tbuckley/cabot-search huggingface dataset:
The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1
Authors: Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L. Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J. Jack Lee, Dihua Yu
Journal: Cancer Cell (2021)
Himalayan Pink Salt as a Healthier Substitute in Lowering the Risk of Dietary Salt Induced Cognitive Insults in Experimental Rats
Authors: P Keerthana, Subramanian Sarada
Journal: Alzheimers Disease & Dementia (2021)

Alzheimer's disease (AD) belonging to the class of tauopathies, is a major cause of dementia globally. Observational studies in the aging population have reported that excessive dietary salt consumption is one of the risk factors that contribute to the pathological processes that underlie dementia and cognitive impairment. Regulation of the daily salt intake and consumption of alternative nutritional salts, if proven, may serve as a cost-effective and feasible approach in lowering the risk of dementia.
Abstract 14375: Maternal Outcomes in Subsequent Pregnancies After Peripartum Cardiomyopathy
Authors: Keerthish C Jaisingh, Pavida Pachariyanon, Hari Bogabathina, Runhua Shi, Sampath Singireddy, Kalgi A Modi
Journal: Circulation (2021)

Introduction: Peripartum cardiomyopathy (PPCM) is a rare cardiomyopathy associated with pregnancy and has a high maternal morbidity and mortality during both index and subsequent pregnancies. Data to help guide women with subsequent pregnancies is sparse. The purpose of this large retrospective study is to perform a comparative analysis of maternal outcomes in women with recovered left ventricular ejection fraction (LVEF) and persistent left ventricular (LV) dysfunction during subsequent pregnancies after PPCM. Methods: We identified 46 patients who had a subsequent pregnancy and an echocardiogram prior to their subsequent pregnancy in our registry of 121 patients with PPCM. Data in the registry was gathered by retrospective chart review. LVEF recovery was defined as improvement to &gt;50%. We divided patients into a recovered group (RG) (n=16) and non-recovered group (NRG) (n=30). Results: Total maternal mortality among women with PPCM and subsequent pregnancy was 19%. Mortality in the RG was 22% compared to 25% in the NRG. Mortality among African Americans (AA) was 83% when compared to other ethnic groups (17%). Discussion: Maternal mortality related to PPCM in the US ranges from 7% to 20%. In our study, we found that the risk of maternal mortality among women who had one or more subsequent pregnancies was 19%. It is well known that women with non-recovered LV function before subsequent pregnancy carries a worse maternal outcome when compared to women who enter the subsequent pregnancy with recovered LV function. Our findings reaffirm this, as we found that mortality rate in the NRG was higher when compared to the RG. Our findings also align with previous studies in that, AA women had a higher mortality rate when compared to other ethnic groups. Conclusion: Recovery of LVEF predicts a better prognosis but is not an absolute protection from the risk of mortality and/or recurrent PPCM. Hence close monitoring of LVEF with serial echocardiograms is still indicated during a subsequent pregnancy. African ethnicity carries a worse maternal prognosis.
