tbuckley/cabot-search huggingface dataset:
CTIM-10. REPRODUCIBILITY OF CLINICAL TRIALS USING CMV-TARGETED DENDRITIC CELL VACCINES IN PATIENTS WITH GLIOBLASTOMA
Authors: Kristen Batich, Duane Mitchell, Patrick Healy, James Herndon, Gloria Broadwater, Gunn Michael, Min-Nung Huang, Kelly Hotchkiss, Luis Sanchez-Perez, Smita Nair, Kendra Congdon, Pam Norberg, Kent Weinhold, Gary Archer, Elizabeth Reap, Weihua Xie, Steven Shipes, Emily Albrecht, Katherine Peters, Dina Randazzo, Margaret Johnson, Daniel Landi, Annick Desjardins, Henry Friedman, Gordana Vlahovic, David Reardon, James Vredenburgh, Darell Bigner, Mustafa Khasraw, Roger McLendon, Eric Thompson, Steven Cook, Peter Fecci, Patrick Codd, Scott Floyd, Zachary Reitman, John Kirkpatrick, Allan Friedman, David M Ashley, John Sampson
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Vaccination with dendritic cells (DCs) fares poorly in primary and recurrent glioblastoma (GBM). Moreover, GBM vaccine trials are often underpowered due to limited sample size. METHODS To address these limitations, we conducted three sequential clinical trials utilizing Cytomegalovirus (CMV)-specific DC vaccines in patients with primary GBM. Autologous DCs were generated and electroporated with mRNA encoding for the CMV protein pp65. Serial vaccination was given throughout adjuvant temozolomide cycles, and 111Indium radiolabeling was implemented to assess migration efficiency of DC vaccines. Patients were followed for median overall survival (mOS) and OS. RESULTS Our initial study was the phase II ATTAC study (NCT00639639; total n=12) with 6 patients randomized to vaccine site preconditioning with tetanus-diphtheria (Td) toxoid. This led to an expanded cohort trial (ATTAC-GM; NCT00639639) of 11 patients receiving CMV DC vaccines containing granulocyte-macrophage colony-stimulating factor (GM-CSF). Follow-up data from ATTAC and ATTAC-GM revealed 5-year OS rates of 33.3% (mOS 38.3 months; CI95 17.5-undefined) and 36.4% (mOS 37.7 months; CI95 18.2-109.1), respectively. ATTAC additionally revealed a significant increase in DC migration to draining lymph nodes following Td preconditioning (P=0.049). Increased DC migration was associated with OS (Cox proportional hazards model, HR=0.820, P=0.023). Td-mediated increased migration has been recapitulated in our larger confirmatory trial ELEVATE (NCT02366728) of 43 patients randomized to preconditioning (Wilcoxon rank sum, Td n=24, unpulsed DC n=19; 24h, P=0.031 and 48h, P=0.0195). In ELEVATE, median follow-up of 42.2 months revealed significantly longer OS in patients randomized to Td (P=0.026). The 3-year OS for Td-treated patients in ELEVATE was 34% (CI95 19-63%) compared to 6% given unpulsed DCs (CI95 1-42%). CONCLUSION We report reproducibility of our findings across three sequential clinical trials using CMV pp65 DCs. Despite their small numbers, these successive trials demonstrate consistent survival outcomes, thus supporting the efficacy of CMV DC vaccine therapy in GBM.
