tbuckley/cabot-search huggingface dataset:
EPEN-03. ZFTA/C11ORF95 FUSIONS DRIVE SUPRATENTORIAL EPENDYMOMA VIA SHARED ONCOGENIC MECHANISMS
Authors: Tuyu Zheng, David R Ghasemi, Konstantin Okonechnikov, Andrey Korshunov, Kendra K Maaß, Martin Sill, Johannes Gojo, Ulrich Schüller, Till Milde, Stephen C Mack, Richard J Gilbertson, Andreas von Deimling, David T W Jones, Marcel Kool, Stefan M Pfister, Felix Sahm, Daisuke Kawauchi, Kristian W Pajtler
Journal: Neuro-Oncology (2021)

Abstract The majority of supratentorial ependymomas (ST-EPN) are driven by fusion genes between RELA and zinc finger translocation associated, ZFTA, previously named C11orf95. Apart from fusions with a portion of the Hippo effector YAP1, which affects a small group of infant patients, the oncogenic mechanism of remaining ST-EPNs remains unclear. Aiming at refining the molecular classification of ST-EPNs, we have analyzed methylation profiles, RNA and DNA sequencing results as well as clinical data in a cohort of 613 ST-EPNs. An unbiased approach revealed distinct methylation clusters composed of tumors with ependymal but also various other histological features containing alternative translocations that shared ZFTA as a partner gene. Tumors within these additional clusters were characterized by fusions of ZFTA to numerous fusion partners different from RELA, e.g. MAML2, MAML3, NCOA2 and SS18, implying a general role of ZFTA in tumorigenesis of ST-EPN. Indeed, the transforming capacity of newly identified fusion genes was validated using an electroporation-based in vivo gene transfer technology in mice. All fusion genes themselves were sufficient to drive malignant transformation in the developing cerebral cortex and resulting tumors faithfully recapitulated molecular characteristics of their human counterparts. We found that both, the partner gene and the zinc finger DNA binding domain of ZFTA, were essential to exert tumorigenesis. Together with two additional studies, we performed a comprehensive analysis across datasets to derive a 93 gene signature of ZFTA-RELA-driven tumors, in which the Sonic Hedgehog effector gene GLI2 was identified as a promising downstream target. Subsequent co-expression of ZFTA:RELA and a dominant negative form of Gli2 indeed hampered tumorigenesis. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating GLI2 as a critical regulator of ZFTA fusion-positive tumorigenesis as well as a potential therapeutic vulnerability in these tumors.
Changes in national rates of psychiatric beds and incarceration in Central Eastern Europe and Central Asia from 1990-2019: A retrospective database analysis
Authors: Adrian P Mundt, Enzo Rozas Serri, Mathias Siebenförcher, Valbona Alikaj, Fuad Ismayilov, Yury E Razvodovsky, Mevludin Hasanovic, Petar Marinov, Tanja Frančišković, Pavla Cermakova, Jaanus Harro, Lela Sulaberidze, Miklós Péter Kalapos, Marat Assimov, Saltanat Nurmagambetova, Nazmie F Ibishi, Elena Molchanova, Māris Taube, Jana Chihai, Jovo Dedovic, Paweł Gosek, Nicoleta Tataru, Andrei Golenkov, Dusica Lecic-Tosevski, Dunja Randjelovic, Lubomira Izakova, Vesna Švab, Mutabara Vohidova, Nina Kerimi, Oleksii Sukhovii, Stefan Priebe
Journal: The Lancet Regional Health - Europe (2021)

Numbers of psychiatric beds (general, forensic, and residential) and prison populations have been considered to be indicators of institutionalisation of people with mental illnesses. The present study aimed to assess changes of those indicators across Central Eastern Europe and Central Asia (CEECA) over the last three decades to capture how care has developed during that historical period.We retrospectively obtained data on numbers of psychiatric beds and prison populations from 30 countries in CEECA between 1990 and 2019. We calculated the median of the percent changes between the first and last available data points for all CEECA and for groups of countries based on former political alliances and income levels.Primary national data were retrieved from 25 out of 30 countries. Data from international registries were used for the remaining five countries. For all of CEECA, the median decrease of the general psychiatric bed rates was 33•8% between 1990 and 2019. Median increases were observed for forensic psychiatric beds (24•7%), residential facility beds (12•0%), and for prison populations (36•0%). Greater reductions of rates of psychiatric beds were observed in countries with lower per capita income as well as in countries that were formerly part of the Soviet Union. Seventeen out of 30 countries showed inverse trends for general psychiatric beds and prison populations over time, indicating a possible shift of institutionalisation towards correctional settings.Most countries had decreased rates of general psychiatric beds, while there was an increase of forensic capacities. There was an increase in incarceration rates in a majority of countries. The large variation of changes underlines the need for policies that are informed by data and by comparisons across countries.Agencia Nacional de Investigación y Desarrollo in Chile, grant scheme FONDECYT Regular, grant number 1190613.
Case 17-2021: An 82-Year-Old Woman with Pain, Swelling, and Ecchymosis of the Left Arm
Authors: Kathleen M. Finn, Patrick D. Sutphin, Jonathan C.T. Carlson, Kevin A. Raskin, Elizabeth M. Van Cott
Journal: New England Journal of Medicine (2021)

