tbuckley/cabot-search huggingface dataset:
The European Training Network ETUDE (Encompassing Training in fUnctional Disorders across Europe): a new research and training program of the EURONET-SOMA network recruiting 15 early stage researchers
Authors: J.G. Rosmalen, C. Burton, A. Carson, F. Cosci, L. Frostholm, N. Lehnen, T.C. Olde Hartman, C.U. Rask, J. Rymaszewska, J. Stone, L.M. Tak, M. Witthöft, B. Löwe
Journal: Psychotherapy and Psychosomatics (2021)
An ROS‐Activatable Nanoassembly Remodulates Tumor Cell Metabolism for Enhanced Ferroptosis Therapy
Authors: Yuchen Zhang, Liqi Li, Yanan Li, Yang Fei, Chencheng Xue, Xuemei Yao, Youbo Zhao, Xuan Wang, Menghuan Li, Zhong Luo
Journal: Advanced Healthcare Materials (2021)

Abstract Ferroptosis is an emerging antitumor option and has demonstrated unique advantages against many tumor indications. However, its efficacy is potentially hindered by the endogenous lipid peroxide‐scavenging mechanisms and the reliance on acidic pH. Herein, a nanointegrated strategy based on clinically‐safe components to synergistically remodel glutathione and lactate metabolism in tumor cells for enhanced ferroptosis therapy is developed. First ferrocene is conjugated on PEGylated polyamidoamine dendrimers via reactive oxygen species (ROS)‐cleavable thioketal linkage, which would further self‐assemble with the glutathione (GSH)‐depleting agent diethyl maleate (DEM) and monocarboxylate transporter 4‐inhibiting siRNA (siMCT4) to afford biostable nanoassemblies (siMCT4‐PAMAM‐PEG‐TK‐Fc@DEM). The nanoassemblies can be activated by the elevated ROS levels in tumor intracellular environment and readily release the incorporated therapeutic contents, afterward DEM can directly conjugate to GSH to disrupt the glutathione peroxidase 4 (GPX4)‐mediated antioxidant defense, while siMCT4 can block the MCT4‐mediated efflux of lactic acid and acidify the intracellular milieu, both of which can improve the ferrocene‐catalyzed lipid peroxidation and induce pronounced ferroptotic damage. The siMCT4‐PAMAM‐PEG‐TK‐Fc@DEM nanoplatform demonstrates high ferroptosis‐based antitumor potency and good biocompatibility in vitro and in vivo, which may offer new avenues for the development of more advanced antitumor therapeutics with improved translatability.
TCT-30 A Comparative Analysis of Patient Characteristics in Cardiogenic Shock Trials: Differences Between Randomized Trials and Real-World Registries
Authors: Michael Megaly, Kevin Buda, Khaldoon Alaswad, Emmanouil Brilakis, Allison Dupont, Srihari Naidu, Magnus Ohman, L. Christian Napp, William O'Neill, Mir Basir
Journal: Journal of the American College of Cardiology (2021)
From a Lancet Commission to the NCDI Poverty Network: reaching the poorest billion through integration science
Authors: Gene Bukhman, Ana Olga Mocumbi, Neil Gupta, Mary Amuyunzu-Nyamongo, Moses Echodu, Anu Gomanju, Yogesh Jain, Biraj Karmacharya, Sharon Kapambwe, Aimée Lulebo, Julie Makani, Jones Kaponda Masiye, Paladie Kampuhwe Mategeko, Eunice Owino
Journal: The Lancet (2021)
Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant
Authors: Ze Lin, Yuan Xiong, Weilin Meng, Yiqiang Hu, Lili Chen, Lang Chen, Hang Xue, Adriana C. Panayi, Wu Zhou, Yun Sun, Faqi Cao, Guodong Liu, Liangcong Hu, Chenchen Yan, Xudong Xie, Chuanchuan Lin, Kaiyong Cai, Qian Feng, Bobin Mi, Guohui Liu
Journal: Bioactive Materials (2021)