Use of Denosumab after Zoledronic Acid in Patients with Multiple Myeloma: Real-World Experience from 2015 to 2019 at Yale Cancer Center
Authors: Talib Dosani, Anna Poteraj, Terri L. Parker, Noffar Bar, Sabrina L. Browning, Elan Gorshein, Tara Anderson, Karl Insogna, Natalia Neparidze
Journal: Blood (2021)
Abstract 13763: Usefulness of Echocardiography to Diagnose Diabetic Cardiomyopathy in Real World Practice
Authors: Iwona Swiatkiewicz, Neeja T Patel, Pam R Taub
Journal: Circulation (2021)

Introduction: Diabetic Cardiomyopathy (DbCM) is an underrecognized form of stage B heart failure (SBHF) which is associated with increased risk of overt heart failure (HF) in patients with type 2 diabetes (T2D). Two-dimensional echocardiography (2DE) can aid in identifying T2D patients with DbCM. This study aims to evaluate the usefulness of 2DE parameters for diagnosing DbCM. Hypothesis: Combination of echocardiographic features can help identify patients with DbCM. Methods: Retrospective review of medical records of T2D patients who had 2DE at UC San Diego Medical Center within 2016-2017 was conducted. Patients with DbCM were defined as T2D patients without overt HF and with echocardiographic demonstration of SBHF defined as left ventricular ejection fraction (LVEF) ≥45% and at least one of the following echocardiographic criteria: left atrial volume index (LAVI) ≥34 mL/m 2 , left ventricular mass index (LVMI) &gt;95 g/m 2 in women and &gt;115 g/m 2 in men, peak early mitral inflow velocity to early diastolic mitral annular velocity ratio (E/E’) ≥13, and right ventricular systolic pressure (RVSP) &gt;35 mmHg, while excluding co-morbidities which can contribute to SBHF. Our study did not evaluate impaired longitudinal strain (GLS), an additional echocardiographic early indicator of SBHF and DbCM. Results: Out of 499 T2D patients who had 2DE, 454 (91%) had LVEF≥45%. Of them, 256 patients (56.4%) had at least one additional echocardiographic criterion, thus met criteria for SBHF. After excluding patients with overt HF, uncontrolled hypertension, coronary artery disease, valvular heart disease, or other cardiomyopathies, 14.8% of patients with SBHF met criteria for DbCM. Elevated LAVI, LVMI, E/E’ and RVSP were found in 63.2%, 26.3%, 44.7% and 34.2% of DbCM patients, respectively. Elevated LAVI and E/E’ occurred in 81.6% of DbCM patients, providing the most robust parameters for diagnosing DbCM. Conclusions: In T2D patients with preserved LVEF and probable DbCM, left atrial enlargement and elevated E/E’ are the most prevalent echocardiographic findings. The LAVI, E/E’, RVSP and LVMI, which are all readily detectable by 2DE, improve identification of patients at high-risk of developing overt HF in T2D patients with preserved LVEF in support of DbCM diagnosis.
Age-Related Changes in Human HSC Methylomes Affect Gene Regulatory Elements Critical to HSC Function and Reveal Novel HSC Aging Candidate Genes
Authors: Abdul-Habib Rahimi, Reka Toth, Dieter Weichenhan, Julia K. Herzig, Ekaterina Panina, Michael Heuser, Maximilian Schönung, Daniel B. Lipka, Pavlo Lutsik, Christoph Plass, Christian Buske
Journal: Blood (2021)
PRK-1 kinase regulates endothelial migration and is novel target for anti-angiogenesis therapy
Authors: Mark Powell, Wayne Lang, Alison Pan, Chris Franci, Marina Gelman, Vadim Markovtsov, Anabelle Friera, Ruby Daniel, Raj Singh, Don Payan, James Lorens, Yasumichi Hitoshi, Sacha Holland
Journal: Cancer Research (2007)

3828  Endothelial cell migration is an important event that occurs during angiogenesis. Activated endothelial cells expressing integrins undergo physical migration (haptotaxis) towards newly established gradients of adhesive glycoproteins present on the surface of the extracellular matrix (ECM). One important such interaction is the haptotaxis of avb3 expressing endothelial cells towards the ECM ligand vitronectin. In order to identify novel genes that control haptotactic migration of endothelial cells, we developed a novel retroviral-based functional screen to probe pathways involved in avb3 mediated haptotaxis in primary human endothelial cells (HUVECs).  Over 200 independent library inserts were selected in this screen. One genetic effector that inhibited haptotaxis towards vitronectin, was derived from a cDNA fragment encoding PRK-1 (protein kinase C related), a serine/threonine kinase regulated by Rho. RNAi-mediated PRK-1 silencing blocked endothelial cell haptotaxis as well as chemotaxis. Importantly RNAi-mediated knockdown of PRK-1 also disrupted endothelial tubule formation in a HUVEC-smooth muscle cell co-culture system. These observations are substantiated by in vivo experiments demonstrating that sustained, RNAi-mediated PRK-1 knockdown impaired formation of functional human blood vessels in a mouse model of human angiogenesis.  Summary: We have shown that PRK-1 regulates angiogenesis and is a novel kinase drug target for anti-angiogenic therapy. Subsequently we performed a high-throughout biochemical screen against the Rigel compound library and identified cell permeable small molecule inhibitors of PRK-1. We plan to test PRK-1 inhibitors in preclinical in vivo models of tumor angiogenesis to identify clinical candidates.
