tbuckley/cabot-search huggingface dataset:
Immunomodulatory Effects of Lenvatinib Plus Anti–Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma
Authors: Laura Torrens, Carla Montironi, Marc Puigvehí, Agavni Mesropian, Jack Leslie, Philipp K. Haber, Miho Maeda, Ugne Balaseviciute, Catherine E. Willoughby, Jordi Abril‐Fornaguera, Marta Piqué‐Gili, Miguel Torres‐Martín, Judit Peix, Daniel Geh, Erik Ramon‐Gil, Behnam Saberi, Scott L. Friedman, Derek A. Mann, Daniela Sia, Josep M. Llovet
Journal: Hepatology (2021)

Background and Aims Lenvatinib is an effective drug in advanced HCC. Its combination with the anti‐PD1 (programmed cell death protein 1) immune checkpoint inhibitor, pembrolizumab, has generated encouraging results in phase Ib and is currently being tested in phase III trials. Here, we aimed to explore the molecular and immunomodulatory effects of lenvatinib alone or in combination with anti‐PD1. Approach and Results We generated three syngeneic models of HCC in C57BL/6J mice (subcutaneous and orthotopic) and randomized animals to receive placebo, lenvatinib, anti‐PD1, or combination treatment. Flow cytometry, transcriptomic, and immunohistochemistry analyses were performed in tumor and blood samples. A gene signature, capturing molecular features associated with the combination therapy, was used to identify a subset of candidates in a cohort of 228 HCC patients who might respond beyond what is expected for monotherapies. In mice, the combination treatment resulted in tumor regression and shorter time to response compared to monotherapies ( P &lt; 0.001). Single‐agent anti‐PD1 induced dendritic and T‐cell infiltrates, and lenvatinib reduced the regulatory T cell (Treg) proportion. However, only the combination treatment significantly inhibited immune suppressive signaling, which was associated with the TGFß pathway and induced an immune‐active microenvironment ( P &lt; 0.05 vs. other therapies). Based on immune‐related genomic profiles in human HCC, 22% of patients were identified as potential responders beyond single‐agent therapies, with tumors characterized by Treg cell infiltrates, low inflammatory signaling, and VEGFR pathway activation. Conclusions Lenvatinib plus anti‐PD1 exerted unique immunomodulatory effects through activation of immune pathways, reduction of Treg cell infiltrate, and inhibition of TGFß signaling. A gene signature enabled the identification of ~20% of human HCCs that, although nonresponding to single agents, could benefit from the proposed combination.
Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice
Authors: Kerri R. Thomas, Eric J. Allenspach, Nathan D. Camp, Michelle N. Wray-Dutra, Socheath Khim, Anna Zielinska-Kwiatkowska, Andrew E. Timms, Joseph P. Loftus, H. Denny Liggitt, Katia Georgopoulos, Sarah K. Tasian, Richard G. James, David J. Rawlings
Journal: Leukemia (2021)
chemical conversion of human fibroblasts into functional schwann cells
Authors: Eva C. Thoma, Claudia Merkl, Tobias Heckel, Rachel Haab, Frederic Knoflach, Corinne Nowaczyk, Nicholas Flint, Ravi Jagasia, Sannah Jensen Zoffmann, Hoa Hue Truong, Pascal Petitjean, Sebastian Jessberger, Martin Graf, Roberto Iacone
Journal: Nature Reviews Gastroenterology & Hepatology (2014)
Aging-Associated Inflammation Due to Elevated Levels of TNF-α Increases Activation of the Integrin αIIbβ3 and the Procoagulant Potential of Platelets
Authors: Pavel Davizon-Castillo, Ken L. Jones, Sonia Aguila, David Bark, Katrina J. Ashworth, Kelly Higa, Eric Martin Pietras, Robert A. Campbell, Lauren Christine Shih, Natalie Saunders, James DeGregori, Matthew T. Rondina, Jorge Di Paola
Journal: Blood (2017)
Evaluation of Coronary Artery Plaque Tissue Characterization by Cardiac Magnetic Resonance Imaging
