tbuckley/cabot-search huggingface dataset:
CTNI-15. CLINICAL EFFICACY OF ONC201 IN NEWLY DIAGNOSED DIPG AND IN PREVIOUSLY IRRADIATED PEDIATRIC H3 K27M-MUTANT GLIOMAS
Authors: Sharon Gardner, Carl Koschmann, Rohinton S Tarapore, Jeffrey Allen, Wafik Zaky, Yazmin Odia, Matthew Hall, Doured Daghistani, Ziad Khatib, Dolly Aguilera, Tobey MacDonald, Maryam Fouladi, Susan McGovern, Sabine Mueller, Cassie Kline, Nicholas Vitanza, Guangrong Lu, Joshua Allen, Soumen Khatua
Journal: Neuro-Oncology (2020)

Abstract ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. In adults, the recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated. Radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. This multi-arm, dose-escalation and dose-expansion trial determined the pediatric RP2D of ONC201 administered as an oral capsule (Arm A) or liquid formulation (Arm E) in post-radiation H3 K27M-mutant glioma (Arm A) or in newly diagnosed DIPG (Arm B) patients. Molecular assessments include intratumoral ONC201 concentrations (Arm C) and CSF H3 K27M DNA levels (Arm D). Enrollment as of April 30, 2020 is complete in Arm A (22) and Arm E (26) and continues in Arm B (18/24), Arm C (5/12), and Arm D (22/24). The RP2D of weekly 625mg ONC201 scaled by body weight was confirmed when administered as a capsule or a liquid formulation as a single agent or in combination with radiation without dose-limiting toxicity. The most frequent adverse events regardless of attribution to the drug were predominantly low grade: ONC201 capsule alone was headache (54.5%), nausea (36.4%), and fatigue (36.4%); ONC201 liquid formulation was vomiting (31.8%), headache (22.7%), VIth nerve disorder (22.7%); ONC201 capsules in combination with radiation (Arm B) was headache (47.1%), vomiting (52.9%), nausea (41.2%). Pharmacokinetic analysis in plasma of Arm A patients revealed T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL, with similar exposure across body weights. In conclusion, when scaled by body weight the ONC201 capsule or liquid formulation alone or in combination with radiation were associated with safety and pharmacokinetic profiles in pediatric H3 K27M-mutant diffuse midline glioma patients that are similar to the experience in adults.
Reduced Global Genetic Differentiation of Exploited Marine Fish Species
Authors: Miguel Gandra, Jorge Assis, Manuel Ramos Martins, David Abecasis
Journal: Molecular Biology and Evolution (2020)

Knowledge on genetic structure is key to understand species connectivity patterns and to define the spatiotemporal scales over which conservation management plans should be designed and implemented. The distribution of genetic diversity (within and among populations) greatly influences species ability to cope and adapt to environmental changes, ultimately determining their long-term resilience to ecological disturbances. Yet, the drivers shaping connectivity and structure in marine fish populations remain elusive, as are the effects of fishing activities on genetic subdivision. To investigate these questions, we conducted a meta-analysis and compiled genetic differentiation data (FST/ΦST estimates) for more than 170 fish species from over 200 published studies globally distributed. We modeled the effects of multiple life-history traits, distance metrics, and methodological factors on observed population differentiation indices and specifically tested whether any signal arising from different exposure to fishing exploitation could be detected. Although the myriad of variables shaping genetic structure makes it challenging to isolate the influence of single drivers, results showed a significant correlation between commercial importance and genetic structure, with widespread lower population differentiation in commercially exploited species. Moreover, models indicate that variables commonly used as proxy for connectivity, such as larval pelagic duration, might be insufficient, and suggest that deep-sea species may disperse further. Overall, these results contribute to the growing body of knowledge on marine genetic connectivity and suggest a potential effect of commercial fisheries on the homogenization of genetic diversity, highlighting the need for additional research focused on dispersal ecology to ensure long-term sustainability of exploited marine species.
