tbuckley/cabot-search huggingface dataset:
Taking Aim at Contraceptive Coverage — The Trump Administration’s Attacks on Reproductive Rights
Authors: Cynthia H. Chuang, Carol S. Weisman
Journal: New England Journal of Medicine (2019)

Interview with Dr. Cynthia Chuang on federal efforts to weaken the ACA's contraceptive-coverage mandate. (06:58)Download On January 14, Trump administration rules that would broadly allow employers to deny contraceptive coverage to their employees on the basis of religious or moral objections were temporarily blocked by a federal court. But the legal battle is likely to continue.
<i>Sleeping Beauty</i> Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors
Authors: Pauline J. Beckmann, Jon D. Larson, Alex T. Larsson, Jason P. Ostergaard, Sandra Wagner, Eric P. Rahrmann, Ghaidan A. Shamsan, George M. Otto, Rory L. Williams, Jun Wang, Catherine Lee, Barbara R. Tschida, Paramita Das, Adrian M. Dubuc, Branden S. Moriarity, Daniel Picard, Xiaochong Wu, Fausto J. Rodriguez, Quincy Rosemarie, Ryan D. Krebs, Amy M. Molan, Addison M. Demer, Michelle M. Frees, Anthony E. Rizzardi, Stephen C. Schmechel, Charles G. Eberhart, Robert B. Jenkins, Robert J. Wechsler-Reya, David J. Odde, Annie Huang, Michael D. Taylor, Aaron L. Sarver, David A. Largaespada
Journal: Cancer Research (2019)

Abstract Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.
Abstract 20372: Emery Dreifuss Muscular Dystrophy is Caused by Change of Nuclear Invagination and Calcium Transient
Authors: Masaya Shimojima, Shinsuke Yuasa, Chiaki Nakanishi, Masakazu Yamagishi, Keiichi Fukuda
Journal: Circulation (2017)

Introduction: Emery-Drefuss muscular dystrophy(EDMD) causes cardiomyopathy with conduction disorder. One nuclear membrane protein, is encoded by EMD, and an EMD mutation causes EDMD. Alteration of ...
Daratumumab (DARA) in Combination with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) in Patients with Newly Diagnosed Multiple Myeloma (MMY1001): Updated Results from an Open-Label, Phase 1b Study
Authors: Ajai Chari, Saad Z Usmani, Amrita Krishnan, Sagar Lonial, Raymond Comenzo, Kaida Wu, Jianping Wang, Parul Doshi, Brendan M Weiss, Jordan Schecter, Andrzej J. Jakubowiak
Journal: Blood (2017)
Enhancements in pancreatic protocol CT as a prognostic indicator in pancreatic cancer.
Authors: Jaewon Park, In Kuk Cho, Jong-Chan Lee, Jongchan Lee, Young Hoon Kim, Jaihwan Kim, Jin-Hyeok Hwang
Journal: Journal of Clinical Oncology (2019)

216 Background: Pancreatic protocol CT (pCT) is widely used to evaluate stage and resectability of pancreatic ductal adenocarcinoma (PDAC). Recent studies show that CT enhancement patterns are related to the patient’s prognosis in several cancers, however it is not well described that pCT enhancement has prognostic effect in resectable PDAC so far. We aimed to show correlaton between pCT enhancements and prognosis in resectable PDAC. Methods: We retrospectively enrolled 159 patients (median age, 67.8 years) who underwent pCT before curative resection in Seoul National University Bundang Hospital between January 2010 and December 2015, with final pathological diagnosis of PDAC. CT enhancement ratio (CTER) of each primary lesion was calculated as proportional difference between maximum Houndsfield Unit (HU) of pancreatic phase (PP) image and maximum HU of non-contrast image; [(max HU of PP) - (max HU of non-contrast)] / (max HU of non-contrast). Patients were classified into two groups, based on CTER. Kaplan–Meier analysis and Cox proportional hazards models were used to correlate CTER with overall survival (OS) and recurrence free survival (RFS). Results: Median overall survival was 22.0 months during a median follow-up period of 18.5 months. Based on CTER with cut-off value of 1.8, higher (CTER ≥ 1.8) group (N = 43) was compared with lower (CTER &lt; 1.8) group (N = 116) in terms of OS and RFS. Lower group showed significantly shorter median OS (18.5 months versus 39.3 months, P &lt; 0.001) and median RFS (9.9 months versus 21.5 months, P = 0.006) than those of higher group. Multivariate regression analysis showed that lower group had shorter OS (HR 1.70; CI 1.01-2.85, P = 0.044) and RFS (HR 1.84; CI 1.10-3.06, P = 0.019). Conclusions: Our study suggests that lower enhancement in pancreatic phase of pCT is related to poor prognosis in PDAC. Therefore, active surveillance would be required in resected PDAC patients with CTER less than 1.8.
Abstract 19737: Decannulation of Extracorporeal Membrane Oxygenation Guided by Transthoracic Echocardiography Assessment of Left Ventricular Recovery After Refractory Ventricular Fibrillation Arrest
Authors: Felipe Kazmirczak, Kathleen Carlson, Jason A. Bartos, Cindy Martin, Ganesh Raveendran, KP Madhu, Ranjit John, Demetris Yannopoulos, Emil Missov
Journal: Circulation (2017)

