tbuckley/cabot-search huggingface dataset:
Letter to the Editor: Toxin‐induced graft injury following liver transplantation for yellow phosphorus poisoning
Authors: Joy Varghese, Selvakumar Malleswaran, Karattupaayam Mouleeswaran
Journal: Hepatology (2021)

We read with interest the article by Jasper S. et al.(1) regarding toxin induced liver injury (TLI) after liver transplantation (LT) in yellow phosphorus (YP) poisoning. The authors postulate that early allograft dysfunction (EAD) is secondary to TLI from YP released from non-hepatic tissues after LT. We believe that there are theoretical and practical problems with this hypothesis.
SGLT2 Inhibition in Heart Failure with a Preserved Ejection Fraction — A Win against a Formidable Foe
Authors: Mark H. Drazner
Journal: New England Journal of Medicine (2021)

Mark Drazner comments on the findings of the EMPEROR-Preserved trial, which assessed the potential benefit of empagliflozin in patients with a preserved EF. He notes that the findings represent a major win against a medical condition that had previously proved formidable.
Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation
Authors: Sarah C. Huen, Andrew Wang, Kyle Feola, Reina Desrouleaux, Harding H. Luan, Richard Hogg, Cuiling Zhang, Qing-Jun Zhang, Zhi-Ping Liu, Ruslan Medzhitov
Journal: The Journal of Experimental Medicine (2021)

Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor 21 (FGF21), and decreases survival. Consistent with this observation, FGF21-deficient mice are more susceptible to mortality from endotoxemia and polybacterial peritonitis. Here, we report that increased circulating FGF21 during bacterial inflammation is hepatic derived and required for survival through the maintenance of thermogenesis, energy expenditure, and cardiac function. FGF21 signaling downstream of its obligate coreceptor, β-Klotho (KLB), is required in bacterial sepsis. However, FGF21 modulates thermogenesis and chronotropy independent of the adipose, forebrain, and hypothalamus, which are operative in cold adaptation, suggesting that in bacterial inflammation, either FGF21 signals through a novel, undescribed target tissue or concurrent signaling of multiple KLB-expressing tissues is required.
Elucidation of Tumor-Stromal Heterogeneity and the Ligand-Receptor Interactome by Single-Cell Transcriptomics in Real-world Pancreatic Cancer Biopsies
Authors: Jaewon J. Lee, Vincent Bernard, Alexander Semaan, Maria E. Monberg, Jonathan Huang, Bret M. Stephens, Daniel Lin, Kimal I. Rajapakshe, Brian R. Weston, Manoop S. Bhutani, Cara L. Haymaker, Chantale Bernatchez, Cullen M. Taniguchi, Anirban Maitra, Paola A. Guerrero
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. With molecular subtypes of PDAC gaining relevance in the context of therapeutic stratification, the ability to characterize heterogeneity of cancer-specific gene expression patterns is of great interest. In addition, understanding patterns of immune evasion within PDAC is of importance as novel immunotherapeutic strategies are developed. Experimental Design: Single-cell RNA sequencing (scRNA-seq) is readily applicable to limited biopsies from human primary and metastatic PDAC and identifies most cancers as being an admixture of previously described epithelial transcriptomic subtypes. Results: Integrative analyses of our data provide an in-depth characterization of the heterogeneity within the tumor microenvironment, including cancer-associated fibroblast subclasses, and predicts for a multitude of ligand-receptor interactions, revealing potential targets for immunotherapy approaches. Conclusions: Our analysis demonstrates that the use of de novo biopsies from patients with PDAC paired with scRNA-seq may facilitate therapeutic prediction from limited biopsy samples.
Abstract 11768: Diagnostic and Prognostic Significance of Serum Levels of Selenoprotein P in Patients With Pulmonary Arterial Hypertension
Authors: Nobuhiro Kikuchi, Kimio Satoh, Taijyu Satoh, Junichi Omura, Ryo Kurosawa, Nobuhiro Yaoita, Mohammad Abdul Hai Siddique, Satoshi Miyata, Hiroaki Shimokawa
Journal: Circulation (2019)

