tbuckley/cabot-search huggingface dataset:
Abstract 10514: Inguinal Fat Tissue Biopsy to Identify Transthyretin Amyloidosis in Patients Undergoing Transcatheter Aortic Valve Implantation
Authors: Yuki Muto, Akiomi Yoshihisa, Yukiko Sugawara, Satoshi Abe, Masayoshi Oikawa, ATSUSHI KOBAYASHI, Hiroyuki Kunii, Kazuhiko Nakazato, Tsuyoshi Fujimiya, Shinya Takase, Yasuchika Takeishi
Journal: Circulation (2021)

Background: Several studies have recently reported that transthyretin (ATTR) amyloidosis is present in patients with aortic stenosis (AS). This study aimed to 1) examine the utility of inguinal fat tissue biopsy in AS patients who underwent transcatheter aortic valve implantation (TAVI) to detect ATTR amyloidosis, 2) compare clinical characteristics between AS patients with ATTR (ATTR group) and those without ATTR (non-ATTR group). Methods and Results: We prospectively analyzed consecutive 56 patients who underwent transfemoral TAVI from December 2018 to December 2020 in our hospital. To screen ATTR in these patients, we performed inguinal fat tissue biopsy from cut down or puncture site during TAVI. Of 56 AS patients, 5 (8.9%) patients were diagnosed as ATTR by inguinal fat biopsy. Compared with non-ATTR group, ATTR group presented higher levels of B-type natriuretic peptide (BNP, 566.4 vs. 242.5 ng/ml, P=0.0045), higher levels of troponin I (0.053 vs. 0.024 ng/ml, P=0.003), lower left ventricular ejection fraction (LVEF, 49.3 vs. 60.3%, P=0.0035), larger left ventricular mass index (150.2 vs. 115.5 g/m 2 , P=0.019), larger aortic valve area (0.84 vs. 0.63 cm 2 , P=0.029) and lower peak velocity of aortic valve (3.8 vs. 4.4 m/s, P=0.041). In contrast, age, sex, STS score, clinical frailty scale, prevalence of diabetes, chronic kidney disease and AF, levels of albumin, and eGFR were comparable between the two groups. Electrocardiogram and other echocardiographic parameters including interventricular septal wall thickness, posterior wall thickness, stroke volume index and E/A ratio did not differ between the two groups. Although TAVI was successfully completed in all patients, the incidence of life-threatening bleeding and 30-day readmission was higher in ATTR group than in non-ATTR group (40.0 vs. 5.9%, P=0.011 and 20.0 vs. 0.0%, P=0.001). There was no difference in occurrence of myocardial infarction, stroke, acute kidney injury, major vascular complication, pacemaker implantation and 30-day mortality. Conclusions: In AS patients, especially in those with increased BNP and troponin I levels and low-flow low-gradient pattern, ATTR should be considered. In this population, inguinal fat tissue biopsy is a novel and safe approach to identify ATTR.
