tbuckley/cabot-search huggingface dataset:
TAMI-19. IMMUNOHISTOLOGICAL ANALYSIS OF ANGIOGENIC FACTORS OTHER THAN VEGF IN GLIOBLASTOMAS IN RELATION TO THE USE OF BEVACIZUMAB
Authors: Taketo Ezaki, Ryota Tamura, Toshihide Tanaka, Yuki Kuranari, Keisuke Miyake, Yohei Yamamoto, Jun Takei, Yasuharu Akasaki, Yuichi Murayama, Takashi Tamiya, Hikaru Sasaki
Journal: Neuro-Oncology (2021)

Abstract Although bevacizumab was shown to improve progression-free survival and performance status of the patients with high-grade gliomas, clinical trials consistently showed lack of benefit in terms of patients’ overall survival. The recurrent tumors are inevitably more aggressive and invasive as compared with the original tumors, and the in-situ observation in actual human specimens is essential to elucidate the mechanism of resistance. In Japan, bevacizumab was approved not only for recurrent but also for newly diagnosed cases. The safety as well as efficacy of resection following neoadjuvant bevacizumab has been reported, and a phase II study is currently ongoing (UMIN-000025579). In the present study, the expression of angiogenic factors other than VEGF (basic fibroblast growth factor (bFGF), placenral growth factor (PlGF), angiopoietin1/2 and ephrinA2) was investigated by immunohistochemistry to be compared among tumors with no previous bevacizumab treatment, those resected following bevacizumab, and those refractory to bevacizumab. Fifty-nine samples from 42 patients were included; 24 of newly diagnosed glioblastomas with no previous bevacizumab (naïve group), 16 resected following neoadjuvant bevacizumab (effective group), and 6 resected after recurrence or autopsied (refractory/autopsied group). 12 were paired samples (8 naïve and refractory, 4 effective and refractory). The expression of PlGF significantly increased in the effective group as compared with the naïve group (p=0.003). In the paired specimens, there was a trend towards increased expression of PlGF in the second specimens (refractory/autopsied group) as compared with the specimens of initial surgery (p=0.083). Angiopoietin1, angiopoietin2 and ephrinA2 were characteristically expressed in the microvessels less than 15μm. The increased expression of PlGF might be associated with the recurrence after bevacizumab.
EXTH-49. FOCUSED ULTRASOUND AND 5-ALA MEDIATED ELIMINATION OF DIFFUSE MIDLINE GLIOMA
Authors: Luana Schaab, Yann Ferry, Mehmet Ozdas, Bettina Kritzer, Sulayman Mourabit, Stuart Marcus, Javad Nazarian
Journal: Neuro-Oncology (2021)

Abstract Diffuse midline glioma (DMG) is a devastating and incurable childhood brain cancer. With a median survival of only 9 to 11 months, over 90% of children affected by DMG die within two years of diagnosis. Despite decades of research and a growing understanding of the biology of these tumors, there have been no advancements in therapies for DMGs. Tumor heterogeneity and diffuse infiltration in inoperable brain regions make these tumors uniquely difficult to manage both surgically and pharmacologically. Therefore, there is an urgent need for the exploration of novel treatment regimens. Focused Ultrasound (FUS) is an emerging technology with significant clinical potentials. Sonodynamic therapy (SDT) is an up-and-coming treatment strategy aiming to non-invasively eliminate tumor cells by acting through compounds known as sonosensitizers, which render tumor cells sensitive to ultrasound energy. Recently, 5-Aminolevulinic acid (5-ALA), an FDA-approved molecule, has been proposed as a sono-sensitizing agent. 5-ALA mediated SDT prolonged survival in C6 rat glioma models by selective elimination of tumor cells upon sonication. Mechanistically, it is thought that 5-ALA uptake and metabolic conversion into Protoporphyrin IX (PpIX) occurs preferentially in tumor cells due to differential activity of enzymes involved in heme metabolism. Here, we investigated SDT in DMG cells treated with 5-ALA. PpIX fluorescence increased linearly up to 24 h upon 5-ALA treatment and accumulated significantly more (1.6-fold, p &amp;lt; 0.01) when compared to C6 cells. Consequently, FUS sonication of 5-ALA treated DMG cells at 250 kHz significantly (p &amp;lt; 0.05) decreased DMG cell viability compared to treatment with 5-ALA or FUS alone. Here, we show the first 5-ALA mediated sonodynamic effect in DMG cells, leading to enhanced cell death. Our findings provide a rationale for considering clinical investigation of 5-ALA mediated sonodynamic therapy in DMG.
Abstract 10699: Predictors of Health Activation in Rural Caregivers with Multiple Cardiovascular Disease Risks
Authors: Misook L Chung, Geunyeong Cha, Chin-Yen Lin, Jennifer Miller, Terry A Lennie, Mary Kay Rayens, Frances J Feltner, Debra K Moser
Journal: Circulation (2021)

