tbuckley/cabot-search huggingface dataset:
RBIO-04. LACTATE DEHYDROGENASE A (LDHA) MEDIATES NOVEL CROSSTALK BETWEEN METABOLIC GLYCOLYSIS AND CHROMATIN REMODELING
Authors: Jie Li, Jianfang Ning, Tomoyuki Koga, Ming Li, Shan Zhu, Andrew Venteicher, Birra Taha, Johnny Akers, Clark Chen
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Lactate dehydrogenase A (LDHA) encodes an enzyme that catalyzes the inter-conversion between pyruvate and lactate in glycolysis. Here, we demonstrate that LDHA mediates a novel role in DNA repair independent of this metabolic function. METHODS siRNA screen, The Cancer Genome Atlas (TCGA) survival analysis, ionizing radiation (IR), g-H2AX, and chromatin assays, site-directed mutagenesis. RESULTS In an orthogonal siRNA-informatic screen to identify genes 1) when silenced caused IR sensitivity in patient-derived glioblastoma lines and 2) lowered expression is associated with improved survival in TCGA, LDHA surfaced as the top candidate. The survival association was validated by LDHA immunohistochemical staining in an independent collection of glioblastoma samples. In vitro and in vivo, silencing of LDHA sensitized glioblastoma lines to IR and enhanced radiation-induced g-H2AX accumulation. Such sensitization was not observed after treatment with an LDHA inhibitor, suggesting the metabolic function of LDHA is distinct from its role in DNA repair. Supporting this hypothesis, truncation mutations that suppressed the LDHA glycolysis function minimally affected its role in DNA repair. Mechanistically, cytoplasmic LDHA translocates into the nucleus in response to IR. This translocation was associated with subsequent chromatin transition into an open conformation and enhanced homologous recombination. CONCLUSION The novel LDHA function in DNA repair suggests intricate crosstalks between glycolytic metabolism and DNA repair, offering a new platform for glioblastoma therapeutic development.
Magnetism-Induced Cell-Targeting Transplantation Improves Early Hematopoietic Reconstitution in a Murine Bone Marrow Transplantation Model
Authors: Qiusui Mai, Yongjun Zhou, Zhangyuan Wang, Quanfeng Chen, Yufang Lv, Qiaolan Wu, Hao Huang, Qiuxia Zhang, Linlin Zhang, Chengyao Li, Qifa Liu, Qianli Jiang
Journal: Blood (2021)
Abstract 12929: Heterogeneity in Primary and Secondary Prevention Studies of Statins and PCSK9 Inhibitors: Does One Size Fit All?
Authors: Saheli Nandi, Simarjeet Brar, Natalie Dal'Bo, Sardar Ijaz, Sarju Ganatra, Sourbha Dani
Journal: Circulation (2021)

Background: We aim to assess the heterogeneity of demographics, gender variability and outcomes reporting for subjects enrolled in RCTs studying the role of statins and PCSK9 inhibitors in primary and secondary prevention of CAD. Methods: RCTs and metanalyses were searched for the use of statins and PCSK9 inhibitors published in journals with impact factor &gt; 4 between 1995 and 2020. RCT data was analyzed for gender, race and geographic location. Metanalyses were searched for the outcomes-level heterogeneity. Results: A total 31 statin-based RCTs for primary and secondary prevention of CAD were found, of which 29 were included with a total 172,871 patients (71.4% males vs. 28.6% females). In WOSCOPS trial, all 6595 subjects were males. Though most of these trials included global patient populations, 10% of the trials included exclusively North Americans. Fifteen of the RCTs (52%) did not have race data. Of the 14 RCTs which reported race: 67% White, 4% Black. The mean number of White and non-White patients were 3950 and 1768 respectively. For PCSK9 inhibitors with a total of 13 RCTs included in our study there were cumulative 85,806 patients with globally enrolled patient population and predominantly male 71% vs 29% females. Ten RCTs (77%) reported race: 82% White, 0.3% Black. The mean number of White and non-White patients were 4671 and 1058 respectively. The eleven statin metanalyses included 823,936 patients. Ten of the eleven metanalyses reported statistical heterogeneity via I 2 % (mean 53%) for different outcomes. Five of the eleven metanalyses included primary outcomes of all-cause mortality, and the rest included onset/progression of different types of cardiovascular disease. The seven PCSK9 inhibitor metanalyses pooled 376,885 patients. All 7 metanalyses reported heterogeneity via I 2 % (mean 48%) for different outcomes, of which 2 included primary outcomes of all-cause mortality. Conclusions: Significant gender and racial disparities exist in RCTs for primary and secondary prevention lipid lowering therapies. Enrollment in PCSK9 inhibitor trials was global and significant treatment effect heterogeneity existed in metanalyses. Inequalities in female and non-White participation may hamper generalizability of these crucial medications.
Abstract 9725: Autonomic Modulation Mitigates Perivascular and Perirenal Adipose Inflammation and Consequent Cardiorenal Involvement in Prediabetes
Authors: Safaa Hammoud, Ibrahim AlZaim, Amira Bekdash, Nahed Mougharbil, Hana A Itani, Ahmed F El-Yazbi
Journal: Circulation (2021)

