tbuckley/cabot-search huggingface dataset:
Synergistic and Antagonistic Drug Combinations against SARS-CoV-2
Authors: Tesia Bobrowski, Lu Chen, Richard T. Eastman, Zina Itkin, Paul Shinn, Catherine Z. Chen, Hui Guo, Wei Zheng, Sam Michael, Anton Simeonov, Matthew D. Hall, Alexey V. Zakharov, Eugene N. Muratov
Journal: Molecular Therapy (2020)

Antiviral drug development for coronavirus disease 2019 (COVID-19) is occurring at an unprecedented pace, yet there are still limited therapeutic options for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2, thus generating better antiviral efficacy. Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro. Sixteen synergistic and eight antagonistic combinations were identified; among 16 synergistic cases, combinations of the US Food and Drug Administration (FDA)-approved drug nitazoxanide with remdesivir, amodiaquine, or umifenovir were most notable, all exhibiting significant synergy against SARS-CoV-2 in a cell model. However, the combination of remdesivir and lysosomotropic drugs, such as hydroxychloroquine, demonstrated strong antagonism. Overall, these results highlight the utility of drug repurposing and preclinical testing of drug combinations for discovering potential therapies to treat COVID-19. Antiviral drug development for coronavirus disease 2019 (COVID-19) is occurring at an unprecedented pace, yet there are still limited therapeutic options for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2, thus generating better antiviral efficacy. Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro. Sixteen synergistic and eight antagonistic combinations were identified; among 16 synergistic cases, combinations of the US Food and Drug Administration (FDA)-approved drug nitazoxanide with remdesivir, amodiaquine, or umifenovir were most notable, all exhibiting significant synergy against SARS-CoV-2 in a cell model. However, the combination of remdesivir and lysosomotropic drugs, such as hydroxychloroquine, demonstrated strong antagonism. Overall, these results highlight the utility of drug repurposing and preclinical testing of drug combinations for discovering potential therapies to treat COVID-19.
Noninvasive Differentiation Between Active and Healed Myocarditis by Cardiac Magnetic Resonance: Are We There Yet?⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Heiko Mahrholdt, Udo Sechtem
Journal: JACC. Cardiovascular imaging (2009)
RADT-29. EFFECT OF RADIATION THERAPY ON OVERALL SURVIVAL FOLLOWING SUBTOTAL RESECTION OF ADULT PILOCYTIC ASTROCYTOMA
Authors: Adham Khalafallah, Adrian Jimenez, Henry Brem, Debraj Mukherjee
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pilocytic astrocytoma (PCA) is a low-grade glioma common in children but also rarely diagnosed in adults. The role of adjuvant radiation therapy (RT) in treating these tumors remains unclear. OBJECTIVE We investigated the effect of RT on overall survival, specifically among adult patients who had undergone subtotal PCA resection. METHODS Information on adult patients (age 18 years old) who had undergone subtotal PCA resection between 2004 and 2016 was collected from the National Cancer Database (NCDB). A multivariate Cox proportional hazards model was utilized to determine factors independently associated with overall survival. RESULTS A total of 451 patients were identified. The mean age of our patient cohort was 36.8 years old, and the majority of patients (83.4%) did not receive radiation treatment following subtotal PCA resection. Overall median survival was 93.8 months. Survival was longer (p &amp;lt; 0.001) in the patients who did not receive post-surgical RT (median: 98.3 months) compared to patients who did (median: 54.8 months). Patients who had older age at diagnosis (hazard ratio [HR]=1.05, 95% confidence interval [CI]=1.03-1.07, p &amp;lt; 0.01), were Black or African American (HR=2.76, CI=1.12-6.46, p=0.019), received radiation during their initial treatment (HR=4.53, CI=2.08-9.89, p &amp;lt; 0.01), or had a Charlson/Deyo score of &amp;gt; 1 (HR=3.68, CI=1.55, p=0.003) had a significantly higher risk of death following subtotal PCA resection. CONCLUSION Postoperative RT is independently associated with a significantly higher risk of death among adults who underwent subtotal PCA resection. Our findings provide a rationale for further investigation into the efficacy and safety of RT within this patient population.
