tbuckley/cabot-search huggingface dataset:
Circulating tumor DNA (ctDNA) as a prognostic marker for recurrence in resected pancreas cancer.
Authors: Judy Sing-Zan Wang, Mark Sausen, Sonya Parpart-Li, Derek M Murphy, Victor E Velculescu, Laura D. Wood, Sara Solt-Linville, Elizabeth Sugar, Bjarne Bartlett, Cherie Blair, Tianna Dauses, Elizabeth M. Jaffee, Ralph H. Hruban, Dan Laheru, Luis A. Diaz
Journal: Journal of Clinical Oncology (2015)

11025 Background: Despite aggressive therapeutic interventions with pancreaticoduodenectomy and adjuvant chemo/chemoradiotherapy, recurrence rates remain high for patients with resectable pancreas cancer. Additionally, current post-operative surveillance methods including tumor marker CA19-9, clinical symptoms, and CT scans lack sensitivity and specificity for early recurrence. Hence, a practical, blood-based biomarker that could identify cancer at an earlier time point, and prompt a change in management, would be clinically important. Methods: Using a highly sensitive digital DNA quantification approach, we measured KRAS mutation-associated circulating tumor DNA (ctDNA) in the archived sera of 46 resected pancreas adenocarcinoma patients taken 8-10 weeks post-operatively, after confirming the mutational presence in the primary tumor. Approximately 10 years of patient data were available from chart review and clinical databases to assess disease recurrence. A mutant allele fraction > 0.02% was considered positive. Results: In a subgroup analysis, patients whose tumor had a p.G12V KRAS mutation and who did not have detectable levels of ctDNA had significantly longer time to disease recurrence than did patients with detectable ctDNA (p = 0.02; CI 1.037 to 12.77). Amongst patients whose tumor harbored a p.G12R KRAS mutation, those with undetectable ctDNA also had significant longer time to disease recurrence as compared to those with detectable ctDNA (p = 0.01; CI 1.241 to 36.99). In combination, 14 of the total 46 patients who had undetectable ctDNA following their resection trended, though statistically insignificant, towards longer time to disease recurrence (median time 545 to 471 days; HR = 0.58; p = 0.3) including 3 ctDNA-negative patients who still remain disease free. Conclusions: This retrospective analysis demonstrates that ctDNA can be detected in peripheral blood, and may be a valuable clinical marker for specific tumor mutations. Additional larger, prospective studies are needed to validate the clinical utility as a prognostic biomarker for recurrence in resected pancreas cancer.
Abstract 367: Exercising Exacerbates the Hypertrophic Response of Female Transgenic Mice Expressing Elevated Myocardial Na <sup>+</sup> /H <sup>+</sup> Exchanger Isoform 1
Authors: Fatima Mraiche, Larry Fliegel
Journal: Circulation Research (2012)

Cardiac hypertrophy (CH) is heart growth in response to environmental demands, and a variety of hormonal, paracrine and autocrine stimuli. It is a means to reduce stress on the ventricular wall. The Na+/H+ exchanger isoform 1 (NHE1) has been implicated in the development and progression of CH. To better understand the involvement of NHE1, male and female transgenic mice that express cardiac specific active NHE1 expression were studied. N-line mice expressed wild-type NHE1, and K-line mice expressed activated NHE1. NHE activity of adult ventricular cardiomyocytes and protein expression were elevated by approximately 2 and 3-fold in the N- and K-line mice vs. control. The K-line female mice assessed by echocardiography demonstrated significant global cardiac dysfunction. Left ventricular fractional cell shortening and ejection fraction were significantly decreased in the K-line mice (23.1 ± 3.8% and 45.2 ± 6.9% K-line vs. 36.5 ± 1.1% and 66.4 ± 1.5% control, respectively; p&lt;0.05). The K-line female mice also exhibit myocardial remodeling. The heart weight to body weight ratio was significantly greater in the K-line mice (143 ± 10.0% of control; P&lt;0.05). Cross sectional area (K-line 195.6 ± 16.4% of control; p&lt;0.05) and interstitial fibrosis (K-line: 275.4 ± 11.6% of control; p&lt;0.05) were also elevated. Increased expression of active NHE1 protein in male mice was also much more detrimental than expression of the wild type protein as was seen with the female transgenic mice. Therefore, the NHE1 induced hypertrophic effect was not gender dependent. However, NHE1 expression induced gender specific differences with exercise. Exercising exaggerated the HW/BW ratio in female mice expressing activated NHE1 compared to males. These results suggest that gender specific activation of NHE1 may be critical in promoting hypertrophy in females in comparison with males.
Differential activity of ARRY-543, a potent, small molecule inhibitor of EGFR/ErbB-2 compared to lapatanib in in vivo xenograft models
Authors: Karyn Bouhana, Tracy Pheneger, Rich Woessner, Gene Tarlton, Ira Von Carlowitz, Keith Hoffman, Eli Wallace, Kevin Koch, Jim Winkler, Shannon Winski, Patrice Lee
Journal: Cancer Research (2008)