Background: Early metabolic impairment is associated with significant cardiorenal risk. Specifically, subtle serum insulin and lipids changes in prediabetes trigger cardioautonomic and renovascular deterioration. Interestingly, data from our laboratory suggest that these insidious alterations are triggered by perirenal and perivascular adipose inflammation in response to hypoxia evoked by a localized increase in uncoupling protein1 (UCP1) expression and activity. This affects the adjacent organs in a paracrine manner. Hypothesis: Increased UCP1 expression is triggered by sympathetic stimulation. The sympathovagal imbalance in early metabolic dysfunction underlies the observed localized adipose pool involvement. Pharmacological interventions to offset the sympathetic predominance should prevent increased UCP1 expression and inflammation, and reverse cardiorenal manifestations. Methods: A non-obese prediabetic rat model was induced by twelve weeks of hypercaloric feeding. Moxonidine and galantamine were administered orally at daily doses of 2.4 mg/Kg and 4 mg/Kg for the last two weeks of feeding to reduce and facilitate sympathetic and parasympathetic discharge, respectively. Baroreflex sensitivity and renovascular reactivity were assessed by invasive hemodynamics and in isolated perfused kidneys, respectively. Adipose tissue T Cell distribution and macrophage polarization were examined by flow cytometry. Results: Correcting the autonomic imbalance in prediabetic rats with either moxonidine or galantamine restored cardioautonomic and renovascular activity to those observed in control rats. Although prediabetic rats showed an increased oxidative stress and proinflammatory cytokine production in both adipose pools, no change in T Cell population distribution was observed. However, the increased M 1 /M 2 macrophage polarization profile observed in prediabetic rats was reversed by either drug treatment. This was associated with a normalization of UCP1 expression and hypoxic status. Conclusions: Pharmacological interventions to reverse sympathetic predominance could be of therapeutic value treating perivascular and perirenal adipose inflammation that cause early cardiorenal manifestations of prediabetes.
Abstract 12603: Impaired Coronary Flow Reserve in Athletes With Long-Term Cardiovascular Symptoms After COVID-19
Authors: Daniel E Clark, Sean G Hughes, Jeffrey M M Dendy, Kimberly Crum, Debra Dixon, Kristen George-Durrett, Justin M Gregory, Neil J Phillips, Elliot J Stein, Lena E Tran, Jean W Wassenaar, Eric D Austin, Jonathan Soslow
Journal: Circulation (2021)

Introduction: Cardiovascular symptoms post-acute sequelae of SARS-CoV-2 infection (CV-PASC) have been increasingly recognized, but the underlying pathobiology is unclear. Endothelial and cardiac pericyte ACE2 receptors are important targets of SARS-CoV-2, resulting in virally-induced endothelial activation, which may adversely affect the coronary microvasculature and impair myocardial performance. We hypothesized that athletes with CV-PASC have microvascular and subclinical myocardial dysfunction. Methods: We compared 15 athletes with CV-PASC with 7 control athletes without prior COVID-19 using regadenoson stress cardiac magnetic resonance (CMR). All athletes participated in &gt;6 hours of endurance activities per week. We analyzed CMR volumes, function, global circumferential strain (GCS), late gadolinium enhancement (LGE), and coronary flow reserve (CFR) by coronary sinus method. Values presented as median [IQR]. Results: CMR in CV-PASC athletes occurred 102 [66,123] days post-SARS-CoV-2 infection. There were no differences in chamber volumes, function, or LGE between groups. One CV-PASC athlete had acute myocarditis (7%). CV-PASC athletes had decreased CFR compared with control athletes ( Figure 1 ). Multiple CV-PASC participants had CFR below the 95% CI of the controls and reported normal values from the literature (2.9 and 2.5, respectively). GCS was worse in CV-PASC athletes at the base (-23.7% [-21.6,-26.4] vs -31.1% [-27.3,-33.0], p=0.01), mid-LV (-21.5% [-18.5,-22.8] vs -28.5 [-25.4,-29.9], p=0.008), and apex (-27.1% [-24.1,-29.9] vs -30.6% [-27.8,-38], p=0.07), though the apex did not reach statistical significance. Conclusions: This pilot case-control study found CV-PASC athletes had reduced CFR and associated subclinical myocardial dysfunction as assessed by GCS compared to control athletes. These findings suggest coronary microvascular dysfunction related to endothelial injury may mediate CV-PASC symptoms.
Código de deontología médica
Journal: JAMA (1934)