DIPG-44. A GAIN OF FUNCTION Ezh2 MUTATION DELAYS DIFFUSE INTRINSIC PONTINE GLIOMA PROGRESSION
Authors: Swati Dhar, Samantha Gadd, Daniel Brat, Oren Becher
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diffuse Intrinsic Pontine Glioma (DIPG) remains an incurable pediatric brain cancer. The oncohistone H3K27M implicated in 80% of the cases, is also predicted to target Enhancer of Zeste Homolog 2 (Ezh2), the catalytic component of the Polycomb Repressor Complex 2 (PRC2). There are no reported mutations of Ezh2 and its function in DIPG is not fully determined. This work aims to address the role of Ezh2 in DIPG. METHODS Brainstem tumors were established by intracranial injections of Nestin;Tv-a; Ezh2Y641F/+ (NTv-a; Ezh2Y641F/+) neonatal pups using Replication Competent Avian Sarcoma leucosis virus long terminal repeat with splice acceptor (RCAS) viruses, expressing PDGF-B, p53 shRNA, and RCAS-CRE/Y. Immunohistochemical staining for Ki-67 and H3K27me3 were performed on the Discovery ULTRA (Ventana). RESULTS Ezh2 overexpression (Ezh2Y641F/+, RCAS CRE) conferred a survival advantage of approximately 10 days (n=20 mice/group, p&amp;lt;0.001). H3K27me3 levels were significantly upregulated in RCAS CRE group (50% vs 20% in RCAS Y, n=4 tumors/group, p&amp;lt;0.03), with a concomitant lower Ki-67 staining (30% vs. 55% in RCAS Y, n=3 tumors/group, p&amp;lt;0.05). Interestingly, pathological review categorized more RCAS-CRE tumors as ‘atypical’. RNA-sequencing of virus-infected neural precursor cells revealed a suppression of inflammatory/interferon gene signature in the Ezh2 overexpression group. CONCLUSIONS AND FUTURE DIRECTIONS: Enhanced Ezh2 activity appears to delay DIPG pathogenesis. Ongoing work aims to highlight the contribution of differentially expressed gene signatures that contribute to this phenotype.
RADT-17. RADIOTHERAPY IN THE MANAGEMENT OF OPTIC NERVE SHEATH MENINGIOMAS: AN INTERNATIONAL SYSTEMATIC REVIEW AND META-ANALYSIS OF EIGHTEEN STUDIES
Authors: Yash J Vaishnav, Raj Singh, Prabhanjan Didwania, Eric J Lehrer, Tatiana Bakaeva, Timothy Harris, Michael E Migliori, Daniel M Trifiletti
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Optic nerve sheath meningiomas (ONSMs) are often managed with radiotherapy (RT) with the goal of achieving radiographic local control (LC) to prevent further decline in visual acuity (VA); however, reports on outcomes are limited to small retrospective series. Thus, we aimed to perform a systematic review and meta-analysis of outcomes for patients with ONSM treated with RT. METHODS A PICOS/PRISMA/MOOSE selection criteria was utilized to identify studies for inclusion. Primary outcomes were stable or improved VA and radiographic LC at last follow-up. The secondary outcome was incidence of radiation-induced retinopathy. Weighted random effects meta-analyses using the DerSimonian and Laird methods were conducted to characterize effect sizes. Mixed effects regression models were used to examine potential correlations between gross tumor volume (GTV) and outcomes. RESULTS In total, 381 patients with ONSM across 18 published studies were included. Of these, 332 and 386 treated ONSMs had information on VA or LC, respectively. Median age was 46.75 (range: 9-87), median/mean GTV was 2.905cc (range: 0.28-26.3), and median follow-up was 51.15 months (range: 1-248.4 months). The estimated LC rate at last follow-up was 100% (95% CI: 98-100%), and the estimated proportion of patients with stable or improved VA at last follow-up was 89% (95% CI: 84-93%). The rate of chronic radiation retinopathy was estimated to be 7% (95% CI: 5-11%). GTV was significantly associated with VA (p=0.014) with estimated VA rates of 96.4%, 91.4%, and 80.5% for GTVs of 2.0, 3.0, and 4.0ccs, respectively. CONCLUSIONS RT was well-tolerated in the treatment of ONSM with excellent LC achieved. Nearly 90% of patients noted either stability or improvement in VA. Larger ONSMs were found to be associated with poorer VA. Incidences of radiation-induced retinopathy were limited and estimated to be less than 10%.