A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation. Over-active and continuous inflammation, however, impairs fracture healing and leads to excessive tissue damage. Adequate fracture healing could be promoted through suppression of local over-active immune cells in the fracture site. In the present study, we achieved an enriched concentration of PD-L1 from exosomes (Exos) of a genetically engineered Human Umbilical Vein Endothelial Cell (HUVECs), and demonstrated that exosomes overexpressing PD-L1 specifically bind to PD-1 on the T cell surface, suppressing the activation of T cells. Furthermore, exosomal PD-L1 induced Mesenchymal Stem Cells (MSCs) towards osteogenic differentiation when pre-cultured with T cells. Moreover, embedding of Exos into an injectable hydrogel allowed Exos delivery to the surrounding microenvironment in a time-released manner. Additionally, exosomal PD-L1, embedded in a hydrogel, markedly promoted callus formation and fracture healing in a murine model at the early over-active inflammation phase. Importantly, our results suggested that activation of T cells in the peripheral lymphatic tissues was inhibited after local administration of PD-L1-enriched Exos to the fracture sites, while T cells in distant immune organs such as the spleen were not affected. In summary, this study provides the first example of using PD-L1-enriched Exos for bone fracture repair, and highlights the potential of Hydrogel@Exos systems for bone fracture therapy through immune inhibitory effects.
TCT-127 Diagnostic Yield of Routine Invasive Coronary Physiology Assessment in Patients With Ischemia and No Obstructive Coronary Artery Disease
Authors: Steffne Kunnirickal, Natalija Odanovic, Leslie Yingzhijie Tseng, Steven Pfau, Erica Spatz, Samit Shah
Journal: Journal of the American College of Cardiology (2021)
NF-κB regulates brown adipocyte function through suppression of ANT2
Authors: Shiqiao Peng, Xiaoying Zhang, Lili Yu, Yanhong Xu, Yang Zhou, Shengnan Qian, Xinyu Cao, Xiaotong Ye, Jiajun Yang, Weiping Jia, Jianping Ye
Journal: Acta Pharmaceutica Sinica B (2021)

The transcription factor nuclear factor of kappa-light-chain-enhancer of activated B cells (NF-κB) is expressed in brown adipocytes, but its role remains largely unknown in the cells. This issue was addressed in current study by examining NF-κB in brown adipocytes in vitro and in vivo. NF-κB activity was increased by differentiation of brown adipocytes through elevation of p65 (RelA) expression. The transcriptional activity of NF-κB was induced by the cold stimulation with an elevation in S276 phosphorylation of p65 protein. Inactivation of NF-κB in brown adipocytes made the knockout mice [uncoupling protein 1 (Ucp1)-CreER-p65f/f, U-p65-KO] intolerant to the cold environment. The brown adipocytes exhibited an increase in apoptosis, a decrease in cristae density and uncoupling activity in the interscapular brown adipose tissue (iBAT) of p65-KO mice. The alterations became severer after cold exposure of the KO mice. The brown adipocytes of mice with NF-κB activation (p65 overexpression, p65-OE) exhibited a set of opposite alterations with a reduction in apoptosis, an increase in cristae density and uncoupling activity. In mechanism, NF-κB inhibited expression of the adenine nucleotide translocase 2 (ANT2) in the control of apoptosis. Data suggest that NF-κB activity is increased in brown adipocytes by differentiation and cold stimulation to protect the cells from apoptosis through down-regulation of ANT2 expression.
Transcatheter Mitral Valve Therapy in the United States
Authors: Michael Mack, John D. Carroll, Vinod Thourani, Sreekanth Vemulapalli, John Squiers, Pratik Manandhar, G. Michael Deeb, Wayne Batchelor, Howard C. Herrmann, David J. Cohen, George Hanzel, Thomas Gleason, Ajay Kirtane, Nimesh Desai, Kim Guibone, Karen Hardy, Joan Michaels, J. Michael DiMaio, Barbara Christensen, Susan Fitzgerald, Carole Krohn, Ralph G. Brindis, Fred Masoudi, Joseph Bavaria
Journal: Journal of the American College of Cardiology (2021)
Cholesterol-Lowering Intervention Decreases mTOR Complex 2 Signaling and Enhances Antitumor Immunity
Authors: Yanping Wang, Sungyong You, Shengchen Su, Austin Yeon, Eric M. Lo, Sungjin Kim, James L. Mohler, Michael R. Freeman, Hyung L. Kim
Journal: Clinical Cancer Research (2021)

