tbuckley/cabot-search huggingface dataset:
Abstract 332: Novel Peptide Administered During CPR Improves Long-Term Survival After Prolonged Cardiac Arrest
Authors: Jing Li, Xiangdong Zhu, Chunpei Lee, Rong-Wen Tain, Kejia Cai, Terry L Vanden Hoek
Journal: Circulation (2019)

Introduction: Cardiac arrest (CA) is a leading cause of death in the United State, affecting 600,000 people annually with overall survival rate of less than 10%. CPR and cooling are the few effective treatments that improve CA survival. No drugs are currently available to improve survival. Active cooling is more effective than targeted temperature management in improving survival, but can be difficult to implement clinically. We have developed a novel peptide (TAT-PHLPP) that inhibits PH domain and Leucine rich repeat Protein Phosphatases (PHLPP). When this peptide was administered intravenously (i.v.) during CPR, it expresses in both heart and brain within 5 min of intravenous injection and significantly improved 4 h survival in a 12 min mouse asystole arrest model. Hypothesis: We hypothesize that TAT-PHLPP improves neurologically intact long-term survival following SCA with improved early metabolic recovery. Methods: C57BL6 mice (n=20) were randomized to receive peptide treatment and appropriate blinding was ensured. A 12 min asystolic arrest was induced with KCl. CPR was started along with TAT-PHLPP (7.5 mg/kg) via i.v. Three day Survival was evaluated. Cerebral blood flow (CBF) and metabolic chemical exchange saturation transfer (CEST) contrast were measured with endogenous and dynamic arterial spin labeling (ASL) and CEST MRI respectively. Glucose utilization was assessed by pyruvate dehydrogenase (PDH) phosphorylation and ATP generation. Further, blood taurine and glutamate were measured. Results: Baseline characteristics including weight, temperature, heart rate, MAP were indistinguishable between the control (normal saline, NS) and peptide group. Compared to NS, TAT-PHLPP significantly improved 3-day survival with better neurological function. It progressively increased CBF and metabolic CEST contrast. It decreased p-PDH (increased activity) at 15 min post-ROSC and enhanced ATP generation in both heart and brain. It also reduced plasma taurine and glutamate concentrations as early as 5 min post-ROSC. Further, high levels of taurine and glutamate were detected in non-survivors. Conclusions: This novel therapy may have a high translational potential to reproduce critical outcomes of CPR cooling without physical cooling.
Exercise and the immune system: taking steps to improve responses to cancer immunotherapy
Authors: Michael P Gustafson, Courtney M Wheatley-Guy, Allison C Rosenthal, Dennis A Gastineau, Emmanuel Katsanis, Bruce D Johnson, Richard J Simpson
Journal: Journal for ImmunoTherapy of Cancer (2021)

The remarkable success of cancer immunotherapies has provided new hope to cancer patients. Unfortunately, a significant proportion of patients remain unable to respond to immunotherapy or maintain durable clinical responses. The lack of objective responses likely results from profound immune dysfunction often observed in patients with cancer. There is substantial evidence that exercise and physical activity can reduce incidence and improve outcomes in cancer patients. As the immune system is highly responsive to exercise, one potential avenue to improve immune function is through exercise and physical activity. A single event of dynamic exercise results in the substantial mobilization of leukocytes with increased functional capacities into the circulation. Chronic, or long-term, exercise leads to higher physical fitness in terms of greater cardiorespiratory function and/or muscle strength and endurance. High aerobic capacity, as measured by maximal oxygen uptake, has been associated with the reduction of dysfunctional T cells and improvements in the abundance of some T cell populations. To be sure, however, the mechanisms of exercise-mediated immune changes are both extensive and diverse. Here, we examine the evidence and theorize how acute and chronic exercise could be used to improve responses to cancer immunotherapies including immune checkpoint inhibitors, dendritic cell vaccines, natural killer cell therapies, and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells. Although the parameters of optimal exercise to yield defined outcomes remain to be determined, the available current data provide a compelling justification for additional human studies and clinical trials investigating the adjuvant use of exercise in immuno-oncology.
The effects of transcranial direct current stimulation on gait in patients with Parkinson’s disease: a systematic review
Authors: Fateme Pol, Mohammad Ali Salehinejad, Hamzeh Baharlouei, Michael A. Nitsche
Journal: Translational Neurodegeneration (2021)

