tbuckley/cabot-search huggingface dataset:
Abstract P554: Multiple Social Determinants of Health and Incident Stroke in the Reasons for Geographic and Racial Differences in Stroke Study
Authors: Evgeniya Reshetnyak, Laura C. Pinheiro, Monika M. Safford, Mariella Ntamatungiro, April P. Carson, Kimberly Martin, Dawn O Kleindorfer
Journal: Circulation (2020)

Introduction: Although social determinants of health (SDOH) were shown to be individually associated with incident stroke, few studies explored the effect of multiple SDOH within the same individuals on incident stroke. To address this limitation, we operationalized SDOH as a count and examined its association with incident stroke. This approach is practically appealing in clinical settings - it is easy to calculate and interpret. Hypothesis: We hypothesized that a greater number of SDOH within individuals would be significantly associated with a higher risk of incident stroke. Methods: REGARDS is a prospective cohort of 30,239 black and white adults aged &gt; 45 years recruited in 2003-2007. Sociodemographic, medical history, and stroke risk factors were collected at baseline. To define exposure, we followed the Healthy People 2020 framework, and initially used 10 SDOH to represent 5 domains: education, health, social, economic and neighborhood factors. We selected SDOH that were significantly associated with incident stroke: race, education, income, zip code poverty, health insurance, social isolation, and residence in states with poor public health infrastructure. We then created a primary exposure - a count of SDOH for each individual. The outcome was expert adjudicated incident strokes. Cox proportional hazards models examined associations between a count of SDOH (0, 1, 2, 3+) and incident stroke, adjusting for confounders. Results: This study included 27,813 individuals free from stroke at baseline. We observed 1470 incident strokes during the follow-up. A significant interaction between SDOH count and age resulted in stratification at 75 years. In fully adjusted Cox models, among individuals &lt;75 years, risk of stroke amplified with each increase in number of SDOH. This pattern was not observed among those 75+ years (Table 1). Conclusions: Individuals &lt;75 years with a greater number of SDOH had higher risk of stroke. Targeting individuals with multiple SDOH, especially those &lt;75 years, may help reduce risk of stroke.
Increased photodynamic therapy sensitization in tumors using a nitric oxide-based nanoplatform with ATP-production blocking capability
Authors: Qinyanqiu Xiang, Bin Qiao, Yuanli Luo, Jin Cao, Kui Fan, Xinghua Hu, Lan Hao, Yang Cao, Qunxia Zhang, Zhigang Wang
Journal: Theranostics (2020)

Photodynamic therapy (PDT) efficacy in cancer cells is affected by sub-physiological hypoxia caused by dysregulated and "chaotic" tumor microvasculature. However, current traditional O2-replenishing strategies are undergoing their own intrinsic deficiencies. In addition, resistance mechanisms activated during PDT also lead the present situation far from satisfactory. Methods: We propose a nitric oxide (NO)-based theranostic nanoplatform by using biocompatible poly-lactic-co-glycolic acid nanoparticles (PLGA NPs) as carriers, in which the outer polymeric layer embeds chlorin e6 (Ce6) and incorporates L-Arginine (L-Arg). This nanoplatform (L-Arg@Ce6@P NPs) can reduce hyperactive O2 metabolism of tumor cells by NO-mediated mitochondrial respiration inhibition, which should raise endogenous O2 tension to counteract hypoxia. Furthermore, NO can also hinder oxidative phosphorylation (OXPHOS) which should cause intracellular adenosine triphosphate (ATP) depletion, inhibiting tumor cells proliferation and turning cells more sensitive to PDT. Results: When the L-Arg@Ce6@P NPs accumulate in solid tumors by the enhanced permeability and retention (EPR) effect, locally released L-Arg is oxidized by the abundant H2O2 to produce NO. In vitro experiments suggest that NO can retard hypoactive O2 metabolism and save intracellular O2 for enhancing PDT efficacy under NIR light irradiation. Also, lower intracellular ATP hinders proliferation of DNA, improving PDT sensitization. PDT phototherapeutic efficacy increased by combining these two complementary strategies in vitro/in vivo. Conclusion: We show that this NO-based nanoplatform can be potentially used to alleviate hypoxia and sensitize tumor cells to amplify the efficacy of phototherapy guided by photoacoustic (PA) imaging.
DIPG-22. DISSECTING THE ONCOGENIC ROLE OF <i>FOXR2</i> IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Jessica W Tsai, Smruti K Patel, Heather Bear, Frank Dubois, Prasidda Khadka, Sophie Lu, Elizabeth Gonzalez, Keith Ligon, Pratiti Bandopadhayay, Timothy N Phoenix
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diffuse intrinsic pontine gliomas (DIPGs) pose particular challenges for treatment. We recently completed a genomic analysis of close to 200 DIPGs and high-grade gliomas. We identified that nearly 10% of all DIPGs have increased expression of the fork head domain transcription factor FOXR2. We hypothesize that FOXR2 accelerates gliomagenesis in histone mutant DIPGs and represents a previously unexplored therapeutic target. METHODS To determine whether FOXR2 is sufficient to mediate gliomagenesis, we applied an integrative genomics approach using both in vitro and in vivo DIPG models: mouse neural stem cell models expressing FOXR2, in vivo mouse models using in utero brainstem electroporation, patient-derived DIPG cell lines, and RNA sequencing analysis of human and mouse tumors expressing FOXR2. RESULTS Our data shows that FOXR2 indeed is an oncogene that rapidly accelerates gliomagenesis using an in vivo brainstem in utero electroporation model of DIPG. In human tumors, increased FOXR2 expression is mutually exclusive with MYC amplification suggesting functional redundancy. In vivo, FOXR2 results in large brainstem gliomas and rapid neurologic decline of animals. Transcriptional profiling of these tumors demonstrates activation of MYC signaling pathways. In vitro, we have further identified patient-derived cell lines with increased expression of FOXR2. CONCLUSION FOXR2 is sufficient to enhance gliomagenesis and represents a previously understudied therapeutic target for patients with the devastating disease DIPG.
Targeting transforming growth factor-β signaling for enhanced cancer chemotherapy
Authors: Jitang Chen, Ze-yang Ding, Si Li, Sha Liu, Chen Xiao, Zifu Li, Bi-xiang Zhang, Xiao-ping Chen, Xiangliang Yang
Journal: Theranostics (2020)

