tbuckley/cabot-search huggingface dataset:
95MO Characteristics of patients with brain metastases from HER2-positive breast cancer
Authors: E. Laakmann, I. Witzel, T. Neunhöffer, T-W. Park-Simon, R. Weide, K. Riecke, A. Polasik, M. Schmidt, J. Puppe, C. Mundhenke, K. Lübbe, T. Hesse, M. Thill, D-M. Zahm, C. Denkert, T. Fehm, V. Nekljudova, J. Rey, S. Loibl, V. Mueller
Journal: Annals of Oncology (2021)
Abstract 15256: Predicting Out-of-office Blood Pressure in United States Adults
Authors: Brandon K Bellows, Jingyu Xu, James P Sheppard, Joseph E Schwartz, Daichi Shimbo, Paul Muntner, Richard McManus, Andrew E Moran, Kelsey B Bryant, Laura P Cohen, Adam P Bress, Jordan B King, James M Shikany, Beverly Green, Yuichiro Yano, Donald Clark, Yiyi Zhang
Journal: Circulation (2020)

Introduction: The Predicting Out-of-Office Blood Pressure in the Clinic (PROOF-BP) algorithm accurately estimates out-of-office BP to guide ambulatory BP monitoring (ABPM) among adults in the UK and Canada with suspected high BP. We tested the validity of PROOF-BP in a diverse US population and developed a US-specific algorithm. Methods: We pooled data from four US studies (CARDIA, JHS, Masked Hypertension Study, and Improving Detection of Hypertension Study) that assessed both office BP and 24-hour ABPM. We included participants with &gt;=2 office and &gt;=10 daytime ambulatory BP readings. PROOF-BP estimates the difference between office systolic BP (SBP) and diastolic BP (DBP) and daytime ambulatory SBP and DBP using clinic BP measurements and patient characteristics. We examined the performance of PROOF-BP in US data and then used multivariable linear regression to develop a new algorithm optimized for the US population. We tested the ability of PROOF-BP to discriminate high awake ambulatory SBP and DBP (SBP/DBP &gt;=130/80 mm Hg) using the area under the receiver-operator curve (AUROC). Models were developed in a 70% randomly selected derivation set and tested in a 30% validation set. The optimal predicted ambulatory BP thresholds were defined as those that resulted in the smallest proportion of individuals recommended for ABPM with an overall classification error &lt;20% among those not screened. Results: We analyzed 3,080 individuals with a mean (SD) age of 52.0 (11.9) years, 38% were male, and 54% were black. Mean (SD) office SBP/DBP was 121.8 (16.6)/75.3 (9.8) mm Hg, mean (SD) awake ambulatory SBP/DBP was 127.3 (13.5)/78.6 (8.8) mm Hg, and 51% had awake ABPM &gt;=130/80 mm Hg. The discrimination for high awake ABPM was similar between the existing (AUROC SBP = 0.77, DBP = 0.73) and US-specific models (AUROC SBP = 0.77, DBP = 0.72). Optimal predicted ambulatory BP thresholds with the US-specific algorithm were 125-134/75-84 mm Hg, resulting in 55% of the pooled cohort recommended for ABPM; compared to 66% recommended by the 2017 ACC/AHA guidelines. Conclusions: Both the original and US-specific PROOF-BP algorithms predicted high out-of-office BP among US adults. PROOF-BP may be used to guide clinical decisions and resource allocation among individuals considered for ABPM.
Abstract 13080: Myocardial G Protein-Coupled Receptor Kinase 5 Contributes to Impaired Cardiac Function and Immune Cell Recruitment in Ischemic Heart Failure
Authors: Claudio De Lucia, Laurel A. Grisanti, Giulia Borghetti, Michela Piedepalumbo, Jessica Ibetti, Anna Maria Lucchese, Eric W. Barr, Erhe Gao, Giuseppe Rengo, Steven R Houser, Douglas G Tilley, Walter J Koch
Journal: Circulation (2019)

Introduction: Myocardial ischemia (MI) is the most common cause of heart failure (HF) in the United States. G protein-coupled receptor (GPCR) kinase 5 (GRK5) has been found to be upregulated in fai...
Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity
Authors: Zining Wang, Feifei Xu, Jie Hu, Hongxia Zhang, Lei Cui, Wenhua Lu, Wenzhuo He, Xiaojuan Wang, Mengyun Li, Huanling Zhang, Wenjing Xiong, Chunyuan Xie, Yongxiang Liu, Penghui Zhou, Jinyun Liu, Peng Huang, Xiaofeng Frank Qin, Xiaojun Xia
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Dendritic cells (DCs) play a critical role in antitumor immunity, but the therapeutic efficacy of DC-mediated cancer vaccine remains low, partly due to unsustainable DC function in tumor antigen presentation. Thus, identifying drugs that could enhance DC-based antitumor immunity and uncovering the underlying mechanism may provide new therapeutic options for cancer immunotherapy. Methods In vitro antigen presentation assay was used for DC-modulating drug screening. The function of DC and T cells was measured by flow cytometry, ELISA, or qPCR. B16, MC38, CT26 tumor models and C57BL/6, Balb/c, nude, and Batf3 −/− mice were used to analyze the in vivo therapy efficacy and impact on tumor immune microenvironment by clotrimazole treatment. Results By screening a group of small molecule inhibitors and the US Food and Drug Administration (FDA)-approved drugs, we identified that clotrimazole, an antifungal drug, could promote DC-mediated antigen presentation and enhance T cell response. Mechanistically, clotrimazole acted on hexokinase 2 to regulate lactate metabolic production and enhanced the lysosome pathway and Chop expression in DCs subsequently induced DC maturation and T cell activation. Importantly, in vivo clotrimazole administration induced intratumor immune infiltration and inhibited tumor growth depending on both DCs and CD8+ T cells and potentiated the antitumor efficacy of anti-PD1 antibody. Conclusions Our findings showed that clotrimazole could trigger DC activation via the lactate-lysosome axis to promote antigen cross-presentation and could be used as a potential combination therapy approach to improving the therapeutic efficacy of anti-PD1 immunotherapy.
Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke
Authors: Ligen Shi, Zeyu Sun, Wei Su, Fei Xu, Di Xie, Qingxiu Zhang, Xuejiao Dai, Kartik Iyer, T. Kevin Hitchens, Lesley M. Foley, Sicheng Li, Donna B. Stolz, Kong Chen, Ying Ding, Angus W. Thomson, Rehana K. Leak, Jun Chen, Xiaoming Hu
Journal: Immunity (2021)
Response to Comment on Dawson-Hughes et al. Intratrial Exposure to Vitamin D and New-Onset Diabetes Among Adults With Prediabetes: A Secondary Analysis From the Vitamin D and Type 2 Diabetes (D2d) Study. Diabetes Care 2020;43:2916–2922
Authors: Bess Dawson-Hughes, Jason Nelson, Anastassios G. Pittas
Journal: Diabetes Care (2020)

We thank Dr. Davidson for his comment (1) on our article (2). We agree that weight loss is critically important in reducing risk of diabetes; weight loss can also result in increased 25-hydroxyvitamin D [25(OH)D] levels. We did not adjust for weight change because weight remained fairly stable during the trial. Nonetheless, in response to Dr. Davidson’s request, we have examined the impact of adjustment for change in weight (final − baseline weight) in the fully adjusted models shown in our article. In …
Candidate Selection in BALB/c Mice towards a Single Dose AAV-Based COVID19 Prophylactic Vaccine
Authors: W. L. Dai, N. Zabaleta, U. Bhatt, R. Estelien, D. Li, D. Maciorowski, J. Sanmiguel, R. Chauhan, A. Cucalon, C. Diop, M. Kim, A. Sheridan, L. H. Vandenberghe
Journal: Molecular Therapy (2021)
Abstract 15509: <i>SYNE2</i> Expression Regulates Calcium Cycling and Mitochondria Function in Cardiomyocytes: Implications for Association With Atrial Fibrillation
Authors: Nana Liu, Conner Witherow, Sathyamangla V Prasad, John Barnard, David Van Wagoner, Mina K Chung, Jonathan D SMITH
Journal: Circulation (2020)