Frailty, mortality, and health care utilization after liver transplantation: From the Multicenter Functional Assessment in Liver Transplantation (FrAILT) Study
Authors: Jennifer C. Lai, Amy M. Shui, Andres Duarte‐Rojo, Daniel R. Ganger, Robert S. Rahimi, Chiung‐Yu Huang, Frederick Yao, Matthew Kappus, Brian Boyarsky, Mara McAdams‐Demarco, Michael L. Volk, Michael A. Dunn, Daniela P. Ladner, Dorry L. Segev, Elizabeth C. Verna, Sandy Feng
Journal: Hepatology (2021)

Abstract Background and Aims Frailty is a well‐established risk factor for poor outcomes in patients with cirrhosis awaiting liver transplantation (LT), but whether it predicts outcomes among those who have undergone LT is unknown. Approach and Results Adult LT recipients from 8 US centers (2012–2019) were included. Pre‐LT frailty was assessed in the ambulatory setting using the Liver Frailty Index (LFI). “Frail” was defined by an optimal cut point of LFI ≥ 4.5. We used the 75th percentile to define “prolonged” post‐LT length of stay (LOS; ≥12 days), intensive care unit (ICU) days (≥4 days), and inpatient days within 90 post‐LT days (≥17 days). Of 1166 LT recipients, 21% were frail pre‐LT. Cumulative incidence of death at 1 and 5 years was 6% and 16% for frail and 4% and 10% for nonfrail patients (overall log‐rank p = 0.02). Pre‐LT frailty was associated with an unadjusted 62% increased risk of post‐LT mortality (95% CI, 1.08–2.44); after adjustment for body mass index, HCC, donor age, and donation after cardiac death status, the HR was 2.13 (95% CI, 1.39–3.26). Patients who were frail versus nonfrail experienced a higher adjusted odds of prolonged LT LOS (OR, 2.00; 95% CI, 1.47–2.73), ICU stay (OR, 1.56; 95% CI, 1.12–2.14), inpatient days within 90 post‐LT days (OR, 1.72; 95% CI, 1.25–2.37), and nonhome discharge (OR, 2.50; 95% CI, 1.58–3.97). Conclusions Compared with nonfrail patients, frail LT recipients had a higher risk of post‐LT death and greater post‐LT health care utilization, although overall post‐LT survival was acceptable. These data lay the foundation to investigate whether targeting pre‐LT frailty will improve post‐LT outcomes and reduce resource utilization.
The impact of hepatitis B vaccination in the United States, 1999–2018
Authors: Wen‐Qiang He, Guan Nan Guo, Chenxi Li
Journal: Hepatology (2021)

Abstract Background and Aims Hepatitis B vaccine has been included in the infant immunization schedule since 1991 in the United States. We aimed to assess its effectiveness against HBV infection and its impact on mortality. Approach and Results The study population was participants aged 6+ years with an HBV vaccination history and an HBV serologic test from the National Health and Nutrition Examination Survey, 1999–2018. Participants aged 18+ years with linked mortality records from 1999–2014 were followed for mortality analysis. Multivariable logistic regression was used to compute vaccine effectiveness (VE) overall, by year of birth, and by age. Cox regression was used to estimate HRs for all‐cause, cancer‐related, and cardiovascular disease–related mortality. A total of 64,107 participants were included in the main analysis, with 29,600 (40.7%) having completed HBV vaccination (three or more doses, vaccinated). The highest vaccination uptake was found among those born after 1991, at 86.5%. Vaccinated participants had higher prevalence of vaccine‐induced immunity than the unvaccinated (47.2% vs. 7.4%). Among those born after 1991, VE was found at 58% (95% CI, 18%–79%) overall and 85% for those aged ≥20 years (mean age, 22), whereas no effect was found among those born prior to 1990. HBV vaccination was associated with reduced risk of all‐cause mortality (HR, 0.78; 95% CI, 0.68–0.90) and cancer‐related mortality (HR, 0.76; 95% CI, 0.58–1.00) but not for cardiovascular disease–related mortality. Conclusions In the universal infant vaccination era, the HBV vaccine has shown substantial effectiveness against HBV infection and maintained strong protection for 20 years. It was also associated with reduced risk of all‐cause and cancer‐related mortality.
