tbuckley/cabot-search huggingface dataset:
An arts-based approach to community documentation and revitalization of nutritious and drought-tolerant indigenous crops for climate change adaptation
Authors: Saori Ogura
Journal: The Lancet Planetary Health (2019)

Indigenous knowledge and traditional practices around indigenous small grains are critical tools in the quest to improve community health and adapt to climate change. As a scholar and an artist, I work with Indigenous communities in Sikkim in the Indian Himalayas and in Mazvihwa, Zimbabwe, documenting nutritious and drought-tolerant indigenous small grains using arts-based methodologies, such as drawing. This course of study began with my 13 months of fieldwork (2011–12) in the Lepcha Indigenous community in Sikkim. I demonstrated how dependence on a monocultural cardamom agricultural system introduced in the 1950s had collapsed due to plant disease while local agricultural biodiversity was being lost. This research used both qualitative and quantitative methods, involving case studies at three scales on land use changes in the Lepcha territory following the expansion of cardamom. The first is a coarse-grained GIS study of land use change for the village from 1989 to 2012. The other two are fine-grained key-informant interview studies—one on land use change, and the second on the persistence of traditional food plants. I found a decline in crop diversity in the area devoted to the monocultural cardamom cash crop system. Thus I documented 36 neglected traditional food plants with my illustrations, including 16 indigenous small grains, and 20 gathered plants, representing 14 different plant families. Decreased cash crop production was also evident in Mazvihwa. During the preliminary field study in 2016, I found that indigenous small grains survived in the fields significantly more often than monocultural maize. There I conducted drawing workshops, created an opportunity for community members to reconnect to the neglected plants, and to revalue their Indigenous knowledge. My project builds a collective community resource as communities reflect on their traditional skills and knowledge around neglected small grains, contributing to maintaining agricultural biodiversity and ultimately contributes to planetary health. Funding Scott Travel Scholarship from the Department of Landscape Architecture and Environmental Planning, UC Berkeley, and the Public Scholar Initiative of The University of British Columbia. Declaration of interests I declare no competing interests.
Are Antiplatelet Agents Beneficial in Prevention of Infective Endocarditis?—Reply
Authors: Patrizio Lancellotti, Lucia Musumeci, Cécile Oury
Journal: JAMA Cardiology (2019)

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OS8.2 Risk stratification in chordoid meningioma depends on mutation status and epithelial differentiation
Authors: M M Georgescu, Y Li, A Olar, B Mobley, P Faust, J Raisanen
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Meningiomas are heterogenous tumors and their pathologic classification in the WHO Classification of Tumors of the CNS comprises 13 recognized histologic variants. Chordoid meningioma is a rare and more aggressive histologic variant of meningioma. Due to paucity of cases, the molecular profiling and patient risk stratification were not addressed in this variant. MATERIAL AND METHODS We performed an integrated clinical, NHERF1 immunohistochemical (IHC) and next generation sequencing (NGS) analysis of WHO grade II chordoid meningiomas from 30 patients (35 cases), representing the largest study to date. The NGS was performed by using a custom Agilent-generated 295-gene library containing genes with recurrent mutations in adult and pediatric, primary and metastatic brain cancer. Five of these cases cases were confirmed by performing NGS at Tempus on the xT panel containing 596 genes, and an additional 10 atypical (non-chordoid) meningioma, WHO grade II, cases were sequenced at Tempus, for comparison. RESULTS The patients with chordoid meningioma have demographic characteristics different from the general population: younger age of onset (45 vs 65), skull base (SB) location for the female patients (6:1), and increased recurrence rate (25% at 5 years). NHERF1 microlumen extent directly correlated with skull base location (p=0.0002), and segregated tumors into three cell differentiation categories -fibroblastic (13.3%), epithelial/poorly-differentiated (26.7%) and epithelial/well-differentiated (60%). NGS identified NF2 and TRAF7, as the most common mutated genes, correlating with the location and epithelial differentiation of the tumors. Mutations in AKT1, KLF4 and MN1 were found in isolated well-differentiated skull base tumors. Mutations in genes not previously involved in meningioma pathogenesis were also found. CONCLUSION The integrated tumor analysis stratified the patients into: (1) HIGH RECURRENCE RISK , characterized by tumors harboring NF2 mutations and low epithelial differentiation and (2) LOW RECURRENCE RISK , characterized by tumors exhibiting either epithelial differentiation, skull base location and TRAF7/AKT1/KLF4 mutations, or fibroblastic differentiation, non-skull base location and other mutations. This is the first study of the integrated mutational landscape of chordoid meningioma with important implications for patient risk stratification and management.