Abstract Background Gait problems are an important symptom in Parkinson’s disease (PD), a progressive neurodegenerative disease. Transcranial direct current stimulation (tDCS) is a neuromodulatory intervention that can modulate cortical excitability of the gait-related regions. Despite an increasing number of gait-related tDCS studies in PD, the efficacy of this technique for improving gait has not been systematically investigated yet. Here, we aimed to systematically explore the effects of tDCS on gait in PD, based on available experimental studies. Methods Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) approach, PubMed, Web of Science, Scopus, and PEDro databases were searched for randomized clinical trials assessing the effect of tDCS on gait in patients with PD. Results Eighteen studies were included in this systematic review. Overall, tDCS targeting the motor cortex and supplementary motor area bilaterally seems to be promising for gait rehabilitation in PD. Studies of tDCS targeting the dorosolateral prefrontal cortex or cerebellum showed more heterogeneous results. More studies are needed to systematically compare the efficacy of different tDCS protocols, including protocols applying tDCS alone and/or in combination with conventional gait rehabilitation treatment in PD. Conclusions tDCS is a promising intervention approach to improving gait in PD. Anodal tDCS over the motor areas has shown a positive effect on gait, but stimulation of other areas is less promising. However, the heterogeneities of methods and results have made it difficult to draw firm conclusions. Therefore, systematic explorations of tDCS protocols are required to optimize the efficacy.
CD8<sup>+</sup> tissue‐resident memory T cells recruit neutrophils that are essential for flare‐ups in contact dermatitis
Authors: Anders B. Funch, Veronika Mraz, Anne‐Sofie Ø. Gadsbøll, Mia H. Jee, Julie F. Weber, Niels Ødum, Anders Woetmann, Jeanne D. Johansen, Carsten Geisler, Charlotte M. Bonefeld
Journal: Allergy (2021)

Allergic contact dermatitis (ACD) is classically described as a delayed-type hypersensitivity reaction. However, patients often experience flare-ups characterized by itching erythema, edema, and often vesicles occurring within hours after re-exposure of previously sensitized skin to the specific contact allergen. Recent studies have indicated that skin-resident memory T (TRM ) cells play a central role in ACD. However, the pathogenic role of TRM cells in allergen-induced flare-ups is not known.By the use of various mouse models and cell depletion protocols, we investigated the role of epidermal TRM cells in flare-up reactions to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene. The inflammatory response was measured by changes in ear thickness, and the cellular composition in epidermis was determined by flow cytometry and confocal microscopy. Finally, adaptive transfer and inhibitors were used to determine the role of TRM cells, neutrophils, and CXCL1/CXCL2 in the response.We show that CD8+ TRM cells initiate massive infiltration of neutrophils in the epidermis within 12 h after re-exposure to the contact allergen. Depletion of neutrophils before re-exposure to the allergen abrogated the flare-up reactions. Furthermore, we demonstrate that CD8+ TRM cells mediate neutrophil recruitment by inducing CXCL1 and CXCL2 production in the skin, and that blockage of the C-X-C chemokine receptor type 1 and 2 inhibits flare-up reactions and neutrophil infiltration.As the first, we show that epidermal CD8+ TRM cells cause ACD flare-ups by rapid recruitment of neutrophils to the epidermis.
Efficacy and safety of tocilizumab in 48-week treatment in children with systemic juvenile idiopathic arthritis
Authors: Yokota S, Imagawa T, Mori M, Ozawa R, Miyamae T, Ito S, Aihara Y, Nerome Y, Imanaka H, Takei S, Kawano Y, Iwata N, Tomiita M, Miyoshi M, Murata T, Umebayashi H, Nishimoto N, Kishimoto T
Journal: Annals of the Rheumatic Diseases (2007)
Sustained cancer clinical trial activity in a French hospital during the first wave of the COVID-19 pandemic
Authors: Arnaud Bayle, Capucine Baldini, Patricia Martin-Romano, Jean-Marie Michot, Stéphane Champiat, Rastilav Bahleda, Anas Gazzah, Aurélien Marabelle, Loic Verlingue, Arthur Geraud, Daphné Morel, Stefan Michiels, Antoine Hollebecque, Laurence Albiges, Benjamin Besse, Jean-Charles Soria, Christophe Massard, Fabrice Barlesi, Sophie Postel-Vinay
Journal: Cancer Cell (2021)
Limited protection against SARS-CoV-2 infection and virus transmission after mRNA vaccination
Authors: Lea Hsu, Hilmar Wisplinghoff, Annelene Kossow, Julia Hurraß, Gerhard A. Wiesmüller, Barbara Grüne, Dennis Hoffmann, Jessica Lüsebrink, Sabrina Demuth, Oliver Schildgen, Verena Schildgen
Journal: Journal of Infection (2021)
Abstract 14113: Parallel Induction of Circulating Fatty Acid Binding Protein 4 and Norepinephrine During Exercise: Implication for a Novel Biomarker for Sympathetic Nervous Activity
Authors: Tatsuya Iso, Hiroaki Sunaga, Naomi Ohshima, Hikari Haruyama, Nozomi Furukawa, Hiroaki Matsui, Tomoyuki Yokoyama, Masahiko Kurabayashi
Journal: Circulation (2016)

