tbuckley/cabot-search huggingface dataset:
Abstract A20: Genomic study of KRAS/NRAS mutations of metastatic colorectal cancer in eastern Algeria
Authors: Khaoula Mazouzi
Journal: Cancer Research (2017)

Abstract Background: Biological advances made a big lap in the treatment of metastatic patients where several therapeutic options are now available for patients based on research of gene. For colorectal cancer, it is essential to test KRAS-BRAF-NRAS mutations before starting any treatment and it is known in the literature that these mutations are found in approximately 45% of patients, that what made us thinking about analyzing the results of our patients' mutational tests. Methods: It is a Prospective study that aims to analyze the KRAS/NRAS mutational profile of metastatic colorectal cancer patients treated at CHU Constantine-Anti Cancer Center during the period of January 2014 - August 2016. The molecular study includes: codon 12 and 13 of exon 2, codons 59 and 61 of exon 3 and codons 117 and 146 of exon 4 of K-Ras gene. The exons 2, 3 and 4 for the N-Ras gene have also been tested and no molecular testing has been done for B-RAF mutation. The search for mutations was performed by the Allele Specific PCR technique and a second confirmation by sequencing was done. Results: 490 patients with colorectal cancer were registered; 34.69% were presented with metastases, of which 61, 17% are men and 38, 82% women. The extremes of age is 27 to 77 years, the average age is 52.6 years. 67.64% of these tumors have colic origin, 28.82% of rectal origin 3.52% from the recto sigmoidal junction. The histological presentation is: 95.29% adenocarcinoma [57.40% well differentiated, 37.03% moderately differentiated, 2.46% poorly differentiated and 3.08% are undifferentiated], 2.35% are adenocarcinomas with colloid component and 2.35% are independent cell carcinomas. 42.94% were wild type, 51.17% are mutated and 5.88% remained without status given the small quantity of DNA available for testing (not sufficient DNA) and the impossibility of re-biopsy. The mutational profile for K-Ras gene was: 94.5% mutated in exons 2 with 76.82% in codon 12 and 23.17% in codon 13. 3.44% had mutations exons 3 without any detail of codons mentioned and 2.29% had rare mutations in the N-Ras gene without any extensive information. Conclusion: The analysis of data find that the mutational profile of our patients is different than the profile presented in the literature, therefore, extensive molecular and genetic studies should be conducted in our area in search of explanations and in the hope of future therapeutic implications. Citation Format: Khaoula Mazouzi. Genomic study of KRAS/NRAS mutations of metastatic colorectal cancer in eastern Algeria [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A20.
Abstract 68: Functional interactions of HPV and PARP-1 in head and neck cancer
Authors: Cyril S. Gary, Michael Hajek, Asel Biktasova, Andrew Sewell, Yarbrough G. Wendell, Natalia Issaeva
Journal: Clinical Cancer Research (2017)

Abstract Though the overall incidence of head and neck cancer has been declining over the last several decades, there has been a concomitant and worrisome rise in human-papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). HPV infection is a necessary but not sufficient condition for cancer development. Unlike in cervical cancer, where several co-factors including smoking and co-infection with other agents are well established, how HPV drives malignant transformation in head and neck cancer and which cellular factors are required are not well characterized. Recent evidence from our group has shown that poly (ADP-ribose) polymerase-1 (PARP-1) is overexpressed and overactive in HPV-positive (HPV(+)), but not HPV-negative (HPV(-)), oropharyngeal squamous cell carcinoma (OPSCC). The significance of PARP-1 overexpression and hyperactivation in cancer is only beginning to emerge. High levels of PARP-1 are found in a fraction of hepatocellular and breast cancers and correlate with poor prognosis. Recently, PARP-1 was implicated in prostate cancer progression. This study explores the role of PARP-1 in HPV infection and HNSCC carcinogenesis. Biochemical methods were used to determine PARP activity in vitro, in head and neck tumors, and during infection with HPV16 pseudovirus (PsV) or overexpression of HPV16 proteins in epithelial cells. The response to PARP inhibition was evaluated with clonogenic survival assays. HPV L1 mRNA in HNSCC was detected using quantitative real-time PCR and HPV L1 protein levels were determined by immunohistochemistry. Here, we show that the HPV16 major capsid protein L1 directly binds PARP-1 and activates poly(ADP-ribosyl)ation in the absence of DNA damage in vitro and in HPV(-) cells. Using PARP-1 knockout cells, we found that PARP-1 expression and enzymatic activity supports initial HPV infection. Furthermore, HPV(-) cells were sensitized to PARP inhibition both after L1 overexpression and after infection with HPV16 PsV particles. In conclusion, we report functional interactions between the viral capsid and cellular protein, signifying a vital role played by PARP-1 in HPV infection and carcinogenesis. Importantly, our data provide a mechanistic explanation for pharmacological PARP inhibition as an intriguing therapeutic opportunity for HPV(+) head and neck cancers. Citation Format: Cyril S. Gary, Michael Hajek, Asel Biktasova, Andrew Sewell, Yarbrough G. Wendell, Natalia Issaeva. Functional interactions of HPV and PARP-1 in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 68.
Cbx3 inhibits vascular smooth muscle cell proliferation, migration, and neointima formation
Authors: Cheng Zhang, Dan Chen, Eithne Margaret Maguire, Shiping He, Jiangyong Chen, Weiwei An, Mei Yang, Tayyab Adeel Afzal, Le Anh Luong, Li Zhang, Han Lei, Qingchen Wu, Qingzhong Xiao
Journal: Cardiovascular Research (2017)