Recurrent genetic fusions redefine <i>MLL </i>germ line acute lymphoblastic leukemia in infants
Authors: Grazia Fazio, Michela Bardini, Paola De Lorenzo, Andrea Grioni, Manuel Quadri, Lucia Pedace, Lilia Corral Abascal, Sonia Palamini, Chiara Palmi, Barbara Buldini, Luciana Vinti, Rosanna Parasole, Elena Barisone, Marco Zecca, Claudio Favre, Franco Locatelli, Valentino Conter, Carmelo Rizzari, Maria Grazia Valsecchi, Andrea Biondi, Giovanni Cazzaniga
Journal: Blood (2020)
Особенности показателей функционального состояния печени, иммунного звена, цитокиновой регуляции и углеводного обмена у больных хроническими диффузными заболеваниями печени токсического генеза
Authors: V.I. Didenko, О.M. Tatarchuk, S.L. Melanich, O.P. Petishko
Journal: GASTROENTEROLOGY (2020)

Актуальность. Проблема развития и прогрессирования хронических диффузных заболеваний печени в настоящее время является одной из наиболее важных в со­временной гастроэнтерологии, имеет общемедицинское и социальное значение. Цель: определить особенности показателей функционального состояния печени, иммунного звена, цитокиновой регуляции и углеводного обмена у больных хроническими диффузными заболеваниями печени алкогольного и медикаментозного генеза. Материалы и методы. Под наблюдением было 50 больных хроническими диффузными заболеваниями печени: 27 пациентов с алкогольной болезнью печени (АБП), среди которых 16 (59,3 %) мужчин и 11 (40,7 %) женщин, средний возраст составил (37,6 ± 2,4) года; 23 обследованных с токсическим медикаментозным гепатитом (ТМГ) — 6 мужчин (26,1 %) и 17 (73,9 %) женщин в возрасте (49,2 ± 3,1) года. Всем больным проведено биохимическое и иммунологическое исследование крови. Также определяли уровень интерлейкина-6 (ИЛ-6), интерлейкина-10 (ИЛ-10), тумор-некротизирующего фактора роста α (TNF-α), индекс HOMA-IR. Результаты. Для большинства больных АБП и ТМГ характерно наличие цитолитического и холестатического синдромов, преимущественно минимальной степени активности. Признаки гиперкоагуляции были установлены в 2 раза чаще среди пациентов с АБП, чем среди больных с ТМГ (χ2 = 4,43; р &lt; 0,05). При медикаментозном поражении печени в 6,5 раза чаще наблюдалось повышение уровня протромбинового индекса (χ2 = 10,87; р &lt; 0,01). У пациентов с медикаментозным поражением печени установлено достоверное снижение количества Т-киллеров в 1,8 раза (р &lt; 0,05) относительно группы контроля, тогда как у больных АХП определена активация гуморального звена иммунитета. При алкогольном поражении печени имело место достоверное увеличение ИЛ-6, TNF-α, соотношение провос­палительных и противовоспалительных цитокинов, развитие инсулинорезистентности, в то время как для больных с ТМГ характерно существенное снижение ИЛ-10. Выводы. Проведенный анализ особенностей функционального состояния печени, иммунного звена, цитокиновой регуляции и углеводного обмена у обследованных больных позволил выявить показатели, которые можно рассматривать в качестве лабораторных маркеров развития и прогрессирования токсических поражений печени.
