tbuckley/cabot-search huggingface dataset:
Unbiased Estimation of Linkage Disequilibrium from Unphased Data
Authors: Aaron P Ragsdale, Simon Gravel
Journal: Molecular Biology and Evolution (2019)

Abstract Linkage disequilibrium (LD) is used to infer evolutionary history, to identify genomic regions under selection, and to dissect the relationship between genotype and phenotype. In each case, we require accurate estimates of LD statistics from sequencing data. Unphased data present a challenge because multilocus haplotypes cannot be inferred exactly. Widely used estimators for the common statistics r2 and D2 exhibit large and variable upward biases that complicate interpretation and comparison across cohorts. Here, we show how to find unbiased estimators for a wide range of two-locus statistics, including D2, for both single and multiple randomly mating populations. These unbiased statistics are particularly well suited to estimate effective population sizes from unlinked loci in small populations. We develop a simple inference pipeline and use it to refine estimates of recent effective population sizes of the threatened Channel Island Fox populations.
Prospective Evaluation of Alternative Donor from Unrelated Volunteer Donor and Cord Blood in Adult Acute Leukemia and Myelodysplastic Syndrome: No Difference between Unrelated Donor and Cord Blood
Authors: Seitaro Terakura, Tetsuya Nishida, Masashi Sawa, Tomonori Kato, Kotaro Miyao, Yukiyasu Ozawa, Tatsunori Goto, Akio Kohno, Kazutaka Ozeki, Yasushi Onishi, Noriko Fukuhara, Nobuharu Fujii, Hisayuki Yokoyama, Masanobu Kasai, Hiroatsu Iida, Nobuhiro Kanemura, Tomoyuki Endo, Hiroatsu Ago, Makoto Onizuka, Satoshi Iyama, Yuichiro Nawa, Mika Nakamae, Yasuyuki Nagata, Shingo Kurahashi, Yasuo Tomiya, Atsumi Yanagisawa, Ritsuro Suzuki, Yachiyo Kuwatsuka, Yoshiko Atsuta, Koichi Miyamura, Makoto Murata
Journal: Blood (2019)
Factor VIIa Interaction with Endothelial Cell Protein C Receptor: Its Role in Hemostatic Effect of rFVIIa in Treating Hemophilia
Authors: Shiva Keshava, Jagan Sundaram, Anuradha Rajulapati, Charles T. Esmon, Usha R. Pendurthi, L. Vijaya Mohan Rao
Journal: Blood (2016)
Osler: “Knowledge is proud that he has learnt so much; wisdom is humble that he knows no more”
Authors: Joseph Zacharias
Journal: BMJ (2019)

Morgan1 and Abbasi2 highlight the importance of humility in medicine. Morgan seems to suggest that the phrase “I don’t know” is a term to admit the limits of one’s knowledge. Abbasi suggests these three words are the foundation of wisdom. Most of …
Postgraduate education and the doctor.
Authors: D C Evered, H D Williams
Journal: BMJ (1980)

Training a doctor is expensive and time-consuming.Substantial public funds (about £100 000 000 a year in the UK) are invested in this process and yet little has been done to ensure that the community obtains the maximum return on its investment.The medical schools accept only the most gifted students and then expose them to an educational process so rigid in its structure and limited in its horizons that at graduation the medical student is the best informed but most poorly educated of all graduates.This system, which is designed to eliminate the incompetent, also often succeeds in stifling the inventiveness and imagination of the most competent and signally fails to develop those intellectual attitudes necessary for continuing self-education.These errors are subsequently compounded by the creation of systems of continuing medical education that have rarely been subjected to objective evaluation and often seem inappropriate to the needs of the medical graduate.The object of this paper is to review the systems of continuing medical education described in publications, with an emphasis on those papers purporting to contain objective data.