To investigate the role of chromobox protein homolog 3 (Cbx3) in vascular smooth muscle cell (VSMC) proliferation, migration, and neointima formation following vascular injury.Overexpression of Cbx3 led to a significant increase in VSMC contractile gene expression and VSMC apoptosis as well as a dramatic decrease in collagen gene expression, VSMC proliferation, and migration. Meanwhile, the opposite was observed following inhibition of endogenous Cbx3. Luciferase activity assays revealed that Notch signalling, but neither β-catenin nor NF-κB signalling, is regulated by Cbx3 in VSMCs, and among the four Notch receptors, Notch3 is selectively down-regulated by Cbx3 through a transcriptional repression mechanism. Notch3 gene activation recapitulates the effects of Cbx3 knockdown on VSMC proliferation and migration. Consequently, the inhibitory effects of Cbx3 over-expression on VSMC proliferation and migration were reversed by Notch3 gene reactivation. In a model of vascular damage by carotid wire injury, we observed that Cbx3 expression was dramatically down-regulated in the injured arteries. Local ectopic over-expression of Cbx3 in the injured arteries significantly inhibited Notch3 expression, thereby reducing VSMCs proliferation and causing an overall decrease in neointima formation. Additionally, injury-induced neointimal SMC hyperplasia was significantly reduced by aortic inhibition of Notch3. Importantly, a decreased expression level of Cbx3, but an increased expression level of Notch3, was observed in human femoral arteries with atherosclerotic lesions.Cbx3 modulates VSMC contractile and collagen gene expression, as well as VSMC proliferation, migration, and apoptosis via a Notch3 pathway, and plays an important role in controlling injury-induced neointima formation.
Exhaustion of Airway Basal Progenitor Cells in Early and Established Chronic Obstructive Pulmonary Disease
Authors: Moumita Ghosh, York E. Miller, Ichiro Nakachi, Jennifer B. Kwon, Anna E. Barón, Alexandra E. Brantley, Daniel T. Merrick, Wilbur A. Franklin, Robert L. Keith, R. William Vandivier
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Up to 40% of smokers develop chronic obstructive pulmonary disease (COPD) over a period that spans decades. Despite the importance of COPD, much remains to be learned about susceptibility and pathogenesis, especially during early, prediagnostic stages of disease. Airway basal progenitor cells are crucial for lung health and resilience because of their ability to repair injured airways. In COPD, the normal airway epithelium is replaced with increased basal and secretory (mucous) cells and decreased ciliated cells, suggesting that progenitors are impaired.Objectives: To examine airway basal progenitor cells and lung function in smokers with and without COPD.Methods: Bronchial biopsies taken from smokers at risk for COPD and lung cancer were used to acquire airway basal progenitor cells. They were evaluated for count, self-renewal, and multipotentiality (ability to differentiate to basal, mucous, and ciliated cells), and progenitor count was examined for its relationship with lung function.Measurements and Main Results: Basal progenitor count, self-renewal, and multipotentiality were all reduced in COPD versus non-COPD. COPD progenitors produced an epithelium with increased basal and mucous cells and decreased ciliated cells, replicating the COPD phenotype. Progenitor depletion correlated with lung function and identified a subset of subjects without COPD with lung function that was midway between non-COPD with high progenitor counts and those with COPD.Conclusions: Basal progenitor dysfunction relates to the histologic and physiologic manifestations of COPD and identifies a subset that may represent an early, prediagnostic stage of COPD, indicating that progenitor exhaustion is involved in COPD pathogenesis.
Enzyme targeting strategies for prevention and treatment of cancer: Implications for cancer therapy
Authors: Mohammad Hassan Baig, Mohd Adil, Rosina Khan, Surendar Dhadi, Khurshid Ahmad, Gulam Rabbani, Tufail Bashir, Mohammad Azhar Imran, Fohad Mabood Husain, Eun Ju Lee, Mohammad Amjad Kamal, Inho Choi
Journal: Seminars in Cancer Biology (2017)
The Association Between L-Asparaginase Hypersensitivity and Genetic Variants in Japanese Childhood ALL Patients
Authors: Yoichi Tanaka, Kevin Y Urayama, Takahisa Kawaguchi, Makiko Mori, Daisuke Hasegawa, Sae Ishimaru, Yuichi Taneyama, Kazuki Terada, Masakatsu Yanagimachi, Setsuo Ota, Hiroyuki Takahashi, Takeshi Inukai, Daisuke Toyama, Dai Keino, Koichi Moriwaki, Masatoshi Takagi, Junya Fujimura, Yujin Sekinaka, Kozue Nakamura, Yuya Sato, Keitaro Matsuo, Akira Ohara, Katsuyoshi Koh, Fumihiko Matsuda, Atsushi Manabe
Journal: Blood (2016)
Hydroquinidine Prevents Life-Threatening Arrhythmic Events in Patients With Short QT Syndrome
Authors: Andrea Mazzanti, Riccardo Maragna, Gaetano Vacanti, Anna Kostopoulou, Maira Marino, Nicola Monteforte, Raffaella Bloise, Katherine Underwood, Valentina Tibollo, Eleonora Pagan, Carlo Napolitano, Riccardo Bellazzi, Vincenzo Bagnardi, Silvia G. Priori
Journal: Journal of the American College of Cardiology (2017)
Getting the systematic review basics right helps clinical practice: 4 common pitfalls for systematic review authors to avoid
Authors: Lisa Bero
Journal: British Journal of Sports Medicine (2017)

