PGI2 receptor IP (IP KO) had impaired suppressive capabilities during allergic airway inflammatory responses compared with mice in which PGI2 signaling was intact. IP KO Tregs had significantly enhanced expression of immunoglobulin-like transcript 3 (ILT3) compared with WT Tregs, which may contribute to the impairment of the IP KO Treg's ability to suppress Th2 responses. Using fate-mapping mice, we reported that PGI2 signaling prevents Treg reprogramming toward a pathogenic phenotype. PGI2 analogs promoted the differentiation of naive T cells to Tregs in both mice and humans via repression of β-catenin signaling. Finally, a missense variant in IP in humans was strongly associated with chronic obstructive asthma. Together, these data support that PGI2 signaling licenses Treg suppressive function and that PGI2 is a therapeutic target for enhancing Treg function.
Abstract 15488: Arrhythmogenicity of Superior Vena Cava at Repeat Ablation Procedure for Paroxysmal Atrial Fibrillation; Comparison Between Post- Second Generation Cryoballoon Ablation and Post-Radiofrequency Ablation
Authors: Nobuaki Tanaka, Koichi Inoue, Yuko Hirao, Koji Tanaka, Takafumi Oka, Yuichi Ninomiya, Masato Okada, Ryo Kitagaki, Yasushi Koyama, Atsunori Okamura, Katsuomi Iwakura, Kenshi Fujii
Journal: Circulation (2018)

Background: Cryoballoon ablation (CBA) is non-inferior to radiofrequency catheter ablation (RFCA) in efficacy and safety as a treatment for paroxysmal atrial fibrillation (AF). However, little is k...
Abstract IA010: Immunology of endometrial cancers: Tumor genetics, immune recognition, and immunotherapy response
Authors: Dmitriy Zamarin
Journal: Clinical Cancer Research (2021)

Abstract Immune checkpoint blockade therapy targeting the T cell immune inhibitory receptors (e.g. PD1 and CTLA4) has reinvigorated the field of cancer immunotherapy and demonstrated the power of harnessing the adaptive immune system to fight cancers. However, fundamental challenges and questions remain. Endometrial cancers specifically, are largely resistant to immune checkpoint blockade, while the underlying mechanisms of why T cell-mediated tumor elimination largely fails in EC are not well understood. Endometrial cancer encompasses a number of genetically-distinct diseases characterized by recurrent molecular alterations driving each disease subtype. Specifically, four major molecular subtypes have been identified, including POLE-ultramutated, MSI-high, and microsatellite stable copy-number high (serous-like) and copy number-low (endometrioid) cancers. In MSI-H endometrial cancers specifically, response rates of over 50% to single agent PD-1/PD-L1 blockade have been reported across a number of studies. Unfortunately, in non-MSI-H tumors, responses to immune checkpoint inhibitors have been rather limited, calling for novel combinations. Importantly, a trial of combination of multi-targeted tyrosine kinase inhibitor (TKI) lenvatinib with pembrolizumab (anti-PD1) demonstrated response rates of close to 40% irrespective of MMR status, which established this combination as a new standard of care treatment in metastatic endometrial cancer. Nevertheless, even with these promising findings: 1) A large proportion of patients does not benefit; 2) Predictive biomarkers and mechanisms defining immunotherapy response or resistance remain unknown; and 3) Insights into the mechanistic basis underlying the TKI/anti-PD-1 synergy are desperately needed. There is a growing appreciation that intrinsic tumor genomic features are critical in shaping the composition and phenotype of the immune microenvironment, including the recruitment, infiltration, phenotypes and functional states of tumor infiltrating lymphocytes. Understanding how these features predict response to immune checkpoint blockade will be key to development of novel biomarkers and therapeutic combinations. Citation Format: Dmitriy Zamarin. Immunology of endometrial cancers: Tumor genetics, immune recognition, and immunotherapy response [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA010.
Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection
Authors: Suma Thomas, Divyang Patel, Barbara Bittel, Kathy Wolski, Qiuqing Wang, Anirudh Kumar, Zachary J. Il’Giovine, Reena Mehra, Carla McWilliams, Steve E. Nissen, Milind Y. Desai
Journal: JAMA Network Open (2021)