Introduction: SYNE2 encodes a nuclear membrane protein that connects the nucleus with the cytoskeleton. rs1152591 is a common SNP in the SYNE2 gene that is associated with atrial fibrillation (AF) and with reduced expression of SYNE2α1 , a short isoform, in human left atrial appendage tissue. We previously found that SYNE2α1 over expression (OE) acts as a dominant negative for the nuclear phenotype, similar to the SYNE2 knockdown (KD), leading to enlarged nuclear size and decreased nuclear stiffness. Objectives: To determine if GFP- SYNE2α1 (OE) and KD of all SYNE2 isoforms show similar effects on gene expression and cell physiology in human induced pluripotent stem cell-derived cardiomyocytes (iCMs). Methods and Results: RNAseq after SYNE2α1 OE or SYNE2 KD revealed both congruent changes in expression of specific genes, supporting the dominant negative role of SYNE2α1 , but also divergent changes in expression of some genes, showing specific effects of the SYNE2α1 short isoform. We identified both mitochondrial function and sarcoplasmic reticulum (SR) function as differentially expressed pathways comparing OE vs. KD iCMs. Fura-2 photometry was used to study Ca 2+ cycling in beating iCMs, and revealed delayed calcium reuptake in the SYNE2 KD cells (15.9% increase in reuptake time as % of each contraction, p&lt;0.0001), but not in the GFP- SYNE2α1 OE cells (not significant). Flow cytometry showed significantly lower SERCA2 expression in the SYNE2 KD cells but not in the SYNE2α1 OE cells (12% decrease, p=0.029). Immunofluorescence microscopy revealed that GFP-SYNE2α1 not only localized to the nuclear membrane but also to the SR, stained with anti-SERCA2. Flow cytometry after MitoTracker Orange staining, to monitor the cellular volume of functional mitochondria, was significantly increased in both the SYNE2α1 OE and SYNE2 KD iCMs vs. their respective controls. Thus, despite differential expression of mitochondrial pathway genes, SYNE2α1 mimics the KD of all SYNE2 isoforms in regard to mitochondrial function. Conclusions: SYNE2α1 OE, unlike KD of all SYNE2 isoforms, preserves SR Ca 2+ reuptake activity, and this may contribute to the mechanism by which the AF risk allele in the SYNE2 gene, associated with decreased expression of SYNE2α1, predisposes carriers to AF.
Mechanisms and Models in Heart Failure
Authors: Douglas L. Mann, G. Michael Felker
Journal: Circulation Research (2021)

Despite multiple attempts to develop a unifying hypothesis that explains the pathophysiology of heart failure with a reduced ejection fraction (HFrEF), no single conceptual model has withstood the test of time. In the present review, we discuss how the results of recent successful phase III clinical development programs in HFrEF are built upon existing conceptual models for drug development. We will also discuss where recent successes in clinical trials do not fit existing models to identify areas where further refinement of current paradigms may be needed. To provide the necessary structure for this review, we will begin with a brief overview of the pathophysiology of HFrEF, followed by an overview of the current conceptual models for HFrEF, and end with an analysis of the scientific rationale and clinical development programs for 4 new therapeutic classes of drugs that have improved clinical outcomes in HFrEF. The 4 new therapeutic classes discussed are ARNIs, SGLT2 (sodium-glucose cotransporter 2) inhibitors, soluble guanylate cyclase stimulators, and myosin activators. With the exception of SGLT2 inhibitors, each of these therapeutic advances was informed by the insights provided by existing conceptual models of heart failure. Although the quest to determine the mechanism of action of SGLT2 inhibitors is ongoing, this therapeutic class of drugs may represent the most important advance in cardiovascular therapeutics of recent decades and may lead to rethinking or expanding our current conceptual models for HFrEF.
