tbuckley/cabot-search huggingface dataset:
Practical Guide to Implementation Science
Authors: Heather B. Neuman, Amy H. Kaji, Elliott R. Haut
Journal: JAMA Surgery (2020)

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The e Antigen Is an Interferon Resistance Protein That Allows the Hepatitis B Virus to Evade the Early Immune Response.
Authors: Zina Valaydon, Gregor Ebert, Liana Mackiewicz, Simon Preston, Paul V Desmond, Vitina Sozzi, Peter Revill, Alexander Jv Thompson, Marc Pellegrini
Journal: Hepatology (2018)
Human umbilical cord mesenchymal stromal cells-derived extracellular vesicles exert potent bone protective effects by CLEC11A-mediated regulation of bone metabolism
Authors: Yin Hu, Yan Zhang, Chu-Yu Ni, Chun-Yuan Chen, Shan-Shan Rao, Hao Yin, Jie Huang, Yi-Juan Tan, Zhen-Xing Wang, Jia Cao, Zheng-Zhao Liu, Ping-Li Xie, Ben Wu, Juan Luo, Hui Xie
Journal: Theranostics (2020)

Osteoporosis and osteoporotic fractures severely compromise quality of life in elderly people and lead to early death. Human umbilical cord mesenchymal stromal cell (MSC)-derived extracellular vesicles (hucMSC-EVs) possess considerable therapeutic effects in tissue repair and regeneration. Thus, in the present study, we investigated the effects of hucMSC-EVs on primary and secondary osteoporosis and explored the underlying mechanisms. Methods: hucMSCs were isolated and cultured. EVs were obtained from the conditioned medium of hucMSCs and determined by using transmission electron microscopy, dynamic light scattering and Western Blot analyses. The effects of hucMSC-EVs on ovariectomy-induced postmenopausal osteoporosis and tail suspension-induced hindlimb disuse osteoporosis in mouse models were assessed by using microcomputed tomography, biomechanical, histochemical and immunohistochemical, as well as histomorphometric analyses. Proteomic analysis was applied between hucMSC-EVs and hucMSCs to screen the candidate proteins that mediate hucMSC-EVs function. The effects of hucMSC-EVs on osteogenic and adipogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs), and osteoclastogenesis of the macrophage cell line RAW264.7 in vitro were determined by using cytochemical staining and quantitative real-time PCR analysis. Subsequently, the roles of the key protein in hucMSC-EVs-induced regulation on BMSCs and RAW264.7 cells were evaluated. Results: hucMSCs were able to differentiate into osteoblasts, adipocytes or chondrocytes and positively expressed CD29, CD44, CD73 and CD90, but negatively expressed CD34 and CD45. The morphological assessment revealed the typical cup- or sphere-shaped morphology of hucMSC-EVs with diameters predominantly ranging from 60 nm to 150 nm and expressed CD9, CD63, CD81 and TSG101. The systemic administration of hucMSC-EVs prevented bone loss and maintained bone strength in osteoporotic mice by enhancing bone formation, reducing marrow fat accumulation and decreasing bone resorption. Proteomic analysis showed that the potently pro-osteogenic protein, CLEC11A (C-type lectin domain family 11, member A) was very highly enriched in hucMSC-EVs. In addition, hucMSC-EVs enhanced the shift from adipogenic to osteogenic differentiation of BMSCs via delivering CLEC11A in vitro. Moreover, CLEC11A was required for the inhibitory effects of hucMSC-EVs on osteoclast formation. Conclusion: Our results suggest that hucMSC-EVs serve as a critical regulator of bone metabolism by transferring CLEC11A and may represent a potential agent for prevention and treatment of osteoporosis.
Immune Checkpoint Blockade in Combination with Stereotactic Body Radiotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma
Authors: Changqing Xie, Austin G. Duffy, Gagandeep Brar, Suzanne Fioravanti, Donna Mabry-Hrones, Melissa Walker, Cecilia Monge Bonilla, Bradford J. Wood, Deborah E. Citrin, Elizabeth M. Gil Ramirez, Freddy E. Escorcia, Bernadette Redd, Jonathan M. Hernandez, Jeremy L. Davis, Billel Gasmi, David Kleiner, Seth M. Steinberg, Jennifer C. Jones, Tim F. Greten
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The effectiveness of immune checkpoint inhibitors (ICI) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC. Patients and Methods: Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohorts A1 and A2 received durvalumab every 2 weeks plus either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day −3 to +1. Cohorts B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day −3 to +1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT. Results: Fifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose-limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months [95% confidence intervals (CI), 0.8–2.0 months] and 3.3 months (95% CI, 1.2–6.6 months) in cohort A1; 2.5 months (95% CI, 0.1–3.7 months) and 9.0 months (95% CI, 0.5–18.4 months) in A2; 0.9 months (95% CI, 0.7–2.1 months) and 2.1 months (95% CI, 1.1–4.3 months) in B1; and 2.3 months (95% CI, 1.9–3.4 months) and 4.2 months (95% CI, 2.9–9.3 months) in B2. Conclusions: The combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.
Abstract 12524: Sustained Ventricular Tachycardia on the Exercise Test: Frequency, Patient Characteristics, and Outcomes
Authors: Maria I Barillas, Thomas G Allison, Amanda Bonikowske, Suraj Kapa, Julie Erdie
Journal: Circulation (2019)