An 82-year-old woman was admitted with pain, swelling, and discoloration of the left arm. CT revealed hematoma involving the brachioradialis muscle. The prothrombin time was 13.3 seconds (normal range, 11.5 to 14.5) and the activated partial-thromboplastin time 72.4 seconds (normal range, 22 to 36). A diagnostic test was performed.
APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β
Authors: Axel Montagne, Angeliki M. Nikolakopoulou, Mikko T. Huuskonen, Abhay P. Sagare, Erica J. Lawson, Divna Lazic, Sanket V. Rege, Alexandra Grond, Edward Zuniga, Samuel R. Barnes, Jacob Prince, Meghana Sagare, Ching-Ju Hsu, Mary J. LaDu, Russell E. Jacobs, Berislav V. Zlokovic
Journal: Nature Aging (2021)
Early versus late patient discussions in multidisciplinary tumor boards: Quality time for quality care.
Authors: Sharif Ahmed, Greg Kubicek
Journal: Journal of Clinical Oncology (2021)

e13539 Background: Multi-disciplinary tumor boards (MTB) are a way to generate quality patient care by allowing different specialties to provide insight into patient care. While the vast majority of hospital systems have MTB there are several aspects of how to run the most efficient MTB. The aim of this study was to determine if there was a difference in patients presented early versus late in MTB. Methods: At our institution we have disease specific weekly MTB. Patients are added to MTB based on order they are received (physicians or APN will send patient name to the disease specific nurse navigator). We recorded the time devoted to each patient and the number of providers that gave a comment or suggestion per patient. The time and number of comments were compared for patients presented at the start of MTB versus towards the end of MTB. Unpaired T test was used to compare time and comments. Results: We analyzed a total of 25 MTBs which corresponded to 241 patients. The median number of patients discussed per MTB was 9 (range 5 to 16). The median time spent per patient was 5.21 minutes and the median number of providers providing comments was 3 (range 1 to 9) with an average of 3.2. When analyzed by the first 8 patients versus the remainder, the median time spent was 6.1 minutes on the first 1-8 patients and 3.4 for &gt; 8 (P &lt; 0.0001). The mean number of comments was 3.4 for the first 1-8 patients and 2.4 for &gt; 8 (P &lt; 0.0001). Conclusions: We found that patients discussed towards the end of weekly MTB had less amount of time per devoted per patient and less discussion (as measured by number of providers supplying comments and suggestions). While the impact on long-term patient care is unclear we feel that this data is important in helping to ensure productive MTB discussions and avoid any arbitrary factor for reduced multidisciplinary insight. MTB should be cognitive of this time and attention biases.
Clinical outcomes in patients (pts) with a history of central nervous system (CNS) metastases receiving talazoparib (TALA) or physician’s choice of chemotherapy (PCT) in the phase 3 EMBRACA trial.
Authors: Jennifer Keating Litton, Johannes Ettl, Sara A. Hurvitz, Miguel Martin, Henri Roche, Kyung-Hun Lee, Annabel Goodwin, Tiziana Usari, Silvana Lanzalone, Carolin Guenzel, Joanne Lorraine Blum, Hope S. Rugo
Journal: Journal of Clinical Oncology (2021)