Background: Selenoprotein P (SeP) is a glycoprotein secreted mainly from hepatocytes and other various kinds of cells including pulmonary artery smooth muscle cells (PASMCs) to maintain cellular me...
Abstract 21: Ploidy Alteration of Murine Cardiac Progenitor Cells in Response to Infarction Injury
Authors: Kathleen M Broughton, Bingyan J Wang, Taeyong Kim, Sadia Mohsin, Dieter Kubli, Pearl Quijada, Megan Monsanto, Natalie Gude, Tiffany Khieu, Nicky Nguyen, Michael Rosa, Mark A Sussman
Journal: Circulation Research (2017)

Introduction: Discovery of endogenous cardiac progenitor cells (CPC) prompted intense research efforts in multiple experimental animal models and clinical trials for heart failure treatment. Our lab identified a fundamental difference in ploidy content between rodent (rat, mouse) CPCs possessing mononuclear tetraploid (4n) chromosome content versus large mammal (human, swine) CPCs with mononuclear diploid (2n) content. Ploidy differences raise provocative questions regarding translational applicability of myocardial regeneration in rodents as polyplodization often correlates with enhanced regenerative potential. Hypothesis: Mononuclear chromatin duplication in CPCs improves regenerative capacity of the heart through higher stress resistance and overriding senescence cell-cycle arrest. Methods and Results: Ploidy of cultured CPCs is consistent and stable ploidy content over increased passages with samples from eight humans, two swine strains, six mouse strains, and seven rat clonal lines as determined by karyotype, confocal microscope and flow cytometry analyses. In situ ploidy analysis of CPCs reveals diploid content in human tissue and a mixture of mononuclear diploid and tetraploid nuclei in mouse, confirmed using freshly isolated Lin- c-kit+ CPCs. Tetraploid nuclear phenotype of murine CPCs is markedly different from predominantly diploid (2n) murine c-kit+ cells located in other tissues such as intestine and bone marrow. Higher ploidy content concurrent with expansion of the CPC pool are evident in the border zone at seven days post-infarction in adult FVB mice compared to age and gender matched non-injured hearts. Conclusion: Tetraploid c-kit+ cells found within the rodent heart may contribute to species-specific characteristics of stem cells and myocardial regenerative capacity. Future studies will focus upon the biological properties of diploid versus tetraploid CPCs and advantages of polyploid content for mediating myocardial regeneration.
Cytotoxic T Lymphocytes Specific for a Nonpolymorphic Proteinase 3 Peptide Preferentially Inhibit Chronic Myeloid Leukemia Colony-Forming Units
Authors: Jeffrey J. Molldrem, Emmanuel Clave, Yin Zheng Jiang, Dimitrios Mavroudis, Anastasios Raptis, Nancy Hensel, Vaishali Agarwala, A. John Barrett
Journal: Blood (1997)
Phase I/II trial of a long peptide vaccine (LPV7) plus toll-like receptor (TLR) agonists with or without incomplete Freund’s adjuvant (IFA) for resected high-risk melanoma
Authors: Sapna P Patel, Gina R Petroni, Jason Roszik, Walter C Olson, Nolan A Wages, Kimberly A Chianese-Bullock, Mark Smolkin, Nikole Varhegyi, Elizabeth Gaughan, Kelly T Smith, Kathleen Haden, Emily H Hall, Sacha Gnjatic, Patrick Hwu, Craig L Slingluff
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background We performed a clinical trial to evaluate safety and immunogenicity of a novel long peptide vaccine administered in combinations of incomplete Freund’s adjuvant (IFA) and agonists for TLR3 (polyICLC) and TLR7/8 (resiquimod). We hypothesized that T cell responses to minimal epitope peptides (MEPs) within the long peptides would be enhanced compared with prior vaccines with MEP themselves and that T cell responses would be enhanced with TLR agonists, compared with IFA alone. Methods Participants with resected stage IIB-IV melanoma were vaccinated with seven long melanoma peptides (LPV7) from tyrosinase, gp100, MAGE-A1, MAGE-A10, and NY-ESO-1, each containing a known MEP for CD8 + T cells, plus a tetanus helper peptide (Tet) restricted by Class II MHC. Enrollment was guided by an adaptive design to one of seven adjuvant combinations. Vaccines were administered at weeks 1, 2, 3, 6, 9, 12 at rotating injection sites. T cell and IgG antibody (Ab) responses were measured with IFN-gamma ELIspot assay ex vivo and ELISA, respectively. Results Fifty eligible participants were assigned to seven study groups, with highest enrollment on arm E (LPV7+Tet+IFA+polyICLC). There was one dose-limiting toxicity (DLT) in Group E (grade 3 injection site reaction, 6% DLT rate). All other treatment-related adverse events were grades 1–2. The CD8 + T cell immune response rate (IRR) to MEPs was 18%, less than in prior studies using MEP vaccines in IFA. The CD8 + T cell IRR trended higher for IFA-containing adjuvants (24%) than adjuvants containing only TLR agonists (6%). Overall T cell IRR to full-length LPV7 was 30%; CD4 + T cell IRR to Tet was 40%, and serum Ab IRR to LPV7 was 84%. These IRRs also trended higher for IFA-containing adjuvants (36% vs 18%, 48% vs 24%, and 97% vs 60%, respectively). Conclusions The LPV7 vaccine is safe with each of seven adjuvant strategies and induced T cell responses to CD8 MEPs ex vivo in a subset of patients but did not enhance IRRs compared with prior vaccines using short peptides. Immunogenicity was supported more by IFA than by TLR agonists alone and may be enhanced by polyICLC plus IFA. Trial registration number NCT02126579 .
Gather wisdom to overcome barriers: Well-designed nano-drug delivery systems for treating gliomas
Authors: Jiwei Cui, Yuanxin Xu, Haiyan Tu, Huacong Zhao, Honglan Wang, Liuqing Di, Ruoning Wang
Journal: Acta Pharmaceutica Sinica B (2021)