Clinical Outcomes of Patients with Anaplastic Large Cell Lymphoma, Anaplastic Lymphoma Kinase-Negative (ALCL, ALK-): Analysis of 203 Patients Prospectively Registered in the International T-Cell Project
Authors: Andrei Shustov, Monica Bellei, Stefano A. Pileri, Silvia Montoto, Martina Manni, Steven M. Horwitz, Maria Elena Cabrera, Carlos Chiattone, Arnon Nagler, Sonia González de Villambrosia, Maria Angeles Perez Saenz, Francesco Merli, Andrés J M Ferreri, Maria Virginia Prates, Kenneth R. Carson, Alessandro Re, Luigi Rigacci, Luca Nassi, Vittorio Ruggero Zilioli, Massimo Federico
Journal: Blood (2017)
Molecular Definition of Activated B Cell-like (ABC) DLBCL Identifies Patients Who May Benefit from Front-Line Intensive R-HDS Chemotherapy with ASCT
Authors: Federica Melle, Giovanna Motta, Marco Fabbri, Valentina Tabanelli, Angelica Calleri, Riccardo Bruna, Enrico Derenzini, Chiara Corsini, Corrado Tarella, Alessandro M. Gianni, Alessandro Rambaldi, Alessandra Cesano, Stefano A. Pileri
Journal: Blood (2017)
INNV-25. PATIENT CENTERED MULTI-DISCIPLINARY NEURO-ONCOLOGIC CARE AS DIRECTED BY NEW PATIENT STAKEHOLDERS
Authors: Rachel Hunt, Adam Robin, Lisa Scarpace, Nestelynn Gay, Ian Lee, Tobias Walbert, James Snyder
Journal: Neuro-Oncology (2020)

Abstract Multidisciplinary oncology care requires a team of experts which should include patient stakeholders. The Henry Ford Health System (HFHS) Hermelin Brain Tumor Center (BTC) patient and family advisory council (PFAC) recommended a focus group of patient stakeholders newly diagnosed with glioblastoma(GBM) to better understand this experience. Our PFAC, comprised primarily of long-term survivors and patient advocates, felt the perspective of newly diagnosed patients may not be adequately represented. We reviewed the BTC tumor board records, identified patients within six months from GBM diagnosis, and invited these patients and their advocates to participate in an in-person session held November 2019. The BTC Patient Resource Coordinator who is also a brain tumor survivor led the session. Predefined questions prompted discussion of their neuro-oncologic care experience. Patient perspectives and recommendations were disseminated to the BTC PFAC and health system leaders. Nine patients and ten caregivers participated. Key feedback included the need for improved communication in the peri-operative period (symptom presentation until pathology results consultation). Participants requested more information prior to surgery on what to expect after surgery and with a brain tumor diagnosis. The PFAC-developed BTC experience handbook was declared useful, but patients did not receive this book until 2-weeks after surgery. As a result, we ensured that patients received a copy of the handbook at the time of diagnosis. Additionally, the development of a brain tumor surgery “prehab” course is underway. Use of a focus group to obtain input from patients recently diagnosed with GBM provided valuable insight into their experience that can be used to align care pathways with patient needs. Feedback was used to improve the delivery of neuro-oncologic care and enhance patient communication. In the constantly evolving landscape of GBM diagnosis and treatment, it is important to remain attuned to our patients’ perspectives on the care we deliver.
Aldosterone Signaling in Atrial Fibrillation: Another Piece in the Puzzle of Atrial Remodeling**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Panagiotis Korantzopoulos, John A. Goudevenos
Journal: Journal of the American College of Cardiology (2010)
PATH-05. A RETROSPECTIVE STUDY OF TREATMENT STRATEGIES AND OUTCOMES IN WHO GRADE II AND III ISOCITRATE DEHYDROGENASE (IDH) WILD-TYPE ASTROCYTOMA
Authors: Ashley Aaroe, Antonio Dono, Michael Youssef, Kristin Alfaro-Munoz, Shiao-Pei Weathers, Barbara O’Brien, Nazanin Majd, Rebecca Harrison, Monica Loghin, Zaid Soomro, Garret Williford, Gregory Fuller, W K Alfred Yung, Debra Yeboa, Yoshua Esquenazi, Leomar Y Ballester, John de Groot, Carlos Kamiya-Matsuoka