State-Level Variation in Waitlist Mortality and Transplant Outcomes Among Patients Listed for Heart Transplantation in the US From 2011 to 2016
Authors: Emmanuel Akintoye, Doosup Shin, Paulino Alvarez, Alexandros Briasoulis
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Little is known about geographic variation in the outcomes of adult patients listed for heart transplantation in the US. Identifying the patterns and extent of variation is important to minimize disparity in outcomes. <h3>Objective</h3> To evaluate the geographic patterns, extent, and factors associated with state-level variation in outcomes of adult patients listed for heart transplantation in the US. <h3>Design, Setting, and Participants</h3> This nationwide retrospective cohort study used data from the United Network for Organ Sharing database to identify adult patients listed for heart transplantation at status 1A between January 1, 2011, and December 31, 2016. Patients were followed up until March 31, 2018. Data were analyzed from November 1, 2019, to September 19, 2020. <h3>Main Outcomes and Measures</h3> The study evaluated state-level variation in the 3 main organ transplant measures: waitlist mortality, transplant rate, and risk-adjusted 1-year graft survival. The rate of death while on the waitlist and the rate of transplant were calculated for each state per 1000 waitlist person-days listed at status 1A over the study period. Risk-adjusted 1-year graft survival was calculated based on the Scientific Registry of Transplant Recipients risk-adjustment model. State-level variation in each outcome measure was evaluated via multivariable-adjusted models. <h3>Results</h3> Across 50 states and the District of Columbia, a total of 15 036 patients (mean [SD] age, 52 [13] years; 3531 women [24%]; 9626 White [64%]) were listed at status 1A for adult heart transplantation between 2011 and 2016. Of those, 2146 patients (14.3%) died while on the waitlist, and 10 982 patients (73.0%) received transplants. Among those who received transplants, the median time on the waitlist was 31 days (interquartile range, 13-61 days). State-level outcomes ranged from 1.0 to 7.8 deaths per 1000 waitlist person-days for waitlist mortality, 5.6 to 34.5 transplants per 1000 waitlist person-days for transplant rate, and 87% to 92% for risk-adjusted 1-year graft survival. In a comparison of the highest and lowest quartiles, significant state-level variation was found in waitlist mortality (hazard ratio [HR], 1.53; 95% CI, 1.27-1.86), transplant rate (HR, 1.57; 95% CI, 1.31-1.87), and 1-year graft survival (odds ratio, 2.07; 95% CI, 1.64-2.62). <h3>Conclusions and Relevance</h3> The study’s findings indicate that significant state-level variation exists in the outcomes of patients listed for heart transplantation in the US. Identifying and addressing the factors associated with these geographic variations in outcomes is important to ensure a fair allocation system.
EPID-12. TREATMENT OUTCOMES OF MIDLINE GLIOMAS WITH H3K27 M: OUR BARROW NEUROLOGICAL INSTITUTE EXPERIENCE
Authors: Amir Azadi, Ekokobe Fonkem, Tejas Ranade
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND H3 K27M glioblastoma is an aggressive grade IV tumor located in midline structures, added in 2016 by the WHO. Current outcomes are poor. The rarity of these tumors presents a challenge for definitive research on developing optimal treatments. METHODS We conducted a case series of 12 patients at the Barrow Neurological Institute who were diagnosed with biopsy-proven H3 K27M glioblastoma. The clinical status of these patients was followed from dates of first and last contact. Factors included first line treatment, best response to first line treatment, recurrences, second line treatments, response assessment criteria for all treatment rounds, any discovered metastases, and vital status by date of last contact. RESULTS Of the initial 12 patients, 5 were lost to follow-up before meaningful clinical outcomes could be recorded. Of the remaining 7, all underwent temozolomide and radiation as components of first-line treatment. After first-line treatment, 1/7 (14.2%) had partial response, 3/7 (42.8%) had stable disease, and 3/7 (42.8%) had progressive disease. 4 patients elected to undergo second line treatment: 2 underwent bevacizumab with lomustine, 1 underwent bevacizumab and irinotecan, and 1 underwent surgery with carmustine. Of the 2 who underwent bevacizumab and lomustine, 1 (50%) improved from progressive to stable disease and 1 (50%) stayed at stable disease. Of the 1 patient who underwent bevacizumab and lomustine, outcome worsened from stable to progressive disease. Of the 1 patient who underwent surgery and carmustine, outcome improved from progressive to stable disease. CONCLUSIONS H3 K27M is a highly aggressive tumor with poor outcomes. This case series demonstrates that multiple treatment rounds with chemotherapy and radiation therapy may benefit patients, with bevacizumab/lomustine and surgery/carmustine appearing to lead to promising outcomes. Further research is needed to establish evidence-based protocols so quality of life and survival time in these patients may improve.
