tbuckley/cabot-search huggingface dataset:
BIOM-26. MOLECULAR PREDICTORS OF RESPONSE TO SELINEXOR IN RECURRENT GLIOBLASTOMA (GBM)
Authors: Christopher Walker, Yao Shen, Morten Mau-Soerensen, Patrick Wen, Martin van den Bent, Scott Plotkin, Annemiek Walenkamp, Adam Green, Andrea Califano, Hua Chang, Sharon Tamir, Leah Henegar, Sharon Shacham, Mariano Alvarez, Yosef Landesman, Andrew Lassman
Journal: Neuro-Oncology (2020)

Abstract The nuclear export protein exportin 1 (XPO1) is overexpressed in many cancers, including GBM. Selinexor is an inhibitor of XPO1 that crosses the blood-brain-barrier and targets cancer cells by sequestering tumor suppressor proteins and oncoprotein mRNAs in the nucleus, inducing cancer cell apoptosis. We previously reported encouraging results from a phase II trial of selinexor for molecularly unselected patients with recurrent GBM (ASCO 2019). Pre-treatment tumors from 57 patients were exome and RNA sequenced to explore molecular correlates of response, in a hypothesis generating, post-hoc, exploratory analysis. We compared overall survival (OS) and progression-free survival (PFS) between mutated and wild-type patients. Two mutated genes were associated with longer survival in selinexor treated patients: DOCK8 (n=7; PFS, P=0.013, hazard ratio [HR]=3.75 [1.32–10.62]; overall survival, P=0.009, HR=15.39 [2.00–118.34]) and PDX1 (n=5, PFS, P=0.014, HR=4.468 [1.361–14.670]). Other commonly mutated genes in glioma, including IDH1 (n=9) were observed but not associated with survival. RNAseq data were used to infer differential protein activities, which were input into a machine learning model that compared patients with selinexor sensitive disease (best response of partial or complete response, n=7) and resistant disease (best response of progressive disease, n=23). We found the inferred activities of three proteins emerged as the most associated with response and could be combined in a model to accurately predict benefit from selinexor treatment (area under the ROC curve from leave one out cross validation = 0.89 permutation test P&amp;lt; 0.04). The three proteins were ZC3H12A (also called MCPIP-1), a negative regulator of inflammation; RAB43, a member of the RAS family that binds GTP and regulates vesicle trafficking, and SOCS3, a suppressor of cytokine signaling that can antagonize JAK/STAT signaling. Together these data identified mutations and proteins activities for identifying patients most likely to benefit from selinexor treatment. Further studies are required for validation. ClinicalTrials.gov:NCT01986348.
Abstract 3386: Mechanism Of Mitral Regurgitation In Patients With Idiopathic Dilated Cardiomyopathy: Importance Of Augmented Posterior Mitral Leaflet Tethering With Aberrant Tendinous Chords
Authors: Takeshi Uemura, Shiro Yoshifuku, Kennichi Nakashiki, Maki Yuko, Naoko Mizukami, Kunitsugu Takasaki, Eiji Kuwahara, Kayoko Kubota, Mihoko Kono, Akira Kisanuki, Chuwa Tei
Journal: Circulation (2007)

Objectives The purpose of this study was to test the determinants of mitral regurgitation (MR) and the effect of aberrant tendinous chords on MR in patients with idiopathic dilated cardiomyopathy (...