Outcomes in Adult Philadelphia-Positive Acute Lymphoblastic Leukemia Patients Using Tyrosine Kinase Inhibitors Combined with the Modified University of Southern California (USC ALL) Regimen without Pegaspargase in the Era of Novel Agents; A Retrospective Study
Authors: Vincent Louie Ramos Mendiola, Catherine Ly, Thuy Bui, Jennifer Wang, Jack Rodman, Karrune Woan, Eric Tam, Maria E. Vergara-Lluri, Preet M. Chaudhary, Dan Douer, Abdullah Ladha, George Yaghmour
Journal: Blood (2021)
RESHAPE AND SECURE HCC MANAGING DURING COVID-19 PANDEMIC: A SINGLE CENTER ANALYSIS OF FOUR PERIODS IN 2020 VERSUS 2019
Authors: M. Iavarone, B. Antonelli, A. M. Ierardi, M. Bruccoleri, M. Topa, A. Sangiovanni, A. Gori, F. Ceriotti, C. Oggioni, D. Consonni, G. Rossi, G. Carrafiello, L. Chiappa, P. Lampertico
Journal: Hepatology (2021)
Abstract 12403: Type 1 Diabetes Alters Estrogen-Stimulated microRNA Expression and Impairs Nitric Oxide Production in Human Coronary Artery Endothelial Cells
Authors: Jingli Wang, Benjamin Hofeld, Venkata K Puppala, Rong Ying, Ryan A Harris, Michael E Widlansky
Journal: Circulation (2021)

Introduction: Women developed CAD about 1 decade after men. This advantage is erased in T1DM women, and the mechanisms remain unclear. Estrogen (E2) stimulates endothelial NO production via estrogen receptors, and microRNA (miR) have emerged as critical regulators of endothelial function. Whether E2 stimulation of NO production is impaired in T1DM and whether E2 stimulates different miR expression patterns are unknown. Hypothesis: E2-stimulated NO production will be impaired in T1DM endothelial cells which will also express differences in miR expression with E2 exposure. Methods: All experiments were done with and without incubation with 1 nM 17β-estradiol for 24 hours. MicroRNA was isolated from culture human coronary artery endothelial cells (HCAECs) from a woman with and a woman without T1DM. MicroRNA was isolated from HCAECs with four different exposure conditions (T1DM ± 1 nM 17β-estradiol for 24 hr and non-T1DM± 1 nM 17β-estradiol for 24 hr, N=4 biological replicates for all exposures). Fold changes in expression comparing T1DM and non-T1DM cells with and without estradiol stimulation were generated at significance testing performed using DESeq2 with FDR set at 5%. NO production was measured in HCAECs under the same 4 conditions using DAF2-DA and HPLC. Results: 249 miRs were differentially expressed inT1DM HCAECs compared to non-T1DM HCAECs in non-E2 stimulated samples. In E2-stimulated samples, 201 miRs were differentially expressed. Cross-referencing these comparisons showed 16 miRs differentially expressed in T1DM HCAECs relative to non-T1DM HCAECs both with and without E2 stimulation. 4 of these (miRs 548-ar-3p, 625-3p, 369-3p, and 376a-5p) were significantly changed in the opposite direction with estrogen stimulation compared to unstimulated HCAECs, suggesting changes in the expression were due to changes in E2 signaling in T1DM HCAECs. Further, estradiol stimulation of T1DM HCAECS demonstrates a significantly blunted NO production compared to non-T1DM HCAECs (N=6, P&lt;0.05). Conclusions: E2-stimulated NO production is impaired and E2-stimulated changes in miR expression differ in the T1DM endothelium. Further work is necessary to determine whether these differences in miR expression impact E2-stimulated NO production in T1DM.
Abstract 11412: Methyltransferase Smyd2 Mediate Atherosclerotic Plaque Calcification
Authors: Shaligram Sharma, Xiaoqing Guan, Yuning Hou, Bethany Goodlett
Journal: Circulation (2021)

Introduction: Clinical manifestation of atherosclerosis is marked by calcification of vasculature, including the expression of mineralization regulating proteins (Sox9, Msx2, and Runx2) by vascular smooth muscle cells (VSMCs). This pathogenic remodeling of VSMCs into osteochondrogenic cell types is accompanied by increased proliferation, migration, and secretion of extracellular matrix proteins. This study aimed to determine the spatiotemporal role of SMYD2 in atherosclerotic plaque progression and calcification. Methods: SMC-specific SMYD2 knockout was generated in ApoE -/- mice (SMYD2 ΔSMC ApoE -/- ). Age and body weight-matched mice were fed with Western diet (WD) for 18 or 26 weeks. The distribution of atherosclerotic plaque was examined by En-face Oil-Red-O staining (ORO) of freshly collected aorta. Atherosclerotic plaque burden was determined by Hematoxylin &amp; Eosin (H&amp;E) staining. Collagen content and calcification of atherosclerotic plaque were determined by Masson's trichrome staining and von Kossa staining, respectively. The calcification-regulatory genes (MGP1, AGG and transcription factors SOX9, MSX2, BMP2, and RUNX2) in the aorta were analyzed by RT-qPCR. Results: SMC-specific deletion of SMYD2 protected mice from atherosclerotic plaque calcification. En-face ORO and H&amp;E analysis of Brachiocephalic artery demonstrated a significant decrease in ORO positive area, total plaque size, and necrotic core area in SMYD2 ΔSMC ApoE -/- mice as compared to ApoE-/- mice, with no change in the distribution of collagen fibers. Von Kossa staining showed hydroxyapatite depots at the medial lining of the vasculature (microcalcification) in ApoE -/- mice fed with 18-week Western diet, while a smaller depot of macrocalcification was observed in SMYD2 ΔSMC ApoE -/- mice compared with ApoE -/- mice when fed with 26-week WD. mRNA analysis of key calcification transcription factors showed significant suppression of SOX9 and MSX2 genes in aortas of SMYD2 ΔSMC ApoE -/- mice compared with ApoE -/- mice, with downward trends of BMP2 and RUNX2 in both 18- or 26-week WD. Conclusion: SMYD2 ablation attenuates atherosclerotic plaque formation and calcification, suggests targeting SMYD2 can be a potential therapeutic strategy for atherosclerosis.