Abstract Purpose: There is a need for strategies to prevent prostate cancer. Cholesterol-lowering interventions are employed widely and safely to reduce risk of cardiovascular disease and has been proposed for chemoprevention. Using preclinical models and a window-of-opportunity clinical trial, we describe an adaptive antitumor immunity resulting from cholesterol lowering. Experimental Design: Statins do not reliably lower serum cholesterol in mice. Therefore, oral ezetimibe was administered to mice to lower serum cholesterol to clinically relevant levels and evaluated the final adaptive immune response. T-lymphocytes-specific mTORC2 knockout mice were used to evaluate mTOR signaling and antitumor immunity. Pretreatment and posttreatment prostate tumors and lymphocytes were examined from a window-of-opportunity clinical trial where men with prostate cancer were treated with 2 to 6 weeks of aggressive cholesterol-lowering intervention prior to radical prostatectomy. Results: Mice treated with oral ezetimibe exhibited enhanced antitumor immunity against syngeneic cancers in a CD8+ lymphocyte-dependent manner, produced immunity that was transferrable through lymphocytes, and had enhanced central CD8+ T-cell memory. In mice and in patients undergoing prostatectomy, lowering serum cholesterol inhibited mTORC2 signaling in lymphocytes and increased infiltration of CD8+ lymphocytes into prostate tumors. T-lymphocyte-specific mTORC2 knockout mice demonstrated enhanced CD8+ lymphocyte function and antitumor capacity. In patients, cholesterol-lowering intervention prior to prostatectomy decreased the proliferation of normal prostate and low-grade adenocarcinomas. Conclusions: Lowering serum cholesterol decreased signaling through mTORC2 and enhanced antitumor CD8+ T-cell memory. We provide a rationale for large-scale clinical testing of cholesterol lowering strategies for prostate cancer chemoprevention.
Targeting CD47 for cancer immunotherapy
Authors: Zhongxing Jiang, Hao Sun, Jifeng Yu, Wenzhi Tian, Yongping Song
Journal: Journal of Hematology & Oncology (2021)

Much progress has been made in targeting CD47 for cancer immunotherapy in solid tumors (ST) and hematological malignancies. We summarized the CD47-related clinical research and analyzed the research trend both in the USA and in China. As of August 28, 2021, there are a total 23 related therapeutic agents with 46 clinical trials in the NCT registry platform. Among these trials, 29 are in ST, 14 in hematological malignancies and 3 in both solid tumor and hematological malignancy. The ST include gastric cancer, head and neck squamous cell carcinoma and leiomyosarcoma, while the hematological malignancies include non-Hodgkin's lymphoma, acute myeloid leukemia, myelodysplastic syndrome, multiple myeloma and chronic myeloid leukemia. Majority of the CD47-related clinical trials are at the early phases, such as 31 at phase I, 14 at phase II and 1 at phase III in the USA and 9, 6, 1, in China, respectively. The targets and spectrums of mechanism of action include 26 with mono-specific and 20 with bi-specific targets in the USA and 13 with mono-specific and 3 with bi-specific targets in China. The new generation CD47 antibodies have demonstrated promising results, and it is highly hopeful that some candidate agents will emerge and make into clinical application to meet the urgent needs of patients.
Impact of the COVID-19 Pandemic on Cardiovascular Science: Anticipating Problems and Potential Solutions: A Presidential Advisory From the American Heart Association
Authors: Elizabeth M. McNally, Mitchell S.V. Elkind, Ivor J. Benjamin, Mina K. Chung, Glenn H. Dillon, Adrian F. Hernandez, Chinwe Ibeh, Donald M. Lloyd-Jones, Louise D. McCullough, Loren E. Wold, Davene R. Wright, Joseph C. Wu
Journal: Circulation (2021)