Background: Sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) induced by exercise (ExVTVF) is associated with adverse prognosis. Few studies report its incidence and outcomes ...
Two birds, one scope: peroral endoscopic myotomy as a treatment for achalasia and esophageal diverticula
Authors: Chelsea Jacobs, Peter V. Draganov, Dennis Yang
Journal: Endoscopy (2020)

See also: Peroral endoscopic myotomy regains anatomical structure and improves emptying for achalasia with multiple esophageal diverticulaEndoscopy 2019; 51(12): E392-E393DOI: 10.1055/a-0969-1757 See also: Reply to Jacobs et al.Endoscopy 2020; 52(02): 154-154DOI: 10.1055/a-1026-6084
A simulation of HIF-1 pathways in tumor angiogenesis
Authors: Amina A. Qutub, Aleksander S. Popel
Journal: Cancer Research (2005)

6138  The transcription factor HIF (hypoxia-inducible factor) plays a critical role in mammalian response to oxygen levels. HIF1, the first characterized member of the HIF family, transcriptionally activates over 70 genes associated with angiogenesis in cancer, energy metabolism, nutrient transport and cell migration [2,3]. The HIF1 pathway has been a recent focus of therapeutic studies with particular hope for malignant glioma. A better fundamental understanding of its mechanisms would help advance translational research. With this goal, we have developed a detailed molecular-based computational models to gain a quantitative understanding of how HIF1 relates to angiogenesis and the expression of VEGF in cancer. The first simulation is a series of biochemical kinetic equations mapping the molecular steps in HIF1α degradation in the presence of oxygen. Initial kinetic values are estimated from in vitro studies on HIF degradation, and results are compared to independent experiments. Input is cellular oxygen level, and output is HIF1α levels in the nucleus in relation to necessary intermediate reactions {including reactions with different prolyl hydroxlylase isoforms, iron, 2-oxoglutarate, ascorbate, von Hippel Lindau ligase, and factor-inhibiting HIF}. The processes associated with hypoxia in the model include: HIF1α transport into the nucleus, HIF1α-HIF1β binding, and transcriptional activation of VEGF at the hypoxia response element site. Using the model’s first results, an existing hypothesis of a switch-like change in HIF1 expression and enzymes in the HIF1 pathway in response to a gradual decrease in oxygen levels to a critical level was tested . The model suggests that based on the environment and characteristics of the specific cell type, the response to hypoxia varies considerably. From these results, a new hypothesis was made. HIF1-activated cellular responses can be divided into two categories depending on the molecular environment: a sharp, switch-like response to oxygen levels, and a gradual one. As the simulation advances and includes validation with bench experiments, results will have implications for the characterization of tumors, and potentially the type and combination of chosen anti-angiogenic therapy. Future studies include expanding the model to represent the hypoxic response and onset of angiogenesis in the molecular environment of glioblastoma multiforme. 1. K.W. Kohn, J. Riss, O. Aprelikova, J.N. Weinstein, Y. Pommier, J.C. Barrett, Properties of switch-like bioregulatory networks studied by simulation of the hypoxia response control system, Mol Biol Cell 15 (2004) 3042-3052. 2. G.L. Semenza, Hydroxylation of HIF-1: oxygen sensing at the molecular level, Physiology (Bethesda) 19 (2004) 176-182. 3. G.L. Wang, B.H. Jiang, E.A. Rue, G.L. Semenza, Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension, Proc Natl Acad Sci U S A 92 (1995) 5510-5514.