Introduction: Caregivers of patients with chronic conditions are at higher risk for cardiovascular disease (CVD) than their urban counterparts. Despite the burden related to caregiving, caregivers need to be activated for their own health to decrease this risk. Health activation has not been studied in rural caregivers. It is particularly relevant because most rural dwellers live in low-resourced, socioeconomically distressed environments where their health activation may be challenging. The purpose of this study was to identify characteristics of rural caregivers with multiple CVD risk factors who were not considered “activated” in their own health. Methods: Rural caregivers who had at least two CVD risk factors completed surveys on caregiver burden (Zarit Burden Interview), adherence to a healthy lifestyle (MOS Specifical Adherence Scale), perceived health status, and caregiving characteristics, and we calculated the Framingham CVD risk score. Health activation was assessed using the Patient Activation Measure, which categorizes people into four categories: overwhelmed, struggling, taking action, and maintaining levels. A multi-nominal logistic regression model was used to determine predictors of patient activation category. Results: Of the total of 269 rural caregivers (mean age= 54.1 years, 78% female), 36% were in the maintaining level, 42% were in the taking action level, and 22% in overwhelmed/struggling level. There were no significant differences in demographic or caregiving characteristics among the groups. Compared to the maintaining group, caregivers who had high caregiving burden (OR = 1.035, P = .007) and high Framingham CVD risk (OR = 1.061, P = .025), and low adherence to healthy behavior (OR = .917, P &lt; .001) were more likely to be in the overwhelmed/struggling group. Caregivers who had a high burden (OR = 1.026, P = .012) and low adherence to healthy behaviors (OR = .926, P &lt; .001) were more likely to be in the taking action group. Conclusions: Most rural caregivers were not activated on their health management even though they have multiple CVD risk factors. Screening health activation levels are needed for caregivers, and developing tailored intervention based on activation levels is needed.
Translating Therapeutic Microgels into Clinical Applications
Authors: Yonca Kittel, Alexander J. C. Kuehne, Laura De Laporte
Journal: Advanced Healthcare Materials (2021)

Microgels are crosslinked, water-swollen networks with a 10 nm to 100 µm diameter and can be modified chemically or biologically to render them biocompatible for advanced clinical applications. Depending on their intended use, microgels require different mechanical and structural properties, which can be engineered on demand by altering the biochemical composition, crosslink density of the polymer network, and the fabrication method. Here, the fundamental aspects of microgel research and development, as well as their specific applications for theranostics and therapy in the clinic, are discussed. A detailed overview of microgel fabrication techniques with regards to their intended clinical application is presented, while focusing on how microgels can be employed as local drug delivery materials, scavengers, and contrast agents. Moreover, microgels can act as scaffolds for tissue engineering and regeneration application. Finally, an overview of microgels is given, which already made it into pre-clinical and clinical trials, while future challenges and chances are discussed. This review presents an instructive guideline for chemists, material scientists, and researchers in the biomedical field to introduce them to the fundamental physicochemical properties of microgels and guide them from fabrication methods via characterization techniques and functionalization of microgels toward specific applications in the clinic.
Abstract 11639: Characteristics of Patients Referred to a Cardiovascular Disease Clinic for Post-Acute Sequelae of SARS-CoV-2 Infection
Authors: Stephen Y Wang, Philip Adejumo, Oyere K Onuma, Edward J Miller, Erica S Spatz
Journal: Circulation (2021)