1090 Background: In the EMBRACA trial (NCT01945775) of pts with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (ABC), the poly(ADP-ribose) polymerase (PARP) inhibitor TALA significantly improved progression-free survival (PFS) vs PCT (8.6 vs 5.6 mo; HR [95% CI] 0.54 [0.41-0.71]; P &lt; 0.0001). Patient-reported outcomes favored TALA, and most common adverse events included anemia, fatigue, and nausea. Previous subgroup analyses found that pts with a history of CNS metastases had improved PFS for TALA vs PCT (HR [95% CI] 0.32 [0.15-0.68]; P = 0.0016) and improved objective response rate (ORR) 63.2% vs 15.8%, respectively (odds ratio [95% CI] 8.95 [1.86-52.26]; P = 0.0013). This retrospective subgroup analysis further explored the clinical characteristics and outcomes in pts with a history of CNS metastases in EMBRACA. Methods: Pts were randomized 2:1 to TALA or PCT. Pts with adequately treated and stable CNS metastases not requiring corticosteroids were included. This analysis assessed intracranial ORR and best overall response (BOR) based on investigator assessment per RECIST 1.1 in pts with intracranial disease at baseline (data cutoff 15-Sep-17), and overall survival (OS; data cutoff 30-Sep-19). Results: In the intent-to-treat (ITT) population, 63 pts (43/287 [15.0%] TALA and 20/144 [13.9%] PCT) had a history of CNS metastases, of which 33 (11.5%) pts (TALA) and 15 (10.4%) pts (PCT) had intracranial disease at baseline. Additional baseline characteristics are shown in the table. Intracranial ORR in pts with intracranial disease at baseline and unconfirmed complete or partial response was 18.2% (TALA) vs 20.0% (PCT) (odds ratio [95% CI] 0.78 [0.13-5.80]; P = 0.765). In pts with intracranial disease at baseline, an intracranial BOR of stable disease was 69.7% for TALA vs 33.3% for PCT. Median OS in pts with a history of CNS metastases was 12.9 mo (95% CI 9.4-15.6) for TALA and 13.4 mo (95% CI 8.8-17.6) for PCT (HR [95% CI] 0.67 [0.37-1.2]; P = 0.1936 [stratified log-rank test]). In the safety population ([n = 43, TALA]; [n = 19, PCT]), median treatment duration (range) with TALA was 5.0 (0.1-36.0) mo compared with 2.1 (0.4-6.9) mo for PCT. Conclusions: In this subgroup analysis, baseline characteristics between pts with a history of CNS metastases treated with TALA or PCT were comparable. More pts with intracranial disease at baseline treated with TALA vs PCT experienced stable disease. Intracranial ORR in pts with intracranial disease was 18.2% for TALA vs 20.0% for PCT. Treatment options for pts with a history of CNS metastases are limited and further investigation in larger data sets is warranted. Clinical trial information: NCT01945775 .[Table: see text]
Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination
Authors: Emma C Wall, Mary Wu, Ruth Harvey, Gavin Kelly, Scott Warchal, Chelsea Sawyer, Rodney Daniels, Philip Hobson, Emine Hatipoglu, Yenting Ngai, Saira Hussain, Jerome Nicod, Robert Goldstone, Karen Ambrose, Steve Hindmarsh, Rupert Beale, Andrew Riddell, Steve Gamblin, Michael Howell, George Kassiotis, Vincenzo Libri, Bryan Williams, Charles Swanton, Sonia Gandhi, David LV Bauer
Journal: The Lancet (2021)
HGG-04. TARGETING GABAERGIC NEURON-GLIOMA SYNAPSES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) THROUGH ANTI-EPILEPTIC DRUG REPURPOSING
Authors: Tara Barron, Vilina Mehta, Pamelyn Woo, Michelle Monje
Journal: Neuro-Oncology (2021)