During the past decades, drugs targeting transforming growth factor-β (TGFβ) signaling have received tremendous attention for late-stage cancer treatment since TGFβ signaling has been recognized as a prime driver for tumor progression and metastasis.Nonetheless, in healthy and pre-malignant tissues, TGFβ functions as a potent tumor suppressor.Furthermore, TGFβ signaling plays a key role in normal development and homeostasis by regulating cell proliferation, differentiation, migration, apoptosis, and immune evasion, and by suppressing tumor-associated inflammation.Therefore, targeting TGFβ signaling for cancer therapy is challenging.Recently, we and others showed that blocking TGFβ signaling increased chemotherapy efficacy, particularly for nanomedicines.In this review, we briefly introduce the TGFβ signaling pathway, and the multifaceted functions of TGFβ signaling in cancer, including regulating the tumor microenvironment (TME) and the behavior of cancer cells.We also summarize TGFβ targeting agents.Then, we highlight TGFβ inhibition strategies to restore the extracellular matrix (ECM), regulate the tumor vasculature, reverse epithelial-mesenchymal transition (EMT), and impair the stemness of cancer stem-like cells (CSCs) to enhance cancer chemotherapy efficacy.Finally, the current challenges and future opportunities in targeting TGFβ signaling for cancer therapy are discussed.
Health Coverage and Care for Transgender People — Threats and Opportunities
Authors: Daphna Stroumsa, Anna R. Kirkland
Journal: New England Journal of Medicine (2020)

Interview with Dr. Daphna Stroumsa on transgender rights, including coverage of gender-affirming health care. (12:25)Download The fate of Russell Toomey's case against Arizona, and of other transgender Americans' access to care, depends on the influence of Bostock v. Clayton County. Meanwhile, the new administration and Congress should undo recent damage to transgender rights protections.
SURG-34. MULTIDISCIPLINARY MANAGEMENT OF A PATIENT WITH OPTIC PATHWAY-HYPOTHALAMIC LANGERHANS CELL HISTIOCYTOSIS: A CASE REPORT
Authors: John Emmanuel Custodio, Kevin Paul Ferraris, Joseph Erroll Navarro, Kenny Seng, Jose Carlos Alcazaren, Ma Angelle Dantes
Journal: Neuro-Oncology (2020)