Due to the special physiological and pathological characteristics of gliomas, most therapeutic drugs are prevented from entering the brain. To improve the poor prognosis of existing therapies, researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy. Although these strategies can be used clinically to overcome the blood‒brain barrier (BBB), the accurate delivery of drugs to the glioma lesions cannot be ensured. Nano-drug delivery systems (NDDS) have been widely used for precise drug delivery. In recent years, researchers have gathered their wisdom to overcome barriers, so many well-designed NDDS have performed prominently in preclinical studies. These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions, drug release in response to the glioma microenvironment, biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein, and carriers created according to the active ingredients of traditional Chinese medicines. We reviewed these well-designed NDDS in detail. Furthermore, we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy, and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.
Improving Diagnostic Value of Echocardiography in Arrhythmogenic Right Ventricular Cardiomyopathy Using Deformation Imaging
Authors: Feddo P. Kirkels, Laurens P. Bosman, Karim Taha, Maarten J. Cramer, Jeroen F. van der Heijden, Richard N.W. Hauer, Folkert W. Asselbergs, Anneline S.J.M. te Riele, Arco J. Teske
Journal: JACC. Cardiovascular imaging (2021)
‘Not relevant’ responses in the era of COVID-19: are we underestimating Dermatology Life Quality Index values?
Authors: N. Kearney, R. Hambly, A. Alsharqi, B. Kirby
Journal: British Journal of Dermatology (2021)

Abstract Since March 2020, the UK and Ireland have entered a series of lockdowns in the wake of the coronavirus pandemic with restrictions resulting in the closure of nonessential retail, hospitality and sports with employees encouraged to work from home. In this retrospective study we have demonstrated a significant decrease in DLQI values, increase in the number of ‘not relevant’ responses (NRRs) in the DLQI and change between DLQI and the modified DLQI-R during the pandemic. Given the restrictions imposed on our patients, it is important for clinicians to identify the number of NRRs in the DLQI and acknowledge the potential effect on treatment decisions and data collection for disease registries and clinical trials during the pandemic.
Diabetes prevalence, process of care and outcomes in relation to practice size, caseload and deprivation: national cross-sectional study in primary care
Authors: C. Millett, J. Car, D. Eldred, K. Khunti, A. G Mainous, A. Majeed
Journal: Journal of the Royal Society of Medicine (2007)