Authors: Matsumoto K, Kanda G, Okajima K, Hayashi T, Kajiya T, Tsukishiro Y, Mizutani K, Shimane A, Taniguchi Y, Ishimoto T, Iwata S, Yamada S, Kumada M
Journal: Circulation (2008)
Abstract 69: Cardiomyocyte GSK-3α Signaling Exacerbate Pressure Overload-induced Dilated Cardiomyopathy and Heart Failure
Authors: Firdos Ahmad, Hind Lal, Vipin K Verma, Qinkun Zhang, James R Woodgett, Thomas L Force
Journal: Circulation Research (2016)

Chronic pressure-overload (PO) induced-dilated cardiomyopathy (DCM) is one of the leading causes of left ventricular (LV) remodeling and heart failure. The role of glycogen synthase kinase-3α (GSK-3α) in PO-induced remodeling is not clear and existing dataset with global transgenic and knockout (KO) models show opposing roles. We sought to identify the specific role of GSK-3α in PO-induced dilatative cardiac remodeling. To better understand the role of GSK-3α, we employed cardiomyocyte-specific GSK3A ( GSK3A fl/fl MerCreMer ) KO mice. Post-tamoxifen treatment, the GSK-3α KO and littermate control mice underwent sham or trans-aortic constriction (TAC) surgery. Heart function was assessed at 0, 2, 4 and 6 week post-TAC using serial M-mode echocardiography. Cardiac function in the KOs and littermate controls declines equally up to 2 weeks of TAC. At 4 week, KO hearts underwent further hypertrophy, retaining concentric LV remodeling and preserved contractile function both at systole and diastole. In contrast, wild-type LV showed significant chamber dilatation with an impaired contractility. Significantly reduced LV chamber dilatation [LVIDd(mm); 5.4±0.4 vs. 4.9±0.4, P =0.01] and preserved contractile function [LVEF(%); 22.2±12.6 vs. 40.0±18.7, P =0.02] remains same in the KO mice until the end of the study (6 wk). Furthermore, LV posterior wall thickness in the KO hearts, both at systole and diastole, were significantly greater in comparison to the controls. Consistent with preserved LV dimension, significantly less mortality was observed in the KO vs. control group during the remodeling phase. Histological analysis of heart sections further revealed better preserved LV chamber and protection against TAC-induced cellular hypertrophy in the GSK-3α KOs. Moreover, KO hearts showed significantly less fibrosis accompanied with low level of cardiomyocyte apoptosis post-6 wk of TAC. Taken together, these observations show that cardiomyocyte-specific deletion of GSK-3α protects against chronic PO-induced adverse LV remodeling and preserves contractile function. Inhibiting specifically GSK-3α using isoform-specific inhibitor could be a viable therapeutic strategy to limit the PO-induced DCM, adverse remodeling and heart failure.
Primary Plasma Cell Leukemia: Clinical Profile and Treatment Outcomes of a Rare Disease from Tertiary Cancer Centre from India
Authors: Mukul Aggarwal, Neha Yadav, Jyotsna Kapoor, Rayaz Ahmed, Narendra Agrawal, Priyanka Verma, Pragya Bhandari, Dinesh Bhurani
Journal: Blood (2017)
A case of blaNDM-1-positive Salmonella Kottbus, Denmark, November 2020
Authors: Hans Linde Nielsen, Philip K. Thomsen, Eva Litrup, Mia Torpdahl, Søren Overballe-Petersen, Frank Hansen, Anne Kathrine Schultz Christensen, Henrik Hasman
Journal: Eurosurveillance (2021)

We present a case of carbapenemase-producing bla NDM-1-positive Salmonella Kottbus in an 82-year-old Danish man. The bla NDM-1 was also identified in Escherichia coli and Citrobacter freundii in the same patient on the same 43 kb IncN2 plasmid, suggesting in vivo inter-species plasmid transfer. A NCBI BLAST analysis of the plasmid (pAMA003584_NDM-1) identified 12 highly similar plasmids, all originating from east and south-east Asia. This case could be the first confirmed case of bla NDM-1-positive Salmonella not related to travel outside Europe.