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND WHO grade II and III IDH wild-type astrocytomas behave more aggressively than their IDH mutated counterparts. A subpopulation shares molecular features with the novel entity proposed in cIMPACT-NOW Update 3 “Diffuse astrocytic glioma, IDH wild-type, with molecular features of glioblastoma (GBM), WHO IV”. METHODS We performed a retrospective analysis of clinical and molecular features, management and survival of 134 adult patients treated for grade II and III IDH wild-type astrocytoma between 06/2012 and 12/2018 at MD Anderson Cancer Center (MDACC - 112) and UT Health Science Center at Houston (UTHSC - 22). All patients had IDH1 sequenced, all but 2 had IDH2 sequenced, and 73 had further next generation sequencing. RESULTS Median age at diagnosis was 53 (interquartile range 18-83). 82 patients (61%) were male. 31 patients were histologically diagnosed with grade II astrocytoma, 102 with grade III astrocytoma, and one with diffuse glioma (insufficient tissue to render histologic grade or perform sequencing). EGFR alterations were found in 31 patients and TERT promoter mutations in 22. 84 (63%) received concurrent chemoradiation and adjuvant temozolomide (grade II, n=9; grade III, n=74; NOS, n=1). PFS overall was 12.0 months (grade II = 17.9; grade III = 10.7). OS in patients treated with concurrent chemoradiation and adjuvant temozolomide was 17.1 months versus 17.7 in patients treated with sequential radiation and temozolomide (p = NS), and 10.6 in patients treated with RT alone or surveillance (p&amp;lt; 0.016). The highest 2-year OS was seen in grade II patients treated with concurrent chemoradiation and adjuvant temozolomide (60%). CONCLUSIONS WHO grade II and III IDHwt astrocytoma survival is similar to historical GBM cohorts. The proportion meeting molecular criteria for GBM is yet undefined. Groups who received chemotherapy may perform better than those who do not. Further analysis of MGMT methylation and other molecular factors is ongoing.
Periprocedural myocardial infarction and mortality: Causality versus association**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Brahmajee K Nallamothu, Eric R Bates
Journal: Journal of the American College of Cardiology (2003)
渡辺遺伝性高脂肪血症ウサギ(家族性結合高脂肪血症モデル)における慢性高トリグリセリド血症は内皮細胞および内側平滑筋の機能障害を促進する
Authors: Shishido T, Takeishi Y, Takasaki S, Miyamoto T, Itoh M, Takahashi H, Tomoike H, Tasaki K, Wakabayashi I
Journal: Circulation (2002)
Day-to-Day Variations in Fasting Plasma Glucose Do Not Influence Gastric Emptying in Subjects With Type 1 Diabetes
Authors: Lea Aigner, Björn Becker, Sonja Gerken, Daniel R. Quast, Juris J. Meier, Michael A. Nauck
Journal: Diabetes Care (2020)

OBJECTIVE Acute experimental variations in glycemia decelerate (hyperglycemia) or accelerate (hypoglycemia) gastric emptying. Whether spontaneous variations in fasting plasma glucose (FPG) have a similar influence on gastric emptying is yet unclear. RESEARCH DESIGN AND METHODS Gastric emptying of a mixed meal was prospectively studied three times in 20 patients with type 1 diabetes and 10 healthy subjects with normal glucose tolerance using a 13C-CO2 octanoate breath test with Wagner-Nelson analysis. The velocity of gastric emptying was related to FPG measured before the test (grouped as low, intermediate, or high). In addition, gastric emptying data from 255 patients with type 1 diabetes studied for clinical indications were compared by tertiles of baseline FPG. RESULTS Despite marked variations in FPG (by 4.8 [95% CI 3.4; 6.2] mmol/L), gastric emptying did not differ among the three prospective examinations in patients with type 1 diabetes (Δ T1/2 between highest and lowest FPG: 1 [95% CI −35; 37] min; P = 0.90). The coefficient of variation for T1/2 determined three times was 21.0%. Similar results at much lower variations in FPG were found in healthy subjects. In the cross-sectional analysis, gastric emptying did not differ between the tertiles of FPG (Δ T1/2 between highest and lowest FPG: 7 [95% CI −10; 23] min; P = 0.66), when FPG varied by 7.2 (6.7; 7.8) mmol/L. However, higher HbA1c was significantly related to slower gastric emptying. CONCLUSIONS Day-to-day variations in FPG not induced by therapeutic measures do not influence gastric emptying significantly. These findings are in contrast with those obtained after rapidly clamping plasma glucose in the hyper- or hypoglycemic concentrations range and challenge the clinical importance of short-term glucose fluctuations for gastric emptying in patients with type 1 diabetes. Rather, chronic hyperglycemia is associated with slowed gastric emptying.