ObjectiveTo examine the association between practice list size, deprivation and the quality of care of patients with diabetes. ResultsThe prevalence of diabetes was 3.3%. Prevalence differed with practice list size and deprivation: smaller and more deprived practices had a higher mean prevalence than larger and more affluent practices (3.8% versus 2.8%). Practices with large patient list sizes had the highest quality of care scores, even after stratifying for deprivation. However, with the exception of retinal screening, peripheral pulses and neuropathy testing, differences in achievement between small and large practices were modest (<5%). Small practices performed nearly as well as the largest practices in achievement of intermediate outcome targets for HbA1c, blood pressure and cholesterol (smallest versus largest practices: 57.4% versus 58.7%; 70.7% versus 70.7%; and 69.5% versus 72.7%, respectively). Deprivation had a negative effect on the achieved scores and this was more pronounced for smaller practices. ConclusionOur study provides some evidence of a volume-outcome association in the management of diabetes in primary care; this appears most pronounced in deprived areas.
SARS-CoV-2 infection and transmission in school settings during the second COVID-19 wave: a cross-sectional study, Berlin, Germany, November 2020
Authors: Stefanie Theuring, Marlene Thielecke, Welmoed van Loon, Franziska Hommes, Claudia Hülso, Annkathrin von der Haar, Jennifer Körner, Michael Schmidt, Falko Böhringer, Marcus A Mall, Alexander Rosen, Christof von Kalle, Valerie Kirchberger, Tobias Kurth, Joachim Seybold, Frank P Mockenhaupt
Journal: Eurosurveillance (2021)

BackgroundSchool attendance during the COVID-19 pandemic is intensely debated.AimIn November 2020, we assessed SARS-CoV-2 infections and seroreactivity in 24 randomly selected school classes and connected households in Berlin, Germany.MethodsWe collected oro-nasopharyngeal swabs and blood samples, examining SARS-CoV-2 infection and IgG antibodies by RT-PCR and ELISA. Household members self-swabbed. We assessed individual and institutional prevention measures. Classes with SARS-CoV-2 infection and connected households were retested after 1 week.ResultsWe examined 1,119 participants, including 177 primary and 175 secondary school students, 142 staff and 625 household members. SARS-CoV-2 infection occurred in eight classes, affecting each 1-2 individuals. Infection prevalence was 2.7% (95% confidence interval (CI): 1.2-5.0; 9/338), 1.4% (95% CI: 0.2-5.1; 2/140), and 2.3% (95% CI: 1.3-3.8; 14/611) among students, staff and household members. Six of nine infected students were asymptomatic at testing. We detected IgG antibodies in 2.0% (95%CI: 0.8-4.1; 7/347), 1.4% (95% CI: 0.2-5.0; 2/141) and 1.4% (95% CI: 0.6-2.7; 8/576). Prevalence increased with inconsistent facemask-use in school, walking to school, and case-contacts outside school. For three of nine households with infection(s), origin in school seemed possible. After 1 week, no school-related secondary infections appeared in affected classes; the attack rate in connected households was 1.1%.ConclusionSchool attendance under rigorously implemented preventive measures seems reasonable. Balancing risks and benefits of school closures need to consider possible spill-over infection into households. Deeper insight is required into the infection risks due to being a schoolchild vs attending school.
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor SHR6390 combined with pyrotinib and letrozole in patients with human epidermal growth factor receptor 2-positive (HER2+), hormone receptor positive (HR+) metastatic breast cancer (MBC): Phase Ib study results.
Authors: Jian Zhang, Yanchun Meng, Biyun Wang, Leiping Wang, Jun Cao, Zhonghua Tao, Ting Li, Wenqing Yao, Xichun Hu
Journal: Journal of Clinical Oncology (2021)