Prospective Phase I/II Study of Eltrombopag for the Treatment of Bone Marrow Failure in Fanconi Anemia
Authors: Ma Evette Barranta, Fariba Chinian, Katherine Roskom, Tarik Lott, Julie Erb-Alvarez, Katherine R. Calvo, Thomas Winkler, Neelam Giri, Andre Larochelle
Journal: Blood (2021)
Rapid and sustained containment of covid-19 is achievable and worthwhile: implications for pandemic response
Authors: Qiulan Chen, Lance Rodewald, Shengjie Lai, George F Gao
Journal: BMJ (2021)

In the 20 months since the World Health Organization declared covid-19 to be a pandemic, more than 250 million cases have been confirmed.More than 5 million deathshave occurred disproportionately by country, with 10% of countries reporting 80% of cases. 1 In a new pandemic, with no vaccines prepared, non-pharmaceutical interventions are the only response.In the first year of the covid-19 pandemic, several countries that aimed to completely interrupt community transmission-China, Singapore, Australia, and New Zealand-achieved and maintained containment. 2 3Here, we analyse China's containment strategy before vaccine roll-out and describe measures for initial and sustained containment and benefits for the country.Containment of covid-19 means stopping transmission of SARS-CoV-2. 4 Core measures of containment include actively finding infected people and treatment in isolation, close contact tracing and quarantine, and restrictions of travel from areas with community transmission.Additional measures that reduce transmission include stay at home orders, cancellation of mass gatherings, closing schools, and use of personal protection measures, such as hand hygiene, respiratory etiquette, keeping at least 1 m distance, and mask wearing.
Abstract 13729: Monotherapy With a P2Y12 Inhibitor versus Aspirin for Secondary Prevention of Atherosclerotic Cardiovascular Disease (ASCVD) Events: A Meta-Analysis of Randomized Trials
Authors: Zainali Chunawala, Devika Aggarwal, Kirtipal S Bhatia, vardhmaan jain, Debabrata Mukherjee, Usman Baber, Sripal Bangalore, ELIANO NAVARESE, Justin p Levisay, Gregory Mishkel, Mark Ricciardi, Muthiah Vaduganathan, Remo Furtado, Thomas A Zelniker, Arman Qamar
Journal: Circulation (2021)

Background: Aspirin is the most frequently used antiplatelet monotherapy for secondary prevention in patients with established ASCVD. Trials comparing monotherapy with a P2Y12i versus aspirin have shown variable results. Methods: Medline, Embase, &amp; Cochrane Central databases were searched to identify RCTs comparing monotherapy with a P2Y12i versus aspirin for secondary prevention in patients with established ASCVD (ischemic stroke, coronary, or peripheral artery disease). The primary outcome of interest was major adverse cardiac events (MACE). Secondary outcomes were myocardial infarction (MI), stroke, all-cause mortality, &amp; major bleeding. The DerSimonian and Laird random-effects model was used to calculate risk ratios (RR) &amp; the corresponding 95% confidence interval (CI). Heterogeneity among studies was assessed using the Higgins I 2 value. Results: 9 eligible RCTs (5 with clopidogrel &amp; 4 with ticagrelor) with 62,336 patients were included in our analyses. Monotherapy with P2Y12i significantly reduced the risk of MACE by 11% (0.89, 95% CI 0.84 - 0.95, I 2 =0), &amp; MI by 19% (0.81, 95% CI 0.71 - 0.92, I 2 =0) as compared with aspirin monotherapy (Figure). There was no significant difference in the risk of stroke (0.85, 95% CI 0.73-1.01), &amp; all-cause mortality (1.01, 95% CI 0.92 - 1.11) between the 2 treatment groups. There was no significant difference in the risk of major bleeding with P2Y12i monotherapy as compared with aspirin (0.97, 95% CI 0.66 - 1.43, I 2 =0). Results were consistent irrespective of the P2Y12i. Conclusion: P2Y12i monotherapy is associated with a significant reduction in atherothrombotic events as compared with aspirin alone without an increased risk of major bleeding.
