tbuckley/cabot-search huggingface dataset:
The β Cell in Diabetes: Integrating Biomarkers With Functional Measures
Authors: Steven E Kahn, Yi-Chun Chen, Nathalie Esser, Austin J Taylor, Daniël H van Raalte, Sakeneh Zraika, C Bruce Verchere
Journal: Endocrine Reviews (2021)

Abstract The pathogenesis of hyperglycemia observed in most forms of diabetes is intimately tied to the islet β cell. Impairments in propeptide processing and secretory function, along with the loss of these vital cells, is demonstrable not only in those in whom the diagnosis is established but typically also in individuals who are at increased risk of developing the disease. Biomarkers are used to inform on the state of a biological process, pathological condition, or response to an intervention and are increasingly being used for predicting, diagnosing, and prognosticating disease. They are also proving to be of use in the different forms of diabetes in both research and clinical settings. This review focuses on the β cell, addressing the potential utility of genetic markers, circulating molecules, immune cell phenotyping, and imaging approaches as biomarkers of cellular function and loss of this critical cell. Further, we consider how these biomarkers complement the more long-established, dynamic, and often complex measurements of β-cell secretory function that themselves could be considered biomarkers.
Effectiveness of IL-12/23 inhibition (ustekinumab) versus tumour necrosis factor inhibition in psoriatic arthritis: observational PsABio study results
Authors: Josef S Smolen, Stefan Siebert, Tatiana V Korotaeva, Carlo Selmi, Paul Bergmans, Elisa Gremese, Beatriz Joven-Ibáñez, Gkikas Katsifis, Wim Noël, Michael T Nurmohamed, Pascal Richette, Petros P Sfikakis, Kurt de Vlam, Elke Theander, Laure Gossec
Journal: Annals of the Rheumatic Diseases (2021)

Objectives To evaluate 6-month effectiveness of ustekinumab versus tumour necrosis factor inhibitor (TNFi), analysing predictors of low disease activity (LDA)/remission. Methods PsABio is a prospective, observational cohort study of patients with psoriatic arthritis (PsA) at 92 sites in eight European countries, who received first-line to third-line ustekinumab or a TNFi. Comparative achievement at 6 months of clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) LDA/remission, and minimal disease activity (MDA)/very LDA using propensity score (PS)-adjusted multivariate logistic regression was assessed. Results In the final analysis set of 868 participants with 6-month follow-up data (ustekinumab, n=426; TNFi, n=442), with long-standing disease and a high mean cDAPSA score (31.0 vs 29.8, respectively), proportions of patients in ustekinumab/TNFi treatment groups achieving cDAPSA LDA at 6 months were 45.7%/50.7%. cDAPSA remission was achieved in 14.9%/19.2%, and MDA in 26.4%/30.8% of patients. PS-adjusted odds ratios (OR; 95% confidence interval (CI)) of reaching cDAPSA LDA and MDA were 0.73 (0.46 to 1.15) and 0.87 (0.61 to 1.25) with ustekinumab versus TNFi, indicating no significant difference. High baseline body mass index or high cDAPSA were associated with a lower chance (OR (95% CI)) of reaching cDAPSA LDA with TNFi (0.94 (0.89 to 0.99) and 0.64 (0.52 to 0.79), respectively). Predictive factors were similar to previously published evidence, with cDAPSA and 12-item Psoriatic Arthritis Impact of Disease scores and chronic widespread pain at baseline appearing as new risk factors for unfavourable outcome. Safety data were similar between groups. Conclusion Treatment targets were reached similarly after 6 months of treatment with ustekinumab and TNFi.
Abstract LB169: Systemic Administration of an antibody/RNA complex results in tumor specific delivery of immunostimulatory RNAs and tumor growth suppression in a mouse model of melanoma
Authors: Elias Quijano, Yanfeng Liu, Stephen Squinto, Bruce C. Turner, Peter M. Glazer
Journal: Cancer Research (2021)

