tbuckley/cabot-search huggingface dataset:
Phase 1 Trial of K0706, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI): In Patients with Chronic Myelogenous Leukemia (CML) and Phildelphia Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Failing ≥ 3 Prior TKI Therapies: Initial Safety and Efficacy
Authors: Jorge E. Cortes, Dong-Wook Kim, Franck E Nicolini, Tapan Saikia, Aude Charbonnier, Jane F. Apperley, Krishna Rathnam, Michael W. Deininger, Hugues De Lavallade, Navin Khattry, Andrew Whiteley, Michael J. Mauro, Gregor Verhoef, Carlo Gambacorti-Passerini, Alessandro Lucchesi, Shashikant Apte, Granacher Nikki, Siu-Long Yao, Mudgal Kothekar, Jayasree Sreenivasan, Bimba HV, Geetanjali Chimote
Journal: Blood (2019)
CRISPR-Mediated Activation of Endogenous Gene Expression in the Postnatal Heart
Authors: Eric Schoger, Kelli J. Carroll, Lavanya M. Iyer, John R. McAnally, Wei Tan, Ning Liu, Claudia Noack, Orr Shomroni, Gabriela Salinas, Julia Groß, Nicole Herzog, Shirin Doroudgar, Rhonda Bassel-Duby, Wolfram-H. Zimmermann, Laura C. Zelarayán
Journal: Circulation Research (2019)

Genome editing by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 is evolving rapidly. Recently, second-generation CRISPR/Cas9 activation systems based on nuclease inactive dead (d)Cas9 fused to transcriptional transactivation domains were developed for directing specific guide (g)RNAs to regulatory regions of any gene of interest, to enhance transcription. The application of dCas9 to activate cardiomyocyte transcription in targeted genomic loci in vivo has not been demonstrated so far.
NUDT15 Variants Confer High Incidence of Secondary Malignancies of ALL in Children
Authors: Masanori Yoshida, Kazuhiko Nakabayashi, Aiko Sato-Otsubo, Shinichi Tsujimoto, Kaoru Yoshida, Ryota Shirai, Tomoo Osumi, Yuki Yuza, Masatoshi Takagi, Hiroyuki Takahashi, Katsuyoshi Koh, Akitoshi Kinoshita, Moeko Hino, Toshihiko Imamura, Yozo Nakazawa, Okuya Mayuko, Harumi Kakuda, Masashi Sanada, Kimikazu Matsumoto, Daisuke Tomizawa, Nobutaka Kiyokawa, Akira Ohara, Atsushi Manabe, Kenichiro Hata, Jun J. Yang, Motohiro Kato
Journal: Blood (2019)
Cystic fibrosis: triple therapy shows promising results
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The triple therapy Trikafta (elexacaftor, tezacaftor, and ivacaftor) has the potential to lead to “transformative improvements in the lives of people with cystic fibrosis,” two phase III trials indicate.

The studies, funded by the drug company Vertex, looked at the efficacy and safety of Trikafta in patients with one copy of Phe508del—the most common gene mutation that causes cystic fibrosis—and patients with two Phe508del mutations.

Both trials reported positive results for the drug, which could benefit many patients, as up to 90% of all people with cystic fibrosis have at least one copy of the Phe508del mutation, and almost 50% have two copies.

The findings came after NHS England was able to …
Androgen Receptor Interaction with Mediator Complex Is Enhanced in Castration-Resistant Prostate Cancer by CDK7 Phosphorylation of MED1
Authors: Joshua W. Russo, Mannan Nouri, Steven P. Balk
Journal: Cancer Discovery (2019)

Abstract Summary: In this issue of Cancer Discovery, Rasool and colleagues show that TF11H/CDK7 phosphorylates the MED1 component of the Mediator complex, which enhances its interaction with androgen receptor (AR), and that this phosphorylation is increased in prostate cancer that is resistant to castration and enzalutamide. A covalent CDK7-specific inhibitor (THZ1) impairs AR-mediated MED1 recruitment to chromatin, and can suppress enzalutamide resistance in vitro and induce tumor regression in a castration-resistant prostate cancer xenograft model, suggesting a novel therapeutic approach for advanced prostate cancer. See related article by Rasool et al., p. 1538.
Detailed Multi-Method Analysis of Bone Marrow from Pediatric Pre-B-ALL Patients Prior to CD19-CAR-T Therapy Subsequently Evidencing Overt CAR-T Resistance
Authors: Katherine Elizabeth Masih, Rebecca Gardner, Berkley Gryder, Abdelmaksoud Abdallah, Justin Lack, Benjamin Stanton, Ashley Wilson, Sivasish Sindiri, Young Song, Zachary Rae, Michael Kelly, Wang Chaoyu, Xinyu Wen, Adam Cheuk, Jun Wei, Michael C. Jensen, Javed Khan, Rimas Orentas
Journal: Blood (2019)
Labour pledges to outspend Conservatives on health with £26bn NHS “rescue plan”
Authors: Gareth Iacobucci
Journal: BMJ (2019)

A Labour government will increase health spending by an average of 4.3% a year over the next four years as part of a “rescue plan” for the NHS, the party has pledged.