The coronavirus disease 2019 (COVID-19) pandemic has had worldwide repercussions for health care and research. In spring 2020, most non-COVID-19 research was halted, hindering research across the spectrum from laboratory-based experimental science to clinical research. Through the second half of 2020 and the first half of 2021, biomedical research, including cardiovascular science, only gradually restarted, with many restrictions on onsite activities, limited clinical research participation, and the challenges associated with working from home and caregiver responsibilities. Compounding these impediments, much of the global biomedical research infrastructure was redirected toward vaccine testing and deployment. This redirection of supply chains, personnel, and equipment has additionally hampered restoration of normal research activity. Transition to virtual interactions offset some of these limitations but did not adequately replace the need for scientific exchange and collaboration. Here, we outline key steps to reinvigorate biomedical research, including a call for increased support from the National Institutes of Health. We also call on academic institutions, publishers, reviewers, and supervisors to consider the impact of COVID-19 when assessing productivity, recognizing that the pandemic did not affect all equally. We identify trainees and junior investigators, especially those with caregiving roles, as most at risk of being lost from the biomedical workforce and identify steps to reduce the loss of these key investigators. Although the global pandemic highlighted the power of biomedical science to define, treat, and protect against threats to human health, significant investment in the biomedical workforce is required to maintain and promote well-being.
Phase I Dose-Escalation Trial of MIW815 (ADU-S100), an Intratumoral STING Agonist, in Patients with Advanced/Metastatic Solid Tumors or Lymphomas
Authors: Funda Meric-Bernstam, Randy F. Sweis, F. Stephen Hodi, Wells A. Messersmith, Robert H.I. Andtbacka, Matthew Ingham, Nancy Lewis, Xinhui Chen, Marc Pelletier, Xueying Chen, Jincheng Wu, Thomas W. Dubensky, Sarah M. McWhirter, Thomas Müller, Nitya Nair, Jason J. Luke
Journal: Clinical Cancer Research (2021)

Abstract Purpose: This phase I study assessed the safety, pharmacokinetics (PKs), and efficacy of MIW815 (ADU-S100), a novel synthetic cyclic dinucleotide that activates the stimulator of IFN genes (STING) pathway, in patients with advanced/metastatic cancers. Patients and Methods: Patients (n = 47) received weekly i.t. injections of MIW815, 50 to 6,400 μg, on a 3-weeks-on/1-week-off schedule. Results: A maximum tolerated dose was not reached. Most common treatment-related adverse events were pyrexia (17%), chills, and injection-site pain (each 15%). MIW815 was rapidly absorbed from the injection site with dose-proportional PK, a rapid terminal plasma half-life (approximately 24 minutes), and high interindividual variability. One patient had a partial response (PR; Merkel cell carcinoma); two patients had unconfirmed PR (parotid cancer, myxofibrosarcoma). Lesion size was stable or decreased in 94% of evaluable, injected lesions. RNA expression and immune infiltration assessments in paired tumor biopsies did not reveal significant on-treatment changes. However, increases in inflammatory cytokines and peripheral blood T-cell clonal expansion suggested systemic immune activation. Conclusions: MIW815 was well tolerated in patients with advanced/metastatic cancers. Clinical activity of single-agent MIW815 was limited in this first-in-human study; however, evidence of systemic immune activation was seen.
A Balancing Act: p53 Activity from Tumor Suppression to Pathology and Therapeutic Implications
Authors: Mengxiong Wang, Laura D. Attardi
Journal: Annual Review of Pathology Mechanisms of Disease (2021)

