tbuckley/cabot-search huggingface dataset:
Abstract 132: Imaging-Based Assay for Screening of Cell Cycle Modifying Substances in Postnatal Cardiomyocytes
Authors: Cora Becker, Carmen Carillo Garcia, Patricia Freitag, Dennis Schade, Bernd K Fleischmann, Michael Hesse
Journal: Circulation Research (2019)

Cardiovascular diseases are the main cause of death in the industrial world. Especially large myocardial infarctions and the potentially resulting left ventricular dysfunction are chronical diseases with a poor prognosis. Due to limited endogenous cardiac repair capacity, we are investigating the regulation of the cell cycle in cardiomyocytes (CMs) as a potential treatment strategy. We hypothesize that controlled induction of cardiomyocyte proliferation will lead to an increase in muscle mass and improvement of cardiac function. We are using CMs from double transgenic αMHC-H2B-mCherry/CAG-eGFP-anillin mice for the analysis of postnatal CM development. This double transgenic system enables us to unequivocally identify CM nuclei as well as cell cycle variations like acytokinetic mitosis (mitosis without cytokinesis), resulting in binucleated CMs, and endoreplication (mitosis without cytokinesis and karyokinesis), leading to polyploid CMs. With the goal of inducing authentic cell division, we are screening for pro-proliferative substances in P1 and P6 postnatal CMs of αMHC-H2B-mCherry/CAG-eGFP-anillin mice. Here we will present the detailed analysis of several screening hits demonstrating an increase in cell cycle activity leading mainly to binucleation but only to limited cell division in CMs.
Abstract 179: Resistin Regulates ATP-citrate lyase Expression a Key Metabolic Enzyme of Lipogenesis and Histone acetylation in Human Macrophage
Authors: Nezam Haider, Pricila Moly, Weifeng Lu, Wei Zhou
Journal: Circulation Research (2019)

BACKGROUND: Human resistin synthesized by macrophages is associated with insulin resistance, type 2 diabetes, atherosclerosis, and chronic inflammation. We used a comparative global protein expression profiling of human macrophage treated with resistin to identify downstream targets and intracellular signaling pathways involving hyper-resistinemia-associated metabolic disorders by HPLC-ESI-MS/MS. ATP-citrate lyase (ACLY), is an essential cytosolic enzyme for generating acetyl-CoA, a key metabolite for glycolysis, de novo lipogenesis, cholesterol synthesis, and histone acetylation. Its dysregulation is associated with diabetes, hypercholesterolemia, and oncogenesis and is a potent therapeutic target . In this study, we explored the regulation of ACLY and its phosphorylation by resistin. METHODS: Mϕ derived from THP1 cells were treated with human resistin for 24-72 hrs. Samples of total protein tryptic digest of untreated control and resistin-treated Mϕ were analyzed by HPLC-ESI-MS/MS. Total protein were also analyzed by western blot for ACLY and its phosphorylation . Gene expression was measured by Quantitative Real-time PCR. RESULTS: ACLY showed a significant (ρ &lt; 0.05) differences in expression between control and resistin treated groups by quantitative mass spectrometry. ACLY formed protein-protein interaction (PPI) with 23 out of 162 significantly differentially regulated proteins. Level of ACLY protein decreased 2 fold after 48 hours of resistin treatment. However, after 72 hours of resistin treatment ACLY proteins increase with a 4-5 fold increase in its serine 455 phosphorylation (Figure 1). In human macrophage, ACLY mRNA also increased ~2 fold after 24 hours of resistin treatment (Figure 2). CONCLUSION: Resistin significantly changed the gene expression of ACLY in humanMϕ. Although there was an initial decrease in ACLY protein with no change in its phosphorylation. However, a longer 72 hours treatment of resistin induce ACLY protein in human macrophages and a very significant increase in its phosphorylation. ACLY plays a pivotal role in many metabolic and epigenetic processes, this late ACLY activation may mediate the effect of resistin on chronic diseases like diabetes, atherosclerosis, and chronic inflammation.