Abstract 13007: Myocardial Ischemia in Anomalous Aortic Origin of a Right Coronary Artery: Medium-term Follow-up in a Large Prospective Cohort
Authors: Tam T Doan, Carlos Bonilla-Ramirez, Shagun Sachdeva, J. Kevin Wilkes, Dana L Reaves-O’neal, Cory V Noel, Prakash Masand, Carlos M Mery, Ziyad Binsalamah, Christopher A Caldarone, E Dean McKenzie, Silvana M Molossi
Journal: Circulation (2020)

Introduction: Anomalous aortic origin of a right coronary artery (AAORCA) may lead to myocardial ischemia (ISCH) and sudden death in the young. Current guidelines deem asymptomatic patients (pts) low-risk if normal exercise stress test (EST). Hypothesis: The frequency of ISCH in AAORCA pts is seen more commonly on stress perfusion imaging (sPI) compared to EST. Method: Pts &lt;21 yrs with AAORCA were prospectively enrolled and managed following a standardized approach (12/2012-04/2020). Coronary CTA was used to define details of AAORCA. EST and sPI were performed in pts &gt;7 yrs and in younger pts if concern for ISCH. sPI included nuclear imaging initially and dobutamine stress cardiac MRI since 06/2014. High-risk features included intramural length (IML), abnormal ostium, symptoms or evidence of myocardial ISCH. Shared decision-making directed medical/surgical management. Results: Of 220 pts (male 135, 61%) enrolled at median age of 12 [IQR 6-15] yrs, 168 (76%) had no/non-exertional symptoms (Group-1) and 52 (24%) had exertional chest pain/syncope (Group-2). Coronary CTA was available in 180 and EST in 164 pts. EST was positive in 2/164 (1%), both had positive sPI. Of 162 negative EST, inducible ISCH was seen in 10/96 (10%) in Group-1 and 8/42 (19%) in Group-2. No difference in IML was noted between pts with/without ISCH (5.7±2.4 vs 6.0±2.1 mm, p=0.6). Surgery was indicated in 67 (30%) pts with high-risk features, not indicated in 143 (65%), and 10 (5%) are undergoing evaluation. In 51 operated pts (38 unroofing; 13 translocation), 3 await post-operative assessment, 48 on normal physical activities; median follow-up of 4.6 [IQR 2.3-6.3] yrs. All patients were alive at last follow-up; median of 2.9 [IQR 1.2-5.1] yrs. Conclusions: AAORCA pts can present with reversible ISCH on sPI regardless of symptoms or IML. EST may be a poor predictor of ISCH and caution should be given to determine low-risk. Most high-risk patients return to exercise and remain well at medium-term follow-up.
ACTR-24. A RANDOMIZED PHASE II TRIAL OF VELIPARIB (V), RADIOTHERAPY (RT) AND TEMOZOLOMIDE (TMZ) IN PATIENTS (PTS) WITH UNMETHYLATED MGMT (uMGMT) GLIOBLASTOMA (GBM): THE VERTU STUDY
Authors: Mustafa Khasraw, Kerrie Leanne McDonald, Mark Rosenthal, Zarnie Lwin, David Ashley, Helen Wheeler, Elizabeth Barnes, Matthew Foote, Eng-Siew Koh, Erik Sulman, Michael Back, Michael Buckland, Hao-Wen Sim, Lauren Fisher, Robyn Leonard, Merryn Hall, Sonia Yip, John Simes
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND TMZ offers minimal benefit in pts with de novo uMGMT GBM. V is synergistic with RT and TMZ in uMGMT preclinical GBM models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. VERTU tested V in pts with uMGMT GBM. METHODS VERTU is a randomized Phase 2 trial comparing Standard Arm (Arm A), RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2D 1–5) every 28 days for 6 cycles vs Experimental Arm (Arm B), RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2D 1–5) + V (40mg bid, D 1–7) every 28 days for 6 cycles in pts with de novo uMGMT GBM according to centralised testing. RESULTS 125 pts were randomized 1:2 (41:84). The 2 groups were matched for age, sex, performance status and extent of resection. Median follow-up was 25.8 months and 91 pts had died. The 6-month Progression-Free Survival (6mPFS) for Arms A and B were 34% (95% CI 20–48) and 46% (95% CI 36–57) respectively. The median PFS for Arms A and B were 4.2m (95% CI 2.5–6.0) and 5.7m (95% CI 4.1–6.6) respectively (HR = 0.80, 95%CI 0.55–1.18). 55% of pts in both arms experienced Grade 3/4 adverse events (AEs) with no significant differences in frequency or severity between the arms. Most common Grade 3/4 AEs were thrombocytopenia, seizures, hyperglycaemia and diarrhoea. CONCLUSION VERTU demonstrated that a novel treatment strategy for patients with de novo uMGMT GBM was feasible and tolerable. The observed 6mPFS and PFS were similar in both arms. Overall survival and other endpoints will be presented. Central MRI review, biomarker analyses, including DNA repair and methylation signature analyses are ongoing. (ANZCTR#ACTRN12615000407594).