Abstract There is intense interest in the development of nucleic acid ligands for immune stimulation of the tumor microenvironment via pattern recognition receptors, especially for the treatment of “cold” tumors. However, delivery of these ligands in a tumor-specific manner to avoid systemic toxicity has been a challenge. Many current efforts rely on direct intra-tumoral injection of RNAs or other stimulatory immune ligands, which is therapeutically sub-optimal, especially for metastatic disease. Here we report studies evaluating the utility of a lupus-derived, cell-penetrating antibody, to deliver nucleic acids including mRNA to tumors in vivo. This antibody, a modified version of 3E10-D31N, forms non-covalent complexes with RNAs and can mediate highly specific delivery broadly into tumors via intravenous injection by targeting the nucleoside transporter ENT2. Studies with labeled RNAs and with mRNAs expressing a GFP reporter gene show tumor specific delivery and functional expression by imaging, with minimal delivery to healthy tissues. Cell culture studies show antibody-mediated delivery of a series of RIG-I ligands, including hairpin RNAs and poly(I:C), resulting in robust RIG-I stimulation and induction of type-1 interferon signaling. Using mouse B16 melanoma tumors as a model, we observe substantial tumor growth suppression upon i.v. injection of a combination of 3E10 complexed with poly(I:C) (synthetic double-stranded RNA). These results highlight a novel approach for the systemic delivery of immunostimulatory RNAs in a targeted manner that may offer treatment advantages over current approaches. Citation Format: Elias Quijano, Yanfeng Liu, Stephen Squinto, Bruce C. Turner, Peter M. Glazer. Systemic Administration of an antibody/RNA complex results in tumor specific delivery of immunostimulatory RNAs and tumor growth suppression in a mouse model of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB169.
Remote Monitoring of Implantable Cardioverter-Defibrillators
Authors: Nirmalatiban Parthiban, Adrian Esterman, Rajiv Mahajan, Darragh J. Twomey, Rajeev K. Pathak, Dennis H. Lau, Kurt C. Roberts-Thomson, Glenn D. Young, Prashanthan Sanders, Anand N. Ganesan
Journal: Journal of the American College of Cardiology (2015)
Impact of High-Deductible Health Plans on Emergency Department Patients With Nonspecific Chest Pain and Their Subsequent Care
Authors: Shih-Chuan Chou, Arthur S. Hong, Scott G. Weiner, J. Frank Wharam
Journal: Circulation (2021)

Timely evaluation of acute chest pain is necessary, although most evaluations will not find significant coronary disease. With employers increasingly adopting high-deductible health plans (HDHP), how HDHPs impact subsequent care after an emergency department (ED) diagnosis of nonspecific chest pain is unclear.Using a commercial and Medicare Advantage claims database, we identified members 19 to 63 years old whose employers exclusively offered low-deductible (≤$500) plans in 1 year, then, at an index date, mandated enrollment in HDHPs (≥$1000) for a subsequent year. We matched them with contemporaneous members whose employers only offered low-deductible plans. Primary outcomes included population rates of index ED visits with a principal diagnosis of nonspecific chest pain, admission during index ED visits, and index ED visits followed by noninvasive cardiac testing within 3 and 30 days, coronary revascularization, and acute myocardial infarction hospitalization within 30 days. We performed a cumulative interrupted time-series analysis, comparing changes in annual outcomes between the HDHP and control groups before and after the index date using aggregate-level segmented regression. Members from higher-poverty neighborhoods were a subgroup of interest.After matching, we included 557 501 members in the HDHP group and 5 861 990 in the control group, with mean ages of 42.0 years, 48% to 49% female, and 67% to 68% non-Hispanic White individuals. Employer-mandated HDHP switches were associated with a relative decrease of 4.3% (95% CI, -5.9 to -2.7; absolute change, -4.5 [95% CI, -6.3 to -2.8] per 10 000 person-years) in nonspecific chest pain ED visits and 11.3% (95% CI, -14.0 to -8.6) decrease (absolute change, -1.7 per 10 000 person-years [95% CI, -2.1 to -1.2]) in visits leading to hospitalization. There was no significant decrease in subsequent noninvasive testing or revascularization procedures. An increase in 30-day acute myocardial infarction admissions was not statistically significant (15.9% [95% CI, -1.0 to 32.7]; absolute change, 0.3 per 10 000 person-years [95% CI, -0.01 to 0.5]) but was significant among members from higher-poverty neighborhoods.Employer-mandated HDHP switches were associated with decreased nonspecific chest pain ED visits and hospitalization from these ED visits, but no significant change in post-ED cardiac testing. However, HDHP enrollment was associated with increased 30-day acute myocardial infarction admission after ED diagnosis of nonspecific chest pain among members from higher-poverty neighborhoods.
Integration of Pediatric Hodgkin Lymphoma Treatment and Late Effects Guidelines: Seeing the Forest Beyond the Trees
Authors: Matthew J. Ehrhardt, Jamie E. Flerlage, Saro H. Armenian, Sharon M. Castellino, David C. Hodgson, Melissa M. Hudson
Journal: Journal of the National Comprehensive Cancer Network (2021)