Whole Genome Sequencing Identifies Small Deletions in Ribosomal Genes Causing Diamond Blackfan Anemia
Authors: David M. Bodine, Jens Lichtenberg, Nancy Seidel, NISC Comparative SequencingProgram, G. Jayashree Jagadeesh, John G Conboy, Jason E. Farrar, Jessica Kang, Lionel Blanc, Evangelia Atsidaftos, Steven Ellis, Jeffrey Michael M Lipton, Adrianna Vlachos
Journal: Blood (2019)
Does Obesity Influence the Efficacy of P2Y12 Inhibitors in Preventing Strokes? a Systematic Review and Meta-Analysis
Authors: Ahmad Abu-Hashyeh, Saad Ullah Malik, Jennifer Dotson, Abdul Mughees Rana, Warda Faridi, Mohammad M Alhousani, Emilia Cindy Leigh, Mohamed Suliman, Faiz Anwer
Journal: Blood (2019)
Disease Risk Index (DRI) and Age but Not HCT Comorbidity Index (HCT-CI) Are Predictive of Overall Survival after Cord Blood Transplantation Supported By Haplo-CD34+ progenitor Cells
Authors: Alexandra Gomez-Arteaga, Nina Orfali, Danielle Guarneri, Usama Gergis, Sebastian A. Mayer, Jingmei Hsu, Adrienne A. Phillips, Tsiporah B. Shore, Koen Van Besien
Journal: Blood (2019)
CBMT-05. GENETIC AND EPIGENETIC MECHANISMS REGULATING SCD INHIBITOR SENSITIVITY IN GLIOBLASTOMA
Authors: Nicole Oatman, Nupur Dasgupta, Biplab Dasgupta, Kwangmin Choi, Mruniya Gawali, Nishtha Gupta, Sreeja Parameswaran, Sean Lawler, Cameron Brennan, Jianqiang Wu, Larry Sallans, Pankaj Desai, Matthew Weirauch, Kakajan Komurov, Biplab Dasgupta
Journal: Neuro-Oncology (2019)

Abstract A status-quo in targeted cancer therapy is that out of the thousands of somatic alterations found in a cancer cell, alterations only in driver genes determine therapeutic strategy. Despite unimpressive results of some driver-targeted therapies, and given that the majority of genomic alterations in cancer are not ‘drivers’, but ‘passengers’ / bystander alterations, it remains underappreciated whether targeting built-in vulnerabilities imposed by passenger gene alterations may provide therapeutic value. The tumor suppressor PTEN undergoes widespread functional inactivation including deletion in human cancer. PTEN deletion occurs frequently in GBM, sometimes as part of the 10q loss or chromosome 10 monosomy. We discovered that several genes including Stearoyl Co-A Desaturase, SCD (10q24.31), located 12 MB telomeric to PTEN is frequently co-deleted hemizygously and unintentionally in PTEN-deleted cancers. Strikingly, in a subset of GBM, SCD was also epigenetically silenced. A combination of SCD deletion and methylation resulted in two molecular subgroups – one that expressed SCD, and another that showed little or no detectable SCD. SCD, is an integral membrane protein of the endoplasmic reticulum and converts saturated fatty acids to monounsaturated fatty acids (Oleic and palmitoleic acids) that are critical for membrane fluidity and function, and thus SCD is generally overexpressed in most cancers. We show that SCD expressing lines are highly sensitive to multiple SCD inhibitors, while non-expressors are resistant. Despite modest BBB penetration, one SCD inhibitor was remarkably efficient in blocking intracranial tumor growth. SCD is an oxygen-dependent enzyme. We show that SCD retains significant enzymatic activity even in highly hypoxic conditions. Finally, through RNAseq, functional proteomics and ATACseq, we demonstrate an evolutionarily conserved mechanism of acquired resistance to SCD inhibitor through drug-induced acute phase signaling response in multiple SCD expressing cancers.
EXTH-60. CONVECTION-ENHANCED DELIVERY OF EZH2 INHIBITOR FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Takahiro Sasaki, Hiroaki Katagi, Stewart Goldman, Rintaro Hashizume
Journal: Neuro-Oncology (2019)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brain tumor and the majority of patients with DIPG die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which prevents total surgical resection and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities. EZH2, histone methyltransferase of polycomb repressive complex 2, is a potential therapeutic target in DIPG. The study aims to assess the efficacy of EZH2 inhibitor by CED against DIPG xenograft model. The biodistribution of EZH2 inhibitor was evaluated by high-performance liquid chromatography (HPLC). HPLC analysis showed that the concentrationof EZH2 inhibitor in the brainstem tumor was only 3.74% of blood concentration by systemic administration. We treated mice bearing human DIPG xenografts with EZH2-inhibitor using intraperitoneal or CED administration. Intracranial tumor growth was monitored by bioluminescence image and therapeutic response was evaluated by animal survival. CED of EZH2 inhibitor suppressed tumor growth and significantly extended animal survival in compared to intraperitoneal administration of EZH2 inhibitor (P=0.0475). Taken together, our results indicate that CED of EZH2 inhibitor would provide an alternative strategy for bypassing the BBB and increasing efficacy of EZH2 inhibitor for the treatment of DIPG.