Abstract LB086: Methylation-derived neutrophil-to-lymphocyte ratio and lung cancer risk and survival
Authors: Naisi Zhao, Mengyuan Ruan, Devin Koestler, Jiayun Lu, Carmen Marsit, Karl Kelsey, Elizabeth Platz, Dominique S. Michaud
Journal: Cancer Research (2021)

Abstract The neutrophil-to-lymphocyte ratio (NLR) is a biomarker of systemic inflammation and can be estimated using DNA methylation data as methylation-derived NLR (mdNLR). We examined associations between mdNLR and lung cancer risk in a nested case-control study, and among the cases, lung cancer survival, using pre-diagnostic blood samples of cases (median of 14 years before diagnosis) and controls in the CLUE I/II cohorts. The final analytic dataset included 208 pairs of lung cancer cases and controls matched on age, sex, and smoking intensity. We computed the mdNLR for each sample based on immune cell-proportion estimates obtained using established reference-based deconvolution methods. Using conditional logistic regression (to take into account matching factors), and further adjusting for BMI, batch effects, and a smoking-based methylation score, we observed a 47% increased risk of non-small cell lung cancer (NSCLC) for one standard deviation increase in mdNLR (n = 150 pairs; OR: 1.47 [1.08, 2.02]). To estimate association between mdNLR and lung cancer survival, we used Cox proportional-hazards models, adjusting age, sex, smoking status, smoking methylation score, BMI, batch effect, and stage. We observed a 27% increased risk of dying from lung cancer for one standard deviation increase in mdNLR (n = 145 deaths in 205 cases; HR: 1.27 [1.08, 1.50]). A 50% increased risk of dying from lung cancer for one standard deviation increase in mdNLR was observed for NSCLC cases (n = 103 deaths in 149 cases; HR: 1.50 [1.19, 1.89]). A better understanding of inflammation-associated biomarkers in lung cancer development could provide insight into critical pathways that may help identify new markers of early disease and survival. Citation Format: Naisi Zhao, Mengyuan Ruan, Devin Koestler, Jiayun Lu, Carmen Marsit, Karl Kelsey, Elizabeth Platz, Dominique S. Michaud. Methylation-derived neutrophil-to-lymphocyte ratio and lung cancer risk and survival [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 LB086.
The Delivery Challenge of Genome Editing in Human Epithelia
Authors: Marcelo Calderón, Sarah Hedtrich
Journal: Advanced Healthcare Materials (2021)

Abstract Despite exciting advances in gene editing, their clinical translation is still hampered by the lack of delivery systems that can encapsulate and deliver gene editing tools like CRISPR‐Cas9 or prime editors to the target side. This is particularly challenging in human epithelia, such as the skin and the lung; the latter of which being a mucosal surface that is covered by a mucus layer. In this perspective, the design and biological assessment of delivery systems for gene editing tools like CRISPR in skin and mucosal surfaces are discussed. The current state‐of‐the‐art, current knowledge, and translational gaps, and guide toward improved translation are highlighted.