Background: The sympathetic nervous system plays a central role in the regulation of cardiovascular and metabolic response in a variety of pathophysiological states. Fatty acid binding protein 4 (F...
Vascular and Lymphatic Malformations: Perspectives From Human and Vertebrate Studies
Authors: Harish P. Janardhan, Sherin Saheera, Roy Jung, Chinmay M. Trivedi
Journal: Circulation Research (2021)

Vascular malformations, affecting ≈1% to 1.5% of the population, comprise a spectrum of developmental patterning defects of capillaries, arteries, veins, and/or lymphatics. The majority of vascular malformations occur sporadically; however, inherited malformations exist as a part of complex congenital diseases. The malformations, ranging from birthmarks to life-threatening conditions, are present at birth, but may reveal signs and symptoms-including pain, bleeding, disfigurement, and functional defects of vital organs-in infancy, childhood, or adulthood. Vascular malformations often exhibit recurrent patterns at affected sites due to the lack of curative treatments. This review series provides a state-of-the-art assessment of vascular malformation research at basic, clinical, genetic, and translational levels.
Basophils balance healing after myocardial infarction via IL-4/IL-13
Authors: Florian Sicklinger, Ingmar Sören Meyer, Xue Li, Daniel Radtke, Severin Dicks, Moritz P. Kornadt, Christina Mertens, Julia K. Meier, Kory J. Lavine, Yunhang Zhang, Tim Christian Kuhn, Tobias Terzer, Jyoti Patel, Melanie Boerries, Gabriele Schramm, Norbert Frey, Hugo A. Katus, David Voehringer, Florian Leuschner
Journal: Journal of Clinical Investigation (2021)

The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6Clo macrophages toward increased numbers of inflammatory Ly6Chi monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of Ly6Chi monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/α-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels.
Abstract 351: Allogeneic C-kit <sup>+</sup> Cardiac Progenitor Cells are Immune Tolerant With Strong Efficacy for Cardiac Functional Recovery
Authors: Srinivasa Raju Datla, Yin Guo, Rachana Mishra, Ling Chen, Progyaparamita Saha, Sudhish Sharma, Grace Bigham, Godly Jack, Sunjay Kaushal
Journal: Circulation Research (2016)

Background: A recent clinical trail using adult autologous c-kit + cardiac progenitor cells (c-kit + CPCs) have demonstrated cardiac functional recovery in myocardial ischemic patients. This autologous approach of ex vivo expansion of c-kit+ CPCs is expensive and time consuming. The immune tolerant properties of c-kit + CPCs have not been investigated as an alternative clinical strategy. In this study, we compared allogeneic and syngeneic c-kit + CPCs immunogenic tolerance and cardiac recovery potentials using divergent inbred rat strains in a myocardial infarction (MI) model. Methods and Results: We isolated rat c-kit + CPCs (rc-kit + CPCs) from male Wistar Kyoto (WKY) rat hearts and human c-kit + CPCs (hc-kit + CPCs) from adult coronary artery bypass graft patient’s right atrial appendage. In vitro, both rat and human c-kit + CPCs expressed MHC class I but not class II or co-stimulatory molecules CD80 and CD86. In mixed lymphocyte reaction (MLR) assay, allogeneic and syngeneic rc-kit + CPCs elicited minimal T-cell proliferation. In vivo, intra-myocardial administration of WKY rc-kit + CPCs after creating MI condition, elicited minimal local, systemic and humoral inflammatory response in allogeneic (Brown Norway (BN) female rats) and syngeneic (WKY female rats) groups compared to the xenogeneic (hc-kit + CPCs in BN male rats). In addition, the allogeneic and syngeneic rc-kit + CPCs groups significantly recovered cardiac function (EF, SV, and CO) compared to the xenogeneic c-kit + CPCs group, which had no functional recoverability. Histological analysis further revealed that allogeneic and syngeneic rc-kit + CPCs groups had significantly decreased scar size by increasing endogenous cardiomyocyte proliferation, c-kit + CPC recruitment and increased neoangiogenesis. Conclusion: Allogeneic c-kit + CPCs are immune tolerant and produce minimal inflammatory response while maintaining their cardiac recovery potentials in immunologically divergent species. Our observation, for the fist time, reports the minimal immunogenic response by c-kit + CPCs and strongly supports the development of an allogeneic c-kit + CPC strategy for clinical trial applications.
A Multicenter Phase I Dose-Finding and Preliminary Efficacy Study of the Histone Deacetylase Inhibitor Romidepsin in Combination with Pegylated Liposomal Doxorubicin for the Treatment of Adults with Relapsed or Refractory Cutaneous and Peripheral T-Cell Lymphomas
Authors: Weiyun Ai, Pierluigi Porcu, Wade Berry, Juliana Engleman, Matthew J. Wieduwilt, Jonathan E Brammer
Journal: Blood (2017)
Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells
Authors: Hiroyuki Hosokawa, Maria Koizumi, Kaori Masuhara, Maile Romero-Wolf, Tomoaki Tanaka, Toshinori Nakayama, Ellen V. Rothenberg
Journal: The Journal of Experimental Medicine (2021)