Background: In December 2015, the Minnesota Resuscitation Consortium (MRC) initiated a protocol to rapidly mobilize patients suffering refractory ventricular tachycardia/ventricular fibrillation (V...
Abstract 20584: The Effect of Substitution of Sitting With Standing on Cardiovascular Risk Factors: A Systematic Review and Meta-Analysis
Authors: Farzane Saeidifard, Jose R Medina-Inojosa, Marta Supervia Pola, Thomas P Olson, Virend K Somers, Francisco Lopez-Jimenez
Journal: Circulation (2017)

Background: Sedentary lifestyle is a risk factor for cardiovascular disease. There is a growing interest regarding the impact of substituting sitting with standing, as a method to decrease sedentar...
A phase II, multicenter, open-label study of [fam-] trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing gastric cancer.
Authors: Kohei Shitara, Yung-Jue Bang, Hyun Cheol Chung, Hiroshi Yabusaki, Satoru Iwasa, Daisuke Sakai, Kei Muro, Naotoshi Sugimoto, Hisateru Yasui, Makio Gamoh, Yasuko Murakawa, Yuji Negoro, Tomohiro Nishina, Hisashi Hosaka, Yasushi Omuro, Yoshinori Kawaguchi, Masahiro Sugihara, Kaku Saito, Rita Dalal, Kensei Yamaguchi
Journal: Journal of Clinical Oncology (2019)

TPS180 Background: There is no HER2-targeted therapy for patients with HER2-positive gastric cancer (GC) who progressed on trastuzumab-based therapy. [fam-] trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody, topoisomerase I inhibitor payload, cleavable peptide-based linker, and high drug-to-antibody ratio of approximately 8. In an ongoing phase I trial, [fam-] trastuzumab deruxtecan showed an acceptable safety profile and promising antitumor activity in salvage-line subjects with HER2+ GC who previously received trastuzumab (confirmed objective response rate [ORR] of 43.2% [19/44]; Iwata et al, ASCO 2018). Methods: The randomized, phase II, multicenter, open-label, DESTINY-Gastric01 study will assess the efficacy and safety of [fam-] trastuzumab deruxtecan in HER2-expressing GC. The primary cohort, HER2+ (IHC 3+ or IHC 2+/ISH+) GC subjects who progressed after ≥ 2 prior regimens and previously received trastuzumab, will be randomized (2:1) to [fam-] trastuzumab deruxtecan (6.4 mg/kg dose; once every 3 weeks) or physician’s choice (irinotecan or paclitaxel). Two nonrandomized exploratory cohorts will assess the efficacy and safety of [fam-] trastuzumab deruxtecan in subjects with HER2-low GC (IHC 2+/ISH- and IHC 1+, respectively) who are treatment-naïve to HER2-targeted therapies. The primary endpoint is ORR assessed by an independent central review; secondary endpoints include overall survival (OS), progression-free survival, duration of response, disease control rate, pharmacokinetics, and safety (as shown in ClinicalTrials.gov). The primary analysis for ORR and interim OS analysis will occur after all subjects complete tumor assessments on week 18 and when approximately 108 OS events are observed, whichever comes later. The primary cohort will enroll 180 subjects; providing 92.9% power to detect a difference between the ORR of 40% for [fam-] trastuzumab deruxtecan vs 15% for physician’s choice. Each exploratory cohort will enroll a maximum of 20 subjects. Enrollment began in October 2017. As of Feb 13, 2018, 12 of 180 subjects have been enrolled. Clinical trial information: NCT03329690.
The Brief Gah Scale (Geriatric Assessment in Hematology) Correlates Well with a Comprehensive Geriatric Assessment in Patients with Hematologic Malignancies
Authors: Raul Cordoba, Ana-Isabel Hormigo, Javier Martinez-Peromingo, Maria Jarana, Marta Perez-Albacete, Teresa Villaescusa, Elham Askari, Jose Luiz Lopez Lorenzo, Maria Angeles Perez-Saenz, Elena Prieto, Maria Pilar Llamas Sillero
Journal: Blood (2018)
Respiration rate and volume measurements using wearable strain sensors
Authors: Michael Chu, Thao Nguyen, Vaibhav Pandey, Yongxiao Zhou, Hoang N. Pham, Ronen Bar-Yoseph, Shlomit Radom-Aizik, Ramesh Jain, Dan M. Cooper, Michelle Khine
Journal: npj Digital Medicine (2019)