4848  ARRY-543 is an orally active, potent small molecule tyrosine kinase inhibitor targeting both EGFR and ErbB2. The compound is a reversible, ATP-competitive inhibitor with nanomolar potency in both in vitro and in cell-based assays. This compound has very good in vivo and in vitro PK/ADME properties and has shown excellent activity in numerous mouse tumor models. In a series of experiments, we show that ARRY-543 has superior activity to lapatinib in several subcutaneous human tumor xenograft models selected for EGFR and ErbB2 expression patterns: A431, H1650 and N87. A431 is a wild-type EGFR-overexpressing epidermoid carcinoma cell line. H1650 is an EGFR overexpressing, lung adenocarcinoma cell line, which has the Exon 19 deletion conferring increased sensitivity to gefitinib and erlotinib. N87 is a gastric carcinoma cell line expressing high levels of both EGFR and ErbB2 and also relies on both for proliferation and survival. For all tumor studies, female nude mice were inoculated with cells subcutaneously in the flank. For tumor growth inhibition (TGI) studies, tumor size was measured at regular intervals for up to 21 days. In the A431 TGI study, ARRY-543 demonstrated significant dose-related TGI; 30, 57 and 81% at doses of 25, 50 and 100 mg/kg, BID, PO, respectively. Lapatinib administration at 50 and 100 mg/kg, BID, PO showed 33 and 52% TGI, respectively. In the H1650 TGI study, animals received oral doses of vehicle, ARRY-543 or lapatinib (100 mg/kg, BID) or erlotinib (100 mg/kg, QD). ARRY-543 demonstrated significant tumor growth inhibition (95%), with 2/8 animals showing tumor regressions. Comparable tumor growth inhibition was seen in the erlotinib group; 6/8 animals with tumor regressions. Lapatinib showed significantly less activity with respect to tumor growth inhibition (~18%; NS); no tumor regressions were observed. In the dual EGFR/ErbB2-over-expressing gastric carcinoma tumor line N87, pharmacodynamic studies were performed evaluating the effects of vehicle, ARRY-543 (100 mg/kg, once) or lapatinib (100 mg/kg, once) on pEGFR and pErb2 levels in tumors at 4 and 12 hrs. post-dose. ARRY-543 inhibited the phosphorylation of both receptors at both timepoints with significant inhibition (~70%) of both receptors at 12 hrs. In a separate study, this level of inhibition resulted in profound TGI. Lapatinib showed mild inhibition (NS) of both receptors at 4 hours post-dose (15-30%) and no effects at the 12 hours post-dose timepoint. These studies demonstrate that ARRY-543 has superior activity over lapatinib with respect to TGI and/or PD effects (extent and duration) on the EGFR and ErbB2 receptors in preclinical mouse tumor models. ARRY-543 is entering Phase II trials in select cancer patient populations.
Phase II trial of irinotecan, carboplatin, and bevacizumab in patients with limited-stage small cell lung cancer
Authors: J. D. Zubkus, D. R. Spigel, F. A. Greco, D. A. Yardley, H. A. Burris, E. Vazquez, C. Farley, J. F. Patton, L. Hart, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2007)