Abstract P467: Cardiac-specific Deletion Of Voltage Dependent Anion Channel 2 Leads To Dilated Cardiomyopathy By Altering Calcium Homeostasis
Authors: Thirupura S Shankar, Dinesh Kumar Anandamurugan Ramadurai, Kira Steinhorst, Salah Sommakia, Rachit Badolia, ASPASIA SPYRIDOULA THODOU KROKIDI, Dallen Calder, Sutip Navankasattusas, Jing Ling, Ohyun Kwon, Emily Cheng, Russel Richardson, Frank B Sachse, Johann Schredelseker, Kenneth Spitzer, Dipayan Chaudhuri, Stavros G Drakos
Journal: Circulation Research (2021)

Voltage dependent anion channel 2 (VDAC2) is a mitochondrial outer membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in cellular calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. Previous literature suggests that improving mitochondrial calcium uptake via VDAC2 rescues arrhythmia phenotypes in genetic models of impaired cellular calcium signaling. However, the direct role of VDAC2 in intracellular calcium signaling and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac-specific deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium during development causes severe impairment in excitation-contraction coupling by reducing mitochondrial calcium uptake (n=3, p&lt;0.05) and thereby impairing intracellular calcium signaling. VDAC2 knock-out mice showed a significant reduction in RYR-mediated calcium release (F/F 0 ) and rate of calcium uptake by SERCA2a [tau(msec)] compared to control mice (N=3, WT=54, KO=38, p&lt;0.0001 (F/F 0 ) and p&lt;0.05 (tau)). We also observed adverse cardiac remodeling which progressed to severe dilated cardiomyopathy and death (N=6, p&lt;0.0001). Reintroducing VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype evident from improvement in ejection fraction and fractional shortening (n=3, p&lt;0.05). Improving mitochondrial calcium uptake via VDAC2 using a VDAC2 agonist efsevin, increased cardiac contractile force in a mouse model of pressure-overload induced heart failure (N=8, n=22, p&lt;0.05). In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing mitochondrial and cellular calcium signaling. Through this role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.