Abstract Pediatric high-grade gliomas, including diffuse intrinsic pontine glioma (DIPG), are the leading cause of brain cancer-related death in children. While enormous progress has been made in recent years for many forms of cancer, high-grade gliomas remain seemingly intractable, indicating that fundamental aspects of glioma growth are not yet sufficiently understood. Neuronal activity drives glioma growth both through paracrine signaling and through direct neuron-to-glioma synapses. Recently glutamatergic, AMPA receptor-dependent synapses were discovered between microenvironmental neurons and malignant glioma cells. The depolarizing current that results from synaptic and other forms of electrical neuron-glioma signaling promotes pediatric high-grade glioma proliferation and regulates growth. Neuron-glioma cell synapses mediated by other neurotransmitters remain largely unexplored, though glioma cells express genes encoding neurotransmitter receptors such as GABAA receptor subunits. Using whole-cell patch clamp electrophysiology in patient-derived DIPG xenografts, we have identified functional GABAergic neuron-to-glioma synapses mediated by GABAA receptors. GABAergic input has a depolarizing effect on glioma cells, but the magnitude of depolarization is heterogeneous between high-grade glioma subtypes and between patient-derived DIPG xenograft models. As membrane depolarization increases glioma proliferation, depolarizing GABAergic inputs to glioma cells could promote DIPG progression. Drugs that stimulate GABA signaling, such as benzodiazepines, are often given to pediatric glioma patients to treat nausea, seizures or anxiety. In patient-derived DIPG xenograftn models, lorazepam, a benzodiazepine that increases GABAA receptor conductance, increases glioma growth. Conversely, levetiracetam, an anti-epileptic drug that reduces synaptic transmission including at GABAergic neuron-glioma synapses, reduces glioma proliferation in patient-derived DIPG xenografts. This emerging understanding of brain cancer neurophysiology reveals new therapeutic targets and highlights commonly used drugs about which more study is required in this disease context.
Predicting biomarkers of hepatic metastasis in Chinese colorectal cancer patients.
Authors: Honghua Peng, Tianhao Mu, Yaping Sheng, Yingmei Li, Peiguo Cao
Journal: Journal of Clinical Oncology (2021)

e15545 Background: Hepatic metastasis is the most common site of distant spread from colorectal cancer. About 15-25% patients with colorectal cancer harbors hepatic metastasis. The molecular mechanism and predicting biomarkers in colorectal cancer are still not fully understood. Methods: 57 Chinese colorectal cancer patients were enrolled in a cohort study. Samples of primary tumor were collected in these patients and underwent whole exome sequencing. Mutation profiles of primary tumors between the patients with metastasis and those without metastasis were analyzed and compared. Results: In the cohort, 54.4% (31/57) patients presented hepatic metastasis at the time of diagnosis, while 45.6% (26/57) did not. The patients were divided into 2 groups—with hepatic metastasis and without hepatic metastasis. The mutation landscape of primary tumor indicated that the Top 3 most frequently mutated genes of both groups were the same and presented mutated TP53, APC, and KRAS. 2. Interestingly, compared with the patients without hepatic metastasis, the patients with hepatic metastasis presented a higher frequency of mutated TCF7L2 (35.5% vs 3.85%) and TRIM77 (16.1% vs 0%). Moreover, in the patients with hepatic metastasis, the patients with TRIM77 mutation in primary tumor showed a worse overall survival (p &lt; 0.0001). Conclusions: TCF7L2 and TRIM77 may be identified as potential candidate predicting biomarkers for hepatic metastasis in colorectal patients. In addition, mutated TRIM 77 predicted a poor overall survival in hepatic metastasis from colorectal cancer.
Abstract 20837: Neurocognitive Function in Atrial Fibrillation: Catheter Ablation versus Medical Management
Authors: Jonathan P Piccini, Jeffrey Browndyke, Mary Cooter, Tiffany Bisanar, Ashley Flynn, Marat Fudim, Nathan H Waldron, Mark F Newman, James P Daubert, Joseph P Mathew
Journal: Circulation (2017)

Introduction: Catheter ablation of atrial fibrillation (AF) can be complicated by cerebral microembolization. We compared neurocognitive function, intracranial white matter lesion volume and brain ...
Dengue — Perils and Prevention
Authors: Davidson H. Hamer
Journal: New England Journal of Medicine (2021)

Dengue virus (DENV) is responsible for an estimated 100 million symptomatic cases of infection and 10,000 deaths annually. The incidence of dengue has been doubling every decade since 1990.1 Dengue has a major negative effect on stretched health care systems in low- and middle-income countries and also places a financial burden on households.2,3 Rising global temperatures due to climate change, widespread distribution of the mosquito vector Aedes aegypti, increasing urbanization, population growth, environmental conditions that are conducive to mosquito breeding, and limited or nonexistent surveillance have all contributed to making dengue a worldwide threat.2 International travelers who contract dengue are . . .
hTERT MNS16A genotype and breast cancer susceptibility in sister-pairs
Authors: Jing Shen, Mary Beth Terry, Irina Gurvich, Ruby Senie, Regina Santella
Journal: Cancer Research (2007)