NFB-09. ENROLLMENT AND CLINICAL CHARACTERISTICS OF NEWLY DIAGNOSED, NEUROFIBROMATOSIS TYPE 1 ASSOCIATED OPTIC PATHWAY GLIOMA (NF1-OPG): PRELIMINARY RESULTS FROM AN INTERNATIONAL MULTI-CENTER NATURAL HISTORY STUDY
Authors: Michael J Fisher, Grant T Liu, Rosalie E Ferner, David H Gutmann, Robert Listernick, Peter de Blank, Janice Zeid, Nicole J Ullrich, Gena Heidary, Miriam Bornhorst, Steven F Stasheff, Tena Rosser, Mark Borchert, Simone Ardern-Holmes, Maree Flaherty, Trent R Hummel, W Walker Motley, Kevin Bielamowicz, Paul H Phillips, Eric Bouffet, Arun Reginald, David S Wolf, Jason Peragallo, David Van Mater, Mays El-Dairi, Aimee Sato, Kristina Tarczy-Hornoch, Laura Klesse, Nick Hogan, Nick Foreman, Emily McCourt, Jeffrey Allen, Milan Ranka, Cynthia Campen, Shannon Beres, Christopher Moertel, Ray Areaux, Duncan Stearns, Faruk Orge, John Crawford, Henry O’Halloran, Michael Brodsky, Adam J Esbenshade, Sean Donahue, Gary Cutter, Robert A Avery
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Because treatment and clinical management decisions for children with NF1-OPG remain challenging, we sought to establish evidence-based guidelines. We prospectively enrolled children with newly-diagnosed NF1-OPGs, and gathered standardized clinical neuro-oncology and ophthalmology assessments. METHODS Only children with NF1 and newly diagnosed OPGs, confirmed by central review, were eligible. Indications for obtaining the initial MRI, as well as factors associated with the decision to treat with chemotherapy or observe without treatment, were obtained. Quantitative visual acuity (VA), other ophthalmic features, and imaging were captured at standard time points. Goal enrollment is 250 subjects. RESULTS One-hundred thirty-three children (52% female) from 20 institutions met inclusion criteria, and were included in this preliminary analysis. Eighty-six percent of subjects were able to perform quantitative VA testing at enrollment. The most common reasons for the diagnostic MRI included screening related to NF1 diagnosis (36.8%), ophthalmologic concerns (29.3%), and non-ophthalmologic concerns (24.8%), such as headache. To date, twenty subjects have initiated treatment with chemotherapy, twelve (9%) at the time of the initial OPG diagnosis. Median age at OPG diagnosis was 3.1 years. Age and sex distribution were similar in subjects immediately entering the observation and treatment arms (median age 3.0 versus 3.5 years, respectively). CONCLUSION Most children with NF1-OPGs are observed at time of their initial OPG diagnosis, rather than treated. Importantly, a large proportion of children are able to complete quantitative VA testing at enrollment. Once enrollment is complete, these data will help to establish evidence-based guidelines for clinical management of NF1-OPGs.
Molecular Pathogenesis of Progressive Refractoriness in MLL -Rearranged AML
Authors: Shinichi Kotani, Keisuke Kataoka, June Takeda, Hiroo Ueno, Yusuke Shiozawa, Tetsuichi Yoshizato, Ayana Kon, Kenichi Yoshida, Yasuhito Nannya, Akinori Yoda, Yuichi Shiraishi, Satoru Miyano, Akifumi Takaori-Kondo, Hideki Makishima, Seishi Ogawa
Journal: Blood (2017)
A Content Analysis of Mental Health Discourse in Popular Rap Music
Authors: Alex Kresovich, Meredith K. Reffner Collins, Daniel Riffe, Francesca R. Dillman Carpentier
Journal: JAMA Pediatrics (2020)

Rap artists are among the most recognizable celebrities in the US, serving as role models to an increasingly diverse audience of listeners. Through their lyrics, these artists have the potential to shape mental health discourse and reduce stigma.To investigate the prevalence and nature of mental health themes in popular rap music amid a period of documented increases in mental health distress and suicide risk among young people in the US and young Black/African American male individuals in particular.Lyric sheets from the 25 most popular rap songs in the US in 1998, 2003, 2008, 2013, and 2018, totaling 125 songs, were analyzed by 2 trained coders from March 1 to April 15, 2019, for references to anxiety, depression, suicide, metaphors suggesting mental health struggles, and stressors associated with mental health risk.Mental health references were identified and categorized based on Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) and Mayo Clinic definitions. Stressors included issues with authorities, environmental conditions, work, and love life. Descriptive language and trend analyses were used to examine changes over time in the proportion of songs with mental health references. Stressors were analyzed for their co-occurrence with mental health references.Most of the 125 analyzed songs featured lead artists from North America (123 [98%]). Most lead artists were Black/African American male individuals (97 [78%]), and artists' mean (SD) age was 28.2 (4.5) years. Across the sample, 35 songs (28%) referenced anxiety; 28 (22%) referenced depression; 8 (6%) referenced suicide; and 26 (21%) used a mental health metaphor. Significant increases were found from 1998 to 2018 in the proportion of songs referencing suicide (0% to 12%), depression (16% to 32%), and mental health metaphors (8% to 44%). Stressors related to environmental conditions (adjusted odds ratio, 8.1; 95% CI, 2.1-32.0) and love life (adjusted odds ratio, 4.8; 95% CI, 1.3-18.1) were most likely to co-occur with lyrics referencing mental health.References to mental health struggles have increased significantly in popular rap music from 1998 to 2018. Future research is needed to examine the potential positive and negative effects these increasingly prevalent messages may have in shaping mental health discourse and behavioral intentions for US youth.