COVID-19 in Africa: Catalyzing change for sustainable development
Authors: Salim S. Abdool Karim, Segenet Kelemu, Cheryl Baxter
Journal: PLoS Medicine (2021)

The Coronavirus Disease 2019 (COVIDAU : PleasenotethatCOVID À 19hasbeendefinedasCoronavirus -19) pandemic has dramatically changed everyone's lives, highlighting the fragility of systems providing public services, especially healthcare and food supply chains, and the need to build resilience, even in countries that are technologically and economically advanced.It is noteworthy how well most African countries have fared against all odds and defying doomsday predictions [1].The first African case of COVID-19 was reported in Egypt on 14 February 2020.By October 2021, there were about 8.4 million cases and 216,000 deaths reported from Africa, accounting for about 3.5% and 4.4% of the world's COVID-19 cases and deaths, respectively [2,3], despite comprising 15.4% of the world's population.Notwithstanding the less resourced healthcare systems, the reported case fatality rate in Africa has been low at 2.6% [4].Thus far, South Africa has been the most severely affected country in Africa, accounting for about a third of all cases on the continent.There are several hypotheses for why Africa has not been as severely affected by COVID-19 compared to countries in Europe, or the United States [5].While underreporting, undertesting, and suboptimal case detection may be contributing to the low rates, there is little indication that large numbers of symptomatic cases are being missed as there are few, if any, queues of patients with acute respiratory distress at hospitals in African countries.An important contributor to the lower cases in Africa is the youth bulge in its population pyramid [6].Approximately 6.1% of the population in Africa is over 60 years [7] compared to 16.2% in the US.While seroprevalence surveys are yet to clarify whether Africa has had similar viral exposure to Europe, its younger population may explain its lower rates of clinical illness and deaths.In addition to Africa's youth dividend, it is likely that there are other contributory factors that are yet to be demonstrated empirically.It has been speculated that prior infections with other coronaviruses may have created cross-reactive immunity [8,9] or that host genetics may be responsible due to unique host-pathogen coevolution in Africa [10].Africa has experienced several challenges in responding to the COVID-19 pandemic, not least because it is simultaneously battling an unprecedented desert locust invasion of eastern Africa, fall armyworm invasion, malaria, HIV, and a multitude of existing health and agricultural concerns.The needs of the pandemic response come on top of significant pressures from political instability, corruption, and large migrant populations acrossAU : Anabbreviationlisthasbeencom the continent.Africa's resource constraints place additional demands on innovation and adaptation for local circumstances.Rising to this challenge has not been easy, especially for the poorest countries, but has been accomplished in several settings across the continent.
Closed-Loop Insulin Delivery Versus Sensor-Augmented Pump Therapy in Older Adults With Type 1 Diabetes (ORACL): A Randomized, Crossover Trial
Authors: Sybil A. McAuley, Steven Trawley, Sara Vogrin, Glenn M. Ward, Spiros Fourlanos, Charlotte A. Grills, Melissa H. Lee, Andisheh Mohammad Alipoor, David N. O’Neal, Niamh A. O’Regan, Vijaya Sundararajan, Peter G. Colman, Richard J. MacIsaac
Journal: Diabetes Care (2021)

OBJECTIVE To assess the efficacy and safety of closed-loop insulin delivery compared with sensor-augmented pump therapy among older adults with type 1 diabetes. RESEARCH DESIGN AND METHODS This open-label, randomized (1:1), crossover trial compared 4 months of closed-loop versus sensor-augmented pump therapy. Eligible adults were aged ≥60 years, with type 1 diabetes (duration ≥10 years), using an insulin pump. The primary outcome was continuous glucose monitoring (CGM) time in range (TIR; 3.9–10.0 mmol/L). RESULTS There were 30 participants (mean age 67 [SD 5] years), with median type 1 diabetes duration of 38 years (interquartile range [IQR] 20–47), randomized (n = 15 to each sequence); all completed the trial. The mean TIR was 75.2% (SD 6.3) during the closed-loop stage and 69.0% (9.1) during the sensor-augmented pump stage (difference of 6.2 percentage points [95% CI 4.4 to 8.0]; P &amp;lt; 0.0001). All prespecified CGM metrics favored closed loop over the sensor-augmented pump; benefits were greatest overnight. Closed loop reduced CGM time &amp;lt;3.9 mmol/L during 24 h/day by 0.5 percentage points (95% CI 0.3 to 1.1; P = 0.0005) and overnight by 0.8 percentage points (0.4 to 1.1; P &amp;lt; 0.0001) compared with sensor-augmented pump. There was no significant difference in HbA1c between closed-loop versus sensor-augmented pump stages (7.3% [IQR, 7.1–7.5] (56 mmol/mol [54–59]) vs. 7.5% [7.1–7.9] (59 mmol/mol [54–62]), respectively; P = 0.13). Three severe hypoglycemia events occurred during the closed-loop stage and two occurred during the sensor-augmented pump stage; no hypoglycemic events required hospitalization. One episode of diabetic ketoacidosis occurred during the sensor-augmented pump stage; no serious adverse events occurred during the closed-loop stage. CONCLUSIONS Closed-loop therapy is an effective treatment option for older adults with long-duration type 1 diabetes, and no safety issues were identified. These older adults had higher TIR accompanied by less time below range during closed loop than during sensor-augmented pump therapy. Of particular clinical importance, closed loop reduced the time spent in hypoglycemic range overnight.