Introduction: There is limited literature on the cardiovascular manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC). Methods: All consecutive adult patients presenting to the cardiology clinic at Yale-New Haven Hospital since July 2020, with positive COVID-19 serologic testing, were included. Results: Of 71 patients, average age was 46 years (range 19-74 years), 44 (62%) were female. 51 (72%) were White. 19 (27%) patients were hospitalized for COVID-19 ( Table ). Comorbidities included Hypertension (27%), hyperlipidemia (25%), diabetes (24%), and obesity (30%). On average, patients presented four months after COVID-19 diagnosis. The most common symptoms at presentation were dyspnea (45%, almost all exertional), palpitations (49%), and chest pain/pressure (49%). Patients also had memory impairment (20%), fatigue (39%), and headache (14%). There was no significant difference in cardiopulmonary symptoms (dyspnea, palpitations, and chest pain/pressure) by hospitalization status (p=0.70). TTE was abnormal in 13 of 62 patients and cardiac MRI was abnormal in 10 of 17 patients. Women experienced more cardiopulmonary symptoms (p=0.02) than men. Hospitalized patients were more likely to have ventricular dysfunction than non-hospitalized patients, although there were no significant differences in abnormal MRI findings (p=0.38). Diagnostic yield included: nonischemic cardiomyopathy (6%); new ischemia (3%); coronary vasospasm (1%); new atrial fibrillation (1%); possible myocarditis based on symptoms, MRI LGE (8%) or inflammation (3%). Two people met POTS criteria; majority of patients had evidence of sinus tachycardia and exertional fatigue consistent with orthostatic intolerance and deconditioning. Conclusions: In this cohort of patients referred to a cardiology clinic for PASC, cardiopulmonary symptoms did not differ by hospitalization status, however women were more likely to experience these symptoms than men.
Cascade-responsive nano-assembly for efficient photothermal-chemo synergistic inhibition of tumor metastasis by targeting cancer stem cells
Authors: Xianqi Zhu, Lin Li, Jin Tang, Chunyu Yang, Hao Yu, Kunpeng Liu, Ziyan Zheng, Xinggui Gu, Qingsong Yu, Fu-Jian Xu, Zhihua Gan
Journal: Biomaterials (2021)
Abstract 12199: Sirtuin1 Mediates Pressure Overload-Induced Cardiac Pathological Hypertrophy Through Regulating Mitochondrial Dynamics
Authors: Van Le, Jiayuan Murphy, Julia Fedorova, Lauryn Bates, Yi Yang, Kayla Davitt, Cole Logan, Di Ren, Ji Li
Journal: Circulation (2021)