Updated Results of TBCRC026: Phase II Trial Correlating Standardized Uptake Value With Pathological Complete Response to Pertuzumab and Trastuzumab in Breast Cancer
Authors: Roisin M. Connolly, Jeffrey P. Leal, Lilja Solnes, Chiung-Yu Huang, Ashley Carpenter, Katy Gaffney, Vandana Abramson, Lisa A. Carey, Minetta C. Liu, Mothaffar Rimawi, Jennifer Specht, Anna Maria Storniolo, Vicente Valero, Christos Vaklavas, Ian E. Krop, Eric P. Winer, Melissa Camp, Robert S. Miller, Antonio C. Wolff, Ashley Cimino-Mathews, Ben H. Park, Richard L. Wahl, Vered Stearns
Journal: Journal of Clinical Oncology (2021)

Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake value corrected for lean body mass (SULmax) on 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) would predict pathologic complete response (pCR) to pertuzumab and trastuzumab (PT).Patients with stage II or III, estrogen receptor-negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percent change in SULmax by C1D15 predicting pCR is ≤ 0.65, with a one-sided type I error rate of 10%.Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 22%. Receiver operator characteristic analysis of percent change in SULmax by C1D15 yielded an area under the curve of 0.72 (80% CI, 0.64 to 0.80; one-sided P = .12), which did not reject the null hypothesis. However, between patients who obtained pCR and who did not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 41.8%; P = .004) and SULmax reduction ≥ 40% was more prevalent (83% v 52%; P = .03; positive predictive value, 31%). Participants not obtaining a 40% reduction in SULmax by C1D15 were unlikely to obtain pCR (negative predictive value, 91%).Although the primary objective was not met, early changes in SULmax predict response to PT in estrogen receptor-negative and HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate tailoring of therapy in this setting.