1035 Background: The combining of HER2 targeted therapy and endocrine therapy (ET) has been demonstrated to be a reasonable therapeutic approach and recommended for highly selected patients (pts) with HR+/HER2+ MBC. CDK4/6 inhibitors could sensitize HER2 targeted therapies in multiple patient-derived xenograft models and delay tumor recurrence in a transgenic model of HER2+ breast cancer. The aim of this phase Ib/II study was to investigate the safety and efficacy of adding a CDK 4/6 inhibitor to the combination. Primary phase Ib results were reported. Methods: Patients with HR+/HER2+ MBC who were eligible for first- or second-line treatment were enrolled, and orally received letrozole, pyrotinib, and a novel CDK4/6 inhibitor SHR6390. In the “3+3” dose-exploring phase, letrozole was given at a fixed dose of 2.5mg/d. Pyrotinib and SHR6390 were initially given at a dose of 400mg/d and 125 mg/d respectively (Level I ). If the initial dose level could be tolerated, subsequent pts were assigned to the higher level (Level H ) with pyrotinib 400 mg/d and SHR6390 150mg/d; otherwise, simultaneously to Level L1 with pyrotinib 400 mg/d, and SHR6390 100 mg/d, or Level L2 with pyrotinib 320mg/d, and SHR6390 125 mg/d. Primary endpoints of phase Ib included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and efficacy. Results: As of 4 Jan 2021, a total of 15 pts (Level I 5 pts, Level L1 6 pts, and Level L2 4 pts) were enrolled in phase Ib and received the study treatment. 6 of them had received systemic therapies in the advanced stage, and 10 of them had been previously treated with trastuzumab. The most frequent grade 3/4 adverse events included neutrophil count decreased (n = 6), white blood cell count decreased (n = 4), stomatitis (n = 4) and diarrhea (n = 3). 3 pts (2 in Level I , and 1 in Level L1 ) had experienced DLTs, all of which were grade 3 stomatitis. Of the 15 pts evaluable for response, 7 pts（46.7%） had achieved confirmed partial responses (1 in Level I , 3 in Level L1 , and 3 in Level L2 ) and 7 pts (46.7%) had stable disease. Based on DLTs and clinical efficacy, pyrotinib 320mg/d, SHR6390 125mg/d, and letrozole 2.5mg/d was declared as RP2D. Conclusions: Data from phase Ib showed the triplet combination of pyrotinib, letrozole, and SHR6390 had an acceptable safety profile and encouraging preliminary efficacy, potentially offering a chemotherapy sparing treatment option for patients with HR+/HER2+ MBC. Enrollment on phase II is ongoing. Clinical trial information: NCT03772353 .
Defining the next steps for artificial intelligence in colonoscopy
Authors: Nicholas G. Burgess
Journal: Endoscopy (2021)

Artificial intelligence (AI) in health care is rapidly advancing, driven by new developments in artificial or convolutional neural networks, which have allowed for an explosion in discriminative prediction complexity [1]. The use of AI in colonoscopy to improve patient outcomes makes intuitive sense. Diagnostic colonoscopy is performed in a standardized manner, images and videos are collected electronically, and the targets for detection and diagnosis are generally well established. More importantly, there is considerable variation in human performance, which has the potential to be improved by incorporating AI technologies [2].
Assessment of the Change of a Continuous Variable as a Function of its Initial Value—Reply
Authors: Daniel P. Marcusa, Robert P. Giugliano, Marc S. Sabatine
Journal: JAMA Cardiology (2021)

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Revitalizing the U.S. Primary Care Infrastructure
Authors: Kevin Grumbach, Thomas Bodenheimer, Deborah Cohen, Robert L. Phillips, Kurt C. Stange, John M. Westfall
Journal: New England Journal of Medicine (2021)

Primary care is undersupported in the United States. Moving forward, an investment plan could include oversight, tools, and resources for rebuilding primary care, with clear accountability vested in a single council and an overarching goal of achieving health equity.