Pulmonary arterial hypertension and CFTR: the paradox of going forward by tacking sideways!
Authors: Tom Kotsimbos, David Kaye, Dominic Keating
Journal: European Respiratory Journal (2021)

<b>An improved understanding of the molecular heterogeneity within cells and the capacity for adaptive functional fitness for specific interacting cell and tissue environments is key to an improved understanding of PAH and CF subtypes</b>https://bit.ly/2UyxFHs
CTNI-25. CASE STUDY OF AN EXCEPTIONAL RESPONDER: ENZASTAURIN LONG TERM EFFICACY IN A PATIENT WITH PRIMARY AND RECURRENT GLIOBLASTOMA MULTIFORME (GBM)
Authors: Jennifer Clarke
Journal: Neuro-Oncology (2021)

Abstract Enzastaurin (ENZA, DB102) is an oral serine/threonine kinase inhibitor targeting the protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/AKT pathways to inhibit tumor cell proliferation, induce tumor cell apoptosis, and suppress tumor-induced angiogenesis. We report the long-term clinical response of a GBM patient treated with ENZA who has survived for 15 years from initial diagnosis, despite tumor recurrence 5 years ago. In 2006, the 44-year-old man was diagnosed with GBM and underwent surgical resection of the tumor. He subsequently enrolled in a Phase I/II trial evaluating ENZA in newly diagnosed GBM and gliosarcoma (NCT00402116), in September 2006. He was treated with radiation and concurrent temozolomide (TMZ) + ENZA, followed by adjuvant TMZ + ENZA, which he tolerated well. He stopped treatment electively in November 2010, after 51 adjuvant cycles, in the setting of stable imaging without evidence of tumor activity. The patient did well until January 2016, when a serial MRI scan showed tumor progression; he underwent a second surgical resection (pathology: recurrent GBM, IDH1 R132H neg, ATRX retained, EGFR amplified, MGMT methylated) followed by re-irradiation with concurrent TMZ. Given the patient’s prior prolonged disease control, he started a compassionate treatment of ENZA in combination with adjuvant TMZ in April 2016. TMZ was stopped in June 2018 after 28 cycles; he continues single agent ENZA to date, with no evidence of tumor progression as of May 2021. Consistent with DGM1 (Denovo Genomic Marker 1) being an ENZA efficacy predicting biomarker, the patient is DGM1 positive. This case provides clinical evidence that the addition of ENZA to standard of care may provide substantial long-term benefit in DGM1 positive patients with GBM. A Phase 3 study of ENZA in DGM1 positive newly diagnosed GBM patients is currently ongoing (ENGAGE study, NCT03776071).