Design and synthesis of selective sphingosine-1-phosphate receptor 1 agonists with increased phosphorylation rates
Authors: Qiong Xiao, Minwan Hu, Si Chen, Yifan Tang, Zeyu Shi, Jing Jin, Jinping Hu, Ping Xie, Dali Yin
Journal: Acta Pharmaceutica Sinica B (2019)

FTY720 and IMMH002, prodrugs for sphingosine-1-phosphate receptor 1 (S1P1) agonists, show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats. In this study, FTY720 or IMMH002 analogues (21–24) were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms. Target compounds were synthesized via a convergent route using the key and optically pure building block 9, which was first synthesized via asymmetrically catalyzed amination. The phosphorylation rates of these analogues in rat or human blood were compared. The new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the parent compound, whereas compound 23 showed improvements in rats, but not in humans. In pharmacokinetics studies of rats, compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and IMMH002. Thus, our study not only yielded new compounds with therapeutic potential, but also showed species differences between rats and humans in response to the structural modifications, which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic.
TRAF1-ALK Fusion Predicts Poor Prognosis for ALK Positive Anaplastic Large Cell Lymphoma Patients with Chemotherapy and ALK Inhibitor
Authors: Ling Huang, Xinmiao Jiang, Hanguo Guo, Liu Sichu, Xiaojuan Wei, Chen Feili, Zhanli Liang, Wenyu Li
Journal: Blood (2019)
CMET-41. OUTCOMES FOLLOWING STEREOTACTIC RADIOSURGERY (SRS) FOR LIMITED BRAIN METASTASES - AN AUSTRALIAN SINGLE INSTITUTIONAL EXPERIENCE
Authors: Lilly Shen, Wee Loon Ong, Briana Farrugia, Anna Seeley, Carlos Augusto Gonzalvo, Morikatsu Wada
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Despite increasing use of stereotactic radiosurgery (SRS) for management of brain metastases (BM), published Australian data is scarce. We aim to report on the outcomes following SRS for limited BM in a single Australian institution. METHODS This is a retrospective cohort of patients with limited BM treated with SRS between August 2015 and March 2019. A dose of 24Gy/3# were prescribed to intact lesion, and 21Gy/3# to surgical cavity post-surgical resection. All patients were followed with 3-monthly surveillance MRI brain. Primary outcomes were: local failure (LF: increased in size of SRS-treated BM lesion/ recurrence in surgical cavity), distant failure (DF: intracranial progression outside of the SRS-treated lesion/ cavity), and overall survival (OS). LF, DF and OS were estimated using the Kaplan-Meier method. Multivariate Cox regressions were used to evaluate factors associated with outcomes of interest, with death as competing-risk events for LF and DF. RESULTS 76 courses of SRS were delivered in 65 patients (54 unresected BM lesions, and 22 surgical cavities). 43 (66%) patients were ECOG 0–1. 35 (54%) patients had solitary BM. 41 (63%) had symptomatic BM. Half of the patients had primary lung cancer. Median follow-up was 4.8 months (range:0.1–39 months). 10 LF were observed at a median of 3.5 month post-SRS, with 6- and 12-month LF cumulative incidence of 14% and 24% respectively. 30 DF were observed at a median of 3.3 months, with 6- and 12-month DF cumulative incidence of 38% and 63% respectively. The 12- and 24-month OS were 39% and 26% respectively. In multivariate analyses, better ECOG status, solitary BM lesion, resection of BM pre-SRS, and use of subsequent systemic therapy were independently associated with improved OS. CONCLUSION This is one of the few Australian series reporting on outcomes following SRS for limited BM, with comparable outcomes to published international series.