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Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps
Authors: Adebowale Adeyemo, Mary K. Balaconis, Deanna R. Darnes, Segun Fatumo, Palmira Granados Moreno, Chani J. Hodonsky, Michael Inouye, Masahiro Kanai, Kazuto Kato, Bartha M. Knoppers, Anna C. F. Lewis, Alicia R. Martin, Mark I. McCarthy, Michelle N. Meyer, Yukinori Okada, J. Brent Richards, Lucas Richter, Samuli Ripatti, Charles N. Rotimi, Saskia C. Sanderson, Amy C. Sturm, Ricardo A. Verdugo, Elisabeth Widen, Cristen J. Willer, Genevieve L. Wojcik, Alicia Zhou
Journal: Nature Medicine (2021)
TAMI-71. EFFECTS OF THE TREATED MICROENVIRONMENT ON GLIOMA CELL PROPERTIES IN AN ORGANOTYPIC BRAIN SLICE MODEL
Authors: Vasiliki Pantazopoulou, Tracy Berg, Alexander Pietras
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is the most aggressive primary brain tumor. Despite treatment all patients invariably recur. Treatment resistance is attributed to the presence of glioma stem-like cells. Initially thought to be a distinct and static cell population, it is becoming increasingly clear that the glioma stem-like cell phenotype represents one of many cellular states and that glioma cells show plasticity between stem-like and non-stem like states. These plastic cell states are affected by the tumor microenvironment. In our lab we have shown that irradiated and hypoxic astrocytes increase the stem-like cell properties of glioma cells. In this study, we aim to evaluate how the treated microenvironment alters glioma cell properties and use ex vivo organotypic brain slices generated from tumor bearing and tumor naïve mice to assess all aspects of the microenvironment. We first characterized organotypic brain slices cultured in different oxygen tensions. We saw that tumor-bearing slices survive for at least 14 days in culture at 21%, 5% or 1% oxygen tension (O2). Tumor cells were more viable in all culture conditions and timepoints compared to non-tumor cells. Moreover, we found that astrocytes seem to be attracted to tumor areas in both 5% and 1% O2 cultures. We then used the organotypic glioma slice culture system to address how preconditioning the microenvironment using radiation or temozolomide affects the properties of glioma cells that are seeded in these pretreated, tumor naïve slices. We saw that fluorescently labelled glioma cells seeded in treated slices can be isolated after two days of culture in the slices and can be used for downstream analyses, such as temozolomide or radiation treatment and colony formation. This study will elucidate the effect of the treated microenvironment on glioma cell properties by using the medium throughput method of organotypic slice cultures.
Broadly Applicable Hydrogel Fabrication Procedures Guided by YAP/TAZ‐Activity Reveal Stiffness, Adhesiveness, and Nuclear Projected Area as Checkpoints for Mechanosensing
Authors: Alessandro Gandin, Veronica Torresan, Lorenzo Ulliana, Tito Panciera, Paolo Contessotto, Anna Citron, Francesca Zanconato, Michelangelo Cordenonsi, Stefano Piccolo, Giovanna Brusatin
Journal: Advanced Healthcare Materials (2021)