Hemopoiesis and Immune Cell Perturbations during Venetoclax Plus Azacytidine Treatment in Acute Myeloid Leukemia
Authors: Valentina Giudice, Idalucia Ferrara, Marisa Gorrese, Francesca D'Alto, Roberto Guariglia, Serena Luponio, Luca Pezzullo, Laura Mettivier, Angela Bertolini, Matteo D'Addona, Danilo De Novellis, Bianca Cuffa, Bianca Serio, Carmine Selleri
Journal: Blood (2021)
EXTH-14. PRECLINICAL EVALUATION OF NOVEL CDK4/6 INHIBITOR GLR2007 IN GLIOBLASTOMA MODELS
Authors: Lei Yin, Zhenglin Yao, Yue Wang, Ying-Hui Huang, Michelle Mazuranic, Ang Yin
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma multiforme (GBM) is characterized by a high frequency of cyclin-dependent kinase (CDK)4 and CDK6 pathway dysregulation. None of the approved CDK4/6 inhibitors are indicated for GBM. Poor blood–brain barrier (BBB) penetration is a potential factor limiting treatment efficacy in GBM. GLR2007 is an investigational CDK4/6 inhibitor with the potential for improved penetration across the BBB. These preclinical studies investigated the anti-tumor efficacy in GBM xenograft models and central nervous system distribution of GLR2007. In vivo evaluation of the anti-tumor efficacy of GLR2007 versus vehicle, abemaciclib, and/or palbociclib was performed in two BALB/c nude mouse GBM xenograft models. Efficacy was expressed as tumor growth inhibition (TGI, change in mean tumor volume from baseline as a percentage of change in vehicle group) or increased survival time. Following 21 days of treatment, TGI in BN2289 subcutaneous xenografts was 39.4% and 56.4% for 25 mg/kg and 50 mg/kg GLR2007 groups, respectively, 34.0% for 25 mg/kg palbociclib, and 24.9% for 25 mg/kg abemaciclib (p &amp;lt; 0.001 in all groups vs vehicle control). In U87-luc orthotopic xenografts, compared with vehicle controls, median survival time was 50.0% (p = 0.0009) longer in the 12.5 mg/kg GLR2007 group, similar to the 150 mg/kg abemaciclib group (54.4%, p = 0.0002), and was 182.6% (p &amp;lt; 0.0001) longer in mice treated with 50 mg/kg GLR2007. Quantitative whole-body autoradiography was used to determine the distribution of [14C]GLR2007 in Sprague Dawley rats following a single oral dose. Total radioactivity levels in the brain exceeded those in plasma by 2.3–4.5-fold from 2–6 h after dosing. These preclinical studies suggest the potential of GLR2007 for the treatment of GBM, supported by evidence that GLR2007 showed numerically greater anti-tumor efficacy than approved CDK4/6 inhibitors palbociclib and abemaciclib in GBM xenograft models, and evidence of substantial central nervous system distribution.