Introduction: Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase. We revealed that the pressure-overload-induced SIRT1 can exacerbate cardiac systolic dysfunction. But the mechanisms by which SIRT1 undermines cardiac function under pathological conditions remain unclear. Hypothesis: SIRT1 induced by pathological hypotrophy disturbs mitochondrial dynamics homeostasis resulting in an exacerbated cardiac dysfunction. Methods: Wild-type littermates SIRT1 f/f (3-5 months) and inducible cardiomyocyte-specific SIRT1 knockout (icSIRT1 -/- ) (3-5 months) C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery for six weeks. Echocardiography assessed cardiac functions and CODA tail-cuff system measured blood pressure. The mitochondrial dynamics were examined by immunoblotting and transmission electron microscopy (TEM). Results: The echocardiography showed that there were significant reductions in ejection fraction (EF) and fractional shortening (FS) of the SIRT1 f/f mice after 6-weeks of TAC-induced pressure overload. The diastolic and systolic blood pressure were increased in SIRT1 f/f mice during TAC surgery. Intriguingly, icSIRT1 -/- versus SIRT1 f/f demonstrated significant resistance to pathological hypertrophy caused by TAC-induced pressure overload as determined with echocardiography and blood pressure measurements. The immunoblotting revealed that the six weeks of TAC surgery caused significantly higher levels of the mitochondrial fusion protein, mitofusin 2 (MFN2), in SIRT1 f/f versus icSIRT1 -/- hearts. In addition, TEM data showed more elongated mitochondria in SIRT1 f/f versus icSIRT1 -/- hearts, indicating a critical role of SIRT1 in maintaining mitochondrial dynamic homeostasis under pathological stress conditions. Metabolomics and proteomics showed that SIRT1 regulates carnitine palmitoyltransferase-1 and long-chain acyl CoA dehydrogenase to modulate fatty acid metabolism in response to TAC-induced stress. Conclusions: Cardiomyocyte SIRT1 plays a key role in cardiac mitochondrial dynamics during pathological stress conditions. Inhibition of SIRT1 activity could be a good strategy to ameliorate pressure overload-induced hypertrophy.
Effective Treatment of Ph-Negative Acute Lymphoblastic Leukemia for Uninsured Hispanic Adolescents and Young Adults with a Low-Cost Outpatient Regimen
Authors: Andres Gomez-De Leon, Ana Varela-Constantino, Perla R. R. Colunga-Pedraza, Alexia Sánchez-Arteaga, Valeria García-Zárate, Nereida Méndez-Ramírez, Eli de Jesús Fuentes-Chávez, Elías Eugenio González López, David Gomez-Almaguer
Journal: Blood (2021)
Abstract 10571: Phase 1 Single-Dose Study to Evaluate Apixaban in Pediatric Subjects at Risk for Venous or Arterial Thrombotic Disorder
Authors: Samira M Garonzik, Wonkyung Byon, Yogesh Patel, Amira Elsrougy, David Marchisin, Vidya Perera, Weidong Chen, Bing He, Bindu Murthy
Journal: Circulation (2021)

Introduction: Standard-of-care antithrombotics in pediatric subjects (peds) include unfractionated/LMW heparin, aspirin, and vitamin K antagonists. Apixaban, a direct factor Xa (FXa) inhibitor indicated for VTE treatment (tx) and prevention in adults, may be an effective and convenient oral tx option with an acceptable safety profile in peds. Objectives: To evaluate pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of apixaban in peds at risk for venous or arterial thrombotic disorder; to support dose selection for apixaban pediatric program trials. Methods: This phase 1 study (NCT01707394) enrolled peds aged &lt; 18 years (y) at risk for venous/arterial thrombotic disorder into groups by age. Peds undergoing tx/procedures or with conditions that may affect bleeding risk or apixaban exposure were excluded. A single apixaban dose (based on BSA; targeted to achieve adult exposures with apixaban 2.5 mg) was administered: 0.1 mg sprinkle capsule for age &lt; 28 days (d); 0.4 mg/mL solution for ages 28 d to &lt; 18 y (dose range: 1.08-2.19 mg/m 2 ). Endpoints included PK, safety, tolerability, and PD (anti-FXa activity). For PK/PD, 4-6 blood samples were collected ≤ 26 h after dosing. A population PK (PPK) model developed with data from adults and peds was used to evaluate PK. Apparent oral clearance (CL/F) included a fixed maturation function based on published data. Results: From Jan 2013 to Jun 2019, 49 peds aged 9 d to 16 y received an apixaban dose. All AEs (n = 15) resolved; most were mild/moderate; none were bleeding-related. SAEs (1 seizure; 1 limb venous thrombosis) were not tx-related. Apixaban CL/F and apparent central volume of distribution increased less than proportionally with body weight. Apixaban CL/F increased with age, reaching adult values in ages 12 to &lt; 18 y. Maturation affected CL/F most notably in ages &lt; 9 months. Plasma anti-FXa activity values were linearly related to apixaban concentrations with no apparent age-related differences, comparable to adults. Conclusions: Single apixaban doses were generally safe and well tolerated in peds. Study data and PPK model supported dose selection for phase 2/3 multiple-dose pediatric trials.
Limitations in Research on Maintenance Treatment for Individuals With Schizophrenia—Reply
Authors: Stefan Leucht, Spyridon Siafis, John M. Davis
Journal: JAMA Psychiatry (2021)

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Abstract 9779: The Utility of Endoscopic Screening in Mitigating the Risk of Gastrointestinal Bleeding After Left Ventricular Assist Device Placement. A Retrospective Chart Review Study
Authors: Wael T Mohamed, Mohamed Azab, Islam Shatla, Yasser Sammour, Mark P Everley, Jessica K Heimes, Brett W Sperry
Journal: Circulation (2021)