A Gastric Carcinosarcoma Patient who Underwent Chemotherapy
Authors: O. Maeda, T. Ando, K. Ishiguro, O. Watanabe, T. Kamiya, S. Mimura, M. Ujihara, Y. Hirayama, K. Morise, K. Funasaka, R. Miyahara, N. Ohmiya, K. Itatsu, Y. Ando, H. Goto
Journal: Annals of Oncology (2012)
Should we shift the paradigm of preclinical models for ARDS therapies?
Authors: William Bain, Gustavo Matute-Bello
Journal: Thorax (2019)

A 10.8-year-old, spayed female toy poodle presented with an esophageal foreign body. The foreign body was removed endoscopically, and a gastrostomy tube was placed to provide nutritional support during esophageal healing. The gastrostomy tube was later removed by endoscopic retrieval of the bulb through the esophagus. Immediately afterward, the dog developed hemothorax and eventually died. It was determined that many small arterial branches were avulsed from the aorta. The involved sections of aorta histopathogically evidenced medial necrosis, which was believed to be related to a prior disruption of blood flow through the vasa vasorum.
Navigating specialty pharmacies to get oral agents to patients in a timely manner.
Authors: Tanya B. Dorff, Mary Mendelsohn, Amis Christian, Hoim Kim
Journal: Journal of Clinical Oncology (2019)

220 Background: Increasing numbers of oncology patients require oral therapies provided by specialty pharmacies. Our experience indicates patients receiving care in a facility without specialty pharmacy dispensing capabilities are at a disadvantage in receiving their medications in a timely manner. Methods: Metastatic prostate patients receiving oral hormonal therapies were identified for chart review. Findings indicated the median time to medication receipt by the patient was 25 days. Interviews with the team, staff and patients revealed that multiple factors contributed to the delays. Patient expectations were to receive prescribed agents within 7 days. Review of our Community Clinics, who employ a centralized process and have relationships with specialty pharmacies, indicated that medications were received by patients within a week. Successful interventions necessitated the patient partnering with the healthcare team to improve efficiencies and reduce time to drug delivery. Results: Delays were multifactorial and extremely difficult to ascertain from chart review. Reasons for delay were clearly noted in 19 out of 97 patient records out of which over 47% charts indicated the pre-approval process as the cause for the delay. Patients were educated regarding the specialty pharmacy process, the name of the prescribed drug and the pharmacy where the prescription was sent. The patient education sheet encouraged patients to become partners in the process and advised them to check with their insurance for their approved specialty pharmacy. If the approved pharmacy varied from the pharmacy initially chosen, patients were asked to notify the clinic staff to initiate a new prescription to the correct pharmacy. Patient response to the education sheet has been positive. Impact on median time to delivery is not yet known. Conclusions: Streamlining the authorization process of specialty pharmacies would benefit oncology patients, as we identified that most delays occur in specialty pharmacy processing. Healthcare facilities may consider increasing patient education or obtaining a specialty pharmacy dispensing license in order to minimize delays for oncology patients receiving oral oncology medications.
Different Treatment Regimens, Optimal Time Points and Threshold Level While Minimal Residual Disease Evaluation in AML Patients
Authors: Tatiana I. Lobanova, Irina V. Galtseva, Yuliya O. Davydova, Nikolay M. Kapranov, Vera V. Troitskaya, Irina A. Lukyanova, Elena Parovichnikova, Sergei M. Kulikov, Larisa Kuzmina, Valery G. Savchenko
Journal: Blood (2018)
Survey results from a patient’s perspective during a phase I/research clinic visit.