Abstract P081: Association Of Homelessness And Anticoagulation Initiation In Veterans With Atrial Fibrillation: A Nationwide Study
Authors: David Wilson, Nadejda Kim, Maria Mor, Micahel Fine, Utibe Essien
Journal: Circulation (2021)

Introduction: Homeless individuals, overrepresented by Veterans, are more likely to have chronic medical conditions and comorbidities. They receive less medical care and have poor health outcomes, though remain understudied. Atrial fibrillation (AF), the most common cardiovascular rhythm disorder, is managed largely through anticoagulation. Direct-acting oral anticoagulants (DOACs) have been shown superior to warfarin anticoagulation in efficacy, safety, and adherence, though costlier. Hypothesis: Homeless Veterans receive a worse standard of care for AF than non-homeless Veterans in terms of initiation of any anticoagulation therapy, and in prescription of DOACs vs warfarin among those who began therapy. Methods: We studied 181,982 Veterans with incident, non-valvular AF in the Veterans Affairs Healthcare system from 2010-2018 who were not previously anticoagulated. Those who died or entered hospice were excluded. We classified Veterans who had experienced homelessness in the 2 years prior to their AF diagnosis using ICD-9/10 diagnosis codes and through VA homeless services use. We used logistic regression to examine the odds of initiation of any, DOAC, or warfarin anticoagulation. Models were adjusted for sociodemographic characteristics (year, age, race, CHA2DS2-VASc stroke risk score, HAS-BLED bleeding risk score, renal disease, BMI) and provider factors (e.g. specialty, had a patient seen a cardiologist within 90 days of their diagnosis). Facility type was modeled as a random effect. Results: Most of our cohort were male (178,400, 98%) and White (155,142, 85.6%). The homeless population of 6,472 was overrepresented by Black patients (1,574, 24.5%) and presented with AF at a younger age. The likelihood of being anticoagulated was lower in all populations before 2014. Having a BMI less than 25, liver disease, or bleeding concerns decreased the likelihood of being anticoagulated, while patients with renal disease were less likely to be prescribed DOACs. Black and Hispanic patients were less likely to be prescribed DOACs, regardless of homelessness status. We found the adjusted odds ratio (aOR) of initiating any anticoagulant therapy for homeless Veterans was 0.71 (95% CI 0.67 - 0.75). Among those who initiated anticoagulation, homeless individuals were less likely than non-homeless Veterans to initiate DOACs (aOR 0.88, 95% CI 0.80-0.96). Conclusions: In a nationwide cohort of Veterans with AF, we found that homeless Veterans were less likely to initiate any anticoagulation, especially more effective DOAC therapy. These findings persisted after adjusting for sociodemographic and clinical factors within an integrated health system with broad access to medical treatment through a uniform drug formulary. Future research must examine and address systematic biases to ensure high quality and equitable care for the most vulnerable populations, including homeless Veterans.
Vectorized SARS-CoV-2 Human IgG Expression in Mice and Ovine Animal Models Is Feasible and Well Tolerated
Authors: A. D. Rghei, L. P. van Lieshout, B. McLeod, Y. L. Pei, H. Faust, G. P. Kobinger, B. Thompson, B. W. Bridle, L. Susta, K. Karimi, S. K. Wootton
Journal: Molecular Therapy (2021)
Inequity in Racial-Ethnic Representation in Randomized Controlled Trials of Diabetes Technologies in Type 1 Diabetes: Critical Need for New Standards
Authors: Halis K. Akturk, Shivani Agarwal, Lilian Hoffecker, Viral N. Shah
Journal: Diabetes Care (2021)

Racial/ethnic inequity exists in all aspects of health care and does not exclude the field of advanced diabetes technology. Despite the recent increase in technological therapeutic options for diabetes management and mounting evidence of positive effects on glycemic outcomes, emerging reports have highlighted that insulin pump and continuous glucose monitor use remain significantly lower in Black and Hispanic compared with White populations (1,2). Critical needs remain to bridge gaps in technology use. An important issue that we in the scientific and research communities can modify is the inclusion of minorities in clinical trials of diabetes devices. The population prevalence estimates of type 1 diabetes in the U.S. were as follows: non-Hispanic White, 72%; Hispanic, 15.7%; non-Hispanic Black, 9.3%; and Asian, 2.4% (3). Adequate racial/ethnic representation in parallel with the prevalence of type 1 diabetes is needed not only to evaluate widespread efficacy and acceptability of diabetes technology but also to create better dissemination and marketing plans that increase use among underrepresented groups.

To evaluate the current state, we investigated racial/ethnic enrollment of participants in published clinical trials of type 1 diabetes technology to estimate whether trial enrollment had adequate representation of racial/ethnic minority groups. We used Medline, Embase, and Cochrane Central databases to systematically search for randomized controlled trials (RCTs) of currently U.S. Food and Drug Administration (FDA)-approved hybrid closed-loop and continuous glucose monitoring devices in the U.S. We included only U.S. studies, as …