Tumor molecular profiling in advanced pediatric brain tumors.
Authors: Gargi D. Basu, Thanemozhi G Natarajan, Szabolcs Szelinger, Candyce M Bair, Tracey White, Janine R LoBello, Nathan Garinger, Ahmet Kurdoglu, Thomas Royce
Journal: Journal of Clinical Oncology (2019)

e21516 Background: With the advent of high-throughput molecular profiling, clinical outcome in pediatric cancers has greatly improved due to our greater understanding of genetic origin of pediatric cancer, and availability of biomarker specific treatment options. However, pediatric brain tumors continue to be challenging in terms of therapy. The goal of this study was to evaluate the utility of integrative clinical sequencing in pediatric patients with brain tumors. Methods: Targeted exome sequencing of 562 genes in paired tumor-normal DNA was performed on 14 patients and tumor DNA and RNA was sequenced on additional 4 patients. Sequence analysis identified SNVs, indels, copy number events, fusions, alternate transcripts, breakpoints, TMB and MSI status. Clinically, actionable alterations were identified which could be targeted by FDA approved agents or clinical trials. Results: A total of 18 patients (1-17 y.o.) with low grade (n = 5) and high grade (n = 13) brain tumors were profiled. The cohort consisted of a spectrum of GBMs (45%), medulloblastomas (10%) astrocytomas (22%), and other brain tumors (23%). At least one targetable, driver alteration was identified in 83% of all patients, and 92% of high-grade patients had at least one targetable driver event. Targetable mutations were identified in histone and chromatin modifier genes like H3F3A in 3/18 cases (17%), SETD2, ARID1A, PBRM1 in 2/18 cases (11%), activation of PI3K/AKT/mTOR pathway genes in 6/18 cases (33%), DNA repair genes NBN, ATRX and BRCA2 in 3/18 cases (17%); BRAF V600E in 3 high-grade and a KIAA1549/BRAF fusion in a low-grade tumor, activation of cell cycle in 2/18 cases (11%), activation of FGFR pathway with FGFR1/TACC1 fusion and activating mutation in 2/18 cases (11%), activation of PDGFRA in 2/18 samples (11%), TP53 mutations in 4/18 cases (22%). A breakpoint translocation concurrent with LOH of PTCH1 locus was noted in a medulloblastoma patient. High TMB or MSI instability was not observed. Conclusions: Our results underline the importance of clinical sequencing in identifying targetable markers in high- risk brain tumors. Although limited by small sample size, our study highlights the need for ongoing clinical trials to integrate the genomic discoveries leading to better clinical outcomes.
Topographic modeling of early human osteoarthritis in sheep
Authors: Tamás Oláh, Jan Reinhard, Liang Gao, Sophie Haberkamp, Lars K. H. Goebel, Magali Cucchiarini, Henning Madry
Journal: Science Translational Medicine (2019)

Early osteoarthritis induced in a clinically relevant ovine model progresses in a highly specific spatiotemporal pattern resembling human OA.