Authors: Stefanie Valeria Beltran, Jessica MacIntyre, Dalissa Tejera, Jaime R. Merchan, Justin M. Watts
Journal: Journal of Clinical Oncology (2019)

216 Background: The University of Miami’s Phase I Program is South Florida’s only academic Phase I center dedicated to drug development for cancer patients. On April 2018, Sylvester Comprehensive Cancer Center opened the Phase I/Experimental Therapeutics (ET) Clinic dedicated to research patients enrolled in Phase I clinical trials and established a multi-disciplinary care team. As Phase I clinical trials are evolving, it is necessary to improve on the patient experience as it pertains to research care. Methods: Using a Likert-type scale, dual language survey (English and Spanish), patients were asked 11 questions about the Phase I/ET Clinic visit ranging from the beginning of their Phase I clinical trial enrollment all the way to provider care during the visit. The survey was conducted from January 2019-April 2019 through a secure, HIPAA compliant online Research Electronic Data Capture software (REDCap). Results: Of the 30 patients that were approached, 26 responded (Renal 26.9%, Myelofibrosis 19.2%, Bladder 15.4%, Head and Neck 7.7%, Acute Myeloid Leukemia 15.4%, Myelodysplastic Syndrome 7.7%, and Other 7.7%). Our results found that 100% of research patients would recommend a Phase I clinical trial to another participant. In addition, 96.2% of patients felt there was continuation of their care through their clinical trial process. As a note, 19.2% of patients positively recognized a Phase I provider including Nurse Practitioners (NPs) and physicians. Of these 19.2% of patients, 50% praised an NP in the free text area of the survey. Lastly, 42.3% of patients positively mentioned the team support received in the Phase I Clinic in the free text area of the survey. Conclusions: Our conclusion based on survey results show that having committed providers and clinic space for research patients on a Phase I clinical trial provided an overall positive and personalized experience. Additionally, the survey reflects on how patients are more inclined to refer to a clinical trial due to a good experience. Future directions should look at developing a similar clinic for all phases of research considering the exceptional patient feedback emphasizing on provider care.
Abstract 795: TRAF2-GRK2 Interaction Mediates Non-Canonical Desensitization of Beta-Adrenergic Receptors to TNF-α
Authors: Sromona Mukherjee, Mohan Maradumane, Sathyamangla V. N Prasad
Journal: Circulation Research (2019)

β- Adrenergic receptor (βAR), a prototypical G-protein coupled receptor (GPCR) is a key regulator of cardiac function. Impaired G-protein coupling (desensitization) of βARs is a key hallmark of heart failure. Desensitization occurs by phosphorylation of βARs by GRK2 to sympathetic overdrive leading to β-arrestin binding and endocytosis. Our studies show that TNFα-induces βAR phosphorylation/desensitization via GRK2 recruitment that is independent of the classical Gβγ mechanism suggesting a non-canonical pathway of GRK2 recruitment. Comorbid conditions like obesity/ hypertension have a higher risk of heart failure and is associated with increase in TNFα, a known cardio-depressant. β-blockers are known to be contra-indicative in obesity which we believe is due to βAR desensitization through non-canonical GRK2 recruitment to the βAR in response to elevated TNFα. However the underlying mechanisms for βAR desensitization are not known and as TNFα recruits TRAF2 to mediate downstream signaling, we hypothesized that TRAF2 recruits GRK2 to the plasma membrane causing receptor phosphorylation and desensitization. Our study shows TNFα drives βAR dysfunction by recruiting GRK2 to βAR complex through TRAF2. Our studies indicate that TRAF2 and GRK2 form a cytosolic complex and is recruited to the receptor complex post-TNFα treatment. Pharmacologic inhibition of GRK2 results in decreased βAR phosphorylation after TNFα. Furthermore, siRNA knockdown of TRAF2 results in reduction of βAR phosphorylation indicating the key role for TRAF2 in TNFα-mediated desensitization. Given that nothing is known about TRAF2 and GRK2 interaction we performed molecular docking using Haddock software to identify that the N-terminal region of GRK2 may interact with TRAF2. Overexpression of GRK2 N-terminal domain as dominant negative strategy resulted in reduced β2AR phosphorylation in response to TNFα, suggesting the requirement of GRK2 N-terminal in non-canonical β2AR desensitization. We are currently using cardiac specific GRK2 and TRAF2 knockout mice to assess their role in cardiac function in response to TNFα showing the role of GRK2-TRAF2-TNFR axis in mediating agonist-independent βAR desensitization/dysfunction.
Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers
Authors: Hao-Xiang Wu, Yan-Xing Chen, Zi-Xian Wang, Qi Zhao, Ming-Ming He, Ying-Nan Wang, Feng Wang, Rui-Hua Xu
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the association of genomic alterations in DNA methylation-related genes and ICI response are lacking. <h3>Methods</h3> Clinical cohorts with annotated response and survival data and matched mutational data from published studies were collected and consolidated. The predictive function of specific mutated genes was first tested in the discovery cohort and later validated in the validation cohort. The association between specific mutated genes and tumor immunogenicity and anti-tumor immunity was further investigated in the Cancer Genome Altas (TCGA) dataset. <h3>Results</h3> Among twenty-one key genes involving in the regulation of DNA methylation, <i>TET1</i>-mutant (<i>TET1</i>-MUT) was enriched in patients responding to ICI treatment in the discovery cohort (<i>P</i> &lt; 0.001). <i>TET1</i> was recurrently mutated across multiple cancers and more frequently seen in skin, lung, gastrointestinal, and urogenital cancers. In the discovery cohort (<i>n</i> = 519), significant differences were observed between <i>TET1</i>-MUT and <i>TET1</i>-wildtype (<i>TET1</i>-WT) patients regarding objective response rate (ORR, 60.9% versus 22.8%, <i>P</i> &lt; 0.001), durable clinical benefit (DCB, 71.4% versus 31.6%, <i>P</i> &lt; 0.001), and progression-free survival (PFS, hazard ratio = 0.46 [95% confidence interval, 0.25 to 0.82], <i>P</i> = 0.008). In the validation cohort (<i>n</i> = 1395), significant overall survival (OS) benefit was detected in the <i>TET1</i>-MUT patients compared to <i>TET1</i>-WT patients (hazard ratio = 0.47 [95% confidence interval, 0.25 to 0.88], <i>P</i> = 0.019), which was, importantly, independent of tumor mutational burden and high microsatellite instability; as well as not attributed to the prognostic impact of <i>TET1</i>-MUT (<i>P</i> &gt; 0.05 in both two non-ICI-treated cohorts). In TCGA dataset, <i>TET1</i>-MUT was strongly associated with higher tumor mutational burden and neoantigen load, and inflamed pattern of tumor-infiltrating T lymphocytes, immune signatures and immune-related gene expressions. <h3>Conclusions</h3> <i>TET1</i>-MUT was strongly associated with higher ORR, better DCB, longer PFS, and improved OS in patients receiving ICI treatment, suggesting that <i>TET1</i>-MUT is a novel predictive biomarker for immune checkpoint blockade across multiple cancer types.
FAS-Mediated Apoptosis Assay in Patients with ALPS-like Phenotype Carrying CASP10 Mutations
Authors: Maurizio Miano, Enrico Cappelli, Agnese Pezzulla, Roberta Venè, Elena Palmisani, Alice Grossi, Paola Terranova, Tiziana Lanza, Rosario Maggiore, Filomena Pierri, Concetta Micalizzi, Michaela Calvillo, Isabella Ceccherini, Giovanna Russo, Carlo Dufour, Francesca Fioredda
Journal: Blood (2018)
Direct Oral Anticoagulants in Antiphospholipid Syndrome: Too Early or Too Late?
Authors: Denis Wahl, Virginie Dufrost
Journal: Annals of Internal Medicine (2019)

Ordi-Ros and colleagues reported the results of a randomized trial comparing rivaroxaban with dose-adjusted VKA therapy for patients with thrombotic APS. The editorial discusses the results in the ...