The successful integration of clinical trials into pediatric oncology has led to steady improvement in the 5-year survival rate for children diagnosed with Hodgkin lymphoma (HL). It is estimated that &gt;95% of children newly diagnosed with HL will become long-term survivors. Despite these successes, survival can come at a cost. Historically, long-term survivors of HL have a high risk of late-occurring adverse health effects and increased risk of nonrelapse mortality compared with the general population. The recognition of late-occurring events paired with the decades of life remaining for children cured of HL have made paramount the need to develop effective treatments that minimize the risk of late toxicity. Toward this goal, multiple, dose-intense, risk- and response-based regimens that use lower cumulative doses of chemotherapy and radiation have been developed. Appropriate frontline treatment selection requires a level of familiarity with the efficacy, acute toxicity, convenience, and late effects of treatments that may be impractical for providers who infrequently treat children with HL. There is an increasing need for guideline developers to begin to merge considerations from both frontline treatment and survivorship guidelines into practical documents that integrate potential long-term health risks. Herein, we take the first steps toward doing so by aligning cumulative treatment exposures, anticipated risks of late toxicity, and suggested surveillance recommendations for NCCN-endorsed Pediatric HL Guidelines. Future studies that integrate simulation modeling will strengthen this integrated approach and allow for opportunities to incorporate regimen-specific risks, health-related quality of life, and cost-effectiveness into decision tools to optimize HL therapy.
Microbiota-derived butyrate is an endogenous HIF prolyl hydroxylase inhibitor
Authors: Ruth X. Wang, Morkos A. Henen, J. Scott Lee, Beat Vögeli, Sean P. Colgan
Journal: Gut Microbes (2021)