TP53, encoding the p53 transcription factor, is the most frequently mutated tumor suppressor gene across all human cancer types. While p53 has long been appreciated to induce antiproliferative cell cycle arrest, apoptosis, and senescence programs in response to diverse stress signals, various studies in recent years have revealed additional important functions for p53 that likely also contribute to tumor suppression, including roles in regulating tumor metabolism, ferroptosis, signaling in the tumor microenvironment, and stem cell self-renewal/differentiation. Not only does p53 loss or mutation cause cancer, but hyperactive p53 also drives various pathologies, including developmental phenotypes, premature aging, neurodegeneration, and side effects of cancer therapies. These findings underscore the importance of balanced p53 activity and influence our thinking of how to best develop cancer therapies based on modulating the p53 pathway.
COVID-19 Among Hospitalized Patients with Kidney Disease: Experience at a Midwestern Medical Center
Authors: Krista L. Lentine, Seyedmahdi Pahlavani, Yasar Caliskan, Ariel A. Schnell, Nikolas E. Marino, Aberdeen X. Taylor, Usama Elewa, Marie D. Philipneri, Amy Mosman, Thanh-Mai N. Vo, Rosemary Ouseph, Sruthi Ainapurapu, Thomas R. Groll
Journal: Journal of the American Society of Nephrology (2021)

Lentine, Krista L.; Pahlavani, Seyedmahdi; Caliskan, Yasar; Schnell, Ariel A.; Marino, Nikolas E.; Taylor, Aberdeen X.; Elewa, Usama; Philipneri, Marie D.; Mosman, Amy; Vo, Thanh-Mai N.; Ouseph, Rosemary; Ainapurapu, Sruthi; Groll, Thomas R. Author Information
Biological relevance of Granzymes A and K during <i>E. coli</i> sepsis
Authors: Iratxe Uranga-Murillo, Elena Tapia, Marcela Garzón-Tituaña, Ariel Ramirez-Labrada, Llipsy Santiago, Cecilia Pesini, Patricia Esteban, Francisco J Roig, Eva M Galvez, Phillip I Bird, Julián Pardo, Maykel Arias
Journal: Theranostics (2021)

Aims:Recent in vitro findings suggest that the serine protease Granzyme K (GzmK) may act as a proinflammatory mediator.However, its role in sepsis is unknown.Here we aim to understand the role of GzmK in a mouse model of bacterial sepsis and compare it to the biological relevance of Granzyme A (GzmA).Methods: Sepsis was induced in WT, GzmA -/-and GzmK -/-mice by an intraperitoneal injection of 2x10 8 CFU from E. coli.Mouse survival was monitored during 5 days.Levels of IL-1α, IL-1β, TNFα and IL-6 in plasma were measured and bacterial load in blood, liver and spleen was analyzed.Finally, profile of cellular expression of GzmA and GzmK was analyzed by FACS.Results: GzmA and GzmK are not involved in the control of bacterial infection.However, GzmA and GzmK deficient mice showed a lower sepsis score in comparison with WT mice, although only GzmA deficient mice exhibited increased survival.GzmA deficient mice also showed reduced expression of some proinflammatory cytokines like IL1-α, IL-β and IL-6.A similar result was found when extracellular GzmA was therapeutically inhibited in WT mice using serpinb6b, which improved survival and reduced IL-6 expression.Mechanistically, active extracellular GzmA induces the production of IL-6 in macrophages by a mechanism dependent on TLR4 and MyD88.Conclusions: These results suggest that although both proteases contribute to the clinical signs of E. coli-induced sepsis, inhibition of GzmA is sufficient to reduce inflammation and improve survival irrespectively of the presence of other inflammatory granzymes, like GzmK.
Glycemic Control and Risk of Sepsis and Subsequent Mortality in Type 2 Diabetes
Authors: Anca Balintescu, Marcus Lind, Mikael Andersson Franko, Anders Oldner, Maria Cronhjort, Ann-Marie Svensson, Björn Eliasson, Johan Mårtensson
Journal: Diabetes Care (2021)