Current methods for continuous respiration monitoring such as respiratory inductive or optoelectronic plethysmography are limited to clinical or research settings; most wearable systems reported only measures respiration rate. Here we introduce a wearable sensor capable of simultaneously measuring both respiration rate and volume with high fidelity. Our disposable respiration sensor with a Band-Aid© like formfactor can measure both respiration rate and volume by simply measuring the local strain of the ribcage and abdomen during breathing. We demonstrate that both metrics are highly correlated to measurements from a medical grade continuous spirometer on participants at rest. Additionally, we also show that the system is capable of detecting respiration under various ambulatory conditions. Because these low-powered piezo-resistive sensors can be integrated with wireless Bluetooth units, they can be useful in monitoring patients with chronic respiratory diseases in everyday settings.
Developing PHY906 as a broad- spectrum modulator of chemotherapeutic agents in cancer therapy
Authors: Shwu-Huey Liu, Zaoli Jiang, Tah-Mun Su, Wen-Yi Gao, Chung-Hang Leung, Yashang Lee, Yung-Chi Cheng
Journal: Cancer Research (2004)

557   PHY906 is a traditional Chinese botanical formulation consisting of 4 different herbs, and it has been used for some 1800 years to treat gastrointestinal ailments, some of which are commonly observed side effects in cancer patients undergoing chemotherapy. We have previously reported that PHY906 reduced chemotherapy-induced toxicities including body weight loss and mortality, and that it also enhanced the antitumor efficacy of a broad-spectrum of anticancer agents, such as CPT-11, 5-FU, CPT-11/5-FU/LV, VP-16, and L-OddC in  in vivo  animal models. PHY906 has been co-administrated with either the oral 5-FU prodrug capecitabine or CPT-11 in human hepatocellular xenografts mouse model, and with gemcitabine in mouse pancreatic cancer model. We have shown that PHY906 significantly enhanced the therapeutic index of chemotherapeutic agents studied in both hepatocellular and pancreatic cancer models. Co-administration of PHY906 with either capecitabine or gemcitabine in animal models did not alter the pharmacokinetic profile of capecitabine, gemcitabine, or their respective metabolites. Our biochemical studies revealed that the PHY906 formulation possesses a wide range of pharmacological activities. The potential mechanism(s) of action of PHY906 include (1) enhancement of oral uptake of pharmacologically active agents with inhibition in intestinal CYP3A4; (2) inhibition of NF-κB activity; (3) inhibition of MMP activity; and (4) destruction of the integrity of sinusoids in hepatoma. These pre-clinical in vivo studies have provided rationale for developing PHY906 in the clinical setting. A phase I/IIA double-blind placebo-controlled, dose escalation study of PHY906 was initiated to evaluate the potential effect of PHY906 in modulating CPT-11-induced diarrhea associated with the bolus, weekly schedule of CPT-11/5-FU/LV in advanced colorectal cancer patients. A second phase I/II open-label dose escalation clinical trial has just been opened to patient accrual to evaluate the role of PHY906 in combination with capecitabine in the treatment of hepatocellular carcinoma.
1197 INSULIN RESISTANCE UNDERMINES THE ADVANTAGES OF IL28B POLYMORPHISM IN THE PEGYLATED INTERFERON a2B AND RIBAVIRIN TREATMENT FOR CHRONIC HEPATITIS C PATIENTS WITH GENOTYPE 1
Authors: E. Ogawa, N. Furusyo, M. Murata, M. Kainuma, K. Toyoda, H. Taniai, T. Koga, K. Eiraku, F. Mitsumoto, K. Okada, Y. Etoh, J. Hayashi
Journal: Journal of Hepatology (2012)
MSI-H testing via hybrid capture based NGS sequencing of liquid biopsy samples.
Authors: Kyle Gowen, Travis A Clark, Jeffrey P. Gregg, Mandy Z. Greene, Annie Murphy, Jared White, Jon Chung, Mark Kennedy, Julia Andrea Elvin, Jeffrey S. Ross, Vincent A. Miller, Jason D. Hughes, Doron Lipson, Lucas Dennis
Journal: Journal of Clinical Oncology (2019)