PU.1 (encoded by Spi1), an ETS-family transcription factor with many hematopoietic roles, is highly expressed in the earliest intrathymic T cell progenitors but must be down-regulated during T lineage commitment. The transcription factors Runx1 and GATA3 have been implicated in this Spi1 repression, but the basis of the timing was unknown. We show that increasing Runx1 and/or GATA3 down-regulates Spi1 expression in pro–T cells, while deletion of these factors after Spi1 down-regulation reactivates its expression. Leveraging the stage specificities of repression and transcription factor binding revealed an unconventional but functional site in Spi1 intron 2. Acute Cas9-mediated deletion or disruption of the Runx and GATA motifs in this element reactivates silenced Spi1 expression in a pro–T cell line, substantially more than disruption of other candidate elements, and counteracts the repression of Spi1 in primary pro–T cells during commitment. Thus, Runx1 and GATA3 work stage specifically through an intronic silencing element in mouse Spi1 to control strength and maintenance of Spi1 repression during T lineage commitment.
Abstract 12545: Ross Autograft Leaflet Response to Systemic Circulation: Expression Profiling Reveals Divergence From Normal Aortic and Pulmonary Valve Leaflets
Authors: Katsuhide Maeda, Xiaoyuan Ma, Ariana Goodman, Christina Greene, Frank L Hanley, Robert K Riemer
Journal: Circulation (2019)

Introduction: The Ross procedure has been employed for many years as treatment for aortic valve disease. It is a unique surgery in that the pulmonary valve, which is inherently designed to support ...
Murine models of clonal haematopoiesis to assess mechanisms of cardiovascular disease
Authors: Ying Wang, Soichi Sano, Hayato Ogawa, Keita Horitani, Megan A Evans, Yoshimitsu Yura, Emiri Miura-Yura, Heather Doviak, Kenneth Walsh
Journal: Cardiovascular Research (2021)

Abstract Clonal haematopoiesis (CH) is a phenomenon whereby somatic mutations confer a fitness advantage to haematopoietic stem and progenitor cells (HSPCs) and thus facilitate their aberrant clonal expansion. These mutations are carried into progeny leucocytes leading to a situation whereby a substantial fraction of an individual’s blood cells originate from the HSPC mutant clone. Although this condition rarely progresses to a haematological malignancy, circulating blood cells bearing the mutation have the potential to affect other organ systems as they infiltrate into tissues under both homeostatic and disease conditions. Epidemiological and clinical studies have revealed that CH is highly prevalent in the elderly and is associated with an increased risk of cardiovascular disease and mortality. Recent experimental studies in murine models have assessed the most commonly mutated ‘driver’ genes associated with CH, and have provided evidence for mechanistic connections between CH and cardiovascular disease. A deeper understanding of the mechanisms by which specific CH mutations promote disease pathogenesis is of importance, as it could pave the way for individualized therapeutic strategies targeting the pathogenic CH gene mutations in the future. Here, we review the epidemiology of CH and the mechanistic work from studies using murine disease models, with a particular focus on the strengths and limitations of these experimental systems. We intend for this review to help investigators select the most appropriate models to study CH in the setting of cardiovascular disease.
A precision medicine classification for treatment of acute myeloid leukemia in older patients
Authors: Alice S. Mims, Jessica Kohlschmidt, Uma Borate, James S. Blachly, Shelley Orwick, Ann-Kathrin Eisfeld, Dimitrios Papaioannou, Deedra Nicolet, Krzysztof Mrόzek, Eytan Stein, Bhavana Bhatnagar, Richard M. Stone, Jonathan E. Kolitz, Eunice S. Wang, Bayard L. Powell, Amy Burd, Ross L. Levine, Brian J. Druker, Clara D. Bloomfield, John C. Byrd
Journal: Journal of Hematology & Oncology (2021)

Abstract Background Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study. Methods We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes. Results Our classification identified core-binding factor and NPM1 -mutated/ FLT3 -ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of &gt; 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17–42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%. Conclusions By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies. Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).
Enhanced osteoclastogenesis in patients with MSMD due to impaired response to IFN-γ
Authors: Miyuki Tsumura, Mizuka Miki, Yoko Mizoguchi, Osamu Hirata, Shiho Nishimura, Moe Tamaura, Reiko Kagawa, Seiichi Hayakawa, Masao Kobayashi, Satoshi Okada
Journal: Journal of Allergy and Clinical Immunology (2021)