Predictive Biomarkers for Adjuvant Capecitabine Benefit in Early-Stage Triple-Negative Breast Cancer in the FinXX Clinical Trial
Authors: Karama Asleh, Heather Ann Brauer, Amy Sullivan, Susanna Lauttia, Henrik Lindman, Torsten O. Nielsen, Heikki Joensuu, E. Aubrey Thompson, Saranya Chumsri
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Recent studies have demonstrated a benefit of adjuvant capecitabine in early breast cancer, particularly in patients with triple-negative breast cancer (TNBC). However, TNBC is heterogeneous and more precise predictive biomarkers are needed. Experimental Design: Tumor tissues collected from TNBC patients in the FinXX trial, randomized to adjuvant anthracycline–taxane–based chemotherapy with or without capecitabine, were analyzed using a 770-gene panel targeting multiple biological mechanisms and additional 30-custom genes related to capecitabine metabolism. Hypothesis-generating exploratory analyses were performed to assess biomarker expression in relation to treatment effect using the Cox regression model and interaction tests adjusted for multiplicity. Results: One hundred eleven TNBC samples were evaluable (57 without capecitabine and 54 with capecitabine). The median follow-up was 10.2 years. Multivariate analysis showed significant improvement in recurrence-free survival (RFS) favoring capecitabine in four biologically important genes and metagenes, including cytotoxic cells [hazard ratio (HR) = 0.38; 95% confidence intervals (CI), 0.16–0.86, P-interaction = 0.01], endothelial (HR = 0.67; 95% CI, 0.20–2.22, P-interaction = 0.02), mast cells (HR = 0.78; 95% CI, 0.49–1.27, P-interaction = 0.04), and PDL2 (HR = 0.31; 95% CI, 0.12–0.81, P-interaction = 0.03). Furthermore, we identified 38 single genes that were significantly associated with capecitabine benefit, and these were dominated by immune response pathway and enzymes involved in activating capecitabine to fluorouracil, including TYMP. However, these results were not significant when adjusted for multiple testing. Conclusions: Genes and metagenes related to antitumor immunity, immune response, and capecitabine activation could identify TNBC patients who are more likely to benefit from adjuvant capecitabine. Given the reduced power to observe significant findings when correcting for multiplicity, our findings provide the basis for future hypothesis-testing validation studies on larger clinical trials.
Soluble Urokinase Receptor and Acute Kidney Injury
Authors: Salim S. Hayek, David E. Leaf, Ayman Samman Tahhan, Mohamad Raad, Shreyak Sharma, Sushrut S. Waikar, Sanja Sever, Alex Camacho, Xuexiang Wang, Ranadheer R. Dande, Nasrien E. Ibrahim, Rebecca M. Baron, Mehmet M. Altintas, Changli Wei, David Sheikh-Hamad, Jenny S.-C. Pan, Michael W. Holliday, James L. Januzzi, Steven D. Weisbord, Arshed A. Quyyumi, Jochen Reiser
Journal: New England Journal of Medicine (2020)

Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target.We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR.The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells.High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.).
Esketamine for treatment resistant depression is not recommended by NICE
Authors: Elisabeth Mahase
Journal: BMJ (2020)

An esketamine nasal spray may not be made available on the NHS for patients with treatment resistant depression because of uncertainties over its clinical and cost effectiveness, says draft guidance from the National Institute for Health and Care Excellence.1

NICE reviewed the effectiveness of esketamine in combination with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor for adults with treatment resistant depression that have not responded to at least two different antidepressants in the current moderate to severe depressive episode.