1731  The expression level of human telomerase reverse transcriptase (hTERT), a catalytic subunit of telomerase, is a major determinant of telomerase activity, and may have a key role in regulating telomere length and affect cancer susceptibility. We explored the associations between a functional variant of hTERT MNS16A and breast cancer risk among 278 sister-sets (296 cases and 353 controls). Variant of hTERT MNS16A was genotyped by a PCR method and classified as carrying short (S: 243 or 272bp) or long (L: 302 or 333bp) alleles according to previous functional studies. Totally, nine genotypes were obtained among the sisters (243/243, 272/243, 302/243, 302/272, 333/243, 333/272, 302/302, 333/302 and 333/333), and three of them were commonly observed (243/243, 302/243 and 302/302). No significant increase in overall breast cancer risk was observed for carriers of hTERT homozygous S allele (OR = 1.46, 95%CI: 0.75-2.84) compared with carriers of L allele (P = 0.26). No case-control differences of hTERT MNS16A genotyping by DNA repair capacity (DRC) status, benign breast disease history, ever use hormonal contraceptives, ever smoking and ever alcohol drink history were observed. These data indicate that variant of hTERT MNS16A may not modulate breast cancer susceptibility.
Racial disparities in lung adenocarcinoma: The contribution of African ancestry.
Authors: Michelle Jeung-Eun Lee, Eric Chang, Manan Shah, Sanjay R. Jain
Journal: Journal of Clinical Oncology (2021)

8516 Background: Racial disparities in lung cancer are well-known with African Americans disproportionally affected by lung cancer in terms of incidence and survival. Previous comparative analyses of molecular features of lung cancer revealed racial differences in genomic profiles, which supports somatic differences arising from genetic ancestry. Using The Cancer Genome Atlas (TCGA), we investigated the genetic alterations in lung adenocarcinomas (LUAD) on individuals of African (AFR) ancestry. Methods: The genomic and clinical data of TCGA PanCancer Atlas LUAD were downloaded through the GDC Data Portal. Given that substantial proportion of the US population consist of genetically admixed populations, we utilized The Cancer Genome Ancestry Atlas (TCGAA) and LAMP for estimates of genetic ancestry and quantitative ancestral compositions. This dataset contains 518 samples, including 393 self-reported whites and 52 African Americans. For each case the proportion of European, AFR, East Asian, native American ancestry was estimated. The dominant ancestry was defined as ≥50% of admixture from one reference population. Differences in gene mutation frequency were analyzed based on AFR ancestry proportion. The Kaplan-Meier curves were generated, and Cox regression analyses were performed. Results: Global ancestry analysis identified 50 AFR ancestry cases with mean ancestry of 78.3%. The dominant AFR ancestry group matched the self-reported race with 96% accuracy. We identified 9 subjects with ≥90% AFR ancestry, 22 subjects with 80-90% AFR ancestry, 12 subjects with 70-80% AFR ancestry, and 7 subjects with 50-70% AFR ancestry. TP53 was the most frequently mutated gene, and ≥90% AFR ancestry had the highest rate of mutations (77.8%) compared with 80-90% AFR ancestry (68.2%), and 70-80% AFR ancestry (66.8%). We evaluated classic driver gene mutations (EGFR, KRAS, NRAS, PIK3CA, ALK) and found only 33% of ≥90% AFR ancestry subjects carry a known driver mutation, compared to 58-77% in lower proportion of AFR ancestry subjects. Higher AFR ancestry was associated with worse overall survival (OS) and progression free survival (PFS). Median OS was 14.5 months for ≥90% AFR ancestry compared to 71.47 months in 70-80% AFR ancestry (P = 0.048). ≥90% AFR ancestry had median PFS of 12.8 months compared to 33.5 months in 80-90% AFR ancestry, and 47.1 months in 70-80% AFR ancestry (P = 0.002). Conclusions: This study demonstrates the power of genomic study to investigate the etiology of health disparities by analyzing the effect of ancestry on genetic alterations in LUAD. Our results reveal different mutation loads even among AFR ancestry patients. We observed that AFR ancestry is associated with worse OS, suggesting possible influence of germline ancestry in subsequent somatic alterations. Further work is needed to explore how genetic ancestry impacts tumorigenesis and cancer progression to eliminate lung cancer disparities.
Elevated dietary ω-6 polyunsaturated fatty acids induce reversible peripheral nerve dysfunction that exacerbates comorbid pain conditions
Authors: Jacob T. Boyd, Peter M. LoCoco, Ashley R. Furr, Michelle R. Bendele, Meilinn Tram, Qun Li, Fang-Mei Chang, Madeline E. Colley, Grace M. Samenuk, Dominic A. Arris, Erin E. Locke, Stephan B. H. Bach, Alejandro Tobon, Shivani B. Ruparel, Kenneth M. Hargreaves
Journal: Nature Metabolism (2021)