Abstract 13536: Snai1 Knockdown Rescues Pulmonary Hypertension-Induced Right Ventricular Failure in Rats by Inhibiting Endothelial-to-Mesenchymal-Transition and Fibrosis via LOXL2 Dependent-H3K4 Methylation Status Remodeling
Authors: Somanshu Banerjee, Varina R Clark, JASON HONG, John Park, Asif Razee, Soban Umar
Journal: Circulation (2021)

Introduction: Pulmonary hypertension (PH)-induced RV failure (PH-RVF), a significant prognostic determinant, is characterized by RV endothelial-to-mesenchymal transition (EndMT) and fibrosis. The regulatory control mechanisms of RV EndMT and fibrosis remain unclear. The action of transcription factor Snai1 in EndMT is proposed to be mediated via LOXL2 recruitment, their nuclear co-translocation and subsequent histone-H3K4 methylation status remodeling. Hypothesis: PH-RVF is associated with EndMT and fibrosis, governed by TGFβ1-Snai1-LOXL2 axis. Targeting Snai1 could serve as a novel therapeutic strategy for PH-RVF. Methods: Male rats received s.c. Monocrotaline (MCT, 60mg/kg, n=7; 30-days) or Sugen (20mg/kg, n=7; 3-wk hypoxia+2-wk normoxia) or PBS (CTRL, n=7). For Snai1-KD, MCT rats received siSnai1 (n=6; 5nM every 3-4d, IV) or scramble (n=7) from day 14-30. Echo and cath were performed. RVs were stained for fibrosis and EndMT. RV RNASeq and PCR validation performed. Human RVs (CTRL n=3; PAH n=7) were stained with trichrome and Snai1/LOXL2. Snai1-KD was performed on human coronary artery endothelial cells (HCAECs) under hypoxia+TGFβ1 (72h). 21 different Histone-H3 modifications were assessed in rat RVs. Values are mean±SD. Results: MCT and SuHx rats had increased RVSP and Fulton Index (FI) and decreased RVFAC (all p &lt;0.001). RNASeq showed EndMT as the top upregulated pathway. RV EndMT, fibrosis and myofibroblast transition were increased in MCT and SuHx rats and PH-RVF patients. RV TGFβ1, Snai1 and LOXL2 were increased in MCT and SuHx. Snai1+LOXL2 colocalized in nucleus in MCT and SuHx rats and human RVs. Snai1-KD showed decreased Snai1 expression (~3-fold), RVSP (45±2 mmHg; p &lt;0.05), FI (0.41±0.01; p &lt;0.05) and increased RVFAC (24±0.01; p&lt;0.05). Snai1-KD resulted in decreased RV LOXL2, EndMT and fibrosis. RNASeq showed EndMT as top downregulated pathway and decreased fibrotic DEGs. Only RV H3K4me2 upregulation was reversed by Snai1-KD. Snai1-KD inhibited hypoxia+TGFβ1-induced EndMT in HCAECs by decreasing Snai1+LOXL2 expression and co-localization. Conclusions: PH-RVF is associated with EndMT, fibrosis and H3K4me2 status remodeling mediated via TGFβ1-Snai1-LOXL2 axis. Targeting Snai1 is a novel therapeutic strategy for PH-RVF.
Abstract 11672: Limited Improvement in Global Quality of Life Measures After TAVR
Authors: Petro Gjini, Alison Massed, Tamara Vesel, Yong Zhan, Hassan Rastegar, Charles Resor, Andrew R Weintraub, Benjamin S Wessler
Journal: Circulation (2021)

Introduction: Transcatheter aortic valve replacement (TAVR) is now the preferred treatment for older adults with symptomatic aortic stenosis (AS). While the goal is often symptom improvement, quality of life (QOL) may be adversely impacted by non-cardiac conditions. We evaluated changes in the global QOL Patient-Reported Outcomes Measurement Information System (PROMIS) Physical survey after TAVR. Methods: Single-center prospective study of 204 patients undergoing TAVR from 10/2019 to 6/2021. Subjects completed The Kansas City Cardiomyopathy Questionnaire (KCCQ) and PROMIS Physical surveys pre-TAVR and 30 days post-TAVR, of whom 85 (42%) had complete data on disease-specific and global QOL. A clinically meaningful change in PROMIS was defined as &gt; 5 points. Good disease specific QOL was defined as KCCQ &gt; 75. The correlation between KCCQ and PROMIS was assessed. Results: The mean age was 78.9 years and 47% identified as female. The mean pre-TAVR PROMIS Physical and KCCQ scores were 42 (SD 9.4) and 62.6 (SD 22.4), respectively. 30-days post TAVR, the average change in KCCQ was +23.0 (SD 24.9), while the average change in PROMIS Physical score was +3.9 (SD 8.8). There was modest correlation between post-procedure disease-specific and global QOL scores ( Figure 1 , R 2 0.48, p &lt;0.001). At 30 days post-procedure, 69 patients (81.2%) reported good disease-specific QOL, while 36 (42.4%) had a clinically meaningful improvement in global QOL. Of patients with improvement in KCCQ, 33 (47.8%) reported a meaningful improvement in global QOL. Conclusions: The majority of patients report good disease-specific QOL after TAVR; however, less than ½ of TAVR treated patients have a clinically meaningful increase in global QOL at 30 days. There is modest correlation between disease-specific (KCCQ) and global (PROMIS) QOL scores following TAVR. Improvement in QOL after TAVR may be limited by conditions unrelated to AS.
