tbuckley/cabot-search huggingface dataset:
EXTH-62. COMBINATORIAL THERAPY TARGETING TRANSCIPTION AND IMMUNO-METABOLISM IN RECURRENT GLIOBLASTOMA
Authors: Pratiksha Dighe, Rinette Woo, Nathan Salomonis, Anu Bhattacharjee, Mehdi Nosrati, Pierre Desprez, Larry Dickinson, Sean McAllister, Liliana Soroceanu
Journal: Neuro-Oncology (2021)

Abstract Recurrent glioblastomas (GBM) are notoriously difficult to treat, and in spite of aggressive chemo- and radiation therapy they inevitably recur in almost all GBM patients within 14 months following initial diagnosis. To interrogate pathways driving therapeutic resistance, we compared matched primary and recurrent IDH wild type glioblastoma samples from a cohort of patients, using RNA-Seq. Our analyses showed that pathways involved with tumor immune and metabolic reprogramming were up-regulated in recurrent GBMs compared to untreated, primary samples. Based on these findings, we tested the anti-tumor efficacy of over 20 rationally selected targeted therapeutic agents alone and in combination in a high-throughput drug screen assay designed to measure long term cell viability of primary tumorspheres from patients who underwent surgery for recurrent GBM. Top performing drug combinations from these screens were validated in vivo using patient-derived intracranial mouse models of glioma. Our data demonstrated that the combination of the transcriptional/metabolic inhibitor TG02 and the dual PI3K/mTOR inhibitor GDC-0084 significantly prolonged in vivo survival of tumor bearing mice, performing better than either drug alone. Notably, both inhibitors are undergoing human clinical trials as single agents with positive initial safety profiles and superior blood brain barrier penetrance. RNA Seq and functional assays of tumor samples from treated mice showed that only the combination treatment (TG02 + GDC-0084) significantly inhibited expression of immunomodulatory cytokines driving tumor progression, including those identified by us to be overexpressed in recurrent human GBM samples. Overall, these data suggest that combining TG02 and GDC-0084 is an effective treatment for recurrent GBMs. Furthermore, our results support the use of a translational research platform consisting of a personalized pharmaco-genomics testing, using patient-derived tumor samples towards designing more effective treatment for recurrent GBM patients.
Abstract 13916: The Obesity Paradox in ST-elevation Myocardial Infarction
Authors: Georgia Mattingly, Mehmet Yildiz, Rebekah Lantz, Brynn Okeson, Frank V Aguirre, Mark Tannenbaum, Santiago Garcia, Timothy D Henry, Odayme Quesada
Journal: Circulation (2021)

Introduction: In patients with known cardiovascular disease (CVD), body mass index (BMI)-defined obesity has been found to be protective against all-cause mortality and CVD events, commonly known as the “obesity paradox”. However, the role of BMI in STEMI outcomes remains poorly understood. Methods: The Midwest STEMI Consortium database of 15,039 consecutive STEMI activations between January 2010 and December 2020 consists of four regional STEMI centers. Using data from two centers with complete follow-up available, Minneapolis Heart Institute and The Christ Hospital, we examined differences by BMI groups defined as normal (18.5-24.9 kg/m 2 ), overweight (25.0-29.9 kg/m 2 ), and obese (≥30.0 kg/m 2 ) in baseline characteristics, treatment, in-hospital death and 1-year MACE and mortality risk. Results: Among 4,682 patients (22% normal BMI, 36% overweight and 42% obese), obese patients were significantly younger but had higher rates of hypertension, diabetes, dyslipidemia, and were taking more cardiac medications prior to admission. Systolic and diastolic blood pressures, heart rate, and creatinine were highest in the obese subgroup. Obese patients had a higher rate of out of hospital cardiac arrest (9.2% vs. 9.6% vs. 12%, p=0.02) and a trend towards higher in-hospital death (5.7% vs. 4.7% vs. 6.4%, p=0.08). Overweight and obese patients had a lower risk of 1-year mortality (4.6% vs. 2.6% vs. 2.9%) and a trend towards lower 1-year MACE events (7.6% vs. 5.5% vs. 5.9%) compared to normal BMI patients (Figure). Discussion: Among individuals presenting with STEMI, despite more risk factors, higher rates of out of hospital cardiac arrest and a trend towards higher in-hospital death, overweight and obese patients had lower 1-year mortality consistent with the obesity paradox. Further research is needed to understand the obesity paradox in STEMI patients.
Abstract 12430: Evolution of Anti-SARS-CoV-2 IgG Antibody and IgG Avidity Post Pfizer and Moderna mRNA Vaccinations
Authors: Kevin Bliden, Tiancheng Liu, Deepika sreedhar, Udaya Tantry, jessica kost, Jessica Hsiung, su zhao, Dingying Shan, Abira Usman, Naval Walia, Alastair Cho, Christophe Jerijan, Hongjie Dai, Meijie Tang, Paul A Gurbel
Journal: Circulation (2021)