Development of Target Modules for Early and Late Stage Cancer Treatment Using Switchable Unicar T Cell Therapy
Authors: Liliana Raquel Loureiro, Anja Feldmann, Ralf Bergmann, Nicole Berndt, Stefanie Koristka, Nicola Mitwasi, Anja Hoffmann, Justyna Jureczek, Martin Bornhaeuser, Michael Bachmann, Claudia Arndt
Journal: Blood (2019)
SYK Inhibitor Entospletinib in Combination with Obinutuzumab Demonstrates Efficacy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
Authors: Adam S. Kittai, Scott R Best, Bria Thurlow, Basak Gokcora, Andrzej Stadnik, Renee MacKinnon, Taylor Hashiguchi Rowland, Daniel O. Persky, Byung Park, Stephen E Spurgeon, Alexey Danilov
Journal: Blood (2019)
Prospects for Research in Diabetes Mellitus
Authors: K. M. Venkat Narayan
Journal: JAMA (2001)

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COMP-10. THE MUTATIONAL PROFILE OF GLIOBLASTOMA-DERIVED CELL-FREE DNA IN PLASMA REPRESENTS A DISTINCT SUBSET OF THE SOMATIC MUTATIONS PRESENT IN GLIOBLASTOMA SOLID TUMOR DNA
Authors: Hunter Underhill, David Nix, Christian Davidson, Sabine Hellwig, Carrie Fuertes, Howard Colman, Mary Bronner, Randy Jensen
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma’s mutational landscape varies widely in the same tumor. Using conventional criteria to identify mutations from a focal tissue specimen (e.g., variant allele frequency &gt; 5%) undersamples glioblastoma’s broad clonal diversity, which may limit detection of glioblastoma-derived circulating cell-free DNA in plasma (i.e., circulating tumor DNA; ctDNA). Here, we sought to enhance somatic variant identification in solid tumor DNA to improve detection and characterize glioblastoma-derived ctDNA. Tumor DNA and plasma cell-free DNA (collected &lt; 24 hours prior to the surgical procedure) were isolated from eight glioblastoma patients. DNA was capture-enriched using a custom-designed, glioblastoma-targeted, next-generation sequencing panel (124 genes, 118 kb) followed by paired-end sequencing. Samples were prepared in duplicate with molecular barcodes to enable detection of very-low frequency variants. Somatic mutations in tumor DNA were identified using variable allele frequency thresholds and were considered positive in ctDNA if present in both duplicate samples. Using a lower allele frequency threshold to identify mutations in tumor DNA significantly increased detection of ctDNA (F(1.04,7.29)=14.81, P=0.006). At a solid tumor allele frequency threshold of ≥ 5%, only a single patient (12.5%) had tumor mutations detected in ctDNA. However, at a threshold ≥ 1%, all patients (100%) had at least one tumor mutation detected in ctDNA. Moreover, at a threshold ≥ 0.5%, 7 out of 8 patients (87.5%) had &gt; 12 tumor mutations present in ctDNA. The increased detection of ctDNA enabled the subsequent discovery that somatic mutations in APC, KIT, MSH6, and NF1 were more likely to be present in ctDNA compared to somatic mutations in ATRX, LZTR1, SLC26A3, and TERT which were absent in ctDNA (χ 2=8.0, P=0.005). Thus, stronger sampling of glioblastoma’s genetic heterogeneity in tumor DNA improves detection of ctDNA allowing comparisons between mutational profiles that may lead to the identification of similarities and differences with key biologic and/or clinical implications.
Cerebral Venous Thrombosis Case Series at a Tertiary Care Hospital: Exploring Treatment Safety and Efficacy of Direct Oral Anticoagulants
Authors: Mohammed Abdullah Alsheef, Mukhtar Alomar, Abdul Rehman Z. Zaidi, Ghaydaa Juma Kullab, Mohammed AlHazzaa, Asaad Bafaraj, Abdullah Badahman
Journal: Blood (2019)
British Society of Gastroenterology
Authors: D Lacombe, J Savage, R Hembry, P Boulos, T O'kelly, Smilgin Humphries, N Scott, P Sagar, J Stewart, G Blair, F Dixon, P Quirke, P Carter, C Whatrup, D Katz, G Kocjan, A Mindei, M Northovfr, J Jankowski, G Coghill, D Hopwood, G Wormsley (, C Barham, J Al-Rawi, D Johnston, G Wormsley, V Jaffe, B Alexander, R Mathie, B Panagamua, N Tulley, A Notghi, M Oya, L Harding, D Kumar
Journal: Gut (1991)

Cambridge) Indirect evidence suggested that collagenase is a factor in colonic anastomotic leakage.This study examined immunohisto- chemically the distribution of collagenase, and other metalloproteinases: stromelysin and gelatinase and their inhibitor, tissue inhibitor of metalloproteinases (TIMP) in a rabbit colonic anastomosis.An anastomosis was formed after transection (group 1 n= 12), after resection of a 3 cm segment of distal colon (group 2 n= 12) and after obstruction by a silicone ring placed the day before resection (group 3 n= 12).Rabbits were killed 0 5, one, three, and seven days later and tissue taken from the anastomosis (A), distal (D) and 3 (P0), 5 (P1), and 20 (P2) cm proximally.In all groups, intra-and extracellular enzyme and TIMP were present at the anastomosis.In group 3 only,intracellular gelatinase occurred in the submucosa of the resected segment and all postoperative tissue, extracellular collagenase, gelatinase, stromelysin, and TIMP were seen in the mucosa of D, A, P0, and P1 but at seven days they were restricted to the anastomosis.In the obstructed colon changes in the metal- loproteinases are less confined and may justify reluctance for primary anastomosis in humans.