QOL-33. THE PROMOTE STUDY: DEVELOPMENT AND TESTING OF KLIK-UK, AN ONLINE PLATFORM, TO ENHANCE OUTPATIENT COMMUNICATION ABOUT HEALTH-RELATED QUALITY OF LIFE (HRQOL) AT THREE UK CHILDREN’S BRAIN TUMOUR TREATMENT CENTRES (CBTTCs)
Authors: Kim Bull, Shelly Stubley, Natalia Kouzoupi, Anne-Sophie Darlington, Martha Grootenhuis, Darren Hargrave, Christina Liossi, Christopher Morris, David Walker, Colin Kennedy
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The HRQoL of survivors of childhood brain tumour is significantly reduced into adulthood but is not systematically assessed. In the UK, referral for appropriate support is often reactive rather than proactive. We developed KLIK, the online Dutch platform, for use to enable the systematic assessment of HRQoL in the UK NHS using patient-reported outcomes measures (PROMs) which could be fed back to clinicians during outpatient review appointments. METHODS PARTICIPANTS: Children aged 5–17.9 years, receiving outpatient care &amp;gt;6 monthly for a brain tumour diagnosed within preceding 5 years and their parents and clinicians. SETTING: Three UK CBTTCs – UHS, Southampton; GOSH, London; and QMC, Nottingham. PROCEDURE: KLIK-UK was developed throughout the study and barriers and opportunities for its use logged. A. Development phase: relevant PROMs were identified through systematic literature review1 and families’ views regarding choice of PROMs, communication needs within consultations, and KLIK-UK were obtained by interview. B: Feasibility phase: KLIK-UK was tested in outpatient review appointments followed by interviews with the family and clinician. RESULTS 57 families and 10 clinicians participated. The PedsQL-Core module was preferred by families. Communication needs and barriers were identified. All clinicians reported that they could see the potential value of using KLIK-UK but views differed as to whether they could use it within their current timetable. Analysis of interviews from the feasibility phase will be reported. CONCLUSION KLIK-UK is ready for use in the UK but will need to be adapted according to local resources, needs, and preferences. 1Bull et al. 2019 https://doi.org/10.1093/nop/npz064
NCMP-13. LEPTOMENINGEAL DISEASE FOLLOWING RESECTION OF INTRAVENTRICULAR MELANOMA METASTASIS DIAGNOSED THROUGH CIRCULATING TUMOR CELLS
Authors: Christopher Wang, Melissa Limia, Peter Forsyth, James Liu
Journal: Neuro-Oncology (2020)

Abstract Leptomeningeal disease in the setting of malignant melanoma metastatic to the brain provides a dismal prognosis. The relationship between intraventricular metastatic tumor seeding following surgical resection and development of leptomeningeal disease (LMD) is not completely clear, although there appears to be correlation. While the mechanisms that drive the development of LMD is not well understood, monitoring of cerebrospinal fluid (CSF) for circulating tumor cells (CTCs) in high risk patients may allow for early intervention for LMD prior to radiographical diagnosis. This report describes a patient with metastatic melanoma who developed ventricular trapping from an intraventricular melanoma metastasis. The patient underwent endoscopic assisted resection of the tumor. Due to concern for leptomeningeal seeding given the location of the tumor and use of surgical resection, CSF analysis was performed. CTC count was increased shortly after surgical resection along with cytology that was suspicious for malignancy. Due to the increase in CTCs, the patient was treated for LMD with whole brain radiation therapy and intrathecal pembrolizumab. Subsequent CSF analysis revealed clearing of malignant cells in the CSF. The patient developed symptoms consistent with LMD approximately 9 months after the surgery and died 21 months after resection of his brain metastasis. This case illustrates a rare occurrence of an intraventricular melanoma metastasis, and the use of CTC presence within the CSF to diagnose LMD for early intervention. This emphasizes that the risk of developing LMD must be considered with intraventricular metastasis or ventricular exposure during tumor resection, and that CTCs may be an effective factor to monitor for early development of disease with possible prolonged survival benefit.
High-Density Lipoprotein Shortens the Ventricular Action Potential: A Novel Explanation for How Statins Prevent Sudden Arrhythmic Death?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Paulus Kirchhof, Larissa Fabritz
Journal: Journal of the American College of Cardiology (2011)
Comparative efficacy and acceptability of psychological interventions for the treatment of adult outpatients with anorexia nervosa: a systematic review and network meta-analysis
Authors: M Solmi, T D Wade, S Byrne, C Del Giovane, C G Fairburn, E G Ostinelli, F De Crescenzo, C Johnson, U Schmidt, J Treasure, A Favaro, S Zipfel, A Cipriani
Journal: The Lancet Psychiatry (2021)