EPCT-08. ACTIVITY OF LAROTRECTINIB IN PEDIATRIC TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION CANCER PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Hiroaki Goto, Birgit Geoerger, Steven G DuBois, Juneko E Grilley-Olson, Cornelis M van Tilburg, Johannes Schulte, Hyoung Jin Kang, Makoto Tahara, Valentina Boni, Sebastien Perreault, Michael Capra, John A Reeves, Nicoletta Brega, Barrett H Childs, Theodore W Laetsch, David S Ziegler, François Doz
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND TRK fusions are oncogenic drivers in a variety of tumors, many involving the CNS. Larotrectinib, a selective FDA- and EMA-approved TRK inhibitor, demonstrated a 79% objective response rate (ORR) and a 35.2-month median duration of response (DoR) in adult and pediatric patients with various non-CNS solid tumors harboring NTRK gene fusions. We report the clinical activity of larotrectinib in pediatric patients with primary TRK fusion CNS tumors. METHODS Patients aged &amp;lt;18 years with primary CNS tumors harboring an NTRK gene fusion detected by local molecular testing who were treated with larotrectinib in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO). RESULTS As of February 2019, 14 pediatric patients with primary TRK fusion CNS tumors were identified. Gene fusions involved NTRK2 (n=10), NTRK1 (n=2), and NTRK3 (n=2). Median age was 7.0 years (range 1.3–16.7). ORR was 45% (95% CI 17–77%) among 11 evaluable patients. Two patients had complete responses (pending confirmation), three had confirmed partial responses, and six had stable disease. 24-week disease control rate was 73%. DoR ranged from 2.6+ to 5.5+ months and progression-free survival ranged from 0.03+ to 13.9+ months. Duration of treatment ranged from 0.03+ to 16.6+ months. Treatment-emergent adverse events were mainly grade 1–2. CONCLUSIONS Larotrectinib resulted in objective responses and durable disease control in pediatric patients with primary TRK fusion CNS tumors. These results support expanded testing for NTRK gene fusions in patients with CNS tumors.
EPID-18. GLIOBLASTOMA CHARACTERIZATION IN FEMALES WITHIN RURAL PENNSYLVANIA: A SINGLE INSTITUTIONAL RETROSPECTIVE REVIEW
Authors: Maia Giombetti, Emilia Jakubek, Na Tosha Gatson, Shane Bross
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma (GBM) is the most common malignant brain tumor in adults with a slightly higher incidence and shortened survival in males as compared to females in the United States. Recently, there has been a focus on specific health disparities between rural versus urban populations. There is growing interest in these disparities as it pertains to CNS tumors. Here, we characterize a rural population of females diagnosed with GBM as part of an ongoing investigation to drive research and further discussion around this important topic. METHODS We performed a single institutional retrospective review of patients with GBM in rural Pennsylvania between 2006 and 2019. We collected clinical, demographic, and tumor specific data including chronic comorbid disease, marital status, age at diagnosis, obstetric history, BMI, and tumor location. RESULTS Of the 611 patients diagnosed with GBM from 2006–2019, 41% (n= 249) were female with a median overall survival of 9.5 months compared to 10.7 months in males. At diagnoses, 69% (n=173) of females had chronic comorbid allergy/immunology disorders, 41% (n=101) had endocrine disorders, 53% (n=132) had hypertension, and 43% (n=106) had mood disorders. Tumor laterality was predominantly right-sided (58%, n=145) and frequently involved the frontal lobe (38%, n=94). The temporal lobe was the second most commonly involved (32%, n=80). The median age at diagnosis was 65-years-old [range, 21–92]. Fifty-six percent (n=140) of women were married with an average of 2.27 childbirths. The median body mass index (BMI) was 27.5 [range, 16.3–64.9] with 66% of females classified as overweight/obese at diagnosis. Greater than 95% of females were insured. CONCLUSION There is a high incidence of chronic comorbid disease and obesity amongst females in this rural population, and females demonstrated a poorer overall survival as compared to males. Further comparisons are needed to characterize rural female GBM populations versus those in urban areas.