IOTG-02. Glioma Supra Marginal Incision Trial (G-SUMIT): a phase II pilot randomized control trial to assess the feasibility of “supra-marginal” surgical resection of malignant glioma
Authors: Carolyn Lai, Alireza Mansouri, Damon Scales, James Perry, Arjun Sahgal, Farhad Pirouzmand
Journal: Neuro-Oncology (2021)

Abstract High grade gliomas are the most common primary malignant brain tumor in adults having a median survival of only 13–16 months. This is despite the current standard of maximal safe surgical resection followed by fractionated radiotherapy and chemotherapy. Extending the tumor resection limit beyond the GAD-enhancing margin (i.e. supra-marginal resection) could in principle provide an added survival benefit as it has been shown that &amp;gt;80% of post-operative tumor recurrence is within a 2cm region surrounding the original GAD-enhancing margin. However, this must be weighed against the risk of potential damage to functional brain tissue. In this phase II pilot randomized control trial (RCT), we aim to assess the feasibility of “supra-marginal” resection extending 1cm beyond the enhancing tumor in adults with radiographic evidence of GAD-enhancing intra-axial tumour consistent with high grade glioma in a safe anatomical location and a Karnofsky Performance Score &amp;gt; 60. With six academic centres participating, we aim to enroll 72 patients over two years. Currently, four patients have already been enrolled in the first four months. Primary outcomes include evaluating the feasibility of performing a large-scale trial with regards to recruitment, allocation and outcome documentation as well as safety data. Secondary outcomes include determining if there is an increased survival benefit with supra-marginal resection and impact on quality of life. Our pilot RCT will test the feasibility of comparing standard gross total resection of GAD-enhancing tumour and supra-marginal resection to prepare for a larger definitive multicentre RCT.
BIOM-21. THE SIGNIFICANCE OF TERT PROMOTER MUTATIONS, TELOMERE LENGTH AND MGMT PROMOTER METHYLATION IN NEWLY DIAGNOSED AND RECURRENT IDH-WILDTYPE GLIOBLASTOMA (GBM): A LARGE MONO-INSTITUTIONAL STUDY
Authors: Giuseppe Lombardi, Silvia Giunco, Francesco Cavallin, Chiara Angelini, Mario Caccese, Giulia Cerretti, Pasquale De Bonis, Anita De Rossi, Vittorina Zagonel
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND the significance of TERT promoter mutations, telomere length and their interactions with MGMT methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a monoinstitutional study to better investigate their impact and their interaction on clinical outcomes. METHODS TERTmutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation were assessed in 278 newly-diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated from Dec2016 to Jan2020. We explored association between gene characteristics and neuroradiological response, PFS, OS. Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio. RESULTS characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS0-1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMTmet in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4-11.37). ORR was reported in 15% of PTS, medianOS was 15 ms (95% CI 13-18 ms), medianPFS was 8 ms (95% CI 7-9 ms). At multivariable analysis, TERT mutations and RTL were not associated with clinical outcomes; about OS, TERT mutations and RTL reported a HR of 1.05 (95% CI 0.64-1.64) and 0.99 (95% CI 0.89-1.10), respectively; MGMTmet tumors showed significant improved PFS and OS with a HR of 0.54(95% CI 0.40-0.71) and 0.47 (95% CI 0.34-0.64), respectively. All interactions among MGMT-status, TERT-mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS0-1 in 60% of PTS, MGMTmet in 37%, TERT mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68-8.87). At multivariable analysis, only MGMTmet tumors resulted significantly associated to prolonged OS(HR0.16;95%CI0.07-0.40). No gene interaction was significant. CONCLUSIONS we analyzed the impact of TERT mutations, RTL and MGMT in newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT status and RTL were not associated with clinical outcomes. MGMT was the only prognostic factor. No significant interaction was demonstrated between TERT mutations, RTL and MGMT
Abstract 10631: Exosome-Encapsulated Adeno-Associated Viruses as a Novel Cardiotropic Vector for Gene Therapy in Heart Failure
Authors: Sabrina La Salvia, Xisheng Li, Yaxuan Liang, Marta Adamiak, Mihir Parikh, Kimberly Okoli, Edgar Gonzalez-Kozlova, Navneet Dogra, Nicole C Dubois, Roger J Hajjar, Susmita Sahoo