18133 Background: In a previously reported phase II trial bevacizumab (B) was used as maintenance therapy following induction with irinotecan (I), carboplatin (C) and radiotherapy (RT) in patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). 1-year progression- free survival (PFS) and overall survival (OS) were 53% and 70%, respectively. In the present multicenter community-based trial B is given with induction chemoradiotherapy and as maintenance therapy. Methods: The primary endpoint is to assess the median PFS. Eligibility criteria: newly diagnosed LS-SCLC, measurable disease, ECOG PS 0–1, and informed consent. Exclusion criteria: hemoptysis and therapeutic anticoagulation. Treatment: I 60mg/m 2 IV D1, 8, 15, C AUC=4 IV D1, and B 10 mg/kg IV D1 and 15 every 28D. Pts received concurrent RT to 61.2 Gy starting with the 3rd cycle, and were restaged every 8 weeks. If no progressive disease (PD) or excessive toxicity after 4 cycles, pts received B x 6 months. Prophylactic cranial irradiation was used at M.D. discretion. This 2-stage trial was designed to achieve a 40% improvement in historical median PFS of 12–14 months. Results: 20 pts were enrolled from 4/06 to 12/06 (trial ongoing, n=50 planned). Data are available for 14 pts in this analysis. Baseline features: median age 64 years; male/female, 21%/79%; and ECOG PS 0/1, 64%/36%. The objective response rate was 78% (95% CI 45%-94%) - all partial responses. No pt had PD. 7 pts were not evaluable: too early, 5 pts; off study (toxic megacolon, 1 pt; intercurrent illness, 1 pt). With a median follow-up of 5 months, the median PFS has not been reached. Grade (G) 3/4 non-hematologic toxicity with induction occurring in more than 2 pts: diarrhea (29%) and esophagitis, fatigue, pain (21% each). G3/4 hematologic toxicity: leukopenia (21%), neutropenia (14%), and thrombocytopenia (43%). There have been 2 G3/4 bleeding events with induction: suspected tracheoesophageal fistula with death (possibly treatment-related), 1 pt; and hematochezia, unrelated, 1 pt. Conclusions: This trial continues to be closely monitored for safety. Further accrual and longer follow-up are necessary to assess if B can be safely combined with chemoradiotherapy and improve efficacy. No significant financial relationships to disclose.
Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug
Authors: Hao Wu, Eduardo Esteve, Valentina Tremaroli, Muhammad Tanweer Khan, Robert Caesar, Louise Mannerås-Holm, Marcus Ståhlman, Lisa M Olsson, Matteo Serino, Mercè Planas-Fèlix, Gemma Xifra, Josep M Mercader, David Torrents, Rémy Burcelin, Wifredo Ricart, Rosie Perkins, José Manuel Fernàndez-Real, Fredrik Bäckhed
Journal: Nature Medicine (2017)
ATRT-07. AN EPIGENOME DIRECTED FUNCTIONAL GENOMIC SCREEN IDENTIFIES SIRT2 AS A SYNTHETIC LETHAL TARGET IN SMARCB1 DEFICIENT ATRT
Authors: Irina Alimova, Sujatha Venkataraman, Ilango Balakrishnan, Angela M Pierce, Jean Mulcahy-Levy, Nicholas K Foreman, Rajeev Vibhakar
Journal: Neuro-Oncology (2017)