Abstract Langerhans cell histiocytosis (LCH) of the Central Nervous System (CNS) is rare. Isolated involvement of the hypothalamic region is much more extremely rare with only 0.04 to 0.6% of the cases. We report a case of a 33 year-old female who presented with a one-year history of amenorrhea and a five-month history of intermittent headache, memory lapse, and somnolence. The patient was of normal body mass index with normal visual acuity and intact visual fields. Laboratory examinations revealed panhypopituitarism with central diabetes insipidus. Cranial magnetic resonance imaging showed a large lobulated mass measuring 1.9 x 2.2 x 2 cm in the suprasellar region which extended to the pituitary infundibulum, hypothalamus and retrochiasmatic region, with surrounding edema. The patient underwent right orbitozygomatic craniotomy and subtotal excision of the mass through subfrontal and transsylvian approaches. Histopathological examination of langerhans cells were observed with positive immunohistochemical stain for CD1a and S100 protein antigen markers establishing a diagnosis of CNS LCH. Thoracoabdominal computed tomography scan and bone scan were done postoperatively and showed no evidence of extracranial lesions. The patient had been receiving prednisone and vinblastine based chemotherapy regimen. She remains to be asymptomatic and on close surveillance. To date, there is no standardized treatment strategy for CNS LCH in the adult population. An accurate histopathologic diagnosis and a specialized multidisciplinary team approach especially involving Oncology, Neurosurgery, Ophthalmology and Endocrinology are critical to optimally tailor possible effective treatment options for patients with this similar disease. Long-term follow-up is crucial due to the increased risk of local recurrence and multisystemic involvement.
CTNI-37. EFFICACY OF ONC201 IN PATIENTS WITH ONC201 FOR RECURRENT H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Isabel Arrillaga-Romany, Sylvia Kurz, Rohinton S Tarapore, Ashley Sumrall, Nicholas Butowski, Rebecca Harrison, John de Groot, Andrew Chi, Nicole Shonka, Yoshie Umemura, Yazmin Odia, Minesh Mehta, Phioanh Nghiemphu, Timothy Cloughesy, Lynne Taylor, Jerome Graber, Lindsay Kilburn, Karan Dixit, Guangrong Lu, Joshua Allen, Tracy Batchelor, Andrew Lassman, Patrick Wen
Journal: Neuro-Oncology (2020)

Abstract H3 K27M-mutant diffuse midline gliomas (DMG) have a dismal prognosis. We report an integrated analysis for ONC201, a DRD2 antagonist and ClpP agonist, in patients with recurrent H3 K27M DMG administered as monotherapy in 3 clinical studies (NCT03295396, n=20; NCT02525692, n=6; or expanded access, n=4) by independent, central radiology review among 30 patients. At baseline, patients had measurable contrast-enhancing disease by RANO criteria, KPS&amp;gt;60, and were &amp;gt;90 days from prior radiation. Patients with primary lesions that involved the pons or spinal cord or had evidence of leptomeningeal or cerebrospinal fluid dissemination were excluded. ONC201 was orally administered at 625 mg (scaled by body weight for patients &amp;lt; 18 years old) weekly in 29 patients and every 3 weeks in 1 patient. Median age was 31 years (range 8–70; two patients &amp;lt; 18). There were 16 women and 14 men. Tumors were predominantly thalamic (73%), with other locations including the cerebellum (5%), brainstem (non-pontine) (3%), basal ganglia (3%), and midbrain (3%). Median time from prior radiation was 7.5 months. The most frequent drug-related adverse events were low grade nausea (10%) and fatigue (10%). Nine patients (30%) had &amp;gt;50% regression of T1 contrast enhancement and 11 (36.7%) patients had regression of T2/FLAIR. Objective response rate and progression-free survival by RANO criteria, as well overall survival will be reported. Among 8 patients with sustained radiographic regressions, 6 were tapered off dexamethasone and 4 had improvement in KPS. Five patients (16.7%) remain on treatment with a median of 9.5 months (range 7.3–12). In conclusion, single agent ONC201 is well tolerated and clinically active in recurrent H3 K27M DMG patients.
QOLP-08. UTILIZING STAKEHOLDER ENGAGEMENT TO DEVELOP A MINDFULNESS-BASED INTERVENTION FOR PATIENTS WITH GLIOBLASTOMA (GBM) AND THEIR CAREGIVERS
Authors: Laura Donovan, Aurelia Driver, Martha Wilkie, Jessica Morris, Grace Hillyer
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Patients with GBM and their caregivers report impaired quality of life (QOL). Distress, fatigue and anxiety are common. Mindfulness-based interventions (MBIs) can help reduce anxiety and depression and improve QOL in patients with chronic diseases and other types of cancer, but have not been well studied in patients with brain tumors and their caregivers. The feasibility and acceptability of an MBI in this population is unknown. METHODS Using the Consolidated Framework for Implementation Research (CFIR), we developed a 15-minute survey for patients with brain tumors and their caregivers to assess attitudes and beliefs toward a MBI. As this study is formative, we chose to assess select domains including intervention characteristics, characteristics of individuals (knowledge and beliefs), and the outer setting (patient needs and resources). Questions were adapted from the literature to reflect constructs from each domain or created by the authors. The survey was published using Qualtrics, an online survey platform. We partnered with OurBrainBank to distribute the survey to key stakeholders using social media platforms. OurBrainBank is a patient-led movement centered around a symptom-tracking app for patients and carers, participation in patient-driven research, improved access to clinical trials, and patient advocacy. RESULTS The survey was published on 5/29/20. In one week, we received 14 responses. 7/14 identified as having a brain tumor or being the primary caregiver for someone with a brain tumor. Of these, 5/7 indicated they would be possibly or definitely interested in participating in a research study testing a MBI. Over the next 5 months, we anticipate 200 people will complete the survey. We will analyze the results using descriptive statistics. DISCUSSION Technology can aid in stakeholder engagement which is critical to intervention development. Results from this survey will be used to develop a MBI tailored to patients with GBM and their caregivers.
Abstract 14762: Influence of Ethnicity on the Incidence of Contrast-Induced Acute Kidney Injury After Percutaneous Coronary Intervention
Authors: Davide Cao, Roxana Mehran, Rishi Chandiramani, Ridhima Goel, Anastasios Roumeliotis, Moritz Blum, Rachel Singleton, George Dangas, Usman Baber, Giulio G Stefanini, Asaad Khan, Prakash Krishnan, Jason C Kovacic, Nitin Barman, Joseph Sweeny, Vishal Kapur, Choudhury Hasan, Javed Suleman, Srinivas Kesanakurthy, Samin K Sharma, Annapoorna Kini
Journal: Circulation (2019)