Identification of Resistance Pathways Specific to Malignancy Using Organoid Models of Pancreatic Cancer
Authors: Mariano Ponz-Sarvise, Vincenzo Corbo, Hervé Tiriac, Dannielle D. Engle, Kristopher K. Frese, Tobiloba E. Oni, Chang-Il Hwang, Daniel Öhlund, Iok In Christine Chio, Lindsey A. Baker, Dea Filippini, Kevin Wright, Tashinga E. Bapiro, Pearl Huang, Paul Smith, Kenneth H. Yu, Duncan I. Jodrell, Youngkyu Park, David A. Tuveson
Journal: Clinical Cancer Research (2019)

Abstract Purpose: KRAS is mutated in the majority of pancreatic ductal adenocarcinoma. MAPK and PI3K-AKT are primary KRAS effector pathways, but combined MAPK and PI3K inhibition has not been demonstrated to be clinically effective to date. We explore the resistance mechanisms uniquely employed by malignant cells. Experimental Design: We evaluated the expression and activation of receptor tyrosine kinases in response to combined MEK and AKT inhibition in KPC mice and pancreatic ductal organoids. In addition, we sought to determine the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition in order to identify malignant-specific vulnerabilities. Results: Combined MEK and AKT inhibition modestly extended the survival of KPC mice and increased Egfr and ErbB2 phosphorylation levels. Tumor organoids, but not their normal counterparts, exhibited elevated phosphorylation of ERBB2 and ERBB3 after MEK and AKT blockade. A pan-ERBB inhibitor synergized with MEK and AKT blockade in human PDA organoids, whereas this was not observed for the EGFR inhibitor erlotinib. Combined MEK and ERBB inhibitor treatment of human organoid orthotopic xenografts was sufficient to cause tumor regression in short-term intervention studies. Conclusions: Analyses of normal and tumor pancreatic organoids revealed the importance of ERBB activation during MEK and AKT blockade primarily in the malignant cultures. The lack of ERBB hyperactivation in normal organoids suggests a larger therapeutic index. In our models, pan-ERBB inhibition was synergistic with dual inhibition of MEK and AKT, and the combination of a pan-ERBB inhibitor with MEK antagonists showed the highest activity both in vitro and in vivo.
Abstract 18886: A Thought-Controlled Immersive Virtual Reality Platform for Motor Learning Applied With Cortical and Basal Ganglia Stroke Survivors
Authors: Alexander J Doud, Kaitlin Cassady, Andrew Grande, Bin He
Journal: Circulation (2013)

An immersive, virtual reality platform using a sensorimotor rhythm- brain-computer interface was used in a cohort of 6 hemiparetic stroke survivors. The subject’s controlled the system with accuracies of up to 81% in a binary classification task. The 3D virtual reality platform displayed photorealistic human hands moving in coordination with the patient’s thoughts, overlaying the patient’s own hands. Background: The National Stroke Association estimated that stroke management cost the United States 73.7 billion dollars in 2010. Evidence based management of the patient’s rehabilitation relies heavily on constraint induced movement therapy, and close work with a physical therapist. Approaches that reduce the burden of retraining the motor system from both a patient and provider standpoint could be of substantial impact. Methods: The system was presented to 6 subjects with histories of basal ganglia or cortical stroke leading to unilateral hemiparesis. The patient’s viewed the stimulus using 3D anaglyph glasses to produce the illusion that they were seeing their own arms through the lid of the stimulus box. EEG data were acquired at 1000Hz during all experimental trials. Results: Using the system described, the subject’s were able to achieve control accuracies as high as 87.4% (Cursor) or 81% (VR) in a binary classification task (reach left or right) and showed progression of skill in as little as three, two-hour experimental sessions. A comparison of this system to a standard cursor feedback control task suggests that use of the immersive virtual reality system allowed subjects to produce more sustained and homogenous motor imagery as assessed by spectral analysis of subject EEG. Discussion: Pairing the motor imagination task with the virtual reality photorealistic motor feedback promotes a consistent and sustained motor imagery signal as compared to a standard cursor control task. Recent controlled trials on the efficacy of brain-computer interface show statistically significant changes in Fugl-Meyer motor scores when using a sensorimotor rhythm based BCI with physical therapy. By creating a training platform that requires low caregiver overhead, the system could serve as an affordable rehabilitation option in the management of stroke.