Announcing the plans in a speech at the Royal Society of Medicine on 13 November, Labour shadow health secretary Jonathan Ashworth and shadow chancellor John McDonnell said the party would increase NHS spending by £26bn (€30.4bn; $33.4bn) in real terms between now and 2023-24 if elected next month, outspending the Conservatives existing commitments by over £6bn.

Labour’s settlement would increase the Department of Health and Social Care budget by an average of 4.3% a year (to £178bn by 2023-24), funded through increased income tax rates for the highest earners. NHS England’s revenue budget—which comes out of the overall department …
EXTH-22. ENHANCED DRUG DELIVERY AND CIRCULATION WITH THE NEURAPHERESIS™ SYSTEM FOR THE TREATMENT OF LEPTOMENINGEAL METASTASES
Authors: Choiselle Marius, Katelyn Ripple, George de Castro, Yutong Chen, Charles Giamberadino, Laura Verbick, Aaron McCabe, Peter Fecci, Shivanand Lad
Journal: Neuro-Oncology (2019)

Abstract Leptomeningeal Metastases, a severe late stage form of cancer progression in which malignant cells metastasize to the subarachnoid space (SAS) and leptomeninges, has a mean survival rate of 3–6 months with treatment. Standard of care intrathecal chemotherapy, delivered via an Ommaya reservoir, is limited by poor diffusion within the SAS and acute drug-related neurotoxicity. Neurapheresis™ therapy (NA) is a novel therapy that uses a dual lumen intrathecal catheter and extracorporeal filtration system to filter cerebrospinal fluid (CSF) in a closed-loop. We have previously demonstrated the ability of NA to decrease cancer cell burden in artificial CSF in vitro. Here, NA is shown to enhance chemotherapeutic drug circulation, delivered intraventricularly, throughout the SAS in vitro. NA was tested with a cranial-spinal model of the SAS that included ventricular, cervical and lumbar sampling sites. Drug distribution was tested by comparing the circulation of a 6mg, 3mL ventricular bolus injection of Methotrexate (MTX) in PBS over 48 hours with and without NA (2.0 mL/min flow rate). Ventricular, cervical, and lumbar samples were collected at t=0.5, 4, 8, 12, 24, and 48 hours following drug administration and analyzed by a MTX-specific enzyme-linked immunosorbent assay (ELISA). Compared to controls, NA demonstrated increased, faster distribution of MTX throughout the neuraxis, with an average increase in MTX concentration of 63.7% and 171.5% in the cervical and lumbar sites, respectively, across time points from 4 to 24 hours. The NA system also rapidly decreased the high, potentially neurotoxic concentration of MTX in the ventricles immediately following drug administration and out to 12 hours post-injection. Future in vivo and in vitro testing focuses on pharmacokinetics (PK) in both animals and an advanced 3D-printed human cranial-spinal model to further evaluate the ability of the NA system to enhance MTX distribution throughout the SAS, while simultaneously removing circulating tumor cells.
SURG-26. READMISSION FOLLOWING RESECTION FOR PATIENTS WITH BRAIN METASTASES IN THE UNITED STATES
Authors: Rupesh Kotecha, Muni Rubens, Sergio Gonzalez-Arias, Vitaly Siomin, Matthew Hall, Yazmin Odia, Michael Vogelbaum, Minesh Mehta
Journal: Neuro-Oncology (2019)