Abstract 265: Identification of MicroRNA in an Ovine Model of Heart Failure
Authors: Lee Lee Wong, Eng Leng Saw, Kar Sheng Lew, Miriam T Rademaker, Leigh J Ellmers, Christopher J Charles, Arthur M Richards, Peipei Wang
Journal: Circulation Research (2016)

Introduction: The sheep ( Ovis aries ) provides a large animal model in cardiovascular research including heart failure (HF). However, microRNA (miR) related work in the sheep model has been limited due to a paucity of information regarding oar-miR. The aim of this study was to identify novel oar-miRs in myocardium and examine their regulation in HF and HF recovery. Methods: Heart tissue was harvested from sheep undergoing 1. HF induced by rapid left ventricular (LV) pacing at 225bpm for 14 days, 2. HF recovery (HF-R) after discontinuation of pacing for an additional 14 days and 3. Sham. LV miRs were examined using next generation deep sequencing (NGS), miR array and stem-loop qPCR. Sequences were aligned with miRBase v20.0 and mapped to ovine genome and miRBase Mature BLAST search engine. Plasma was collected to assess natriuretic peptides (ANP and BNP). Results: Three miR libraries were generated from NGS and a total of 619 miRs were detected. Of these, 93 were oar-miRs; 49 novel miRs (high confidence) mapped to ovine genome and perfectly aligned to mature miRs in other organisms (miRBase v20.0); 69 putative novel miRs (high confidence) that mapped to ovine genome and aligned partially to mature miRs of other species in miRBase v20.0; 168 miRs (low confidence) that mapped to ovine genome but unaligned to any known mature miRs; and 240 miRs (low confidence) that were unmapped to the sheep genome but aligned to either miRBase mature hsa-/mmu-/rno-miRs. Plasma BNP and ANP increased 19-folds and 18- folds respectively in HF, and returned to baseline in HF-R. MiR levels in HF model were examined using miR array. About 1000 miRs were detected from array and at least 301 of them were overlapped with NGS data. Using miR array profiling followed by stem-loop qPCR validation, we found that myocardial enriched miR-133b-3p, miR-208b-3p, miR-21-5p and miR-125a-5p, -125b-5p, -126-3p, -210-3p, and 29a-3p were significantly upregulated in HF (p&lt;0.05 vs. Sham). All trended downwards towards baseline levels during recovery (HF-R) but only miR-210 was significant (p&lt;0.001 vs. HF). Conclusion: We identified 118 novel oar-miRs with high confidence and 408 potential oar-miRs, which is a solid foundation for miR function studies using sheep models. We also identified miR changes in HF and HF-R.
Fenofibrate Use Is Associated With Lower Mortality and Fewer Cardiovascular Events in Patients With Diabetes: Results of 10,114 Patients From the Korean National Health Insurance Service Cohort
Authors: Sang-Ho Jo, Hyewon Nam, Jeongwoo Lee, Sojeong Park, Jungkuk Lee, Dae-Sung Kyoung
Journal: Diabetes Care (2021)

OBJECTIVE We investigated the long-term clinical efficacy of fenofibrate use with regard to mortality and cardiovascular outcomes in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We performed a population-based cohort study using data of the South Korean National Health Insurance Service from 2003 to 2014. Of 63,727 participants with diabetes aged 40–79 years, 5,057 users of fenofibrate only were compared with 5,057 nonusers of fenofibrate and/or omega-3 fatty acid with 1:1 propensity matching. The primary end point was a composite of myocardial infarction, stroke, percutaneous coronary revascularization, and cardiac death for a median of 3 years. RESULTS The primary end point was significantly lower in fenofibrate users compared with those using neither fenofibrate nor omega-3 fatty acid (13.4 vs. 15.5 per 1,000 person-years; hazard ratio [HR] 0.76; 95% CI 0.62–0.94; P = 0.010). Cardiac death (1.8 vs. 3.1 per 1,000 person-years; HR 0.59; 95% CI 0.352–0.987; P = 0.0446), all-cause death (7.6 vs. 15.3 per 1,000 person-years; HR 0.437; 95% CI 0.340–0.562; P &amp;lt; 0.0001), and stroke (6.5 vs. 8.6 per 1,000 person-years; HR 0.621; 95% CI 0.463–0.833; P = 0.0015) were significantly lower in the fenofibrate group. When the duration of fenofibrate use was stratified by quartile, the risk decreased in quartile 4, with an HR of 0.347 (95% CI 0.226–0.532; P &amp;lt; 0.0001). In subgroup analysis, the favorable effect of fenofibrate was sustained consistently across all subsets of patients, including those classified by LDL cholesterol, HDL cholesterol, and triglyceride levels. CONCLUSIONS Use of fenofibrate was associated with a lower rate of total and cardiac mortality and cardiovascular events in patients with type 2 diabetes during a 3-year follow-up in real-world large populations.