It said that …
TGF-β–induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis
Authors: Clara Dees, Sebastian Pötter, Yun Zhang, Christina Bergmann, Xiang Zhou, Markus Luber, Thomas Wohlfahrt, Emmanuel Karouzakis, Andreas Ramming, Kolja Gelse, Akihiko Yoshimura, Rudolf Jaenisch, Oliver Distler, Georg Schett, Jörg H.W. Distler
Journal: Journal of Clinical Investigation (2020)

Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an "autonomous," self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β-dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.
19q13 KRAB zinc-finger protein ZNF471 activates MAPK10/JNK3 signaling but is frequently silenced by promoter CpG methylation in esophageal cancer
Authors: Ran Sun, Tingxiu Xiang, Jun Tang, Weiyan Peng, Jie Luo, Lili Li, Zhu Qiu, Yiqing Tan, Lin Ye, Min Zhang, Guosheng Ren, Qian Tao
Journal: Theranostics (2020)

Zinc-finger proteins (ZFPs) are the largest transcription factor family in mammals, involved in the regulation of multiple physiologic processes including cell differentiation, proliferation, apoptosis and neoplastic transformation. Approximately one-third of ZFPs are Krüppel-associated box domain (KRAB)-ZFPs. Methods: ZNF471 expression and methylation were detected by reverse-transcription PCR and methylation-specific PCR. The impact and mechanism of ectopic ZNF471 expression in esophageal squamous cell carcinoma (ESCC) cells was evaluated in vitro and in vivo. Results: We identified a 19q13 KRAB-ZFP, ZNF471, as a methylated target in ESCC. We further found that ZNF471 is significantly downregulated in ESCC tissues compared with adjacent non-cancer tissues, due to its aberrant promoter CpG methylation, and further confirmed by methylation analysis and treatment with demethylation agent. Restoration of ZNF471 expression in silenced ESCC cells significantly altered cell morphology, induced apoptosis and G0/G1 arrest, and inhibited tumor cell colony formation, viability, migration and invasion. Importantly, ZNF471 was found to activate the expression of MAPK10/JNK3 and PCDH family genes, and further enhance MAPK10 signaling and downstream gene expression through binding to the MAPK10/JNK3 promoter. Conclusion: Our results demonstrate that ZNF471 is an important tumor suppressor and loss of ZNF471 functions hampers MAPK10/JNK3 signaling during esophageal carcinogenesis.
Mussel-inspired conductive Ti<sub>2</sub>C-cryogel promotes functional maturation of cardiomyocytes and enhances repair of myocardial infarction
Authors: Genlan Ye, Zubiao Wen, Feng Wen, Xiaoping Song, Leyu Wang, Chuangkun Li, Yutong He, Sugandha Prakash, Xiaozhong Qiu
Journal: Theranostics (2020)

Rationale: Researches on conductive engineering cardiac patch (ECP) for myocardial infarction (MI) treatment have achieved some progress in the animal while the availability of traditional conductive materials in ECP is still limited because of their controversial cytotoxicity. Here we aim to introduce a novel hydrophilic biocompatible conductive material: MXene Ti2C and mussel-inspired dopamine into PEGDA-GelMA cryogel to construct a bio-functional ECP of which the property closes to natural heart for the repair of MI. Method: MXene Ti2C was etched from MAX Ti2AlC, then uniformly dispersed into the prepolymer composed with dopamine-N', N'-methylene-bisacrylamide, methacrylate-gelatin, and poly (ethylene glycol) diacrylate by simple water bath sonication. The resilient conductive Ti2C-cryogel was fabricated by chemical cryogelation. The conductive ECP was evaluated in vitro and transplanted to the MI rat model for MI treatment. Results: In vitro, the 3D vessels-shape framework was observed in Ti2C-8-cryogel which was seeded with rats aortic endothelial cells. When the Ti2C-cryogels were cocultured with CMs, remarkably aligned sarcomere and the primitive intercalated disc between the mature CMs were formed on day 7. The as-prepared Ti2C-8-cryogel ECP also demonstrated rapid calcium transients and synchronous tissue-like beating. When transplanted into the infarcted heart of the MI rat model, the Ti2C-8-cryogel ECP could improve the cardiac function, reduce the infarct size, and inhibit the inflammatory response. Obvious vasculation especially newly formed arteriole was also found. Conclusion: A novel conductive Ti2C-embedded cardiac patch with suitable conductivity and the mechanical property was developed and could be served as an ideal candidate for MI repair.