Introduction: Left ventricular assist device (LVAD) is a lifesaving bridge to transplantation or destination therapy for patients with end-stage heart failure. More than one-third of patients suffer from gastrointestinal (GI) bleeding within one year of placement. We investigated the yield and safety of endoscopic screening for potential sources of GI bleeding before LVAD insertion. Hypothesis: Endoscopic screening prior to LVAD placement does not necessarily reduce the risk of GI bleed post LVAD. Methods: We performed a retrospective chart review study of patients at Saint Luke’s Mid America Heart Institute who underwent continuous-flow LVAD implantation from 2010 to 2020. Study participants were categorized based on whether or not they underwent screening endoscopy prior to LVAD implantation. Patients were followed for one year after implantation, and outcomes were collected to determine the yield and safety of these procedures. A multivariable logistic regression analysis was performed using SPSS® controlling for the following confounding factors: age, gender, race, and history of GI bleeding. Results: Among 205 patients with an LVAD, 169 patients were included in the study after excluding those with lack of data or those lost to follow up. 68 (40.23%) patients who received pre-LVAD screening by either upper and/or lower endoscopies, and 42 (24.85%) patients who had post-LVAD GI bleed. Patients who underwent pre-LVAD screening had similar rates of GI bleeding after LVAD compared to those who were not screened (odds ratio 1.66, 95% CI 0.648-4.264, P=0.2). Moreover, in patients with post LVAD GI bleed, endoscopy findings were typically different than those pre LVAD. No complications to the endoscopic interventions were reported. Conclusions: While endoscopic screening appears to be safe in patients before LVAD implantation, it had no association with GI bleeding risk or etiology after LVAD.
Abstract 10030: A Novel Multi-Target Drug Prevents Cancer Therapy-Induced Hypertension and Renal Damage
Authors: John D Imig, Wojciech K Jankiewicz
Journal: Circulation (2021)

Introduction: Cardiovascular and kidney damage is associated with cancer therapeutics and has resulted in the clinical specialties of cardio-oncology and nephro-oncolgy. Hypothesis: Investigate a multi-target soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibitor, PTUPB, on cardiovascular and kidney damage that occurs during cancer therapy with sorafenib. Method: Rats were given were administered sorafenib and administered high salt diet for 8 weeks. The study included three experimental groups (n=4-8/group); (1) control group, (2) vehicle group treated with sorafenib (20mg/kg/d), and (3) PTUPB-treated group consisting of rats which were initially treated with sorafenib for 4 weeks and subsequently co-administered PTUPB (10mg/kg/d) from weeks 4 to 8. Blood pressure was measured, and urine collected every two weeks. Plasma and kidney tissue were collected at the end of the treatment period. Additional experiments were conducted in isolated glomeruli and mesangial cell cultures. Results: After 4 weeks, sorafenib-treated rats developed hypertension (177±9 mmHg) and sorafenib resulted in a further elevation in blood pressure at week 8 (205±10 mmHg). PTUPB treatment attenuated the sorafenib-induced blood pressure elevation. After 4 weeks, sorafenib rats developed pronounced proteinuria (9.0±2 Pr/Cr), which intensified significantly (32.0±4 Pr/Cr) by the end of week 8. PTUPB mitigated sorafenib-induced proteinuria and PTUPB reduced proteinuria by 75%. Kidney histopathology revealed glomerular injury, and glomerular nephrin loss in sorafenib rats. PTUPB treatment reduced glomerular injury by 30 to 70% as well as restored glomerular nephrin expression levels. Consistent with renoprotective action, PTUPB reduced sorafenib-induced renal oxidative stress as indicated by 26% lower MDA content. In isolated glomeruli, PTUPB treatment decreased angiotensin II induced glomerular permeability. Sorafenib induced glomerular mesangial cell death was also prevented by PTUPB treatment. Conclusion: Our data demonstrate that PTUPB decreased hypertension and kidney injury associated with the cancer therapeutic sorafenib.