Atypical Teratoid Rhabdoid Tumor (ATRT) is a highly aggressive pediatric brain tumor with poor outcomes. Therapy relies on highly toxic chemotherapy and radiotherapy. The central mechanism of ATRT tumorigenesis is SMARCB1 deficiency that leads to epigenetic dysregulation. To identify key epigenetic regulators that co-operate with SMARB1 deficiency and contribute to the tumorigenesis of ATRT, we performed a RNAi-based functional genomic screen. We targeted 406 genes associated with epigenetic regulation in ATRT cell lines. This screening revealed Sirtuin2 (SIRT2) as one of the top targets required for continued cell growth. SIRT2 is an NAD(+) (nicotinamide adenine dinucleotide)-dependent deacetylase and involved in the direct deacetylation of α-tubulin and histone H4. Inhibition of SIRT2 promotes c-MYC ubiquitination and degradation. C-Myc is an oncogene and highly expressed in ATRT, so SIRT2 is a promising target to treat c-MYC driven cancers. Genetic inactivation of SIRT2 with shRNA significantly suppressed ATRT cell growth, decreased c-MYC expression and activated p53. Recent studies suggest that targeting SIRT2 by small molecule inhibitors is a promising approach to tumor therapy. We found that chemical inhibition SIRT2 with Tenovin6, significantly decreased cells growth, inhibited clonogenic potential, decreased S-phase length and induced apoptosis in ATRT. Moreover, inhibition of SIRT2 by Tenovin6 significantly suppressed the level of c-MYC, and increased p53 expression. In vivo Tenovin6 slowed growth of flank and intracranial orthotopic ATRT tumors, as compared to control animals. Tenovin6 treatment induced apoptosis in ATRT xenografts as measured by cleaved Caspase 3 immunohistochemistry. In addition, there was a significant decrease in proliferation marker ki67 in treated tumors. In summary we demonstrated that ATRT can be targeted by chemical or genetic SIRT2 inhibition. The in vitro and in vivo antitumor activity of Tenovin6 is very promising and further optimization studies are underway.
Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease
Authors: Mukta Agrawal, None Ajazuddin, Dulal K. Tripathi, Swarnlata Saraf, Shailendra Saraf, Sophia G. Antimisiaris, Spyridon Mourtas, Margareta Hammarlund-Udenaes, Amit Alexander
Journal: Journal of Controlled Release (2017)
New-Generation High-Potency and Designer Antibodies: Role in HIV-1 Treatment
Authors: Lucio Gama, Richard A. Koup
Journal: Annual Review of Medicine (2017)

Broadly neutralizing antibodies (bNAbs) have been evaluated as promising agents in the fight against infectious diseases. HIV-1-specific bNAbs, in particular, have been tested in both preventive and therapeutic modalities. Multiple bNAbs have been isolated, characterized, and assessed in vitro and in vivo, but no single antibody appears to possess the breadth and potency that may be needed if it is to be used in the treatment of HIV-1 infection. With the technological advances of the past decades, novel and more effective bNAbs have been identified or engineered for higher neutralizing potency, greater breadth, and increased serum half-life. In this review, we discuss the development of a new generation of anti-HIV-1 bNAbs and their potential to be used clinically for treatment and prevention of HIV-1 infection.
Head and neck size and neck strength minimise the head acceleration during repeated head impacts
Authors: Jaclyn B Caccese, Thomas A Buckley, Ryan T Tierney, William C Rose, Kristy B Arbogast, Joseph J Glutting, Thomas W Kaminski
Journal: British Journal of Sports Medicine (2017)

Objective To identify factors that contribute to head acceleration during purposeful soccer heading. Design Prospective. Setting Biomechanics laboratory. Participants One-hundred soccer players (42 male, 58 female, 17.1±3.5 years (range: 12-24years), 168.5±20.3 cm, 61.5±13.7 kg). Exclusionary criteria: history of neurologic disorder, cervical spine injury, or head injury in the past 6 months. Interventions We implemented a soccer heading paradigm that consists of controlled soccer heading (12 headers at 11.2m/s from a JUGS machine) while measuring 3D motion capture kinematics (torso and head-to-torso range-of-motion), sternocleidomastoid and upper trapezius EMG activity (peak and area), and linear and rotational accelerations using a triaxial accelerometer and gyroscope. Head mass, neck girth, and sternocleidomastoid and upper trapezius strength were also evaluated. Outcome measures Linear and rotational accelerations at the head center-of-gravity. Main results Multiple regression analyses suggest that the ten variables predicted linear (R2=0.272, p=0.002) and rotational (R2=0.259, p=0.004) acceleration; however none of the predictors individually made a significant contribution to the model. Linear and rotational accelerations were correlated with head mass (r=-?0.447, p&lt;0.001; r=-0.467,p&lt;0.001), neck girth (r=-0.465, p&lt;0.001; r=-0.438, p&lt;0.001), sternocleidomastoid strength (r=-0.386, p&lt;0.001; r=-0.410, p&lt;0.001), and upper trapezius strength (r=-0.311, p=0.001; r=-0.351, p&lt;0.001). Conclusions Our findings suggest that head mass, neck girth, and neck strength are important in minimising head acceleration, whereby greater size and strength are associated with lower head accelerations. Soccer players with smaller head-neck segment masses and lower neck strength, may be at risk for greater head acceleration. These athletes may experience a theoretical bobble-head effect, when the neck strength is not great enough to control the mass of the head. Competing interests None.
MEDU-50. TRANSCRIPTIONAL REGULATION OF THE HOMEOBOX GENES CRX AND OTX2 - IMPLICATIONS FOR MEDULLOBLASTOMA GROUP 3
Authors: Maryam Hejazi, Jamie Zagozewski, David Eisenstat
Journal: Neuro-Oncology (2017)

BACKGROUND: Generation of disease-specific models and development of new treatments for non-WNT/non-SHH medulloblastomas (MB) is an urgent need. Group 3 MB is characterized by amplifications of MYC and/or OTX2. Furthermore, transcriptional profiling of group 3 MB shows dysregulation of GABAergic and/or photoreceptor gene expression. The distalless/DLX homeobox genes are required for regulation of GABAergic interneuron differentiation and migration. Furthermore, in the retinas of the Dlx1/Dlx2 double knockout (DKO) mouse, which die at birth, there is marked upregulation of the cone rod homeobox, Crx, as well as the related orthodenticle homeobox gene, Otx2. Moreover, OTX2 activates Crx expression. Otx2 is expressed in three domains of the developing central nervous system (CNS): at the hindbrain/midbrain boundary, the forebrain and retina. METHODS/RESULTS: Using chromatin immunoprecipitation (ChIP) of wild-type mouse embryonic retinas and a specific antibody to DLX2, we have identified regions within regulatory elements of the Crx and Otx2 promoters, respectively. DLX2 protein:Crx/Otx2 DNA binding specificity was confirmed by mobility shift assays, including supershifts using the DLX2 antibody, as well as through site-directed mutagenesis of candidate homeodomain DNA binding motifs. Reporter gene assays demonstrated repression of Crx and/or Otx2 expression when co-transfected with Dlx2 expression constructs in vitro. De-repression of CRX and/or OTX2 expression was confirmed in the Dlx1/Dlx2 DKO in vivo. In addition, crossing of a Crx lacZ reporter mouse with the Dlx1/Dlx2 DKO showed increased lacZ expression in the retinas of the reporter mouse with concurrent loss of of Dlx1 and Dlx2 function. CONCLUSIONS: DLX2 directly binds to both Crx and Otx2 promoters in the embryonic retina and represses expression of Crx and Otx2. We are exploring other upstream transcriptional regulators of OTX2 in the developing CNS towards the development of a group 3 MB mouse model for testing novel therapeutic approaches for children with an intermediate to poor prognosis.
Analysis of Mutational Signatures Suggest That Aid Has an Early and Driver Role in Multiple Myeloma
Authors: Francesco Maura, Niccolo Bolli, Stephane Minvielle, Dominik Gloznik, Raphael Szalat, Anthony Fullam, Inigo Martincorena, Mehmet Kemal Samur, Patrick Tarpey, Helen Davies, Kevin J. Dawson, Serena Nik-Zainal, Moritz Gerstung, Jorge Zamora, Yu-Tsu Tai, Cristiana Carniti, Florence Magrangeas, Philippe Moreau, Paolo Corradini, Kenneth Anderson, David Wedge, Herve Avet-Loiseau, Peter Campbell, Nikhil Munshi
Journal: Blood (2016)
Investigation of knowledge and attitude about concussion diagnosis and management among family medicine residents
Authors: Aneet Mann, Aneet Mann, Charles H Tator, James D Carson
Journal: British Journal of Sports Medicine (2017)