LINC-17. SIROLIMUS AS AN ALTERNATIVE TO SURGICAL RESECTION OF PEDIATRIC TUBEROUS SCLEROSIS COMPLEX-ASSOCIATED BILATERAL SUBEPENDYMAL GIANT CELL ASTROCYTOMAS: AN AFFORDABLE OPTION FOR PATIENTS FROM LOW-MIDDLE INCOME COUNTRIES
Authors: Patricia Orduña
Journal: Neuro-Oncology (2020)

Abstract Subependymal giant cell astrocytomas (SEGA) may lead to significant neurological morbidity in children diagnosed with tuberous sclerosis complex (TSC). Surgical resection is warranted for SEGAs demonstrating continuous growth, causing hydrocephalus and increased intracranial pressure. mTOR inhibitors (sirolimus and everolimus) are alternatives to surgery and have shown efficacy in stabilizing and shrinking SEGAs. Everolimus showed stronger evidence in efficacy, but its cost poses a limitation for this treatment among patients from low-middle income countries. We explored sirolimus as a potentially more cost-effective alternative in our setting. We present a 10-year-old Filipino child with TSC admitted due to headache, vomiting, and increased sleeping time. Neuroimaging revealed large bilateral SEGAs involving the frontal horns and foramina of Monro, causing moderate obstructive hydrocephalus. Surgical excision was offered, but parents opted for medical treatment. Bilateral posterior parietal ventriculoperitoneal shunts were inserted to decrease intracranial pressure. Due to the cost of everolimus, the patient was started on sirolimus at 1mg/m2/day. Imaging done 6 months after initiating therapy demonstrated significant decrease in size of both SEGAs (right: 82.5%, left: 64.1%). Sirolimus levels were maintained at 15.7ng/ml and minimal elevations on cholesterol and triglyceride levels were observed and treated with simvastatin. Results of this case and review of related data suggest that sirolimus can be used as a conservative approach in inducing regression of large bilateral SEGAs, and an affordable alternative to everolimus for pediatric TSC patients from low-middle income countries. Prospective studies and clinical trials are needed to further establish its efficacy, safety and cost-effectiveness in our setting.
Inhibiting autophagy enhances sulforaphane-induced apoptosis via targeting NRF2 in esophageal squamous cell carcinoma
Authors: Zhaoming Lu, Yandan Ren, Li Yang, Ang Jia, Yi Hu, Yu Zhao, Wuduo Zhao, Bin Yu, Wen Zhao, Jianying Zhang, Guiqin Hou
Journal: Acta Pharmaceutica Sinica B (2020)

Sulforaphane (SFN), a natural anti-tumor compound from cruciferous vegetables, has been reported to induce protective autophagy to cancer cells, which might impair the anti-tumor efficiency of SFN. However, the accurate function and mechanism of SFN inducing autophagy in cancers are still obscure, especially in esophageal squamous cell carcinoma (ESCC), one of malignancies with high incidence in North China. Here, we mainly explored the potential function of autophagy upon SFN treatment in ESCC and molecular mechanism. We demonstrated that SFN could inhibit cell proliferation and induce apoptosis by activating caspase pathway. Moreover, we found activation of NRF2 pathway by SFN was responsible for the induction of autophagy and also a disadvantage element to the anti-tumor effects of SFN on ESCC, indicating that SFN might induce protective autophagy in ESCC. We, therefore, investigated effects of autophagy inhibition on sensitivity of ESCC cells to SFN and found that chloroquine (CQ) could neutralize the activation of SFN on NRF2 and enhance the activation of SFN on caspase pathway, thus improved the anti-tumor efficiency of SFN on ESCC in vitro and in vivo. Our study provides a preclinical rationale for development of SFN and its analogs to the future treatment of ESCC.
Abstract 10415: Predicting Mortality in Advanced Heart Failure and Chronic Obstructive Pulmonary Disease Following Cardiopulmonary Rehabilitation
Authors: Cynthia M Dougherty, Youjeong Kang, Robert L Burr, Bonnie G Steele
Journal: Circulation (2018)

Introduction: Cardiopulmonary rehabilitation (CR) improves physical function and quality of life in chronic obstructive pulmonary disease (COPD) and heart failure (HF) populations, but it is unknow...