Abstract 10441: Sex-Specific Decline in Coronary Flow Reserve with Aging
Authors: Takumi Toya, Ali Ahmad, Michel T Corban, Jaskanwal D Sara, Ilke Ozcan, Lilach O Lerman, Amir Lerman
Journal: Circulation (2021)

Introduction: Coronary vasomotor response is different between males and females. Overall, females have lower coronary flow reserve (CFR) than males due to higher baseline coronary flow than males. Hypothesis: Sex has an essential role in the interaction between age and CFR. Methods: We included 668 patients with nonobstructive coronary artery disease who underwent invasive coronary vasoreactivity testing using intracoronary incremental doses of adenosine (18-72 μg). Changes in CFR (hyperemic flow velocity/baseline flow velocity) with aging were separately analyzed between males (N=207, mean age 53±13 years) and females (N=461, mean age 54±12 years). We further divided patients by age of 53 which is average age of menopause. Results: In males, CFR decreased with aging in younger patients &lt;53 years and tended to decrease in older male patients (all ages [N=207]: r=-0.33, P &lt;0.0001; &lt;53 years [N=99]: r=-0.27, P =0.01; ≥53 years [N=108]: r=-0.17, P =0.07) ( Figure A ). In contrast, CFR did not decrease with aging in younger females &lt;53 years, whereas there was a significant negative correlation between CFR and age in older females ≥53 years (all ages [N=461]: r=-0.15, P =0.001; &lt;53 years [N=211]: r=-0.006, P =0.39; ≥53 years [N=250]: r=-0.25, P &lt;0.0001) ( Figure B ). Baseline microvascular resistance (BMR) was similar between younger and older males ( P =0.30), whereas older females had higher baseline BMR than younger females ( P &lt;0.0001) ( Figure C ). Conclusions: CFR decreased with aging in males and older females, but not in younger females, potentially highlighting the role of protective hormonal differences in maintaining low baseline coronary tone in younger females.
Abstract 12254: Predictors of Transthoracic Impedance in Patients Undergoing Electrical Cardioversion
Authors: Gabriel N Redel-Traub, Saurabh Sudesh, Frederick Ehlert, Jose Dizon, Angelo B Biviano, Hasan Garan, Hirad Yarmohammadi
Journal: Circulation (2021)

Introduction: Successful synchronized direct current cardioversion (DCCV) requires adequate current delivery to the heart. However, adequate current for successful DCCV is not yet established. Trans-myocardial current depends on two factors: input energy and transthoracic impedance (TTI). While factors affecting TTI have been studied in animal models, factors affecting TTI in humans have not been well established. Here we explored potential factors that affect TTI in humans. Methods: Retrospective review of consecutive patients undergoing DCCV at a large quaternary medical center between October 2019 and December 2020 was conducted. Pertinent clinical information, including demographics, echocardiography findings, laboratory findings and body characteristics were collected. Cardioversion details including joules delivered and TTI were recorded by the defibrillator for each patient’s first shock. Predictors of thoracic impedance were assessed using multivariable regression analysis after adjustment for confounders. Results: A total of 180 patients were analyzed, 31% of which were female. Mean impedance was 73.15 ± 21.50 (range 39-208). In multivariate analysis, higher TTI was significantly associated with higher BMI (p&lt;0.001, Figure ) and female gender (p=0.006) after adjustment for all confounders. Other factors including age, history of cardiac surgery, left ventricular ejection fraction, left atrial size, brain natriuretic peptide, and antero-posterior chest diameter were not associated with TTI. Conclusion: Our results align with prior studies that body habitus and gender affect TTI and suggest that adjustments in input energy based on these factors may be required for appropriate trans-myocardial current delivery in synchronized cardioversion.