Journal: Circulation (2021)

Adeno-associated viruses (AAVs) are the vectors of choice for long-term delivery of genes to the heart and due to their safety in clinics. Despite its many favorable features, a notable drawback is the presence of preexisting neutralizing antibodies (NAb), which bind to free AAVs and impair their clinical effect. Here, we describe delivery of AAVs encapsulated in extracellular vesicles (eAAV), as a superior cardiac gene delivery system that offers higher NAb resistance. Methods: Ultracentrifuge-isolated eAAVs were characterized using TEM, DLS, qNano, nanoflow cytometry, ExoView, qPCR and Western blot. Gene delivery efficacy of free AAV and eAAVs were compared with and without NAbs using human cardiomyocytes in vitro, and in mice in vivo, using flow cytometry (with mCherry) and bioluminescence imaging (with luciferase). Therapeutic efficacy of gene delivery by free AAV and eAAV in presence and absence of NAb was determined using a cardiac contractile gene SERCA2a in a mouse model of myocardial infarction (MI). eAAV uptake and trafficking was studied both in vitro and in vivo using fluorescence dye-labeled eAAV. Results: eAAV outperformed free AAV in delivering genes even in the presence of NAbs, both in vitro and in vivo. SERCA2a delivered by eAAV significantly improved cardiac function (ejection fraction, %EF, ~60%) compared to when delivered by free AAV (~40%) or saline control (~20%), in intramyocardially injected MI mice with NAb. Fluorescence-tagged eAAVs injected to mouse hearts were internalized into all cell types (CMs and non-CMs), but, eAAV-mCherry was primarily expressed in CMs, indicating that eAAV-mediated gene delivery is cardiotropic. eAAVs were uptaken in to acidic endosomal (Rab5 &amp; 7 positive) compartments of cultured cardiomyocytes and delivered significantly higher amounts of luciferase to the nucleus of human CMs compared to free AAVs. This uptake of eAAVs was inhibited by the proton pump inhibitor in endosomes, Bafilomycin A1. Conclusion: Our study demonstrated that eAAV-mediated gene delivery can circumvent neutralizing antibody (NAb) issue for gene therapy. eAAVs are cardiotropic and deliver genes to the nucleus via uptake into acidic endosomes. eAAV is a superior gene delivery vector and a new platform to treat heart failure.
The impact of comorbidities on selexipag treatment effect in patients with pulmonary arterial hypertension: insights from the <scp>GRIPHON</scp> study
Authors: Stephan Rosenkranz, Richard Channick, Kelly M. Chin, Bartosz Jenner, Sean Gaine, Nazzareno Galiè, Hossein‐Ardeschir Ghofrani, Marius M. Hoeper, Vallerie V. McLaughlin, Camille Du Roure, Lewis J. Rubin, Olivier Sitbon, Victor Tapson, Irene M. Lang
Journal: European Journal of Heart Failure (2021)

Abstract Aims The number of pulmonary arterial hypertension (PAH) patients with comorbidities is increasing and there are limited data on response to PAH‐targeted therapies in this population. These post hoc analyses explored the effect of selexipag in PAH patients with cardiovascular comorbidities in the GRIPHON study. Methods and results Randomized patients ( n = 1156) were classified using three methods: (i) by subgroups defined according to previously published comorbidity count and restrictive haemodynamic criteria: Subgroup A (&lt;3 comorbidities and haemodynamic criteria met; n = 962) and Subgroup B (≥3 comorbidities and/or haemodynamic criteria not met; n = 144); comorbidities included body mass index ≥30 kg/m 2 , essential hypertension, diabetes, history of coronary artery disease; (ii) by number of comorbidities, with addition of atrial fibrillation (0, 1, 2, 3, 4, or 5); (iii) by presence of individual comorbidities. Selexipag to placebo hazard ratios (HR) and 95% confidence intervals (CI) for morbidity/mortality (primary composite endpoint) were estimated using Cox regression adjusting selexipag effect for baseline covariates. Approximately half of the patients in GRIPHON ( n = 584; 50.5%) had comorbidities. Selexipag reduced the risk of a morbidity/mortality event compared with placebo in both Subgroup A (HR 0.66, 95% CI 0.53, 0.82) and Subgroup B (HR 0.50, 95% CI 0.26, 0.96), with no evidence of an inconsistent treatment effect between subgroups (interaction p = 0.432). Consistent results were observed in analyses by number and by specific type of comorbidity. Conclusion Selexipag reduces the risk of a morbidity/mortality event vs. placebo irrespective of patient comorbidity status, suggesting that comorbidity status does not influence the treatment effect of selexipag.