The gut microbiota is essential for human health. Microbial supply of short-chain fatty acids (SCFAs), particularly butyrate, is a well-established contributor to gut homeostasis and disease resistance. Reaching millimolar luminal concentrations, butyrate is sequestered and utilized in the colon as the favored energy source for intestinal epithelia. Given the steep oxygen gradient across the anoxic lumen and the highly oxygenated lamina propria, the colon provides a particularly interesting environment to study oxygen sensing. Previous studies have shown that the transcription factor hypoxia-inducible factor (HIF) is stabilized in healthy colonic epithelia. Here we show that butyrate directly inhibits HIF prolyl hydroxylases (PHDs) to stabilize HIF. We find that butyrate stabilizes HIF in vitro despite eliminating β-oxidation and resultant oxygen consumption. Using recombinant PHD protein in combination with nuclear magnetic resonance and enzymatic biochemical assays, we identify butyrate to bind and function as a unique, noncompetitive inhibitor of PHDs relative to other SCFAs. Butyrate inhibited PHD with a noncompetitive Ki of 5.3 ± 0.5 mM, a physiologically relevant concentration. We also confirm that microbiota-derived butyrate is necessary to stabilize HIF in mice colonic tissue through antibiotic-induced butyrate depletion and reconstitution experiments. Our results suggest that the co-evolution of mammals and mutualistic microbiota has selected for butyrate to impact a critical gene regulation pathway that can be extended beyond the mammalian gut. As PHDs are a major target for drug development in the stabilization of HIF, butyrate holds great potential as a well-tolerated endogenous inhibitor with far-reaching therapeutic impact.
Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes
Authors: Juan P. Frías, Melanie J. Davies, Julio Rosenstock, Federico C. Pérez Manghi, Laura Fernández Landó, Brandon K. Bergman, Bing Liu, Xuewei Cui, Katelyn Brown
Journal: New England Journal of Medicine (2021)

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown.
Empowering clinical research in a decentralized world
Authors: Walter De Brouwer, Chirag J. Patel, Arjun K. Manrai, Isaac R. Rodriguez-Chavez, Nirav R. Shah
Journal: npj Digital Medicine (2021)

The COVID-19 pandemic has been a catalyst for the implementation of decentralized clinical trials (DCTs) enabled by digital health technologies (DHTs) in the field while curtailing in-person interactions and putting significant demands on health care resources. DHTs offer improvements in real-time data acquisition remotely while maintaining privacy and security. Here, we describe the implications of technologies, including edge computing, zero-trust environments, and federated computing in DCTs enabled by DHTs. Taken together, these technologies—in the setting of policy and regulation that enable their use while protecting the users—extend the scope and accelerate the pace of clinical research.
Drug Transporter ABCB1 SNP Predicts Outcome in Patients with Acute Myeloid Leukemia Treated with Gemtuzumab Ozagamicin: A Report from Children's Oncology Group AAML0531 Trial
Authors: Lata Chauhan, Todd A Alonzo, Jim Wang, Michael R. Loken, Jessica A. Pollard, Richard Aplenc, Susana C. Raimondi, Roland B. Walter, Betsy A Hirsch, Irwin D. Bernstein, Alan S Gamis, Soheil Meshinchi, Jatinder Lamba
Journal: Blood (2017)
Long-Term Survival in Myelofibrosis after Allogeneic Hematopoietic Cell Transplantation Using Fludarabine/Melphalan Conditioning Regimen
Authors: Haris Ali, Ibrahim Aldoss, Dongyun Yang, Michelle Afkhami, Monzr M. Al Malki, Thai Cao, Stephen J. Forman, Guido Marcucci, Matthew Mei, Sally Mokhtari, Ryotaro Nakamura, Margaret O'Donnell, Raju Pillai, Vinod Pullarkat, Amandeep Salhotra, Anthony S. Stein, David S. Snyder
Journal: Blood (2017)
Temporal Associations Between Immunization With the COVID-19 mRNA Vaccines and Myocarditis
Authors: Ann Marie Navar, Elizabeth McNally, Clyde W. Yancy, Patrick T. O’Gara, Robert O. Bonow
Journal: JAMA Cardiology (2021)