P04.10 IDH-wildtype low grade gliomas: overall survival and prognostic indicators
Authors: G Berzero, A Di Stefano, S Ronchi, C Villa, Y Marie, K Hoang-Xuan, J Delattre, K Mokhtari, M Sanson
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND IDH-wildtype WHO grade II diffuse gliomas represent a rare subgroup of low grade tumors characterized by poor prognosis. The clinical and molecular profile associated with these tumors has not been fully elucidated yet, and the ongoing uncertainties regarding their biological behavior hamper to establish a standard of treatment. The aim of this study is to define the median overall survival and the main prognostic factors associated with this rare tumor entity. MATERIALS AND METHODS We performed a retrospective research in our center for all patients diagnosed with diffuse WHO grade II and III gliomas from 1976 to 2018. WHO grade II and III gliomas were divided into three molecular subgroups according to the IDH1/2 mutation and the 1p/19q codeletion status (1: IDH-mutant, 1p/19q codeleted; 2: IDH-mutant, 1p/19q non codeleted; 3: IDH-wildtype). We analyzed the clinical and molecular characteristics of the three subgroups, and then the clinical, radiological, histological and molecular features of IDH-wildtype WHO grade II gliomas. RESULTS We identified 445 patients with diffuse WHO grade II gliomas, including 59 IDH1/2-wildtype tumors. IDH-wildtype grade II gliomas affected more frequently male (75% vs. 55%, p = 0.004) and older (mean age: 50.0 vs. 39.6 years, p&lt;0.0001) patients, had frequent fronto-temporo-insular location (41%) and commonly underwent biopsy (53%) rather than resection. We found TERT promoter mutations (18/42, 43%), chromosome 7q gains (12/30, 40%), chromosome 10q losses (12/44, 27%), chromosome 9p losses (7/47, 15%), EGFR amplifications (5/51, 10%) and p16 deletions (4/50, 8%) but no P53 (0/16) mutations. Median overall survival was 46 months (vs. 98 for IDH-mutant non codeleted and 175 for IDH-mutant codeleted WHO grade II gliomas (p&lt;0.0001); vs. 20 months for IDH-wildtype WHO grade III gliomas (p = 0.001)). Survival was not significantly influenced by age, preoperative KPS, tumor location, extent of resection or adjuvant treatment schemes. Chromosome 9p loss had a strong negative impact on overall survival (p=0.002). CONCLUSION The median overall survival associated with IDH-wildtype WHO grade II gliomas does not exceed 4 years from diagnosis. As some genetic alterations seem to have a strong prognostic impact, an exhaustive genetic assessment can be helpful in this rare tumor group for purposes of prognostic stratification and treatment decision.
P14.70 Systemic therapy for brain metastases in elderly patients with lung cancer: A systematic review
Authors: Y Nakasu, K Mitsuya, S Nakasu
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Brain metastases (BM) account for the majority of intracranial malignant tumours in the elderly. Almost 50% of BM originate from lung cancer, particularly non-small cell lung cancer (NSCLC). The objective of this review is to summarize the involvement of elderly patients in emerging systemic therapies especially targeted therapies for the treatment of BM from NSCLC. MATERIAL AND METHODS PubMed database was searched from 2008 to December 2018. Randomized controlled trials and systematic reviews for BM from NSCLC treated with targeted therapy were included. RESULTS A total of 85 studies were evaluated for eligibility, and 23 publications met the eligibility criteria and were screened for inclusion. Of these, only two phase-III studies met all the criteria (Sperduto 2013, Yang 2017), and three other studies of subgroup analysis of trials were focused on BM (Schuler 2016, Gadgeel 2018, Camidge 2018). In the 23 papers, eligibility criteria for age were from 18 years to 75 years old or no upper limits. Actual mean or median ages ranged 51 to 64 years. Population of patients with active BM consisted none to 100% in each study. The two phase-III studies focused on treatment of BM, median ages were 63 and 57 years. The latter reported a TKI showed significantly longer intracranial PFS and no difference in HR was found in age groups older or younger than 60 years. In the three papers of subgroup analysis, response rate of BM or intracranial distant recurrence were examined. Median ages were 51 to 62 years, ranged from 18 to 86 years. However in these analytical efforts, no results were reported about age as an outcome factor. CONCLUSION Patients with active or treated BM have become included in randomized controlled trials of systemic pharmacotherapies. Elderly patients also have become included in trials. However, outcomes focused on BM are not clearly understood especially in elderly patients. We need prospective studies and assessment of targeted therapy for elderly patients with BM for better understanding of treatment strategies and options for those patients increasing in number.