Introduction: Messenger RNA (mRNA) based vaccines (Pfizer/BioNTech and Moderna) have shown to be highly effective at providing immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Aims: To study the duration of immunity, evolution of IgG antibody levels and IgG avidity (an index of antibody-antigen binding strength), and differences in immune responses between (mRNA) based vaccines. Methods: We performed a prospective study of 72 subjects without a history of SARS-CoV-2 who received both doses of either the Pfizer (n=55) or Moderna (n=17) mRNA vaccine. Anti-spike protein receptor binding domain (RBD) IgG antibody levels and IgG avidity indices were measured longitudinally using a qualitative finger stick MidaSpot™ rapid test at the point-of-care and a quantitative dry blood spot-based pGOLD™ laboratory test over ~ 4 months post-vaccination. Results: On average, anti-RBD IgG antibody levels peaked at ~2 weeks after second vaccination dose and declined thereafter, while antibody avidity increased suggesting antibody maturation (Figure). Moderna vaccine recipients exhibited higher side effect severity, higher peak anti-RBD IgG antibody levels and higher avidity up to the 90 days point, when compared to Pfizer vaccine recipients. Nevertheless, the differences in antibody and avidity levels diminished at ~ 120 days post- vaccination, in line with the similar efficacy of the two vaccines. A qualitative MidaSpot finger stick rapid test detected 100% anti-SARS-CoV-2 RBD positivity for fully vaccinated subjects in both Pfizer and Moderna cohorts and turning negative greater than 90 days post-vaccination for 9% of subjects in the Pfizer cohort whose quantitative anti-IgG fell below the 25-percentile levels. Conclusions: Longitudinal quantitative measurements of anti-RBD antibody and avidity levels provide insight to immune responses and could aid the assessment of immunity and vaccine effectiveness.
Abstract 11266: Murine Adult Epicardium Requires Hypoxia for Progenitor and Multipotency Ability
Authors: Angeliqua Sayed, Szimonetta Turoczi, Francisca Soares-da-Silva, Giovanna Marazzi, Jean S Hulot, David Sassoon, Mariana Valente
Journal: Circulation (2021)

Introduction: The epicardium is a source of the coronary vasculature and stroma during heart development. Although quiescent in the physiological adult heart, increasing evidences indicate the potential epicardium activation and differentiation into its progeny after cardiac injury; however, this remains debated. Hypothesis: We hypothesize that in vivo hypoxia exposure can mimic the embryonic cardiac profile and prime the adult epicardial progenitor cell to a more immature profile. Methods: Perinatal and adult BL6 and Pw1 nLacz hearts were used to track the expression of PW1 - progenitor cell marker - together with cell surface proteins. In vivo hypoxia (10% O 2 ) exposure was used to stimulate the adult heart. Histology, protein expression profiles and single cell analysis were assessed. Freshly FACS isolated Gp38 + PW1 + epicardial cells were cultured to determine their progenitor cell potential (clonogenicity, self-renewal and cell fate potential). Results: Here, we report that PW1 expression decreases during postnatal life, but is maintained in the cardiac hypoxic niche epicardium and subepicardium. Adult mice exhibit increased PW1 expression in epicardial/subepicardial cells and endothelial cells in response to hypoxia. The epicardium and subepicardium are activated to undergo cell proliferation and re-express a subset of embryonic genes in response to hypoxia. We established a new in vitro model to study purified PW1 + /Gp38 + epicardial cells, and we found properties of clonogenicity, self-renewal and multipotency (fibroblast, smooth muscle and endothelial cells) at single cell level in the developing epicardial cells. Cell fate potential towards an endothelial profile is dependent upon low levels of oxygen, and the in vitro ability to grow in culture is restore after in vivo priming of the adult heart. Conclusions: In conclusion our data support that the resident PW1 + /Gp38 + epicardial cells are a reminiscent progenitor population in adult mammalian heart that can be reactivated by exposure to hypoxia, highlighting the potential therapeutic role of hypoxia in regenerative medicine.
Integrative Study of a High-Grade B-Cell Lymphoma Cohort of 45 Patients: A Single Institution Real Life Study
Authors: Louise Roulin, Elsa Poullot, Paul Blanc-Durand, Cyrielle Robe, Francois Lemonnier, Fabien Le Bras, Romain Gounot, Karim Belhadj, Jehan Dupuis, Mohammad Hammoud, Taoufik El Gnaoui, Sebastien Mule, Christiane Copie Bergman, Thierry Molina, Marie Helene Delfau Larue, Emmanuel Itti, Philippe Gaulard, Corinne Haioun
Journal: Blood (2021)
Abstract 13007: Change in QRS 3D Voltage Time Integral (3D QRS Area) Predicts Left Ventricular Reverse Remodeling in Sacubitril-Valsartan Treated Patients With Left Bundle Branch Block
Authors: Nikhil K Parimi, Uzair Mahmood, Anas Abudan, Farhad Sami, Sean Lacy, Christopher J Harvey, Madhu Reddy, Seth H Sheldon, Amit Noheria
Journal: Circulation (2021)