504 Background: Microsatellite instability (MSI) testing has become critically important in clinical cancer care of patients with cancer given the recent pan-tumor FDA approval of pembrolizumab for use in patients with MSI-High (MSI-H) tumors. We previously demonstrated the robustness of a novel proprietary algorithm for determination of MSI status via NGS from solid tumor biopsy specimens (J Clin Oncol 34, 2016 (suppl; abstr 1523)). Traditional MSI tests such as PCR or IHC are impractical for pan-tumor adoption, as MSI-H prevalence outside of gastrointestinal and endometrial cancers is usually &lt; 1%. NGS-based ctDNA profiling provides an opportunity for both MSI and actionable alteration testing in patients in whom tissue-based biopsy is not available. Methods: Genomic DNA (gDNA) from five previously characterized MSI-H cell lines: (DLD1, 22Rv1, LNCap, RL952, CL188), and one MSS cell line (SCC9) was enzymatically-fragmented to simulate ctDNA and titrated to various dilution levels with DNA from a healthy hapmap subject (NA12878). Samples were screened with a 70-gene panel, FoundationOne Liquid, that includes 180 mononucleotide repeat sequences (8-26bp long in the human reference genome). Length variability in the 180 repeat loci was utilized to generate an overall MSI score via principal components analysis. The NGS based MSI algorithm was applied to all the samples. Results: Assessment of these six cell lines, targeting five dilution levels confirmed by SNP mixing ratios, show that our NGS based MSI test for liquid biopsies has 96% sensitivity at &gt; 2% tumor fraction with 100% PPV. The regression intercept of the MSI-H dilution samples with the pre-established MSI-H calling threshold shows our method has a LOD of 1.03% tumor fraction. MSI-H prevalence data from liquid biopsies of gastrointestinal tumors obtained during clinical care will also be presented. Conclusions: These data demonstrate the feasibility of using NGS-based liquid biopsy assays for MSI testing. This ctDNA-based approach will allow for increased access to checkpoint inhibitors in a pan-tumor setting, which would be especially relevant for cancers where routine MSI testing is impractical or when tissue is not available.
Withholding anti-EGFR, the impact on outcome in <i>RAS</i> wild-type metastatic colorectal tumors (WAIT or ACT trial).
Authors: Lola-Jade Palmieri, Laurent Mineur, David Tougeron, Benoit Rousseau, Victoire Granger, Jean-Marc Gornet, Denis Michel Smith, Astrid Lièvre, Marie-Pierre Galais, Solene Doat, Simon Pernot, Anne Laure Bignon, Jean-Philippe Metges, Nabil Baba-Hamed, David Sefrioui, Stephane Obled, Carole Vitellius, Olivier Bouche, Julie Henriques, Romain Coriat
Journal: Journal of Clinical Oncology (2019)