Introduction: Contrast-induced acute kidney injury (CI-AKI) after PCI predicts worse cardiovascular outcomes. Physiologic mechanisms, genetic predisposition and socioeconomic disparities related to...
LGG-21. MR-GUIDED LASER INTERSTITIAL THERMAL THERAPY FOR UNRESECTABLE AND SYMPTOMATIC PEDIATRIC LOW GRADE GLIOMA
Authors: David Kram, Jessica Benjamin-Eze, Roy Strowd, Stephen Tatter
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pediatric low-grade gliomas (LGG) not amenable to resection, while often indolent, represent a significant source of cancer-related morbidity and an unmet therapeutic need. Standardly, these patients are treated with sequential lines of chemotherapy, while delaying as long as possible radiation. Magnetic resonance-guided laser interstitial therapy (LITT) is a minimally invasive procedure that utilizes real-time MR thermography to ablate brain lesions. METHODS A 15-year-old girl was diagnosed with a suprasellar, hypothalamic LGG, BRAF V600E mutation positive. The tumor was unresectable, and due to progressive vision loss and headaches, the patient underwent treatment. Despite sequential trials of thioguanine/procarbazine/lomustine/vincristine, carboplatin/vincristine, dabrafenib, and combination dabrafenib/trametinib, the patient continued to experience debilitating headaches, malnutrition, school absenteeism, and overall poor quality-of-life. Using real-time, sequential MRI-thermometry and the Neuroblate cooled directional laser catheter, the bulk of the enhancing tumor was heated to a killing temperature. RESULTS At 1-year post LITT, the patient’s symptoms were dramatically improved, including greatly improved headaches, malnutrition, school absenteeism, and overall quality of life. LITT was generally well tolerated, though the patient had slight progressive left homonymous hemianopia, thought secondary to LITT impact on the optic tracts. The tumor progressively shrank over the year post-LITT to a peak of 42% volume reduction. CONCLUSION We report a case of a pediatric patient with an unresectable low grade glioma who underwent LITT with excellent clinical and radiographic effects. LITT should be considered for children with unresectable and morbid LGGs that fail to respond to more conventional therapies.
Association of Left Anterior Descending Coronary Artery Radiation Dose With Major Adverse Cardiac Events and Mortality in Patients With Non–Small Cell Lung Cancer
Authors: Katelyn M. Atkins, Tafadzwa L. Chaunzwa, Nayan Lamba, Danielle S. Bitterman, Bhupendra Rawal, Jeremy Bredfeldt, Christopher L. Williams, David E. Kozono, Elizabeth H. Baldini, Anju Nohria, Udo Hoffmann, Hugo J. W. L. Aerts, Raymond H. Mak
Journal: JAMA Oncology (2020)