Introduction: The instantaneous absolute 3D ECG voltage integrated over the duration of QRS (VTI QRS-3D ) is an improved marker of left ventricular (LV) electrical dyssynchrony compared to QRS duration (QRSd). Among patients with left bundle branch block (LBBB) receiving heart failure medical therapy, the relationship between electrical remodeling assessed by VTI QRS-3D and structural LV remodeling is unclear. Hypothesis: Reduction in VTI QRS-3D is correlated with left ventricular reverse remodeling. Methods: We retrospectively studied heart failure patients with underlying LBBB who were treated with sacubitril-valsartan for ≥3 months between January 2014 - June 2019. Echocardiograms and 12-lead ECGs were collected pre and post sacubitril-valsartan treatment. ECGs were converted to orthogonal X, Y, Z leads using Kors matrix, to then obtain VTI QRS-3D . Echocardiographic LV measures included end-diastolic volume (LVEDV), end-systolic volume (LVESV) and ejection fraction (LVEF). We calculated the Pearson correlations between electrical variables and changes in echocardiographic measures pre to post treatment. Results: We included 56 patients (mean age 64.0±13.5 years, men 53.6%, baseline LVEF 25.2±9.1%). ΔVTI QRS-3D was strongly correlated with improvement in all 3 echocardiographic measures (all p ≤0.01). ΔVTI QRS-3D outperformed ΔQRSd in predicting echocardiographic response (Table). Conclusions: In heart failure patients with LBBB on medical therapy, electrical remodeling assessed as reduction in VTI QRS-3D is strongly predictive of LV structural and functional reverse remodeling.
Anlotinib Induces a T Cell–Inflamed Tumor Microenvironment by Facilitating Vessel Normalization and Enhances the Efficacy of PD-1 Checkpoint Blockade in Neuroblastoma
Authors: Yudong Su, Bingying Luo, Yao Lu, Daowei Wang, Jie Yan, Jian Zheng, Jun Xiao, Yangyang Wang, Zhenyi Xue, Jie Yin, Peng Chen, Long Li, Qiang Zhao
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Anlotinib has achieved good results in clinical trials of a variety of cancers. However, the effects of anlotinib on the tumor microenvironment (TME) and systemic immunity have not been reported. There is an urgent need to identify the underlying mechanism to reveal new opportunities for its application in neuroblastoma (NB) and other cancers. Understanding the mechanism will hopefully achieve the goal of using the same method to treat different cancers. Experimental Design: This study used bioinformatics, NB syngeneic mouse models, flow cytometry, RNA-seq, and immunofluorescence staining to explore the mechanisms of anlotinib on the TME, and further explored anlotinib-containing combination treatment strategies. Results: We proved that anlotinib facilitates tumor vessel normalization at least partially through CD4+ T cells, reprograms the immunosuppressive TME into an immunostimulatory TME, significantly inhibits tumor growth, and effectively prevents systemic immunosuppression. Moreover, the combination of anlotinib with a PD-1 checkpoint inhibitor counteracts the immunosuppression caused by the upregulation of PD-L1 after monotherapy, extends the period of vascular normalization, and finally induces NB regression. Conclusions: To our knowledge, this study is the first to dynamically evaluate the effect of a multitarget antiangiogenic tyrosine kinase inhibitor on the TME. These findings have very important clinical value in guiding the testing of related drugs in NB and other cancers. Based on these findings, we are conducting a phase II clinical study (NCT04842526) on the efficacy and safety of anlotinib, irinotecan, and temozolomide in the treatment of refractory or relapsed NB, and hopefully we will observe patient benefit.
Management of Myeloproliferative Neoplasms during Pregnancy: A Systematic Review
Authors: Karun Neupane, Tehniat Faraz, Adeel Masood, Vinayak Aryal, Saman Bahram, Laila Khalid, Nazma Hanif, Abdul Rafae, Hira G. Shaikh, Zahoor Ahmed, Mohammad Ebad Ur Rehman, Muhammad Salman Faisal, Faiz Anwer
Journal: Blood (2021)
The mental health of transgender and gender non-conforming people in China: a systematic review
Authors: Yezhe Lin, Hui Xie, Zimo Huang, Quan Zhang, Amanda Wilson, Jiaojiao Hou, Xudong Zhao, Yuanyuan Wang, Bailin Pan, Ye Liu, Meng Han, Runsen Chen
Journal: The Lancet Public Health (2021)