<h3>Importance</h3> There is limited evidence regarding early treatment of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to mitigate symptom progression. <h3>Objective</h3> To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory patients with SARS-CoV-2 infection. <h3>Design, Setting, and Participants</h3> This multicenter, single health system randomized clinical factorial open-label trial enrolled 214 adult patients with a diagnosis of SARS-CoV-2 infection confirmed with a polymerase chain reaction assay who received outpatient care in sites in Ohio and Florida. The trial was conducted from April 27, 2020, to October 14, 2020. <h3>Intervention</h3> Patients were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care. <h3>Outcomes</h3> The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements. <h3>Results</h3> A total of 214 patients were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall<i>P</i> = .45). There was no significant difference in secondary outcomes among the treatment groups. <h3>Conclusions and Relevance</h3> In this randomized clinical trial of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT04342728
Role Of Il-6 (-174 G/C) Polymorphism and Renal Biopsy, Clinical &amp; Immunoinflammatory Markers In Pathogenesis Of Type 2 Diabetic Nephropathy
Authors: K. Ramanjaneyulu, G. Srilatha Reddy, K. Keerthi, S. Nivas, P. Kaushik, N. Raju, Sree Bhushan Raju, H. Surekha Rani
Journal: Metabolism (2021)
Association Of Dog Exposure and Early-Life IgE Production In The Microbes, Asthma, Allergy and Pets (MAAP) Birth Cohort
Authors: Ahmed Elisa, Abigail Chatfield, Suzanne Havstad, Alexandra Sitarik, Haejin Kim, Kyra Jones, Ganesa Wegienka, Christine Joseph, Nicholas Lukacs, Christine Johnson, Dennis Ownby, Susan Lynch, Edward Zoratti
Journal: Journal of Allergy and Clinical Immunology (2021)
A carrier-free anti-inflammatory platinum (II) self-delivered nanoprodrug for enhanced breast cancer therapy
Authors: Lei Xing, Chen-Xi Yang, Di Zhao, Li-Jun Shen, Tian-Jiao Zhou, Yu-Yang Bi, Zhang-Jian Huang, Qiong Wei, Ling Li, Fei Li, Hu-Lin Jiang
Journal: Journal of Controlled Release (2021)
Decline in Receipt of Vaccines by Medicare Beneficiaries During the COVID-19 Pandemic — United States, 2020
Authors: Kai Hong, Fangjun Zhou, Yuping Tsai, Tara C. Jatlaoui, Anna M. Acosta, Kathleen L. Dooling, Miwako Kobayashi, Megan C. Lindley
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

On March 13, 2020, the United States declared a national emergency concerning the novel coronavirus disease 2019 (COVID-19) outbreak (1).In response, many state and local governments issued shelter-in-place or stay-at-home orders, restricting nonessential activities outside residents' homes (2).CDC initially issued guidance recommending postponing routine adult vaccinations, which was later revised to recommend continuing to administer routine adult vaccines (3).In addition, factors such as disrupted operations of health care facilities and safety concerns regarding exposure to SARS-CoV-2, the virus that causes COVID-19, resulted in delay or avoidance of routine medical care (4), likely further affecting delivery of routine adult vaccinations.Medicare enrollment and claims data of Parts A (hospital insurance), B (medical insurance), and D (prescription drug insurance) were examined to assess the change in receipt of routine adult vaccines during the pandemic.Weekly receipt of four vaccines (13-valent pneumococcal conjugate vaccine [PCV13], 23-valent pneumococcal polysaccharide vaccine [PPSV23], tetanus-diphtheria or tetanus-diphtheria-acellular pertussis vaccine [Td/Tdap], and recombinant zoster vaccine [RZV]) by Medicare beneficiaries aged ≥65 years during January 5-July 18, 2020, was compared with that during January 6-July 20, 2019, for the total study sample and by race and ethnicity.Overall, weekly administration rates of the four examined vaccines declined by up to 89% after the national emergency declaration in mid-March (1) compared with those during the corresponding period in 2019.During the first week following the national emergency declaration, the weekly vaccination rates were 25%-62% lower than those during the corresponding week in 2019.After reaching their nadirs of 70%-89% below 2019 rates in the second to third week of April 2020, weekly vaccination rates gradually began to recover through mid-July, but by the last study week were still lower than were those during the corresponding period in 2019, with the exception of PPSV23.Vaccination declined sharply for all vaccines studied, overall and across all racial and ethnic groups.While the pandemic continues, vaccination providers should emphasize to patients the importance of continuing to receive routine vaccinations and provide reassurance by explaining the procedures in place to ensure patient safety (3).Medicare enrollment and insurance claims data for beneficiaries enrolled in a fee-for-service plan during weeks 2-29 of
Classification and effectiveness of different oxygenation goals in mechanically ventilated critically ill patients: network meta-analysis of randomised controlled trials
Authors: Xu Zhao, Huaping Xiao, Feng Dai, Daniel Brodie, Lingzhong Meng
Journal: European Respiratory Journal (2021)