To investigate the nature of the relationship between HbA1c and sepsis among individuals with type 2 diabetes, and to assess the association between sepsis and all-cause mortality in such patients.We included 502,871 individuals with type 2 diabetes recorded in the Swedish National Diabetes Register and used multivariable Cox regression and restricted cubic spline analyses to assess the association between time-updated HbA1c values and sepsis occurrence between 1 January 2005 and 31 December 2015. The association between sepsis and death was examined using multivariable Cox regression analysis.Overall, 14,534 (2.9%) patients developed sepsis during the study period. On multivariable Cox regression analysis, compared with an HbA1c of 48-52 mmol/mol (6.5-6.9%), the adjusted hazard ratio for sepsis was 1.15 (95% CI 1.07-1.24) for HbA1c <43 mmol/mol (6.1%), 0.93 (0.87-0.99) for HbA1c 53-62 mmol/mol (7.0-7.8%), 1.05 (0.97-1.13) for HbA1c 63-72 mmol/mol (7.9-8.7%), 1.14 (1.04-1.25) for HbA1c 73-82 mmol/mol (8.8-9.7%), and 1.52 (1.37-1.68) for HbA1c >82 mmol/mol (9.7%). In the cubic spline model, a reduction of the adjusted risk was observed within the lower HbA1c range until 53 mmol/mol (7.0%), with a hazard ratio of 0.78 (0.73-0.82) per SD; it increased thereafter (P for nonlinearity <0.001). As compared with patients without sepsis, the adjusted hazard ratio for death among patients with sepsis was 4.16 (4.03-4.30).In a nationwide cohort of individuals with type 2 diabetes, we found a U-shaped association between HbA1c and sepsis and a fourfold increased risk of death among those developing sepsis.
Macroscopic assessment of protective effect of cryopreserved placenta extract in ibuprofen-induced gastroenterocolonopathy
Authors: F.V. Hladkykh
Journal: GASTROENTEROLOGY (2021)

Background. Over-the-counter use of nonsteroidal anti-inflammatory drugs leads to their uncontrolled consumption among the population, which in some cases makes it impossible to prevent and timely detect adverse drug effects, and their effectiveness does not always satisfy clinicians. The purpose was to characterize the cytoprotective properties of cryopreserved placenta extract according to the condition of the mucous membrane of the proximal (esophagus and stomach) and distal (small and large intestine) parts of the gastrointestinal tract on the model of ibuprofen-induced esophagogastroenterocolonopathy. Materials and methods. In vivo experimental studies were performed on 28 male rats. Subchronic ibuprofen-induced gastrointestinal lesions were reproduced by intragastric administration of ibuprofen to rats at a dose of 310 mg/kg. The condition of the gastrointestinal tract mucous membrane was assessed macroscopically on a scale. Results. The therapeutic and prophylactic efficacy of esomeprazole statistically significantly (р &lt; 0.05) took place in the proximal parts of the gastrointestinal tract but had little effect on the prevalence of ulcerative lesions in the intestine. At the same time, unlike esomeprazole, which is known to have only gastroprotective activity, cryopreserved placenta extract had a cytoprotective effect both in the stomach and in the distal parts of the gastrointestinal tract — small and large intestine. Thus, the prevalence of ibuprofen-induced both entero- and colonopathy on the background of the study of the extract was almost twice lower than in rats that did not receive correction drugs. Conclusions. It is established that the use of cryopreserved placenta extract in the treatment-and-prophylactic mode has comparable to esomeprazole gastroprotective activity. In addition, it was found that the use of the studied cryoextract was accompanied by a decrease in the multiplicity of ulcerative defects in the small and large intestine of rats, by 4.6 and 3.8 times, respectively, compared to the control animals.