High Resolution Melt Analysis for Rapid and Cost-Effective Screening of TP53 Mutations in Patients with Myeloid Malignancies
Authors: Takuto Mori, Yuichiro Ono, Hayato Maruoka, Yoshimitsu Shimomura, Nobuhiro Hiramoto, Satoshi Yoshioka, June Takeda, Yasuhito Nannya, Seishi Ogawa, Takayuki Ishikawa
Journal: Blood (2018)
Weekly Screening for Multidrug-Resistant Organisms Identifies High Number of Colonizations in Patients Undergoing Stem Cell Transplantation
Authors: Silvia Monsalvo, Pascual Balsalobre, Nieves Dorado Herrero, Laura Solán, Ana Fernandez-Cruz, Marina Machado, Maria Dolores Vigil-Escribano, Javier Anguita, Jose Luis Díez-Martín, Mi Kwon
Journal: Blood (2018)
Lost to Follow-up Rates Are Higher in Pediatric Than Adult Survivors, but Not By Transplant Type: A Report from the Center for International Blood and Marrow Transplant Research
Authors: David K. Buchbinder, Ruta Brazauskas, Khalid Bo-Subait, Karen K. Ballen, Theresa E. Hahn, Tami D John, Susan K Parsons, Shahrukh K. Hashmi, Nandita Khera, William A. Wood, Wael Saber
Journal: Blood (2018)
Carfilzomib and Bortezomib Containing Regimens Yield High Rates Of MRD Negative Autologous Hematopoietic Progenitor Cell (HPC) Grafts In Multiple Myeloma (MM) and High Risk Smoldering Myeloma (SMM)
Authors: Nishant Tageja, Neha Korde, Constance Yuan, Kristen Cole, Jennifer Hsu, Sheila Phang, Daniele N. Avila, Tiffany Taylor, Marcia Mulquin, Diamond Zuchlinski, Hanh Khuu, Maryalice Stetler-Stevenson, Susan F. Leitman, Ola Landgren, Claude Sportes
Journal: Blood (2013)
Association of preterm birth with lipid disorders in early adulthood: A Swedish cohort study
Authors: Casey Crump, Jan Sundquist, Kristina Sundquist
Journal: PLoS Medicine (2019)

Background Preterm birth has previously been linked with cardiovascular disease (CVD) in adulthood. However, associations with lipid disorders (e.g., high cholesterol or triglycerides), which are major risk factors for CVD, have seldom been examined and are conflicting. Clinicians will increasingly encounter adult survivors of preterm birth and will need to understand the long-term health sequelae. We conducted the first large population-based study to determine whether preterm birth is associated with an increased risk of lipid disorders. Methods and findings A retrospective national cohort study was conducted of all 2,235,012 persons born as singletons in Sweden during 1973 to 1995 (48.6% women), who were followed up for lipid disorders identified from nationwide inpatient, outpatient, and pharmacy data through 2016 (maximum age 44 years). Cox regression was used to adjust for other perinatal and maternal factors, and co-sibling analyses assessed the potential influence of unmeasured shared familial (genetic and/or environmental) factors. A total of 25,050 (1.1%) persons were identified with lipid disorders in 30.3 million person-years of follow-up. Each additional 5 weeks of gestation were associated with a 14% reduction in risk of lipid disorders (adjusted hazard ratio [HR], 0.86; 95% CI, 0.83–0.89; P < 0.001). Relative to full-term birth (gestational age 39–41 weeks), the adjusted HR associated with preterm birth (<37 weeks) was 1.23 (95% CI, 1.16–1.29; P < 0.001), and further stratified was 2.00 (1.41–2.85; P < 0.001) for extremely preterm (22–27 weeks), 1.33 (1.19–1.49; P < 0.001) for very preterm (28–33 weeks), and 1.19 (1.12–1.26; P < 0.001) for late preterm (34–36 weeks). These findings were similar in men and women (e.g., preterm versus full-term, men: HR, 1.22; 95% CI, 1.14–1.31; P < 0.001; women: HR, 1.23; 1.12–1.32; P < 0.001). Co-sibling analyses suggested that they were substantially though not completely explained by shared genetic or environmental factors in families. The main study limitation was the unavailability of laboratory data to assess specific types or severity of lipid disorders. Conclusions In this large national cohort, preterm birth was associated with an increased risk of lipid disorders in early- to midadulthood. Persons born prematurely may need early preventive evaluation and long-term monitoring for lipid disorders to reduce their future cardiovascular risks.