Objective To assess knowledge, attitude and learning needs about concussion among family medicine residents Design A web-based prospective survey Setting Toronto, Canada. Participants Family medicine residents at the University of Toronto. Intervention A link to the survey was disseminated via e-mail by the Department of Family and Community Medicine post-graduate office at the University of Toronto. Data collection occurred over 5 weeks from January to March 2015 with reminder emails sent out to all 348 family medicine residents at 2 weeks and 4 weeks of the study period. Outcome measures Survey answers to assess knowledge and attitude about concussion. Main results The residents who responded (n=73/348, response rate 21%) scored an average of 5.2 correct answers out of 9 (57.8%) questions regarding the diagnosis and management of concussion. Seventy-one percent of residents who responded did not recognise chronic traumatic encephalopathy and only 63% recognised second impact syndrome as consequences of repetitive concussions. Moreover, 32% of residents did not think that “every concussed individual should see a physician” as part of management. Conclusions We found significant gaps in knowledge surrounding concussion diagnosis and management among family medicine residents. This lack of knowledge should be addressed at both the undergraduate medical education and residency training levels to improve concussion-related care and patient outcomes. Competing interests None.
Knowledge, attitudes and intended behaviours in relation to concussion in professional rugby union players
Authors: Keith Stokes, Simon Kemp, Miss Rachel Michell, Martyn Standage, Carly McKay
Journal: British Journal of Sports Medicine (2017)

Objective To investigate knowledge, attitudes and intended behaviours in relation to concussion in professional Rugby Union players. Design Cross-sectional study. Setting English Premiership and Championship (the highest levels of domestic competition in England). Participants 1236 professional male players enrolled on a compulsory online concussion education module were invited to respond to an online survey in October 2014. 383 players completed the survey (age 17–40 years; 0.5–19 years of professional rugby). Outcome measures Number of career self-reported concussions; pre-module concussion identification and management knowledge score (5 multiple-choice questions); attitudes towards concussion (14 7-point Likert-scale questions; higher scores represent more favourable attitudes); intended behaviours regarding concussion reporting (3 7-point Likert-scale questions; lower scores represent more favourable intended behaviours). Main results 271 players (71%) recalled at least one concussion during their playing career; 249 (65%) recalled 1–5, 17 (4%) recalled 6-10 and 3 (1%) recalled &gt;10 concussions. Knowledge scores (n=292) ranged from 0 to 5 correct answers out of 5; mean(SD) 3.4 (1.8). Attitudes scores (n=383) ranged from 42 to 98 out of a possible 98; mean(SD), 75.7 (11.9). Intended behaviour scores (n=383) ranged from 6 to 21 out of a possible 21; mean(SD), 10.2 (3.3). Spearmans Rank indicated that knowledge scores and concussion history were not associated with attitudes or intended behaviours; however, more favourable attitude scores were associated with more favourable intended behaviour scores (rs=−0.34, p&lt;0.001). Conclusions Concussion education interventions should focus on positively influencing player attitudes towards concussion as this has the greatest potential to improve player behaviour. Competing interests Dr. Keith Stokes – Receives research funding from the Rugby Football Union Dr. Simon Kemp – Employed by the Rugby Football Union Miss Rachel Michell – Employed by Rugby Players Associationis Dr. Martyn Standage, Dr. Carly McKay - None.
The Law and Ethics of Medical Research: International Bioethics and Human Rights
Journal: BMJ (2005)

From Bioethics to Human Rights in Biomedicine Human Rights and Non-Therapeutic Research: Domestic Remedies and Convention Rights Stem Cell Research: Human Dignity and the Right to Life The Rights of the Dead: Research on Human Tissue and Body Parts after Bristol and Alder Hey Research in Developing Countries: New Ethics and New Threats to Human Rights.