Jay Montgomery, MD; Margaret Ryan, MD, MPH; Renata Engler, MD; Donna Hoffman, MSN; Bruce McClenathan, MD; Limone Collins, MD; David Loran, DNP; David Hrncir, MD; Kelsie Herring, MD; Michael Platzer, MD; Nehkonti Adams, MD; Aliye Sanou, MD; Leslie T. Cooper Jr, MD
Diverse and Distinct Human Hematopoietic Differentiation Programs Generate By Bone Marrow and G-CSF Mobilized Hematopoietic Stem and Progenitors Cells
Authors: Emmanuelle Six, Agathe Guilloux, Christopher Nobles, Rawya Zreik, Arnaud Lecoules, John Everett, Romain Vilette, Nicolas Cagnard, Frances Male, Alessandra Magnani, Elisa Magrin, Laure Caccavelli, Cecile Roudaut, Clemence Plantier, Anne Galy, Adrian J Thrasher, Isabelle Andre-Schmutz, Charles C Berry, Marina Cavazzana, Frederic D Bushman
Journal: Blood (2017)
Dutch multidisciplinary guideline on Achilles tendinopathy
Authors: Robert-Jan de Vos, Arco C van der Vlist, Johannes Zwerver, Duncan Edward Meuffels, Frank Smithuis, Ronald van Ingen, Florus van der Giesen, Edwin Visser, Astrid Balemans, Margreet Pols, Natasja Veen, Mirre den Ouden, Adam Weir
Journal: British Journal of Sports Medicine (2021)

To provide a comprehensive, evidence-based overview of the risk factors, prevention, diagnosis, imaging, treatment and prognosis for Achilles tendinopathy. To make clinical recommendations for healthcare practitioners and patients.Comprehensive multidisciplinary guideline process funded by the Quality Foundation of the Dutch Federation of Medical Specialists. This process included a development, commentary and authorisation phase. Patients participated in every phase.Multiple databases and existing guidelines were searched up to May 2019. Information from patients, healthcare providers and other stakeholders were obtained using a digital questionnaire, focus group interview and invitational conference.Studies on both insertional and/or midportion Achilles tendinopathy were eligible. Specific eligibility criteria were described per module.To appraise the certainty of evidence, reviewers extracted data, assessed risk of bias and used the Grading of Recommendations Assessment, Development and Evaluation method, where applicable. Important considerations were: patient values and preferences, costs, acceptability of other stakeholders and feasibility of implementation. Recommendations were made based on the results of the evidence from the literature and the considerations.The primary and secondary outcome measures were defined per module and defined based on the input of patients obtained in collaboration with the Netherlands Patient Federation and healthcare providers from different professions.Six specific modules were completed: risk factors and primary prevention, diagnosis, imaging, treatment prognosis and secondary prevention for Achilles tendinopathy.Our Dutch multidisciplinary guideline on Achilles tendinopathy provides six modules developed according to the standards of the Dutch Federation of Medical Specialists. Evidence-based recommendations for clinical practice are given for risk factors, prevention, diagnosis, imaging, treatment and prognosis. This guideline can assist healthcare providers and patients in clinical practice.
Prevalence and factors associated with SARS-CoV-2 seropositivity in the Spanish HIV Research Network Cohort
Authors: Juan Berenguer, Cristina Díez, María Martín-Vicente, Rafael Micán, María J. Pérez-Elías, Lucio J. García-Fraile, Francisco Vidal, Inés Suárez-García, Daniel Podzamczer, Jorge Del Romero, Federico Pulido, José A. Iribarren, Félix Gutiérrez, Eva Poveda, Carlos Galera, Rebeca Izquierdo, Víctor Asensi, Joaquín Portilla, Juan C. López, José R. Arribas, Santiago Moreno, Juan González-García, Salvador Resino, Inmaculada Jarrín
Journal: Clinical Microbiology and Infection (2021)