Safety and Efficacy of Dabigatran Etexilate vs Dose-Adjusted Warfarin in Patients With Cerebral Venous Thrombosis
Authors: José M. Ferro, Jonathan M. Coutinho, Francesco Dentali, Adam Kobayashi, Andrey Alasheev, Patrícia Canhão, Denis Karpov, Simon Nagel, Laura Posthuma, José Mário Roriz, Jorge Caria, Mandy Frässdorf, Holger Huisman, Paul Reilly, Hans-Christoph Diener
Journal: JAMA Neurology (2019)

Patients with cerebral venous thrombosis (CVT) are at risk of recurrent venous thrombotic events (VTEs). Non-vitamin K oral anticoagulants have not been evaluated in randomized controlled trials in CVT.To compare the efficacy and safety of dabigatran etexilate with those of dose-adjusted warfarin in preventing recurrent VTEs in patients who have experienced a CVT.RE-SPECT CVT is an exploratory, prospective, randomized (1:1), parallel-group, open-label, multicenter clinical trial with blinded end-point adjudication (PROBE design). It was performed from December 21, 2016, to June 22, 2018, with a follow-up of 25 weeks, at 51 tertiary sites in 9 countries (France, Germany, India, Italy, the Netherlands, Poland, Portugal, Russia, and Spain). Adult consecutive patients with acute CVT, who were stable after 5 to 15 days of treatment with parenteral heparin, were screened for eligibility. Patients with CVT associated with central nervous system infection or major trauma were excluded, but those with intracranial hemorrhage from index CVT were allowed to participate. After exclusions, 120 patients were randomized. Data were analyzed following the intention-to-treat approach.Dabigatran, 150 mg twice daily, or dose-adjusted warfarin for a treatment period of 24 weeks.Primary outcome was a composite of patients with a new VTE (recurrent CVT, deep vein thrombosis of any limb, pulmonary embolism, and splanchnic vein thrombosis) or major bleeding during the study period. Secondary outcomes were cerebral venous recanalization and clinically relevant non-major bleeding events.In total, 120 patients with CVT were randomized to the 2 treatment groups (60 to dabigatran and 60 to dose-adjusted warfarin). Of the randomized patients, the mean (SD) age was 45.2 (13.8) years, and 66 (55.0%) were women. The mean (SD) duration of exposure was 22.3 (6.16) weeks for the dabigatran group and 23.0 (5.20) weeks for the warfarin group. No recurrent VTEs were observed. One (1.7%; 95% CI, 0.0-8.9) major bleeding event (intestinal) was recorded in the dabigatran group, and 2 (3.3%; 95% CI, 0.4-11.5) (intracranial) in the warfarin group. One additional patient (1.7; 95% CI, 0.0-8.9) in the warfarin group experienced a clinically relevant non-major bleeding event. Recanalization occurred in 33 patients in the dabigatran group (60.0%; 95% CI, 45.9-73.0) and in 35 patients in the warfarin group (67.3%; 95% CI, 52.9-79.7).This trial found that patients who had CVT anticoagulated with either dabigatran or warfarin had low risk of recurrent VTEs, and the risk of bleeding was similar with both medications, suggesting that both dabigatran and warfarin may be safe and effective for preventing recurrent VTEs in patients with CVT.ClinicalTrials.gov identifier: NCT02913326.
Use of Endocrine Therapy for Breast Cancer Risk Reduction: ASCO Clinical Practice Guideline Update
Authors: Kala Visvanathan, Carol J. Fabian, Elissa Bantug, Abenaa M. Brewster, Nancy E. Davidson, Andrea DeCensi, Justin D. Floyd, Judy E. Garber, Erin W. Hofstatter, Seema A. Khan, Maria C. Katapodi, Sandhya Pruthi, Rachal Raab, Carolyn D. Runowicz, Mark R. Somerfield
Journal: Journal of Clinical Oncology (2019)

PURPOSE To update the ASCO guideline on pharmacologic interventions for breast cancer risk reduction and provide guidance on clinical issues that arise when deciding to use endocrine therapy for breast cancer risk reduction. METHODS An Expert Panel conducted targeted systematic literature reviews to identify new studies. RESULTS A randomized clinical trial that evaluated the use of anastrozole for reduction of estrogen receptor–positive breast cancers in postmenopausal women at increased risk of developing breast cancer provided the predominant basis for the update. UPDATED RECOMMENDATIONS In postmenopausal women at increased risk, the choice of endocrine therapy now includes anastrozole (1 mg/day) in addition to exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day). The decision regarding choice of endocrine therapy should take into consideration age, baseline comorbidities, and adverse effect profiles. Clinicians should not prescribe anastrozole, exemestane, or raloxifene for breast cancer risk reduction to premenopausal women. Tamoxifen 20 mg/day for 5 years is still considered standard of care for risk reduction in premenopausal women who are at least 35 years old and have completed childbearing. Data on low-dose tamoxifen as an alternative to the standard dose for both pre- and postmenopausal women with intraepithelial neoplasia are discussed in the Clinical Considerations section of this article. Additional information is available at www.asco.org/breast-cancer-guidelines .