Radiotherapy accelerates coronary heart disease (CHD), but the dose to critical cardiac substructures has not been systematically studied in lung cancer.
HGG-32. UNCOVERING THERAPEUTIC VULNERABILITIES IN MISMATCH REPAIR-DEFICIENT GLIOMAS
Authors: Adam Boynton, Sangita Pal, Mehdi Touat, Naomi Currimjee, Kenin Qian, Charlotte Bellamy, Patricia Ho, Jim Berstler, Keith Ligon, Rameen Beroukhim, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION We have observed that approximately 26% of recurrent gliomas acquire hypermutation following treatment with temozolomide (TMZ). Intriguingly, 91% of these tumors harbor mutations in mismatch repair (MMR) genes. Strategies to target MMR-deficient gliomas thus stand to impact a large number of patients. METHODS We ablated the MMR genes MSH2, MSH6, MLH1, and PMS2 using an all-in-one sgRNA-CRISPR/Cas9 expression vector to generate panels of isogenic MMR knockouts in patient-derived glioma cell lines. We have characterized the phenotype of these MMR-deficient glioma cells, and leveraged high-throughput drug screens to identify therapeutic vulnerabilities induced by loss of MMR. RESULTS We demonstrate that sgRNA-CRISPR/Cas9 targeting of either MSH2 or MLH1 – the two obligatory components of the MutSα and MutLα complexes, respectively – also results in loss of protein expression of their respective binding partner MSH6 or PMS2. Moreover, we show that loss of each MMR component confers resistance to TMZ while maintaining sensitivity to the alkylating nitrosourea CCNU. Furthermore, we show that long-term TMZ treatment of MSH2 and MSH6 knockouts in an MGMT-methylated line induces hypermutation with enrichment of C &amp;gt; T mutations but not in MMR wild-type controls. Lastly, loss of MSH2 or MLH1 confers differential dependencies to small molecule inhibitors. CONCLUSIONS CRISPR/Cas9 knockout of individual MMR pathway members allows us to systematically study the response of MMR-deficient cells to alkylating agents in an isogenic context. MMR deficiencies in glioma confer dependencies to small molecule treatment, which may inform future therapies for MMR-deficient tumors.
RARE-14. DEVELOPMENT OF ANAPLASTIC ASTROCYTOMA AS A THIRD MALIGNANCY IN A PEDIATRIC PATIENT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD): A CASE REPORT AND EVALUATION OF TUMOR GENOMICS IDENTIFYING BIALLELIC <i>MSH6</i> MUTATIONS
Authors: Erin Wright, Alexis Judd, Jennifer Stanke, Sarah Rush, Daniel Pettee
Journal: Neuro-Oncology (2020)

Abstract Congenital mismatch repair deficiency (CMMRD) is a pediatric cancer predisposition syndrome secondary to biallelic mutations in mismatch repair genes including MLH1, MSH2, MSH6, and PMS2. Due to the resulting lack of repair mechanisms, these patients develop a high intracellular mutational burden and have a high risk of development of multiple malignancies at a young age. Similar to patients with Lynch Syndrome (monoallelic mutations in MMR genes), these patients are at risk for development of central nervous system (CNS) tumors including high grade gliomas. Forty-eight percent of patients with CMMRD are diagnosed with a CNS malignancy. In this interesting case, a patient developed three metachronous malignancies prior to the age of 13, including Burkitt lymphoma, T-Cell lymphoma and anaplastic astrocytoma. Genomic analysis revealed a high mutational burden in his initial tumors, with multiple oncogenic mutations, as well as a previously unreported germline compound heterozygous MSH6 E744fs*12 and R248fs*8 alteration. He received a gross total resection of the tumor which in previous studies has been shown to have the highest impact on survival. Surgery was followed by radiation and ongoing treatment with an immune checkpoint inhibitor with stable disease at 6 months. The purpose of this case report is to describe the interesting presentation of CMMRD and discuss the previously unreported biallelic MSH6 mutations.
Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes
Authors: Heejoo Kim, Jelena Perovanovic, Arvind Shakya, Zuolian Shen, Cody N. German, Andrea Ibarra, Jillian L. Jafek, Nai-Pin Lin, Brian D. Evavold, Danny H.-C. Chou, Peter E. Jensen, Xiao He, Dean Tantin
Journal: The Journal of Experimental Medicine (2020)

The transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell–specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell–specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice but diminished in monoclonal models specific to artificial or neoantigens. Rationally designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels and reduced T cell infiltration and proinflammatory cytokine expression in newly diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.