Gastric hyperplastic polyps (hyperplasiogenic polyps): a constant debate!
Authors: Michael Vieth, Markus Neurath
Journal: Endoscopy (2020)

See also: Large gastric hyperplastic polyps: to resect or not to resect, that is the question!Endoscopy 2020; 52(06): 424-426DOI: 10.1055/a-1151-8628 See also: Risk of neoplastic change in large gastric hyperplastic polyps and recurrence after endoscopic resectionEndoscopy 2020; 52(06): 444-453DOI: 10.1055/a-1117-3166
Abstract 14241: Temporal Changes of Biomarkers of Collagen Remodeling in Patients With Myocardial Infarction: The APACHE Cohort
Authors: Signe Holm Nielsen, Lena Jonasson, Magnus Janzon, Morten Karsdal, Tomas L. Lindahl, Federica Genovese, Eva E Swahn, Joakim Alfredsson
Journal: Circulation (2019)

Introduction: Following acute myocardial infarction (MI), the left ventricle undergoes molecular, cellular and extracellular matrix (ECM) changes that alter its geometry and physiology. ECM is a dy...
LGG-12. TRAMETINIB FOR PEDIATRIC LOW GRADE GLIOMAS: A SINGLE INSTITUTION EXPERIENCE
Authors: Mustafa Barbour, Michael Angelo Huang
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Low grade gliomas (LGG) are the most common pediatric brain tumors. Tumors not amenable to resection can recur or progress despite treatment with chemotherapy and/or radiation. Recent discovery of the activation of the mitogen-activated-protein-kinase (MAPK) pathway as the primary oncogenic driver for this group of tumors has led to a shift towards the use of BRAF and MEK inhibitors. METHODS Herein we performed a chart review of seven pediatric LGG treated with trametinib, a MEK inhibitor. While most were treated in the relapse setting, one patient was treated for de novo LGG as a result of experiencing multiple severe adverse effects to conventional agents. RESULTS Median age was 14 years old (range: 5 to 17 years). Six of seven patients had tissue for molecular characterization. The 2 patients with Neurofibromatosis Type 1 (NF-1) carried no other molecular aberrations. Two had the BRAF V600e mutation (1 had a concurrent PTPN11 mutation) and 2 were positive for the KIAA1549-BRAF fusion. Average duration on treatment was 8 months (range: 3 to 31 months). Disease control was achieved in 6 of 7 subjects, with one PR as best response. One patient with concurrent BRAF V600e and PTPN11 mutations progressed on trametinib and was switched to dual BRAF and MEK inhibitor therapy. Most common toxicities were acne (57.1%), oral mucositis (42.9%), skin rash, and paronychia (both 28.6%). Three patients required dose reduction and/or intermittent dose interruption. CONCLUSION Our data supports the use of trametinib for both upfront and relapsed/refractory pediatric LGG.