626 Background: First line of RAS wild-type (WT) unresectable metastatic colorectal cancer (mCRC) can be doublet chemotherapy with an anti-VEGF (Vascular Endothelial Growth Factor), or an anti-EGFR (Epidermal Growth Factor Receptor). Waiting for RAS status, many oncologists initiate chemotherapy and add the anti-EGFR secondly. The objective was to compare the delayed introduction of the anti-EGFR to the immediate introduction of the anti-VEGF in first-line treatment of RAS WT mCRC. Methods: This was a retrospective cohort analysis from 2013 to 2016, multicentric with 28 health care centers. We included patients with RAS WT unresectable mCRC treated between 2013 and 2016 by a doublet chemotherapy with the anti-VEGF introduced immediately or with the anti-EGFR introduced at C2 or C3. Progression free survival (PFS), overall survival (OS) and response rate (RR) for the two cohorts were compared. Hazard ratios (HR) with 95% confidence interval (95%CI) were estimated with cox regression models weighted on propensity score to deal with potential confounders. Results: A total of 262 patients were included, 129 in the immediate anti-VEGF group and 133 in the delayed anti-EGFR group. Median follow-up was 37.9 months. Ninety-two patients had the anti-EGFR introduced at C2, 40 at C3. The median delay of RAS analysis was 19 days (q1-q3: 13-26). Patients treated with anti-VEGFs were more likely men (68% versus 56%), with more metastatic sites ( &gt; 2 sites: 15% versus 9%). A propensity score including the number of metastatic sites and a possible previous treatment was built. Delayed anti-EGFRs were associated with longer PFS compared to immediate anti-VEGFs: 13.8 versus 11.0 months, p = 0.0244. After weighting, delayed anti-EGFRs were still associated with better PFS: HR 0.74, 95%CI [0.61 – 0.90], p = 0.0024. OS was not different between the two arms (30.5 for anti-VEGF versus 29.9 months, p = 0.3934), even after weighting (HR 0.86, 95%CI [0.69 – 1.08], p = 0.2024). There was a better RR with delayed anti-EGFRs: 66.7% versus 45.6%, p = 0.0007. Conclusions: Our findings suggest that, while waiting for RAS status, the delayed introduction of the anti-EGFR is a valid option, compared to the immediate introduction of the anti-VEGF.
Invasive Procedures to Improve Function in Frail Older Adults
Authors: Carolyn D. Seib, Emily Finlayson
Journal: JAMA Internal Medicine (2019)

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A Novel and Potent Inhibitor of E-Selectin, GMI-1687, Attenuates Thrombus Formation and Augments Chemotherapeutic Intervention of AML in Preclinical Models Following Subcutaneous Administration
Authors: John Peterson, Myung-Gi Baek, Silvia Locatelli-Hoops, Ji-Won Lee, Lingquan Deng, David A Stewart, Theodore AG Smith, Daniel Durant Myers, William E Fogler, John L Magnani
Journal: Blood (2018)
Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential
Authors: Claartje Aleid Meddens, Amy Catharina Johanna van der List, Edward Eelco Salomon Nieuwenhuis, Michal Mokry
Journal: Gut (2019)

Genome-wide association studies have identified over 200 loci associated with IBD. We and others have recently shown that, in addition to variants in protein-coding genes, the majority of the associated loci are related to DNA regulatory elements (DREs). These findings add a dimension to the already complex genetic background of IBD. In this review we summarise the existing evidence on the role of DREs in IBD. We discuss how epigenetic research can be used in candidate gene approaches that take non-coding variants into account and can help to pinpoint the essential pathways and cell types in the pathogenesis of IBD. Despite the increased level of genetic complexity, these findings can contribute to novel therapeutic options that target transcription factor binding and enhancer activity. Finally, we summarise the future directions and challenges of this emerging field.
Towards a gamete matching platform: using immunogenetics and artificial intelligence to predict recurrent miscarriage
Authors: Aldo Mora-Sánchez, Daniel-Isui Aguilar-Salvador, Izabela Nowak
Journal: npj Digital Medicine (2019)

The degree of Allele sharing of the Human Leukocyte Antigen (HLA) genes has been linked with recurrent miscarriage (RM). However, no clear genetic markers of RM have yet been identified, possibly because of the complexity of interactions between paternal and maternal genes during embryo development. We propose a methodology to analyse HLA haplotypes from couples either with histories of successful pregnancies or RM. This article describes a method of RM genetic-risk calculation. The proposed HLA representation techniques allowed us to create an algorithm (IMMATCH) to retrospectively predict RM with an AUC = 0.71 (p = 0.0035) thanks to high-resolution typing and the use of linear algebra on peptide binding affinity data. The algorithm features an adjustable threshold to increase either sensitivity or specificity, allowing a sensitivity of 86%. Combining immunogenetics with artificial intelligence could create personalised tools to better understand the genetic causes of unexplained infertility and a gamete matching platform that could increase pregnancy success rates.