Abstract 10731: Evaluation of Patient Perspectives on the Use of Mobile Apps to Support Heart Failure Management
Authors: Bridve Sivakumar, Manon Lemonde, Matthew Stein, Susanna Mak, Abdul Al-Hesayen, Anna Farmer, JoAnne Arcand
Journal: Circulation (2021)

Background: Adherence to diet and medical therapies are key to improving heart failure (HF) outcomes; however, nonadherence is common. While mobile apps may be a promising way to support patients with adherence via education and monitoring, little is known about HF patient opinions regarding adoption of apps for HF management; which is critical to understand for these tools to be successfully developed, implemented, and adopted. Objective: To determine patients’ needs, motivations and challenges on the use of mobile apps to support HF management. Methods: A qualitative descriptive study using focus groups (n=4,60 minutes) was conducted among HF patients (aged ≥18 yrs, smartphone/tablet users, on stable medical therapy without hospital admission for ≥ 6 months) from outpatient HF clinics in Toronto, Canada. The Diffusion of Innovation theory informed a ten-question interview guide. Interview transcripts were independently coded by two researchers and analyzed using content analysis. Results: Nineteen HF patients (65 ± 10 yrs, 12 men) identified technology and app use behaviours, opportunities and challenges across six main themes: 1)‘Patient usage of technology’, many patients already used technology for daily activities and monitoring health; 2) ‘Patient views on adopting new technology’, some patients reported being early adopters of technology, while others would wait; 3) ‘Factors impacting technology use by patients’, included access to accurate information, easy and accessible user-interface; 4) ‘Providing patient support through access to information and self-monitoring’, apps could provide education on HF-related content (e.g., diet, medication, exercise, symptoms); 5) ‘Facilitating connection and communication’, apps could help information sharing with healthcare providers and connect with other patients; 6) ‘Patient preferences of app features’, app features such as reminders for medication, and visuals to show changes in HF symptoms were favoured. Conclusions: HF patients perceive several benefits to app use for HF self-management. Capitalizing on the opportunities apps offer may maximize their adoption by patients and support adherence to diet and medical therapies to improve HF outcomes.
RADT-07. DETERMINATION OF THE OPTIMAL TIME INTERVAL BETWEEN POST-OPERATIVE MRI AND CT SIMULATION FOR STEREOTACTIC RADIOSURGERY PLANNING
Authors: Drishti Panse, Aubrey Rogers, Edward Farhangi, Maria Péris-Celda, Khaled Adil
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The incidence of brain metastasis is approximately 200,000 worldwide annually. Stereotactic radiation therapy of post-operative cavity reduces local recurrence. Surgical cavity size changes significantly with 96.5% demonstrating volumetric change during post-operative period. We sought to define the optimal time interval that preserved the volumetric dimensions between the post-surgical MRI and the CT simulation used for stereotactic radiosurgery planning. METHODS Seven patients with brain metastasis that underwent surgical resection and stereotactic radiation treatment at Albany Medical Center from February 2019 to April 2020 were included in the study. A total of 8 target lesions were included. Brain lab planning system was used for contouring the target volume. A postoperative MRI within 24-48 hours after surgery was obtained. 3 patients required an additional interim MRI 16-50 days after surgery. The planning CT simulation was performed 2 days prior and up to 15 days after the post-operative/interim MRI and target volumes were compared. RESULTS The average volume of the post-surgical cavity contoured by the neurosurgeons on the post-operative/interim MRI was 15.96 cc (± 7.79 cc, range of 6.54 -24.9 cc). The average volume of the post-surgical cavity contoured by the radiation oncologists on the planning CT was 15.71 (± 7.49 cc, range of 6.53 -24.31 cc). There was no noticeable change in volume size between post-operative/interim MRI and planning CT up to the period of 15 days. LIMITATION This was a retrospective pilot study with a small sample size and patients recruited from a single center. CONCLUSION There is no change in size of the cavity volume for up to 15 days between post-operative/interim MRI and planning CT. This knowledge will help understand the optimal time interval between post-operative MRI and CT simulation for the stereotactic radiation therapy planning.
Base Editing Repairs the HbE Mutation Restoring the Production of Normal Globin Chains in Severe HbE/β-Thalassemia Patient Hematopoietic Stem Cells and Erythroid Cells
Authors: Mohsin Badat, Peng Hua, Sachith Mettananda, Christopher Fisher, Noemi Roy, Siobhan Rice, Anindita Roy, Douglas R. Higgs, James Davies
Journal: Blood (2021)