Mechanical signals are pivotal ingredients in how cells perceive and respond to their microenvironments, and to synthetic biomaterials that mimic them. In spite of increasing interest in mechanobiology, probing the effects of physical cues on cell behavior remains challenging for a cell biology laboratory without experience in fabrication of biocompatible materials. Hydrogels are ideal biomaterials recapitulating the physical cues that natural extracellular matrices (ECM) deliver to cells. Here, protocols are streamlined for the synthesis and functionalization of cell adhesive polyacrylamide-based (PAA-OH) and fully-defined polyethyleneglycol-based (PEG-RGD) hydrogels tuned at various rigidities for mechanobiology experiments, from 0.3 to >10 kPa. The mechanosignaling properties of these hydrogels are investigated in distinct cell types by monitoring the activation state of YAP/TAZ. By independently modulating substrate stiffness and adhesiveness, it is found that although ECM stiffness represents an overarching mechanical signal, the density of adhesive sites does impact on cellular mechanosignaling at least at intermediate rigidity values, corresponding to normal and pathological states of living tissues. Using these tools, it is found that YAP/TAZ nuclear accumulation occurs when the projected area of the nucleus surpasses a critical threshold of approximatively 150 µm2 . This work suggests the existence of distinct checkpoints for cellular mechanosensing.
Abstract 13008: Patients Are Often Unaware Of Their Heart Failure Diagnosis, Even After A Heart Failure Hospitalization
Authors: Aowen Zhu, Emily B Levitan, Stephen Clarkson, Todd Brown, Raegan W Durant, Justin Kingery, Megan J Shen, Yulia Khodneva, Elizabeth A Jackson, Monika M Safford, Parag Goyal
Journal: Circulation (2021)

Introduction: Self-reported heart failure (HF) is an important data source for epidemiologic studies of HF for clinicians caring for HF patients. We sought to understand the prevalence, predictors, and outcomes of patients who did not self-report a diagnosis of HF despite a history of a HF-hospitalization. Methods: We studied participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, who experienced an adjudicated hospitalization for HF and completed a computer-assisted telephone interview approximately 10 years following initial recruitment. We compared characteristics and mortality for participants who self-reported a HF history (aware) to those who did not self-report a HF history (unaware). To understand correlates of being aware vs. unaware of a HF diagnosis, we constructed a logistic regression model including demographics, social determinants of health, HF characteristics, comorbid conditions, cognitive status, and health literacy. Results: Among 15,560 eligible participants, 362 participants experienced an adjudicated HF-hospitalization over the 10-year study period, of which 114 (31%) did not self-report a HF diagnosis (unaware). Mortality after the 10-year follow-up was higher among participants who were unaware of their HF diagnosis (Figure). Participants with HFrEF trended toward higher odds of being aware of their HF diagnosis (OR 1.20 95%CI[0.73-1.98]) while less than high school education (OR 0.79 95%CI[0.39-1.61]) and living in a high poverty zip code (OR 0.57 95%CI[0.31-1.04]) were associated with a trend toward lower odds of being aware of a HF diagnosis, though these associations did not reach statistical significance. Conclusions: Nearly one-third of participants with an adjudicated HF-hospitalization may not be aware of their diagnosis of HF. This may result in inaccurate estimates of HF prevalence and may contribute to worse outcomes such as mortality.
Abstract 10205: Usefulness of a Systemic Inflammation-Nutrition Index for the Prediction of Post Discharge Prognosis in Patients with Heart Failure with Preserved Ejection Fraction: Insights from Pursuit-hfpef Registry
Authors: Daisuke Sakamoto, Masahiro Seo, Takahisa Yamada, Shunsuke Tamaki, Masamichi Yano, Takaharu Hayashi, Akito Nakagawa, Yusuke Nakagawa, YOSHIO YASUMURA, Shungo Hikoso, Yohei Sotomi, Yasushi Sakata
Journal: Circulation (2021)

Background: Malnutrition and inflammation are associated with poor outcomes with heart failure (HF). It has been reported that Advanced Lung cancer Inflammation index (ALI), calculated by body mass index х serum albumin level / neutrophil to lymphocyte ratio (NLR) can be used for the prognosis assessment of various malignancies. In addition, it has been reported to be useful as a prognostic factor in HF patients. Then, we sought to clarify the prognostic value of ALI in patients with HF with preserved ejection fraction (HFpEF). Methods and Results: Patients’ data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study, which is a prospective multicenter observational registry for ADHF-HFpEF in Osaka. Laboratory data and body weight measurements were performed just before discharge. We analyzed 821 patients (mean age: 81 years old, male: 45%) after exclusion of patients on dialysis, in-hospital death, missing follow-up data, or missing data to calculate ALI. The primary endpoint of the present study was all-cause death (ACD). During a mean follow-up period of 1.8±1.0 years, 169 patients died. In multivariate Cox analysis, ALI was significantly associated with ACD independently of age, serum sodium level, hemoglobin level, and serum NT-proBNP level after adjustment for sex, NYHA functional class, systolic blood pressure, serum creatinine level, serum CRP level, past medical history of AF and LVEF. By ROC curve analysis, AUC of ALI was significantly greater than that of NLR. Kaplan-Meier curve analysis revealed that patients with lowest ALI (24.16 ≥ ALI categorized by tertile) had higher risk of ACD than those with highest ALI (ALI &gt; 40.10) (32% vs 13%, adjusted HR 2.93. 95%CI [2.01-4.38], p&lt;0.0001). Conclusion: ALI, a systemic inflammation-nutrition index, might be useful for stratifying ADHF patients with HFpEF at risk for the total mortality.
CDK4/6 inhibitors: A potential therapeutic approach for triple negative breast cancer
Authors: Lubaid Saleh, Caroline Wilson, Ingunn Holen
Journal: MedComm (2021)