Abstract OBJECTIVE Up to 30% of cancer patients will develop brain metastasis during the course of their systemic disease with a significant proportion undergoing resection of at least one lesion. The objective of the present study was to characterize the rates, predictors, and costs of 30-day readmissions following craniotomy for brain metastases using a nationally representative database. METHODS This study was a retrospective analysis of data from the Nationwide Readmissions Database (NRD) from 2010–2014. We included patients who underwent craniotomy for brain metastasis, identified using ICD-9-CM diagnosis (198.3) and procedure (01.59) codes. The primary outcome of the study was unplanned 30-day all-cause readmission rates. Secondary outcomes included predictors and costs of readmissions. RESULTS During the study period, there were 44,846 index hospitalizations for patients who underwent resection of brain metastasis. Among this cohort, 17.8% (n=7,965) had unplanned readmissions within the first 30 days after discharge from the index hospitalization. The readmission rate did not change significantly during the study period (P=0.286). The odds of unplanned readmission were significantly greater in patients with thromboembolic complications (aOR, 1.53; 95% CI: 1.18–2.01), patients with Elixhauser comorbidities &gt;3 (aOR, 1.35; 95% CI: 1.22–1.50), male patients (adjusted odds ratio [aOR], 1.29; 95% CI: 1.17–1.42), patients with an initial length of stay ≥5 days (aOR, 1.02; 95% CI: 1.01–1.03). The median per-patient cost for 30-day unplanned readmission was $11,109 and this accounted for a total cost of $132.1 million during the study period. CONCLUSIONS Unplanned readmissions after resection for brain metastases involve substantial healthcare expenditures. Though there have been many interventions for improving surgical quality, post-operative care, and cost metrics, unplanned readmission rates have not changed. Key patient-specific variables and high rates of comorbidities should be considered to focus our efforts on patient selection for resection, and for strengthening existing interventions for high-risk patients.
BTN2A, a New Immune-Checkpoint Targeting Vg9Vd2 T Cell Cytotoxicity
Authors: Carla E Cano, Christine Pasero, Aude De Gassart, René Hoet, Emmanuel Scotet, Erwan Mortier, Agnes Quemeneur, Chirine Rafia, Antoine Briantais, Anne-Charlotte Le Floch, Daniel Olive
Journal: Blood (2019)
Heritability of the Fibromyalgia Phenotype Varies by Age
Authors: Diptavo Dutta, Chad M. Brummett, Stephanie E. Moser, Lars G. Fritsche, Alexander Tsodikov, Seunggeun Lee, Daniel J. Clauw, Laura J. Scott
Journal: Arthritis & Rheumatology (2019)

Many studies suggest a strong familial component to fibromyalgia (FM). However, those studies have nearly all been confined to individuals with primary FM, i.e., FM without any other accompanying disorder. The current 2011 and 2016 criteria for diagnosing FM construct a score using a combination of the number of painful body sites and the severity of somatic symptoms (FM score). This study was undertaken to estimate the genetic heritability of the FM score across sex and age groups to identify subgroups of individuals with greater heritability, which may help in the design of future genetic studies.We collected data on 26,749 individuals of European ancestry undergoing elective surgery at the University of Michigan (Michigan Genomics Initiative study). We estimated the single-nucleotide polymorphism-based heritability of FM score by age and sex categories using genome-wide association study data and a linear mixed-effects model.Overall, the FM score had an estimated heritability of 13.9% (SE 2.9%) (P = 1.6 × 10-7 ). Estimated FM score heritability was highest in individuals ≤50 years of age (23.5%; SE 7.9%) (P = 3.0 ×10-4 ) and lowest in individuals >60 years of age (7.5%; SE 8.1%) (P = 0.41). These patterns remained the same when we analyzed FM as a case-control phenotype. Even though women had an ~30% higher average FM score than men across age categories, FM score heritability did not differ significantly by sex.Younger individuals appear to have a much stronger genetic component to the FM score than older individuals. Older individuals may be more likely to have what was previously called "secondary FM." Regardless of the cause, these results have implications for future genetic studies of FM and associated conditions.
PDCT-02. UNIQUE CONCURRENT ASSOCIATION OF SOMATIC AND GERMLINE NF1 MUTATIONS WITH GERMLINE MISMATCH REPAIR MUTATIONS IN PEDIATRIC GLIOBLASTOMA MULTIFORME
Authors: Muhammed Baig, Greg Fuller, Sumit Gupta, Grace Tran, Maureen Mork, John Slopis, Carlos Kamiya, Soumen Khatua, Wafik Zaky, Zsila Sadighi
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION We report the first known cases of pediatric glioblastoma (GBM) with prior clinical NF1 diagnoses, one with concurrent germline Lynch syndrome (LS) and NF1, and the other with somatic NF1 mutation and germline constitutional mismatch repair deficiency (CMMRD). Pediatric GBMs in NF1 are rare but increase with age. LS and CMMRD differ by inheritance: autosomal dominant with heterozygous germline mutation (LS), or biallelic mutation (CMMRD) of one of the 4 (possibly 5) MMRD genes (MLH1, MSH2, MSH6, PMS2, or MSH3) - both can develop GBM. METHODS Two pediatric GBM cases with prior NF1 clinical diagnoses (neurocutaneous stigmata) were reviewed. Next generation sequencing and immunohistochemical staining were used for somatic and germline NF1 and MMR gene mutation detection, and for MMR protein expression, respectively. RESULTS Sixteen-year-old male with prior NF1 clinical diagnosis had headaches for one year preceding diagnosis and resection of right frontal GBM with somatic mutations of POLE and PMS2, but not NF1. His father had confirmed LS with MSH2 mutation and no neurocutaneous stigmata. Patient’s germline testing revealed pathogenic MSH2 and NF1 mutations, confirming LS and NF1. Current treatment is chemoradiation. Nineteen-year-old male with former NF1 clinical diagnosis had 2 GBMs, first in left midbrain diagnosed and biopsied (after 3 months of right hemiparesis) with somatic PMS2 and NF1 mutations, and a second left frontal lobe tumor diagnosed and resected 11 months later, with 2 pathogenic germline mutations of PMS2, inherited one from each parent, confirming CMMRD without NF1. Treatment was focal radiation administered to both sites followed by adjuvant chemotherapy. CONCLUSION Children with NF1 stigmata and GBM may have either concurrent NF1 and LS, or CMMRD with NF1 somatic mutations. Confirmatory germline and somatic MMR gene and NF1 mutation testing in children with GBM and NF1 stigmata should be considered as the specific diagnosis affects management.
Extensive brainstem infiltration, not mass effect, is a common feature of end-stage cerebral glioblastomas
Authors: Michael R Drumm, Karan S Dixit, Sean Grimm, Priya Kumthekar, Rimas V Lukas, Jeffrey J Raizer, Roger Stupp, Milan G Chheda, Kwok-Ling Kam, Matthew McCord, Sean Sachdev, Timothy Kruser, Alicia Steffens, Rodrigo Javier, Kathleen McCortney, Craig Horbinski
Journal: Neuro-Oncology (2019)