Transgender and gender non-conforming (TGNC) individuals are at a high risk of adverse mental health outcomes due to minority stress—the stress faced by individuals categorised as stigmatised social minority groups. This systematic review sought to summarise the key mental health findings of the research on TGNC individuals in mainland China. We also aimed to consolidate research on the topic, identify specific mental health disparities, and offer new perspectives for future research to inform both policy and clinical practice. An extensive search of the literature, published in English and Chinese, was done between Jan 1, 1990, and Aug 1, 2021, using PubMed, PsycINFO, Scopus, Wanfang (in Chinese), and CNKI (in Chinese). Overall, two qualitative and 28 quantitative articles were identified. The quantitative findings showed a high prevalence of mental health problems, such as depression, anxiety, substance use disorders, and stress-related issues, and greater disparities in psychological wellbeing. High prevalence is also reported in suicidality and self-harm behaviours in this group. Across the two qualitative studies, attributable factors included gender-related discrimination, barriers to accessing health services, low social support, decreased knowledge and awareness of HIV prevention, and demographic characteristics—such as marital status, educational level, and gender identity. This Review also found little evidence of gender-affirming care and mental health interventions in mainland China. Following from these results, the next step is to integrate multi-level, social-psychological interventions with education to reduce cultural stereotypes and transphobia in mainland China. Political and social implications are also discussed to inform a standard set of guidelines for transgender-inclusive health-care services, including advocating for funding to create these special care programmes and services.
Abstract 11008: Hypoglycemia in Stemi is Associated with Higher Mortality and Morbidity, Irrespective of the Presence of Diabetes
Authors: Basel Humos, SOHA DARGHAM, Jassim Al suwaidi, Hani Jneid, Charbel Abi Khalil
Journal: Circulation (2021)

Introduction: Hyperglycemia in patients admitted for STEMI is associated with a worse outcome Hypothesis: We hypothesized that hypoglycemia in patients hospitalized for STEMI is also associated with a higher morbidity and mortality. Methods: We used data from the National Inpatient Sample (2005-2017) to identify adult patients admitted with STEMI as the primary diagnosis. Secondary diagnosis was hypoglycemia. We compared cardiovascular and socio-economic outcomes between STEMI patients with and without hypoglycemia and assessed temporal trends. Results: Hypoglycemia tends to complicate 0.117% of all cases hospitalized for STEMI. The mean age of STEMI patients hospitalized with hypoglycemia has been slightly trending down, from 67.40 ± 15 in 2005 to 63.86 ± 12 in 2017 (p=0.046). Mortality was stable with time, but the prevalence of ventricular tachycardia (VTach) and ventricular fibrillation (Vfib) decreased, total charges and length of stay (LOS) increased. Compared to non-hypoglycemic patients, those with developed hypoglycemia were older, more also likely to be males (64.4%) and whites (72.1%), only 6.7% had a history of diabetes as compared to 28.5% in STEMI patients (p=0.001). Cardiovascular events were more likely to occur in the presence of hypoglycemia: mortality risk increased by almost 4-fold (4.490 [4.174 - 5.848]. There was also a higher risk of cardiogenic shock (OR= 1.718 [21.387 - 2.127], VFib (OR=1.799 [1.406 - 2.301]), AF (OR=1.28 [1.025 - 1.607]), acute renal failure (OR= 2.355 [1.902 - 2.917] but not stroke (all ORs were adjusted, including on the presence of diabetes). Patients who developed hypoglycemia were less likely to have PCI (OR= 0.488 [0.417 - 0.571] but more likely to have CABG (OR= 2.259 [1.814 - 2.814]. They had a longer in-hospital stay and cost more than non-hypoglycemia patients. Sensitivity analysis though propensity-score matching confirmed our findings. Conclusions: Hypoglycemia was found to complicate 0.117% of all patients hospitalized with STEMI. Patients with hypoglycemia were found to have higher odds of mortality and cardiovascular complications during their hospital stay compared to patients without hypoglycemia, irrespective of the presence of diabetes at baseline.
Abstract 12569: Gender Differences in Patients’ Experiences of Discussions About and Attitudes Toward Replacement and Deactivation of Their ICD at End-of-Life
Authors: Muna H Hammash, Gabrielle Mc Kee, Chantal Ski, David Thompson, Ingela Thylen, Jennifer Miller, Kyoung S Lee, Donna Fitzsimons, Sharon O'Donnell, Frances O'Brien, Mary Mooney, Debra K Moser
Journal: Circulation (2021)