Abstract Triple negative breast cancer (TNBC) cells lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor‐2 (HER‐2). Thus, TNBC does not respond to hormone‐based therapy. TNBC is also an aggressive subtype associated with poorer prognoses compared to other breast cancers. Conventional chemotherapeutics are used to manage TNBC although systemic relapse is common with limited benefits being reported as well as adverse events being documented. Here, we discuss current therapies for TNBC in the neo‐ and adjuvant settings, as well as recent advancements in the targeting of PD‐L1‐positive tumors and inclusion of PARP inhibitors for TNBC patients with BRCA mutations. The recent development of cyclin‐dependent kinase (CDK) 4/6 inhibitors in ER‐positive breast cancers has demonstrated significant improvements in progression free survival in patients. Here, we review preclinical data of CDK 4/6 inhibitors and describe current clinical trials assessing these in TNBC disease.
EPID-13. PREDICTIVE VALUE OF SERUM PROLACTIN LEVEL TO THE TUMOR SIZE RATIO FOR PREOPERATIVE DIAGNOSIS OF PROLACTIN-PRODUCING PITUITARY ADENOMA
Authors: Jeong-Hwa Kim, Jung-Won Choi, Ho-Jun Seol, Do-Hyun Nam, Jung-Il Lee, Chang-Ki Hong, Doo-Sik Kong
Journal: Neuro-Oncology (2021)

Abstract PURPOSE Preoperative diagnosis of prolactinomas is critical because medication of dopamine agonists instead of surgical resection has been regarded as a primary treatment. However, serum prolactin level alone is suboptimal for differentiating the prolactin producing adenoma or hyperprolactinemia-causing NFPAs. The author investigated the use of ratio of PRL levels to the tumor size as the optimal cutoff value for prolactin-producing tumor, comparing with the NFPA. METHOD We performed a retrospective review of patients who underwent the transsphenoidal surgery (TSS) for pituitary lesions in the single institute between January 2015 to May 2020. A total of 223 patients with hyperprolactinemia at the initial diagnosis were analyzed in the study, including NFPA patients (n=175) and prolactinoma patients (n=48). Receiver operating curve (ROC) analyses were performed for serum prolactin levels (PRL) and serum prolactin levels/tumor maximal diameter (PRL/MD). RESULT Prolactinoma group showed higher median values in serum PRL (258.6 μg/L) and smaller maximal tumor diameter (16.6 mm), compared to those of NFPA group (serum PRL 44.4 μg/L, p-value = 0.002 and MD 23.9 mm, p-value &amp;lt; 0.001). A moderate correlation was found between serum prolactin level and maximal diameters in prolactinomas (r=0.43, p=0.002), whereas a weak relationship was confirmed in NFPAs (r=0.17, p=0.028). The cutoff was 8.93 μg/L*mm (area under the curve [AUC] = 0.94) for PRL/MD and 99.43 μg/L for PRL (AUC = 0.91). In prolactinomas, there was no statistical difference between the PRL/MD of macroadenomas (n=36, 21.7μg/L*mm) and microadenoma (n=12, 16.8μg/L*mm) (p=0.109). CONCLUSION The serum PRL levels and tumor size exhibited stronger linear correlation in prolactinomas than in NFPAs. The PRL/MD ratio showed better diagnostic value for differentiating two pathologies than the serum PRL levels alone. These findings suggest PRL/MD ratio may be an alternative method to preoperative diagnosis of prolactinomas differentiating from hyperprolactinemia-causing NFPAs.