ObjectivesWe aimed to assess the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and factors associated with seropositivity and asymptomatic coronavirus disease 2019 (COVID-19) among people with HIV (PWH).MethodsThis was a cross-sectional study carried out within the cohort of the Spanish HIV Research Network. Participants were consecutive PWH with plasma collected from 1st April to 30th September 2020. We determined SARS-CoV-2 antibodies (Abs) in plasma. Illness severity (NIH criteria) was assessed by a review of medical records and, if needed, participant interviews. Multivariable logistic regression analysis was used to identify predictors of seropositivity among the following variables: sex, age, country of birth, education level, comorbidities (hypertension, chronic heart disease, diabetes mellitus, non-AIDS-related cancer, chronic kidney disease, cirrhosis), route of HIV acquisition, prior AIDS, CD4+ cell count, HIV viral load, nucleoside/nucleotide reverse transcriptase inhibitor (N [t]RTI) backbone, type of third antiretroviral drug, and month of sample collection.ResultsOf 1076 PWH (88.0% males, median age 43 years, 97.7% on antiretroviral therapy, median CD4+ 688 cells/mm3, 91.4% undetectable HIV viral load), SARS-CoV-2 Abs were detected in 91 PWH, a seroprevalence of 8.5% (95%CI 6.9–10.3%). Forty-five infections (45.0%) were asymptomatic. Variables independently associated with SARS-CoV-2 seropositivity were birth in Latin American countries versus Spain (adjusted odds ratio (aOR) 2.30, 95%CI 1.41–3.76, p 0.001), and therapy with tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) versus tenofovir alafenamide (TAF)/FTC as the N(t)RTI backbone (aOR 0.49, 95%CI 0.26–0.94, p 0.031).ConclusionsMany SARS-CoV-2 infections among PWH were asymptomatic, and birth in Latin American countries increased the risk of SARS-CoV-2 seropositivity. Our analysis, adjusted by comorbidities and other variables, suggests that TDF/FTC may prevent SARS-CoV-2 infection among PWH.
The CD200–CD200R Axis Promotes Squamous Cell Carcinoma Metastasis via Regulation of Cathepsin K
Authors: Iasha Z. Khan, Christina A. Del Guzzo, Anqi Shao, Jiyoon Cho, Rong Du, Adrienne O. Cohen, David M. Owens
Journal: Cancer Research (2021)

Abstract The CD200–CD200R immunoregulatory signaling axis plays an etiologic role in the survival and spread of numerous cancers, primarily through suppression of antitumor immune surveillance. Our previous work outlined a prometastatic role for the CD200–CD200R axis in cutaneous squamous cell carcinoma (cSCC) that is independent of direct T-cell suppression but modulates the function of infiltrating myeloid cells. To identify effectors of the CD200–CD200R axis important for cSCC metastasis, we conducted RNA sequencing profiling of infiltrating CD11B+Cd200R+ cells isolated from CD200+ versus CD200-null cSCCs and identified the cysteine protease cathepsin K (Ctsk) to be highly upregulated in CD200+ cSCCs. CD11B+Cd200R+ cells expressed phenotypic markers associated with myeloid-derived suppressor cell–like cells and tumor-associated macrophages and were the primary source of Ctsk expression in cSCC. A Cd200R+ myeloid cell–cSCC coculture system showed that induction of Ctsk was dependent on engagement of the CD200–CD200R axis, indicating that Ctsk is a target gene of this pathway in the cSCC tumor microenvironment. Inhibition of Ctsk, but not matrix metalloproteinases, significantly blocked cSCC cell migration in vitro. Finally, targeted CD200 disruption in tumor cells and Ctsk pharmacologic inhibition significantly reduced cSCC metastasis in vivo. Collectively, these findings support the conclusion that CD200 stimulates cSCC invasion and metastasis via induction of Ctsk in CD200R+ infiltrating myeloid cells. Significance: These findings highlight the relationship between CD200–CD200R and cathepsin K in cutaneous squamous cell carcinoma metastasis and suggest that either of these components may serve as a viable therapeutic target in this disease.
P07.08 IDO Immune Suppression and Post Surgical Toxicity in Patients with Non-Small Cell Lung Cancer
Authors: D. Pang, W. Chen, J. Zhang, L. Yang, G. Shao, T. Liuru, L. Xu, W. Xu, C. Zhao, M. Luo, L. Ma, F. Zhang, Z. Liang, S. Li, F.(. Kong
Journal: Journal of Thoracic Oncology (2021)