Abstract Background Progress in extending the survival of glioblastoma (GBM) patients has been slow. A better understanding of why patient survival remains poor is critical to developing new strategies. Postmortem studies on GBM can shed light on why patients are dying. Methods The brains of 33 GBM patients were autopsied and examined for gross and microscopic abnormalities. Clinical-pathologic correlations were accomplished through detailed chart reviews. Data were compared with older published autopsy GBM studies that predated newer treatment strategies, such as more extensive surgical resection and adjuvant temozolomide. Results In older GBM autopsy series, mass effect was observed in 72% of brains, with herniation in 50% of all cases. Infiltration of tumor into the brainstem was noted in only 21% of those older cases. In the current series, only 10 of 33 (30%) GBMs showed mass effect (P = 0.0003), and only 1 (3%) showed herniation (P &amp;lt; 0.0001). However, extensive GBM infiltration of the brainstem was present in 22 cases (67%, P &amp;lt; 0.0001), with accompanying destruction of the pons and white matter tracts. There was a direct correlation between longer median patient survival and the presence of brainstem infiltration (16.1 mo in brainstem-invaded cases vs 9.0 mo in cases lacking extensive brainstem involvement; P = 0.0003). Conclusions With improving care, severe mass effect appears to be less common in GBM patients today, whereas dissemination, including life-threatening brainstem invasion, is now more pronounced. This has major implications regarding preclinical GBM models, as well as the design of clinical trials aimed at further improving patient survival.
mTOR inhibitors in combination regimens guided by encyclopedic tumour analysis show superior outcomes compared to monotherapy in refractory cancers
Authors: T. Crook, A. Vaid, S. Limaye, R. Page, D. Patil, D. Akolkar, V. Datta, A. Ghaisas, R. Patil, H. Singh, A. Srinivasan, S. Apurwa, R. Datar
Journal: Annals of Oncology (2019)
Rare Genetic Variants Associated With Sudden Cardiac Death in Adults
Authors: Amit V Khera, Heather Mason-Suares, Deanna Brockman, Minxian Wang, Martin J VanDenburgh, Ozlem Senol-Cosar, Candace Patterson, Christopher Newton-Cheh, Seyedeh M Zekavat, Julie Pester, Daniel I Chasman, Christopher Kabrhel, Majken K Jensen, JoAnn E Manson, J Michael Gaziano, Kent D Taylor, Nona Sotoodehnia, Wendy S Post, Stephen S Rich, Jerome I Rotter, Eric S Lander, Heidi L Rehm, Kenney Ng, Anthony Philippakis, Matthew Lebo, Christine M Albert, Sekar Kathiresan
Journal: Journal of the American College of Cardiology (2019)
The Validation of the BCR/ABL1-like Predictor across Laboratories Shows Reproducibility of Results
Authors: Sabina Chiaretti, Taherinasab Akram, Canichella Martina, Monica Messina, Alfonso Piciocchi, Cyril Šálek, Katerina Machova, Katerina Blagoevova, Jordi Ribera, Josep-Maria Ribera, Manja Meggendorfer, Claudia Haferlach, Anna Guarini, Robin Foà
Journal: Blood (2019)
Interferon-γ-Dependent Inflammatory Signature in Acute Myeloid Leukemia Cells Is Able to Shape Stromal and Immune Bone Marrow Microenvironment
Authors: Marilena Ciciarello, Giulia Corradi, Sabina Sangaletti, Barbara Bassani, Giorgia Simonetti, Jayakumar Vadakekolathu, Giovanni Marconi, Giovanni Martinelli, Mario Paolo Colombo, Sergio Rutella, Michele Cavo, Antonio Curti
Journal: Blood (2019)
Hepatic exosome-derived miR-130a-3p attenuates glucose intolerance via suppressing PHLPP2 gene in adipocyte
Authors: Jiahan Wu, Tao Dong, Ting Chen, Jiajie Sun, Junyi Luo, Jiajian He, Limin Wei, Bin Zeng, Haojie Zhang, Weite Li, Jie Liu, Xingping Chen, Mei Su, Yuechun Ni, Qingyan Jiang, Yongliang Zhang, Qianyun Xi
Journal: Metabolism (2019)
Potently Cytotoxic Natural Killer Cell Potential Initially Emerges from Erythro-Myeloid Progenitors during Mammalian Development
Authors: Carissa Dege, Katherine H Fegan, J Philip Creamer, Melissa M Berrien-Elliott, Stephanie A. Luff, Julia A Wagner, Paul D. Kingsley, Kathleen E. McGrath, Todd A Fehniger, James Palis, Christopher M. Sturgeon
Journal: Blood (2019)
Multicentric Real Life Evaluation of the Impact of Next-Generation Sequencing on the Clinical Management of Chronic Myeloid Malignancies
Authors: Sophie Vantyghem, Pierre Peterlin, Sylvain Thepot, Audrey Ménard, Viviane Dubruille, Camille Debord, Thierry Guillaume, Alice Garnier, Amandine Le Bourgeois, Soraya Wuilleme, Catherine Godon, Olivier Theisen, Marion Eveillard, Jacques Delaunay, Herve Maisonneuve, Bruno Villemagne, Nadine Morineau, Stéphane Vigouroux, Francois Subiger, Elsa Lestang, Marion Loirat, Anne Parcelier, Pascal Godmer, Mélanie Mercier, Damien Luque Paz, Lenaig Le Clech, Ronan Le Calloch, Mathilde Hunault, Valerie Ugo, Philippe Moreau, Steven Le Gouill, Patrice Chevallier, Marie-Christine Bene, Yannick LE Bris
Journal: Blood (2019)
Assessment of computational methods for the analysis of single-cell ATAC-seq data
Authors: Huidong Chen, Caleb Lareau, Tommaso Andreani, Michael E. Vinyard, Sara P. Garcia, Kendell Clement, Miguel A. Andrade-Navarro, Jason D. Buenrostro, Luca Pinello
Journal: Genome biology (2019)