Prognostic Significance of ABCB1 (MDR1) Gene Polymorphisms in De Novo Acute Myeloid Leukemia with t(8;21) or inv(16).
Authors: Yeo-Kyeoung Kim, Hee-Nam Kim, Il-Kwon Lee, Soo-Mee Bang, Deog-Yeon Jo, Jong-Ho Won, Jae-Yong Kwak, Chang-Yeol Yim, Deok-Hwan Yang, Je-Jung Lee, Hyeoung-Joon Kim
Journal: Blood (2007)
Abstract 809: Chronic Testosterone Deficiency Increases Late Inward Sodium Current in Ventricular Myocytes from Aging Male C57BL/6 Mice
Authors: Stefan Heinze-milne, Shubham Banga, Omar Ayaz, Susan Howlett
Journal: Circulation Research (2019)

Clinical studies suggest that testosterone modulates the electrical activity of the heart and that low testosterone promotes cardiac arrhythmias. Here we investigated cellular mechanisms involved in the electrophysiological effects of chronic testosterone deficiency on the heart in aging male mice. Male C57BL/6 mice were subjected to either a gonadectomy (GDX) or a sham surgery at 1 month of age and then aged to 16-18 months. Ventricular myocytes were isolated and transmembrane voltage plus ionic currents were recorded with microelectrodes (20-25 MΩ; current clamp &amp; discontinuous single electrode voltage clamp; 37 o C). Cells were paced at 2 and 4 Hz. Action potential duration at 90% repolarization (APD 90 ) was prolonged by GDX (57.9 ± 1.7 vs 108.2 ± 14.1 msec; p&lt;0.05), while APD 50 and resting membrane potential were unchanged. We next determined whether an increase in late inward sodium current (I Na-L ) contributed to the increase in APD 90 in GDX cells. Voltage clamp studies showed that I Na-L was significantly larger in GDX cells compared to sham cells (-0.70 ± 0.16 vs -1.53 ± 0.27 pA/pF; p&lt;0.05). When myocytes were superfused with the I Na-L antagonist ranolazine (10 μM), the increase in APD 90 was blocked in cells from GDX mice, so that APD 90 no longer differed between the two groups. By contrast, ranolazine had no effect on either APD 50 or resting membrane potential. Ranolazine also blocked the increase in I Na-L in cells from GDX mice. Prolongation of the action potential in GDX myocytes was associated with a significant increase in the incidence of early afterdepolarizations (EADs) when compared to sham controls. EADs were also inhibited by ranolazine. These data demonstrate that long-term GDX prolongs APD 90 at least in part by increasing the magnitude of I Na-L . These findings also suggest that an increase in I Na-L may promote arrhythmias in older men with low circulating testosterone levels.
Laminin 332 in cancer: When the extracellular matrix turns signals from cell anchorage to cell movement
Authors: Patricia Rousselle, Jean Yves Scoazec
Journal: Seminars in Cancer Biology (2019)

Laminin 332 is crucial in the biology of epithelia. This large extracellular matrix protein consists of the heterotrimeric assembly of three subunits - α3, β3, and γ2 - and its multifunctionality relies on a number of extracellular proteolytic processing events. Laminin 332 is central to normal epithelium homeostasis by sustaining cell adhesion, polarity, proliferation, and differentiation. It also supports a major function in epithelial tissue formation, repair, and regeneration by buttressing cell migration and survival and basement membrane assembly. Interest in this protein increased after the discovery that its expression is perturbed in tumor cells, cancer-associated fibroblasts, and the tumor microenvironment. This review summarizes current knowledge regarding the established involvement of the laminin 332 γ2 chain in tumor invasiveness and discusses the role of its α3 and β3 subunits.