The optimal oxygenation in mechanically ventilated critically ill patients remains unclear.We performed a systematic review of randomised controlled trials (RCTs) with the aim to classify oxygenation goals and investigate their relative effectiveness. RCTs investigating different oxygenation goal-directed mechanical ventilation in critically ill adult patients were eligible for the analysis. The trinary classification classified oxygenation goals into conservative (partial pressure of arterial oxygen (PaO2 ) 55-90 mmHg), moderate (PaO2 90-150 mmHg) and liberal (PaO2 >150 mmHg). The quadruple classification further divided the conservative goal from the trinary classification into far-conservative (PaO2 55-70 mmHg) and conservative (PaO2 70-90 mmHg) goals. The primary outcome was 30-day mortality. The secondary outcomes included intensive care unit, hospital and 90-day mortalities. The effectiveness was estimated by the relative risk and 95% credible interval (CrI) using network meta-analysis and visualised using surface under the cumulative ranking curve (SUCRA) scores and survival curves.We identified eight eligible studies involving 2532 patients. There were no differences between conservative and moderate goals (relative risk 1.08, 95% CrI 0.85-1.36; moderate quality), between moderate and liberal goals (relative risk 0.83, 95% CrI 0.61-1.10; low quality) or between conservative and liberal goals (relative risk 0.89, 95% CrI 0.61-1.30; low quality) based on the trinary classification. There were no differences in secondary outcomes among the different goals. The results were consistent between the trinary and quadruple classifications. The SUCRA scores and survival curves suggested that the moderate goal in the trinary and quadruple classifications and the conservative goal in the quadruple classification may be superior to the liberal and far-conservative goals.Different oxygenation goals do not lead to different mortalities in mechanically ventilated critically ill patients. The potential superiority of maintaining PaO2 in the range 70-150 mmHg remains to be validated.
Conditional relative survival among adult patients with chronic myeloid leukemia in the tyrosine kinase inhibitor era: a population-based study in the Netherlands
Authors: Geneviève I. C. G. Ector, Otto Visser, Eduardus F. M. Posthuma, Peter E. Westerweel, Jeroen J. W. M. Janssen, Nicole M. A. Blijlevens, Avinash G. Dinmohamed
Journal: Leukemia (2021)
Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis
Authors: Min Liao, Ruiqing Chen, Yang Yang, Hanqing He, Liqian Xu, Yuxuan Jiang, Zhenxing Guo, Wei He, Hong Jiang, Jianwei Wang
Journal: Acta Pharmaceutica Sinica B (2021)

Aging-elevated DNMT3A R882H-driven clonal hematopoiesis (CH) is a risk factor for myeloid malignancies remission and overall survival. Although some studies were conducted to investigate this phenomenon, the exact mechanism is still under debate. In this study, we observed that DNMT3A R878H bone marrow cells (human allele: DNMT3A R882H) displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult. DNMT3A R878H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation, especially TNFα insults. Mechanistically, we identified that RIPK1-RIPK3-MLKL-mediated necroptosis signaling was compromised in R878H cells in response to proliferation stress and TNFα insults. Briefly, we elucidated the molecular mechanism driving DNMT3A R878H-based clonal hematopoiesis, which raises clinical value for treating DNMT3A R882H-driven clonal hematopoiesis and myeloid malignancies with aging.
WHO SMART guidelines: optimising country-level use of guideline recommendations in the digital age
Authors: Garrett Mehl, Özge Tunçalp, Natschja Ratanaprayul, Tigest Tamrat, María Barreix, David Lowrance, Kidist Bartolomeos, Lale Say, Nenad Kostanjsek, Robert Jakob, John Grove, Bernardo Mariano, Soumya Swaminathan
Journal: The Lancet Digital Health (2021)

WHO publishes clinical, public health policy, and data recommendations to advise countries on health interventions and evidence-based practices for improving the health of individuals and populations. This includes recommendations on who provides health interventions, how they are delivered, and accountability mechanisms. WHO produces international standards for priority indicators, as well as for coding and reporting of data, that include the Family of International Classifications, International Classification of Diseases (ICD), the International Classification of Functioning, Disability and Health, and the International Classification of Health Interventions.