Effect of Escalating Financial Incentive Rewards on Maintenance of Weight Loss
Authors: William S. Yancy, Pamela A. Shaw, Catherine Reale, Victoria Hilbert, Jiali Yan, Jingsan Zhu, Andrea B. Troxel, Gary D. Foster, Kevin G. Volpp
Journal: JAMA Network Open (2019)

Identifying effective strategies for treating obesity is a public health priority.To test an escalating lottery-based incentive tied to daily self-weighing for weight loss maintenance.This 2-phase, 2-arm randomized clinical trial enrolled participants aged 30 to 80 years with an initial body mass index (calculated as weight in kilograms divided by height in meters squared) of 30.0 to 45.0 who lost at least 5 kg during 4 to 6 months in a national online weight management program. Study investigators and outcomes assessors were blinded to participant groups. Data were collected and analyzed from May 23, 2016, through November 13, 2017, based on intention to treat.All participants were advised to weigh themselves daily, with a goal of 6 or more days per week, and received text messaging feedback on their performance. Incentive group participants were eligible for a lottery-based incentive worth an expected value of $3.98 in week 1 that escalated by $0.43 each week they achieved their self-weighing goal during months 1 to 6 (phase 1), followed by no incentives during months 7 to 12 (phase 2).The primary outcome was weight change at the end of phase 1. Secondary outcomes included weight change at the end of phase 2 and changes in self-reported physical activity and eating behaviors.A total of 258 participants (128 in the incentive group and 130 in the control group) had a mean (SD) age of 48.0 (10.5) years and mean (SD) body mass index of 32.1 (3.9); 225 (87.2%) were women; 235 (91.1%) were white; and 102 (39.5%) had an annual income of at least $100 000. Weight measurement was transmitted by 250 participants (96.9%) at 6 months and 227 (88.0%) at 12 months. The percentage of weeks that incentive and control participants achieved a mean self-weighing of at least 6 times was 85.3% vs 75.8%, respectively (P = .002) in phase 1 and 37.7% vs 50.2%, respectively (P = .009) in phase 2. Mean weight changes at the end of phase 1 were -1.1 (95% CI, -2.1 to -0.1) kg in the incentive group and -1.9 (95% CI, -2.9 to -0.8) kg in the control group, with a mean difference of 0.7 (95% CI, -0.7 to 2.2) kg (P = .30 for comparison). At the end of phase 2, mean weight changes were 0.2 (95% CI, -1.2 to 1.7) kg in the incentive group and -0.6 (95% CI, -2.0 to 0.8) kg in the control group, with a mean difference of 0.8 (95% CI, -1.2 to 2.8) kg (P = .41 for comparison).Compared with an active control condition of weekly messages, escalating lottery-based incentives transiently increased rates of self-weighing but did not significantly enhance weight loss maintenance.ClinicalTrials.gov identifier: NCT01900392.
Expansion of T Helper Cell Subsets in Chronic Lymphocytic Leukemia Cell Co-Cultures with Nurselike Cells
Authors: Alicia Vaca, Mariela Sivina, Karen Clise-Dwyer, Ekaterina Kim, Michael J Keating, Alessandra Ferrajoli, William G. Wierda, Dan Li, Qing Ma, Jan A. Burger
Journal: Blood (2019)
Comprehensive Analysis of Hematological Parameter Changes after TKI Discontinuation for Treatment-Free Remission Attempt
Authors: Georgina S. Daher-Reyes, Isabelle Bence-Bruckler, Lambert Busque, Donna L. Forrest, Lynn Savoie, Mary-Margaret Keating, Robert Delage, Anargyros Xenocostas, Elena Liew, Pierre Laneuville, Kristjan Paulson, Jeffrey H. Lipton, Suzanne Kamel-Reid, Brian Leber, Dennis Dong Hwan Kim
Journal: Blood (2019)