CBIO-01. THERAPEUTIC IMPLICATIONS OF CONDITIONAL VULNERABILITIES CAUSED BY TTFIELDS EXPOSURE IN NOVEL COMBINATION THERAPIES FOR NON-SMALL CELL LUNG CANCER AND BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER
Authors: Narasimha Kumar Karanam, Michael Story
Journal: Neuro-Oncology (2020)

Abstract Tumor Treating Fields (TTFields) are low-intensity, intermediate frequency, alternating electric fields which are FDA-approved for glioblastoma and malignant pleural mesothelioma. Clinical trials are ongoing for other solid tumor cancers, including lung, pancreatic, and ovarian cancers. The initial mechanism for tumor cell killing identified for TTFields exposure was through the disruption of mitosis. Subsequently, it has been shown that TTFields causes replication stress and down-regulates DNA repair and cell cycle checkpoint genes. Here, relative quantitative proteomics were employed to elucidate the cause for the downregulation of DNA repair and cell cycle checkpoint genes. STRING database analysis of differentially expressed proteins revealed interaction networks that included cell cycle, DNA damage repair and replication, and transcriptional and translational regulation. Upstream analysis of key genes associated with cell cycle checkpoint and DNA repair identified reduced expression of the transcriptional activators E2F1 and E2F2 and increased expression of the transcriptional repressor E2F6, suggesting that TTFields affects the CDK–RB–E2F axis. This axis is known to control the transcriptional machinery of the key regulators of cell cycle progression and genome replication fidelity, hence may explain the reduced DNA repair capacity and replication fork maintenance in TTFields-exposed cells. The current study results suggest that TTFields-exposure causes a conditional vulnerability environment that renders cells more susceptible to chemotherapeutic agents that block interfere with the E2F-RB-CDK4/6 axis, inducing DNA damage and replication stress. TTFields-exposure synergistically enhanced the efficacy of the E2F inhibitor HLM006474 with or without the CDK4/6 inhibitor abemaciclib. TTFields plus either or combination of cisplatin and etoposide (known enhancers of replication stress) synergistically enhanced cell killing. These results suggest that the combination of cisplatin and etoposide together with TTFields would be beneficial for non-small cell lung cancer patients and patients with brain metastases from non-small cell lung cancer.
PATH-03. CLINICAL UTILITY OF NEXT GENERATION SEQUENCING IN IDH-WILDTYPE GLIOBLASTOMA: THE DANA-FARBER CANCER INSTITUTE EXPERIENCE
Authors: Mary Jane Lim-Fat, Gilbert Youssef, Mehdi Touat, Bryan Iorgulescu, Eleanor Woodward, Sydney Whorral, Marie Allen, Jayne Vogelzang, William Pisano, Rifaquat Rahman, Ugonma Chukwueke, Jose Mcfaline-Figueroa, Lakshmi Nayak, Eudocia Lee, Tracy Batchelor, E Antonio Chiocca, David Meredith, Sandro Santagata, David Reardon, Rameen Beroukhim, Wenya Linda Bi, Keith Ligon, Patrick Wen
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Comprehensive next generation sequencing (NGS) is available through many academic institutions and commercial entities, and is incorporated in practice guidelines for glioblastoma (GBM). We retrospective evaluated the practice patterns and utility of incorporating NGS data into routine care of GBM patients at a clinical trials-focused academic center. METHODS We identified 1,011 consecutive adult patients with histologically confirmed GBM with OncoPanel testing, a targeted exome NGS platform of 447 cancer-associated genes at Dana Farber Cancer Institute (DFCI), from 2013-2019. We selected and retrospectively reviewed clinical records of all IDH-wildtype GBM patients treated at DFCI. RESULTS We identified 557 GBM IDH-wildtype patients, of which 227 were male (40.7%). OncoPanel testing revealed 833 single nucleotide variants and indels in 44 therapeutically relevant genes (Tier 1 or 2 mutations) including PIK3CA (n=51), BRAF (n=9), FGFR1 (n=8), MSH2 (n=4), MSH6 (n=2) and MLH1 (n=1). Copy number analysis revealed 509 alterations in 18 therapeutically relevant genes including EGFR amplification (n= 186), PDGFRA amplification (N=39) and CDKN2A/2B homozygous loss (N=223). Median overall survival was 17.5 months for the whole cohort. Seventy-four therapeutic clinical trials accrued 144 patients in the upfront setting (25.9%) and 203 patients (36.4%) at recurrence. Altogether, NGS data for 107 patients (19.2%) were utilized for clinical trial enrollment or targeted therapy indications. High mutational burden (&amp;gt;17mutations/Mb) was identified in 11/464 samples (2.4%); of whom 3/11 received immune checkpoint blockade. Four patients received compassionate use therapy targeting EGFRvIII (rindopepimut, n=2), CKD4/6 (abemaciclib, n=1) and BRAFV600E (dabrafenib/trametinib, n=1). CONCLUSION While NGS has greatly improved diagnosis and molecular classification, we highlight that NGS remains underutilized in selecting therapy in GBM, even in a setting where clinical trials and off-label therapies are relatively accessible. Continued efforts to develop better targeted therapies and efficient clinical trial design are required to maximize the potential benefits of genomically-stratified data.