Abstract 12300: Impact of Catheter Contact Angle on Local Impedance Drop and Lesion Size Using the INTELLANAV STABLEPOINT Ablation Catheter: Insight From a Porcine Experimental Study
Authors: Gen Matsuura, Hidehira Fukaya, Emiyu Ogawa, Sota Kawakami, Mitani Yutaro, Yusuke Murayama, Daiki Saito, Tetsuro Sato, Hironori Nakamura, Naruya Ishizue, Jun Oikawa, Jun Kishihara, Shinichi Niwano, Junya Ako
Journal: Circulation (2021)

Background: Local impedance (LI) at a distal tip of the ablation catheter can indirectly measure tissue temperature during radiofrequency catheter ablation (RFCA). LI decreases by RFCA, and a degree of LI drop is correlated with lesion size. However, data on the effects of catheter contact angle on LI parameters were scarce. This study aimed to evaluate the influence of catheter contact angle on LI change and lesion size in a porcine experimental model. Methods: Lesions were created on porcine myocardial left ventricles by the LI and Contact force(CF)-sensing ablation catheter (INTELLANAV STABLEPOINT™). Radiofrequency ablation was performed with a power of 30 watts and a duration of 30 seconds. CF (0, 5, 10, 20, and 30g) and catheter contact angle (30°, 45°, and 90°) were changed in each set (total 120 lesions, n=8 each). LI rise by catheter contact, LI drop by RF application, and lesion size (lesion width, surface width, and lesion depth) were evaluated. Results: The values of LI rise increased as CF increased. Regarding the difference of catheter angles, LI rise with 90° was lower than those with 30°. The LI drop also increased as CF increased in all contact angles. The LI drop with 90° was lower than those with 30° in CF 5, 10, 20, and 30 g, respectively. Maximum lesion width and surface width were smaller in 90° than those in 30°, whereas there were no differences in maximum lesion depth except for CF 5g. The approximate curves were well fitted with a quadratic equation in all angles on LI drop vs. maximum lesion width, and lesion depth. Conclusion: Under the same CF, the values of LI drop and lesion width in 90° were significantly lower than those in 30° despite lesion depths were not different among the three angles. LI drop correlates with lesion width and lesion depth at any angle, which may be a good predictor of lesion size.
Abstract 13058: Outcomes With Venoarterial Extracorporeal Membrane Oxygenation for Acute Myocarditis: A 20-year Experience From the ELSO Registry
Authors: Jose I Nunez, Tiago Reyes-Castro, kevin kennedy, Peter Rycus, Joseph Tonna, Marwa A Sabe, Lisa M Fleming, Roy Sriwattanakomen, Pablo A Quintero Pinzon, Shweta R Motiwala, Edward Grandin, Arthur Reshad Garan
Journal: Circulation (2021)

Introduction: Acute myocarditis can result in severe hemodynamic compromise requiring venoarterial extracorporeal membrane oxygenation (VA-ECMO). Outcomes with VA-ECMO and factors associated with mortality are not well described and mostly confined to small cohorts in this population. Methods: We queried the ELSO registry from 2000-2020 for adults with acute myocarditis undergoing VA-ECMO support, excluding patients with non-cardiac support, central cannulation, and multiple ECMO runs. The primary outcome was in-hospital mortality, and secondary outcomes were the incidence of major adverse events during ECMO. We used multivariable logistic regression modeling to examine factors associated with in-hospital mortality. Results: Among 956 patients with acute myocarditis supported with VA-ECMO, 338 (36.2%) died before hospital discharge. The patients had a mean age of 40.7 years, 51.0% were male, 42.5% of Asian race, mean weight was 73.7 kg, and 31.6% suffered a cardiac arrest before support. Prior to ECMO initiation the mean arterial pressure was 63.5 mmHg, pH 7.28, and 26.1% required &gt;2 vasopressors. After multivariable modeling, risk factors for mortality were earlier year of support, older age, higher weight, extracorporeal cardiopulmonary resuscitation modality, lower blood pressure, lower pH, and need for &gt;2 vasopressors prior to VA-ECMO initiation ( Figure: Panel A ). Major complications during VA-ECMO support were more common among non-survivors ( Figure: Panel B ). Conclusions: For patients with myocarditis, outcomes with VA-ECMO are favorable with nearly 2/3 of patients surviving to discharge. Predisposing factors for inpatient mortality include markers of illness severity, including lower blood pressure, lower pH, need for multiple vasopressors, and ongoing cardiopulmonary resuscitation. Use of VA-ECMO prior to severe hemodynamic collapse and minimizing complications during ECMO support could improve outcomes in this population.