Recent innovations in single-cell Assay for Transposase Accessible Chromatin using sequencing (scATAC-seq) enable profiling of the epigenetic landscape of thousands of individual cells. scATAC-seq data analysis presents unique methodological challenges. scATAC-seq experiments sample DNA, which, due to low copy numbers (diploid in humans), lead to inherent data sparsity (1-10% of peaks detected per cell) compared to transcriptomic (scRNA-seq) data (10-45% of expressed genes detected per cell). Such challenges in data generation emphasize the need for informative features to assess cell heterogeneity at the chromatin level.We present a benchmarking framework that is applied to 10 computational methods for scATAC-seq on 13 synthetic and real datasets from different assays, profiling cell types from diverse tissues and organisms. Methods for processing and featurizing scATAC-seq data were compared by their ability to discriminate cell types when combined with common unsupervised clustering approaches. We rank evaluated methods and discuss computational challenges associated with scATAC-seq analysis including inherently sparse data, determination of features, peak calling, the effects of sequencing coverage and noise, and clustering performance. Running times and memory requirements are also discussed.This reference summary of scATAC-seq methods offers recommendations for best practices with consideration for both the non-expert user and the methods developer. Despite variation across methods and datasets, SnapATAC, Cusanovich2018, and cisTopic outperform other methods in separating cell populations of different coverages and noise levels in both synthetic and real datasets. Notably, SnapATAC is the only method able to analyze a large dataset (> 80,000 cells).