Diabetic Ketoacidosis and Mortality in People With Type 1 Diabetes and Eating Disorders
Authors: Nicole K. Gibbings, Paul A. Kurdyak, Patricia A. Colton, Baiju R. Shah
Journal: Diabetes Care (2021)

To determine the risk of diabetic ketoacidosis (DKA) and all-cause mortality among adolescents and young adults with type 1 diabetes with and without an eating disorder.With use of population-level health care administrative data covering the entire population of Ontario, Canada, all people with type 1 diabetes aged 10-39 years as of January 2014 were identified. Individuals with a history of eating disorders were age- and sex-matched 10:1 with individuals without eating disorders. All individuals were followed for 6 years for hospitalization/emergency department visits for DKA and for all-cause mortality.We studied 168 people with eating disorders and 1,680 age- and sex-matched people without eating disorders. Among adolescents and young adults with type 1 diabetes, 168 (0.8%) had a history of eating disorders. The crude incidence of DKA was 112.5 per 1,000 patient-years in people with eating disorders vs. 30.8 in people without eating disorders. After adjustment for baseline differences, the subdistribution hazard ratio for comparison of people with and without eating disorders was 3.30 (95% CI 2.58-4.23; P < 0.0001). All-cause mortality was 16.0 per 1,000 person-years for people with eating disorders vs. 2.5 for people without eating disorders. The adjusted hazard ratio was 5.80 (95% CI 3.04-11.08; P < 0.0001).Adolescents and young adults with type 1 diabetes and eating disorders have more than triple the risk of DKA and nearly sixfold increased risk of death compared with their peers without eating disorders.
Access to Care, and Emergency Department Utilization for Adults and Adolescents with Sickle Cell Disease: Ascq-Me and the SHIP-HU Study
Authors: Wally R. Smith, Donna k McClish, Richard Lottenberg, India Sisler, Thokozeni Lipato, Ian Chen, Shirley Johnson, Ding-Yu Fei, Daniel Sop Mouaffo
Journal: Blood (2017)
急性心筋梗塞患者の再狭窄の強力な予測因子であるプラズマ酸化低密度リポタンパク質(雄牛-LDL)レベル
Authors: Yamashita H, Naruko T, Ueda M, Haze K, Sakanoue Y, Itoh A, Otsuka M, Ehara S, Ohsawa M, Ogami M, Ikura Y, Becker Ae
Journal: Circulation (2001)
Abstract 199: TNF-Alpha Response After Experimental Cardiac Arrest in Rats is Not Attenuated by Thalidomide
Authors: Tomas Drabek, Jason Stezoski, Keri Janesko-Feldman, Patrick Kochanek
Journal: Circulation (2019)

Background: Resuscitation from cardiac arrest (CA) results in systemic cytokines response, and neuroinflammation. Thalidomide has been reported to selectively decrease tumor necrosis factor alpha (TNFa) and shown to be neuroprotective. Hypothesis: Thalidomide would decrease systemic and organ-specific cytokine response and biomarkers of injury after CA in rats. Methods: Adult male rats were subjected to 10 min ventricular fibrillation CA. Three groups were studied (n=4-6 per group): naives, CA treated with vehicle and CA treated with thalidomide (CA+T, 50 mg/kg i.p.). TNFa was assessed at 3 h in the cortex, hippocampus, striatum, cerebellum, plasma, heart and lung (Luminex). NSE and S100b were used to assess neuronal and glial injury, cardiac troponin I (cTnI) cardiac ichemia and IFABP to assess intestinal damage (ELISA). Results: CA resulted in a robust increase of TNFa in plasma (Figure 1) and tissues (Figure 2) with no differences between CA and CA+T groups in any region. NSE, S100b, cTnI and IFABP were increased after CA or CA+T vs. naives (all p&lt;0.05) without differences between CA vs. CA+T. Conclusions: CA resulted in an early massive TNFa response systemically and in target organs, with increased biomarkers of organ injury. Thalidomide in a dose reported previously to improve outcome of in vivo models of brain ischemia did not decrease TNFa levels in plasma, brain or extracerebral organs, or biomarkers of injury in our model of experimental CA. Cytokine response to CA was identified as a therapeutic target for future interventions on systemic and end-organ levels. Other promising anti-TNFa strategies incl. anti-TNFa antibodies are currently being evaluated in CA models.