Abstract 12891: Loss of Stem Cell Antigen-1 Worsens Vessel Remodeling
Authors: Tao Wang, Abdul Momen, Felix Chiu, Faisal Alibhai, Renke Li, Clint S Robbins, Mansoor Husain
Journal: Circulation (2021)

Background: Stem cell antigen-1 (Sca-1)-expressing progenitor cells contribute to vessel remodeling by differentiating into vascular smooth muscle cells and related myofibroblast-like progeny. However, the functional role for Sca-1 expression in vessel remodeling has not been examined. Here, we assessed the requirement for vascular Sca-1 using a mouse model of Sca-1 deficiency. Methods &amp; Results: Male and female Sca-1-deficient mice (Sca1KO) and C57BL/6N wild-type mice (WT) controls, aged 12-14-wk, were subjected to wire denudation injury of the left common carotid artery. Sca1KO displayed larger neointima at 14d post-injury [35±3mm 2 vs. 25±3mm 2 , p&lt;0.05, n=11-12/group], and more adventitial matrix at 8d [87±3mm 2 vs. 58±4mm 2 , p&lt;0.001, n=9-11/group] and 14d post-injury [109±10mm 2 vs. 51±11mm 2 , p&lt;0.01, n=11-12/group] by Masson’s trichrome staining. Underlying these differences, cell numbers per cross-section were increased in adventitia at 8d [649±27 vs. 435±30, p&lt;0.001, n=9-11/group] and 14d post-injury [778±45 vs. 485±47, p&lt;0.001, n=11-12/group]. Non-leukocyte proliferation by CD45 - Ki67 + staining was increased 1.8-fold in neointima [p&lt;0.01, n=9-11/group] and 1.4-fold in adventitia [p&lt;0.05, n=9-11/group] at 8d post-injury in Sca1KO vs. WT. Cell-type analyses of Sca1KO vs. WT revealed increased pro-fibrotic vimentin + cell proportions at 8d [1.4-fold in neointima, p&lt;0.05; 2.5-fold in media, p&lt;0.001; 1.8-fold in adventitia, p&lt;0.001; n=9-11/group] and 14d post-injury [1.5-fold in neointima, p&lt;0.05; 1.8-fold in media, p&lt;0.05; 1.9-fold in adventitia, p&lt;0.001; n=11-12/group]. CD45 + leukocyte proportions were increased 1.5-fold in neointima [p&lt;0.01, n=9-11/group] and 1.4-fold in adventitia [p&lt;0.01, n=9-11/group] at 8d post-injury, which was also increased 1.5-fold in adventitia by 14d [p&lt;0.01, n=11-12/group]. Conclusion: Taken together, our findings suggest that the loss of Sca-1 worsens remodeling by disinhibiting proliferative, pro-fibrotic, and immune responses to injury, demonstrating a critical role for vascular Sca-1 expression, which may inform novel strategies for the prevention and treatment of vessel remodeling.