Introduction: Gender disparities are well documented in cardiovascular care, and women are underrepresented in cardiovascular studies. Gender differences in experiences and attitudes toward replacement and deactivation of implantable cardioverter defibrillators (ICD) at the end-of-life (EOL) are less well studied. Purpose: To determine if there are gender differences in patients’ experiences of discussions about and attitudes toward replacement of their ICD at end-of-service and ICD deactivation at EOL. Methods: This cross-sectional study included 3,465 ICD recipients living in the United States, Australia, Ireland, Sweden, and South Korea (21% women with mean age 65 + 12). We used the experiences subscale (10 items) and attitudes subscale (18 item) of the EOL-ICD questionnaire. Chi-square test was used to explore potential differences in experiences of discussion and attitude toward ICD treatment at EOL by gender; differences between the scale single items were assessed. Results: Women were more likely than men to think about questions concerning EOL, X 2 (2, N = 3,444) = 34.1, p &lt; .001). Women had more experience discussing battery replacement with their clinician ( p &lt; .01) and next of kin ( p &lt; .001), and ICD deactivation at EOL with their next of kin ( p = .01), but they were less likely to discuss their illness trajectory with their clinician ( p = .02)). There were no differences between women and men regarding the time they would like their clinician to start the conversation about ICD deactivation. Men were more reluctant than women to change their ICD battery or turn the device off even if they were dying of cancer or having daily shocks (( p &lt; .001). Conclusion: Gender differences in patients’ attitude toward ICD treatment are evident. This might be related to many factors including prior experience of discussing EOL issues with their clinician. Further studies to explore the reasons for gender differences in patients’ experiences of discussions and attitude toward ICD treatment are warranted.
Intercepting psoriatic arthritis in patients with psoriasis: buy one get one free?
Authors: Dennis G McGonagle, Alen Zabotti, Abdulla Watad, Charlie Bridgewood, Gabriele De Marco, Andreas Kerschbaumer, Daniel Aletaha
Journal: Annals of the Rheumatic Diseases (2021)

Psoriatic arthritis (PsA) mostly develops in patients with an established diagnosis of psoriasis (PsO).1 Following the onset of PsA, structural articular damage and loss of function often occur, leading to impairment in quality of life above and beyond that seen in PsO alone.2 PsO registry studies show a progression to PsA in around 1.5%–3% per year in PsO subjects, although figures may be even higher when PsO associates with other factors (eg, arthralgia).3 Reducing this rate of PsA development and identifying PsO subjects at higher risk for PsA progression is of paramount importance, especially given that many PsO therapies have been independently verified as being efficacious for established PsA. Therefore, by extension, these therapies might also be expected to work at the earliest stages of PsO-associated inflammatory arthritis, where better therapeutic effectiveness is generally expected.4

The ability to characterise the preclinical phases of autoimmune diseases, as initially in type 1 diabetes (T1DM),5 was followed by other diseases, including rheumatoid arthritis (RA)6 or autoimmune connective tissue diseases.7 They provide the unique window of opportunity for therapeutic interventions in the preclinical stage of disease. Interventions applied at this point, as the hypothesis goes, would minimise disease burden and subsequent irreversible joint damage leading to functional impairment and long-term disability, eventually to reducing the complications and socioeconomic impact of disease. Historically, the prevention of diseases, such as T1DM, for example, with cyclosporine, was marred by incomplete responses and drug toxicity.8 Nonetheless, proof of concept for disease prevention was established. In this editorial, we discuss emerging and conflicting evidence about early stage therapy for PsA. Specifically, we will explore the concept of prescription of disease-modifying antirheumatic drugs (DMARDs), including biological DMARDs (bDMARDs), in subjects with moderate-to-severe PsO, at no extra cost to the health payers and …