Declaring interests: necessary but not sufficient
Authors: David B Menkes
Journal: BMJ (2021)

Continuing a decades old narrative in The BMJ , Abbasi emphasises the serious risks posed by doctors’ undisclosed competing interests and usefully extends the principle to scientists, policy makers, and politicians.1 To this list one might add corporate funded “think tanks” and lobbyists advocating policies that affect public health.2 While acknowledging the potential relevance of “less tangible” (non-financial) interests, for the purposes of a UK-wide register of doctors’ interests, Abbasi seems content to focus on the …
Off-tumor IDO1 target engagements determine the cancer-immune set point and predict the immunotherapeutic efficacy
Authors: Lin Xie, Kuan Hu, Yanhong Duo, Takashi Shimokawa, Katsushi Kumata, Yiding Zhang, Cuiping Jiang, Lulu Zhang, Nobuki Nengaki, Hidekatsu Wakizaka, Yihai Cao, Ming-Rong Zhang
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Indoleamine-2,3-dioxygenase 1 (IDO1) has been intensively pursued as a therapeutic target to reverse the immunosuppressive cancer-immune milieu and promote tumor elimination. However, recent failures of phase III clinical trials with IDO1 inhibitors involved in cancer immunotherapies highlight the urgent need to develop appropriate methods for tracking IDO1 when the cancer-immune milieu is therapeutically modified. Methods We utilized a small-molecule radiotracer, 11 C- l -1MTrp, to quantitatively and longitudinally visualize whole-body IDO1 dynamics. Specifically, we first assessed 11 C- l -1MTrp in mice-bearing contralateral human tumors with distinct IDO1 expression patterns. Then, we applied 11 C- l -1MTrp to longitudinally monitor whole-body IDO1 variations in immunocompetent melanoma-bearing mice treated with 1-methyl-l-tryptophan plus either chemotherapeutic drugs or antibodies targeting programmedcell death 1 and cytotoxic T-lymphocyte-associated protein 4. Results 11 C- l -1MTrp positron emission tomography (PET) imaging accurately delineated IDO1 expression in xenograft mouse models. Moreover, we were able to visualize dynamic IDO1 regulation in the mesenteric lymph nodes (MLNs), an off-tumor IDO1 target, where the percentage uptake of 11 C- l -1MTrp accurately annotated the therapeutic efficacy of multiple combination immunotherapies in preclinical models. Remarkably, 11 C- l -1MTrp signal intensity in the MLNs was inversely related to the specific growth rates of treated tumors, suggesting that IDO1 expression in the MLNs can serve as a new biomarker of the cancer-immune set point. Conclusions PET imaging of IDO1 with 11 C- l -1MTrp is a robust method to assess the therapeutic efficacy of multiple combinatorial immunotherapies, improving our understanding of the merit and challenges of IDO1 regimens. Further validation of this animal data in humans is ongoing. We envision that our results will provide a potential precision medicine paradigm for noninvasive visualizing each patient’s individual response in combinatorial cancer immunotherapy, and tailoring optimal personalized combination strategies.