CBIO-15. MDM2 INHIBITOR SYNERGY WITH BCL-XL INHIBITION FOR p53 WILD TYPE GLIOBLASTOMA
Authors: Masum Rahman, Ian E Olson, Rehan Saber, Lucas P Carlstrom, Jibo Jhang, Desmond Brown, Karishma Rajani, Jann Sarkaria, Ian Parney, Terry C Burns
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma (GBM) is an infiltrative, uniformly fatal brain tumor, treated with surgery, radiation, and Temozolomide (TMZ). Chemoradiation induces a senescent-like phenotype, which contributes to disease recurrence. We recently found that, radiated GBM cells can be eliminated by inhibition of BCL-XL. However, it remains unknown whether p53 is involved in this process and whether the elimination of senescent cells by BCL-XL inhibition could be augmented by MDM2 inhibition, a negative p53 regulator. METHODS p53-mutant (GBM6/GBM123) and p53-WT (GBM39/GBM76) human GBM cells were treated with 5Gy or TMZ following 48 hours of MDM2 inhibitor (AMG232) or vehicle treatment and maintained for seven days to establish a senescent-like phenotype. We evaluated the IC50 for BCL-XL inhibitor (A1331852) in radiated vs. non-radiated cells with or without MDM2 inhibitor pre-treatment. RESULTS MDM2-inhibitor treatment prior to radiation increased the expression of p21 and lead to increased cell death when combined with BCL-XL inhibition in p53-WT GBM cells. IC50 of BCL-XL inhibitor after prior MDM2 pretreatment and radiation in GBM76 was 4.5□M compared to 33.5□M, 18.1□M, and 32.3□M in vehicle without radiation, vehicle with radiation, and MDM2 inhibitor-alone treatment groups, respectively(p=0.0036). The IC50 of BCL-XL inhibitor without MDM2-inhibition in non-irradiated and radiated, as well as pre-administration of MDM2 inhibitor in non-irradiated and radiated GBM39 cells was 5618nM, 16117nM, 3926nM and 276.5nM, respectively(p=0.0003). Conversely, MDM2 co-inhibition with BCL-XL did not lead to increased rates of cell death in p53-mutant cell(p&amp;gt;0.05). CONCLUSION We previously identified that BCL-XL inhibition promotes cell death in senescent GBM cells. We build upon that work, demonstrating the increased rates of cell death can be augmented by MDM2 inhibition, but only in p53-WT cells. These findings highlight a novel therapeutic target for treating latent GBM tumors prior to recurrence, with the additional of MDM2 inhibition greatly increasing the efficacy of BCL-XL targeting agents.
Abstract 17369: Addressing Missed Opportunities for Cardiometabolic Primary Prevention of Veterans Referred for Stress Testing
Authors: Ysanne Johnson, Sheila M Mattei, Matthew Burg, Judith L Meadows
Journal: Circulation (2020)

Introduction: Patients presenting to stress testing have a high prevalence of cardiometabolic risk factors (RF) which are not at guideline supported goals. Referral to stress testing is often a patient’s first presentation to CV care and represents a missed opportunity for delivery of risk reduction strategies. Hypothesis: Implementation of a cardiometabolic prevention initiative for cardiology-naïve patients referred to stress testing will result in improved delivery of guideline-directed prevention care. Methods: A consecutive prospective cohort of patients who underwent stress testing (12/1/2019-1/31/2020) after implementation of a linked cardiometabolic prevention referral for those with low risk stress tests was compared to a retrospective standard of care (SOC) cohort (9/1/2019-10/1/2019) from a single center Veterans Hospital. Outcomes assessed were change in CV risk reduction care at 90 days following stress test. Results: Of 181 patients, 62.5% were naïve to cardiology specialty care, had &gt;1 CV risk factor not meeting guideline goals, 6% had typical angina as presenting symptoms, and greater than 70% of stress tests were normal or low risk. Baseline CV RF were common and failed to reach goals in SOC and intervention cohorts respectively with LDL above goal (40 vs. 33%), stage 1 or greater hypertension (67 vs 81%), Diabetes with HgA1c &gt; 7 (48 vs. 21%), overweight or obese (68 vs. 79%), current tobacco (11 vs. 12%), and elevated mean 10-year ASCVD risk (32 vs.20%). At 90 days, 28% of SOC cohort had intensification of CV prevention care as compared to 76% of intervention cohort (X 2 26.8, p&lt;0.05). Conclusions: A stress testing setting represents a valuable opportunity to deliver cardiometabolic prevention care. Integration of risk reduction strategies is imperative to shift from cardiac disease management to patient centered health promotion.
Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury
Authors: Daniel R. Calabrese, Emily Aminian, Benat Mallavia, Fengchun Liu, Simon J. Cleary, Oscar A. Aguilar, Ping Wang, Jonathan P. Singer, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Mary Nakamura, Lewis L. Lanier, Mark R. Looney, John R. Greenland
Journal: Journal of Clinical Investigation (2020)

Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While NK cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell-deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury.