tbuckley/cabot-search huggingface dataset:
Antioxidants and oxidative stress in patients with Li-Fraumeni-like syndrome and <i>TP53</i> p.R337H mutation carriers.
Authors: Gabriel de Souza Macedo, Juliana Giacomazzi, Cristina Netto, Leonardo Motta, Fábio Klamt, Patricia Ashton-Prolla
Journal: Journal of Clinical Oncology (2012)

e21042 Background: Germline mutations in the TP53 gene are the underlying genetic defect of Li-Fraumeni Syndrome (LFS) and its variant, Li-Fraumeni-like (LFL) Syndrome, autosomal dominant disorders characterized by predisposition to multiple early-onset cancers. More recently, p53 is emerging as an important player in redox metabolism and important enzymes involved in defenses against oxidative stress have shown to be regulated by p53, including glutathione peroxidase 1 (GPX1) and mitochondrial superoxide dismutase 2 (SOD2). The aim of the present study was to investigate the redox profile parameters in blood of p.R337H mutation carriers and non-carriers individuals. Methods: A total of 34 individuals were included in the study and they were divided in two groups: mutation carriers (n=17) and non-carriers (n=17). Antioxidant enzyme activities (SOD, CAT, GPx) and oxidative stress parameters (Protein carbonyl content, Sulfhydryl content and TBARS) were measured in plasma, erythrocytes, leukocytes and serum. Results: Erythrocyte SOD and GPx activities, two first-line players in enzimatic antioxidant defense, differed significantly between mutation carriers and non-carriers, with an increased activity in the latter (p&gt;0,05). Plasma Carbonyl content, an indicative of protein damage related to ROS overgeneration, was also increased in carriers (p=0,015). There was no significant difference between groups in all other parameters evaluated. Conclusions: Our findings suggest that TP53 p.R337H mutation carriers present different antioxidant enzyme activities and oxidative stress parameters when compared to non-carriers.
Influence of guideline-concordant adjuvant therapy on all-cause and disease-specific survival among breast cancer patients in rural Georgia.
Authors: Gery P. Guy, Theresa Wicklin Gillespie, Michael Goodman, Lisa Carolyn Richardson, Kevin C. Ward, Joseph Lipscomb
Journal: Journal of Clinical Oncology (2013)

1130 Background: This study examines whether receipt of chemo-, radiation, and hormonal therapy regimens that are jointly guideline concordant improve survival outcomes among women diagnosed with breast cancer in a rural region of the United States. Methods: All women identified by the state cancer registry residing in rural southwest Georgia diagnosed with early stage breast cancer during 2001-2003 were included. Medical chart abstraction and registry data were used to determine treatment concordance with the 2000 NIH consensus development conference guidelines on breast cancer treatment. Patients were Concordant versus Non-Concordant according to whether their receipt (or non-receipt) of each adjuvant therapy type was according to guidelines. To examine the effects of concordance on all-cause and breast cancer-specific survival, Cox models were developed that used both propensity score weighting and 2-stage residual inclusion instrumental variable techniques to adjust for patient selection effects. Results: In all-cause analyses, Concordance versus Non-Concordance was associated with significantly better survival (hazard ratios (HRs) 0.41 (95% CI: 0.24-0.72) to 0.54 (95% CI: 0.33-0.87). Similar findings emerged in breast cancer-specific survival analyses, with HRs significantly less than 1.0 in most cases. Diagnosis at older age or later disease stage strongly predicted poorer survival outcome; being not married was significant in all-cause but not breast cancer-specific models. Survival was not generally associated with surgical treatment delay, insurance status, socioeconomic status, rural/urban status, comorbidities, tumor grade, or hormonal status. HR for black women versus white was greater than 1.0 across models but never significant (p=0.05). Conclusions: Breast cancer patients in rural Georgia who received guideline-concordant adjuvant therapy had significantly better all-cause and breast cancer-specific survival, based on Cox model analyses that attempted to control for multiple clinical and demographic factors, as well as selection effects. These findings extend the evidence that guideline bundles of care improve outcomes.
Abstract 321: Macrophage Elavl1 Regulates Fibrogenesis Through Post-transcriptional Mechanism Under Diabetic Conditions
Authors: Prince Jeyabal, Rajarajan A Thandavarayan, Darukeshwara Joladarashi, Sahana Suresh Babu, Shashirekha Krishnamurthy, Suresh K Verma, Venkata N Garikipati, Raj Kishore, Prasanna Krishnamurthy
Journal: Circulation Research (2015)

Patients with diabetes are predisposed to increased risk of cardiovascular diseases. Persistent interaction of infiltrating macrophages and resident fibroblasts play a critical role in cardiac fibrosis. However, the signaling mechanism is not clear. We hypothesized that macrophage ELAV1 (mRNA stabilizing protein) modulates profibrotic mediators and extracellular matrix turnover by binding to 3′UTR and regulating the mRNA stability of TGF-beta and MMP-9 in hyperglycemic conditions. Mice receiving intramyocardial injection of HuR-specific shRNA showed significant reduction in infarct size and fibrosis area. Reduced fibrosis was associated with decrease in TGF-beta and MMP-9 expression in the myocardium. Conditioned media (CM) from high glucose (HG) treated macrophages significantly increased profibrogenic response (increased mRNA expression of Col1a1, Col3a1 and fibronectin) in fibroblast cell line as compared to fibroblasts incubated with CM from low glucose (LG)-treated macrophages. Knockdown of ELAV1 in HG-treated macrophages abrogated the profibrotic effects in fibroblasts. Indirect immunofluroscence of bone marrow-derived macrophages (BMM) demonstrated that HG increases nuclear ELAV1 export to the cytoplasm. Pharmacological inhibition of Protein kinase C-delta (PKCd) blocked HG-induced ELAV1 nuclear to cytoplasmic translocation. In vitro, stable knockdown of ELAV1 in mouse macrophage cell line RAW 264.7 reduced mRNA expression of TGF-beta and MMP-9 following LPS challenge, accompanied by a marked reduction in the mRNA stability of these genes. Our study here establishes an ELAV1/TGF-beta/MMP-9/PKC-delta signaling axis in the macrophages controlling the profibrogenic responses in fibroblasts, the major contributor in the pathogenesis of fibrosis. Therefore, targeting this signaling pathway might be of therapy value for cardiac fibrosis in diabetic patients.
Computer-aided diagnosis for colonoscopy
Authors: Yuichi Mori, Shin-ei Kudo, Tyler Berzin, Masashi Misawa, Kenichi Takeda
Journal: Endoscopy (2017)

With recent breakthroughs in artificial intelligence, computer-aided diagnosis (CAD) for colonoscopy is gaining increasing attention. CAD allows automated detection and classification (i. e. pathological prediction) of colorectal polyps during real-time endoscopy, potentially helping endoscopists to avoid missing and mischaracterizing polyps. Although the evidence has not caught up with technological progress, CAD has the potential to improve the quality of colonoscopy, with some CAD systems for polyp classification achieving diagnostic performance exceeding the threshold required for optical biopsy. The present article provides an overview of this topic from the perspective of endoscopists, with a particular focus on evidence, limitations, and clinical applications.
FOOT POSTURE AND ITS RELATIONSHIP WITH KNEE KINEMATICS IN BAREFOOT RUNNING OF THE HEALTHY ADULT
Authors: Trina Wong, Bruce Paton
Journal: British Journal of Sports Medicine (2017)

Background Abnormal dynamic knee moments and variations of static foot posture are risk factors for chronic lower limb injury development. However, relationships between the two have yet to be established in the running gait. Objective The primary aim was to investigate the correlation between variations in static foot posture and maximum knee adduction. Secondary aims investigated the correlation of static foot posture with variables that affected dynamic knee motion. Design A single-group prospective exploratory study design was implemented. Setting Laboratory-based study setting. Participants 23 volunteers from University College London social media network(n=3119) recruited in June 2016 met entry criteria of healthy adult 18–59 years) with no lower limb musculoskeletal injury in the last 6 months, history of biomechanical abnormality(including use of prosthesis) or lower limb surgery. All participated and completed study but only 14 sets of data were included due to data-corruption. An a priori sample size calculation determined that 9–14 participants were required to demonstrate significantly different correlations(α=0.05, β=0.20). Assessment of Risk Factors Foot Posture Index scores of each participant's dominant foot was an independent variable during a 13 minute barefoot treadmill gait analysis. Main Outcome Measurements Maximum knee adductor moments, knee tri-planar kinematics, hip tri-planar kinematics, maximum loading force and foot-strike pattern were measured at 3 instances(1.39 m/s; 3.6 m/s; self-selected running speed) as determined prior to data-collection. Results No significant correlation (p&lt;0.05) was found between static foot posture measurements and all outcome variables once confounders were accounted for. When comparing maximum knee adductor moments between the 3 speeds, significant correlations were observed (r=0.66–0.71, p&lt;0.01). Conclusions In the healthy population, static foot posture and dynamic knee motion demonstrate a poor and insignificant relationship. Dynamic motion should be assessed independently in predicting future injury where more evidence is needed to account for variations in knee adductor moments.
Results of a phase II trial of single-agent amrubicin (AMR) in patients with extensive disease small cell lung cancer (ED-SCLC) refractory to first-line platinum-based chemotherapy: An update
Authors: D. S. Ettinger, R. Jotte, P. Lorigan, V. Gupta, L. Garbo, P. Conkling, D. Spigel, R. McNally, M. Renschler, J. Oliver
Journal: Journal of Clinical Oncology (2009)

8103 Background: Amrubicin (AMR), a third-generation synthetic anthracycline and potent topoisomerase II inhibitor, is approved in Japan for the treatment of lung cancer. Patients (pts) with SCLC, who are refractory to first-line chemotherapy or progress within 3 months (mos) of treatment completion, are less likely to respond to additional chemotherapy and have an expected median survival of 3–5 mos. Here, we investigate the efficacy and safety of single-agent AMR in the treatment of Western pts with refractory ED-SCLC. Methods: In this phase II trial, pts with ED-SCLC refractory to prior 1 st -line platinum-based chemotherapy (defined as progression (PD) while on therapy or relapse within 90 days of treatment completion) and ECOG performance status (PS) ≤2 were eligible. Patients were treated with intravenous AMR 40 mg/m 2 /day x 3 days every 21 days until PD or intolerable toxicity. The primary endpoint was response rate (ORR, by RECIST), with a goal to demonstrate an ORR ≥18% (point estimate). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: In all, 75 pts were enrolled with a median age of 63 years (range 43–88), 52% female, 17% PS 2. Response to 1 st -line therapy was 5% complete remission (CR), 36% partial remission (PR) and 28% PD. Median time from completion of 1 st -line therapy to PD was 1.3 mos. Sixty-nine pts received AMR for a median of 4 cycles (range 1–12). Six pts died or discontinued before receiving treatment. The primary endpoint was met with an ORR of 21% (16/75, 95% confidence interval [CI] 13.6% - 31.9%), including CR in 1 pt (1%) and PR in 15 pts (20%). Stable disease was achieved in 40% of pts. Two pts with PD as best response to 1 st line chemotherapy achieved a PR. Median OS was 6.0 mos (95% CI 4.8–7.1 mos). Median PFS was 3.2 mos (95% CI 2.4–4.0 mos). The most common grade 3 or 4 adverse events were neutropenia (65%), thrombocytopenia (39%), and leukopenia (35%). Seven (10%) patients experienced febrile neutropenia. Dose reductions were required in 26 patients (38%). Conclusions: AMR shows promising activity, with an ORR of 21%, and an acceptable safety profile in patients with refractory ED-SCLC, and warrants further study in these pts. [Table: see text]
Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial
Authors: Michael S Avidan, Hannah R Maybrier, Arbi Ben Abdallah, Eric Jacobsohn, Phillip E Vlisides, Kane O Pryor, Robert A Veselis, Hilary P Grocott, Daniel A Emmert, Emma M Rogers, Robert J Downey, Heidi Yulico, Gyu-Jeong Noh, Yonghun H Lee, Christine M Waszynski, Virendra K Arya, Paul S Pagel, Judith A Hudetz, Maxwell R Muench, Bradley A Fritz, Witold Waberski, Sharon K Inouye, George A Mashour, Ginika P Apakama, Karen G Aquino, Virendra K Arya, Michael S Avidan, Arbi Ben Abdallah, Robert S Dicks, Robert J Downey, Daniel A Emmert, Krisztina E Escallier, Bradley A Fritz, Hussein Fardous, Duane J Funk, Keith E Gipson, Leonard N Girardi, Hillary Grocott, Alison T Gruber, Judith A Hudetz, Sharon K Inouye, Natalia S Ivascu, Eric Jacobsohn, Aveek Jayant, Hessam H Kashani, Morvarid S Kavosh, Bryan S Kunkler, Yonghun Lee, Eric J Lenze, George A Mashour, Hannah R Maybrier, Amy S McKinney, Sherry L McKinnon, Angela M Mickle, Marita Monterola, Maxwell R Muench, Matthew R Murphy, Gyu-Jeong Noh, Paul S Pagel, Kane O Pryor, Emma M Rogers, Mariya Redko, Eva M Schmitt, Lingesh Sivanesan, Michele L Steinkamp, Bethany Tellor, Sunu Thomas, Ravi T Upadhyayula, Robert A Veselis, Philip E Vlisides, Christine Waszynski, Heidi Yulico
Journal: The Lancet (2017)
Data sharing in clinical trials: An experience with two large cancer screening trials
Authors: Claire S. Zhu, Paul F. Pinsky, James E. Moler, Andrew Kukwa, Jerome Mabie, Joshua M. Rathmell, Tom Riley, Philip C. Prorok, Christine D. Berg
Journal: PLoS Medicine (2017)

points• Broad sharing of clinical trial data is important for ensuring reproducibility, transparency, and maximal use of the data by the research community.However, in practice, such data sharing typically requires planning, effort, and resources.• Here, we describe a web-based data sharing system, the Cancer Data Access System (CDAS), developed for two large cancer screening trials: the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial and the National Lung Screening Trial (NLST).• Deidentified individual participant data were organized into standard datasets readily downloadable from CDAS via a simple web-based application process that involves minimal scientific review.CDAS provides a "one-stop shop" for access requests, review, and data downloads.• Since the launch of CDAS in November 2012 and through October 2016, 215 requests were received for PLCO data, of which 199 (93%) were approved, and 240 requests were received for NLST, of which 216 (90%) were approved.• The estimated cost of CDAS was around US$300,000 for the initial development, plus additional maintenance and user-support costs of about US$26,000 per month.Because of its modular nature, additional studies can be added to CDAS with relatively little additional cost.
Clinical expert letter:: Improving the identification and management of Lynch syndrome in the UK
Authors: Kevin Monahan, Deborah Alsina, Simon Bach, James Buchanan, John Burn, Sue Clark, Peter Dawson, Farhat V N Din, Sunil Dolwani, Malcolm G Dunlop, James East, Dafydd Evans, Nicola Fearnhead, Ian M Frayling, Rob Glynne-Jones, James Hill, Richard Houlston, Fiona Lalloo, Andrew Latchford, Suzy Lishman, Phil Quirke, Colin Rees, Matt Rutter, Peter Sasieni, Asha Senapati, Doug Speake, Huw Thomas, Ian Tomlinson
Journal: BMJ (2017)
Spatio-Temporal Genomic Heterogeneity, Phylogeny, and Metastatic Evolution in Salivary Adenoid Cystic Carcinoma
Authors: Bin Liu, Yoshitsugu Mitani, Xiayu Rao, Mark Zafereo, Jianjun Zhang, Jianhua Zhang, P. Andrew Futreal, Guillermina Lozano, Adel K. El-Naggar
Journal: JNCI Journal of the National Cancer Institute (2017)

Adenoid cystic carcinoma (ACC), an uncommon and indolent salivary gland malignancy, is characterized by varied morphologic and clinical manifestations. Molecular genetic studies of ACC identified certain structural and mutational alterations that may play a driver role in tumor development. The evolution and regional consistency of these events in ACC development progression are uncertain.To investigate the spatial and temporal clonal landscape of ACC, whole-genome sequencing and variant analyses were performed on 34 regionally sampled primary tumors and their concurrent and metachronous metastatic deposits from eight patients.The average mutation rate per case (primary and metastasis) was 0.32 per million base pairs, and the average incidence of shared mutations in primary and metastatic specimens in each case was 21.9% (range = 0%-44.4%). The analyses revealed considerable spatial clonal differences within and between primary tumors and metastatic disease. Phylogeny formation displayed branching evolution with a main trunk and two distinct mono-splits in all cases. One of the main branches represented intratumor subclonal diversity, and the other delineated metastatic departure and progression. All metastatic tumors shared clonal linkage to their matching primary in concordance with parallel dissemination of metastasis. Synchronous metastases were genomically more similar to their primary than metachronous metastatic disease. Truncal genetic alterations included somatic mutations in the NOTCH pathway genes (NOTCH1 and SPEN) and t(6;9) associated gene fusions.Our study delineated clonal and subclonal phylogeny for primary and metastatic ACC, defined early genetic drivers, and provides a conceptual framework for a rational strategy to integrate heterogeneity in clinical assessment.
DIPG-09. TRX-E-009-1 IS A NOVEL AND A POTENT THERAPEUTIC AGENT FOR DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Anahid Ehteda, Anne Kankean, Arjanna Chitranjan, Maria Tsoli, Jie Liu, Han Shen, Laura Franshaw, Swapna Joshi, Cecilia Chang, Eleanor Ager, David S Ziegler
Journal: Neuro-Oncology (2017)

Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most devastating of all brain tumours. They mostly affect young children and, as there are no effective treatments, almost all will succumb to the disease within 12 months. TRX-E-009-1 is a novel anti-cancer agent in preclinical development with broad anti-cancer activity. Ecto-NOX disulfide-thiol exchanger 2 (ENOX2) is the putative target of benzopyran molecules, a family to which TRXE-009-1 belongs. We have found that ENOX2 is significantly over-expressed in our panel of patient-derived DIPG cell lines, while it is completely absent from normal astrocytes. Given these differences in expression, we examined the anti-tumour activity of TRX-E-009-1 against our DIPG neurosphere cultures and found striking tumour specific activity with an IC50 ranging from 20–100 nM with no activity against normal human astrocyte cells (NHAs). We showed that TRX-E-009-1 exerts its anti-proliferative effect through the induction of apoptotic pathways with marked increases in the levels of cleaved caspase 3 and cleaved PARP. TRX-E-009-1 also suppresses the expression of PDGFR-α while enhancing histone H3.3K27me3 methylation. In a DIPG orthotopic model, survival of mice treated with TRX-E-009-1 was significantly increased compared with controls (median survival control 70.5 days vs. 97 days TRX-E-009-1 treated; P = 0.0029). Further, in vitro, the combination of TRX-E-009-1 with a compound currently under clinical investigation against glioma significantly improved cytotoxic activity against DIPG neurospheres. Our findings indicate that TRX-E-009-1 represents a novel, potentially effective therapy for children with DIPG.
Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial
Authors: Peter Nash, Bruce Kirkham, Masato Okada, Proton Rahman, Benard Combe, Gerd-Ruediger Burmester, David H Adams, Lisa Kerr, Chin Lee, Catherine L Shuler, Mark Genovese, Khalid Ahmed, Jeffrey Alper, Nichol Barkham, Ralph E. Bennett, Francisco Javier Blanco García, Ricardo Blanco Alonso, Howard B. Blumstein, Michael S. Brooks, Gerd-Rüdiger Burmester, Patricia Cagnoli, Paul H. Caldron, Alain Cantagrel, Der-Yuan Chen, Melvin A. Churchill, Christine E. Codding, Benard Combe, Peter M.G. Deane, Jose Del Giudice, Atul A. Deodhar, Rajat K. Dhar, Eva Dokoupilova, Rita M. Egan, Andrea Everding, Eva Galíndez, Mark Genovese, David H. Goddard, Alice Gottlieb, Philippe Goupille, Robert M. Griffin, Ramesh C. Gupta, Stephen Hall, Kalpita Hatti, Mary P. Howell, Yu-Huei Huang, Ramina Jajoo, Namieta M. Janssen, Uta Kiltz, Alan J. Kivitz, Steven J. Klein, Mariusz P. Korkosz, Roshan Kotha, Joel M. Kremer, Cummins Lue, José Luis Marenco de la Fuente, Helena Marzo-Ortega, Jordi Gratacós Masmitja, Philip J. Mease, Pier Luigi Meroni, Eric C. Mueller, Anupama C. Nandagudi, Peter Nash, Antonio Fernández-Nebro, Clark M. Neuwelt, Ana Maria Orbai, Meera R. Oza, Deborah L. Parks, Debendra Pattanaik, Maria E. Rell-Bakalarska, David Rosmarin, Euthalia Roussou, Anna I. Rychlewska-Hanczewksa, David H. Sikes, Michael T. Stack, Prashanth Sunkureddi, Hasan Tahir, Diamant Thaçi, Tsen-Fang Tsai, Anthony M. Turkiewicz, Leonore Unger, Raúl Veiga Cabello, Ulf Wagner, Cheng-Chung Wei, Alvin F. Wells, Peter Youssef, Agnieszka Zielinska
Journal: The Lancet (2017)
AMP-Activated Protein Kinase
Authors: Ian P. Salt, D. Grahame Hardie
Journal: Circulation Research (2017)

The AMP-activated protein kinase (AMPK) is a key regulator of cellular and whole-body energy homeostasis, which acts to restore energy homoeostasis whenever cellular energy charge is depleted. Over the last 2 decades, it has become apparent that AMPK regulates several other cellular functions and has specific roles in cardiovascular tissues, acting to regulate cardiac metabolism and contractile function, as well as promoting anticontractile, anti-inflammatory, and antiatherogenic actions in blood vessels. In this review, we discuss the role of AMPK in the cardiovascular system, including the molecular basis of mutations in AMPK that alter cardiac physiology and the proposed mechanisms by which AMPK regulates vascular function under physiological and pathophysiological conditions.