Artificial intelligence and machine learning‐aided drug discovery in central nervous system diseases: State‐of‐the‐arts and future directions
Authors: Sezen Vatansever, Avner Schlessinger, Daniel Wacker, H. Ümit Kaniskan, Jian Jin, Ming‐Ming Zhou, Bin Zhang
Journal: Medicinal Research Reviews (2020)

Abstract Neurological disorders significantly outnumber diseases in other therapeutic areas. However, developing drugs for central nervous system (CNS) disorders remains the most challenging area in drug discovery, accompanied with the long timelines and high attrition rates. With the rapid growth of biomedical data enabled by advanced experimental technologies, artificial intelligence (AI) and machine learning (ML) have emerged as an indispensable tool to draw meaningful insights and improve decision making in drug discovery. Thanks to the advancements in AI and ML algorithms, now the AI/ML‐driven solutions have an unprecedented potential to accelerate the process of CNS drug discovery with better success rate. In this review, we comprehensively summarize AI/ML‐powered pharmaceutical discovery efforts and their implementations in the CNS area. After introducing the AI/ML models as well as the conceptualization and data preparation, we outline the applications of AI/ML technologies to several key procedures in drug discovery, including target identification, compound screening, hit/lead generation and optimization, drug response and synergy prediction, de novo drug design, and drug repurposing. We review the current state‐of‐the‐art of AI/ML‐guided CNS drug discovery, focusing on blood–brain barrier permeability prediction and implementation into therapeutic discovery for neurological diseases. Finally, we discuss the major challenges and limitations of current approaches and possible future directions that may provide resolutions to these difficulties.
Parent and Pediatrician Preferences for Type 1 Diabetes Screening in the U.S.
Authors: Jessica L. Dunne, Anne Koralova, Jessie Sutphin, Jesse S. Bushman, Barbara Fontanals-Ciera, Joshua R. Coulter, Campbell T. Hutton, Marian J. Rewers, Carol Mansfield
Journal: Diabetes Care (2020)

The purpose of this study was to use a discrete-choice experiment methodology to understand the relative importance of the attributes of screening tests for type 1 diabetes among parents and pediatricians in the U.S.Online surveys presented hypothetical screening test profiles from which respondents chose their preferred test profile. Survey attributes were based on likely screening test options and included the mode of administration, where and when the test was conducted, the type of education and monitoring available to lower the risk of diabetic ketoacidosis (DKA), and whether a treatment was available that would delay onset of insulin dependence. Data were analyzed using random-parameters logit models.Parents placed the highest relative importance on monitoring programs that could reduce the risk of DKA to 1%, followed by treatment to delay onset of insulin dependence by 1 or 2 years, and, finally, avoiding a $50 out-of-pocket cost. Pediatricians placed equal importance on monitoring programs that reduced a patient's risk of DKA to 1% and on avoiding a $50 out-of-pocket cost for the screening test, followed by the option of a treatment to delay the onset of insulin dependence. The mode of administration and location and timing of the screening were much less important to parents and pediatricians.Parents and pediatricians preferred screening tests that were accompanied by education and monitoring plans to reduce the risk of DKA, had available treatment to delay type 1 diabetes, and had lower out-of-pocket costs.