As BJSM readers know, systematic reviews identify, critique and summarise evidence relevant to a specific question. Most importantly, systematic reviews should be transparent and follow a predefined protocol to reduce bias. Since many articles in the scientific literature mislabel systematic reviews,1 journals including BJSM are improving systematic review reporting by adhering to standards such as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines.2 This editorial provides practical tips for systematic review authors relevant to sports and exercise medicine: guidance on four common problems and suggestions on how to address these problems.

There are six keys steps that you should follow for a systematic review:

1.  State a clear question (specifying the Population studied, Intervention(s)or exposure(s), Comparisons (if any) and Outcomes—the PICO).

2.  Conduct a systematic, replicable search for evidence using a prespecified search strategy.

3.  Select studies for the review based on predefined inclusion and exclusion criteria.

4.  Assess the internal validity or ‘risk of bias’ of studies included.

5.  Extract data using predefined variables and coding forms.

6.  Synthesise the characteristics and findings of the included studies (using quantitative (meta-analysis) and/or qualitative methods).



The most straightforward type of systematic review has a focused question and combines summary data from randomised controlled trials that measure outcomes using the same metrics (eg, does the FIFA 11+ programme reduce lower extremity injuries in football?).3 The Cochrane Handbook for Systematic Reviews of Interventions provides guidance for every step of the systematic review process4 that you can apply to systematic reviews of randomised controlled trials studying the effects of exercise, surgery or training on injury prevention, recovery or fitness. More complex systematic reviews may address multiple questions with multiple interventions and outcomes reported in different ways and synthesise observational or qualitative studies (eg, what is …
Interpretation of the ATHENA Trial—Caveats and Future Directions
Authors: João Pedro Ferreira, Nicolas Girerd, Faiez Zannad
Journal: JAMA Cardiology (2017)

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Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis
Authors: M Angelyn Bethel, Rishi A Patel, Peter Merrill, Yuliya Lokhnygina, John B Buse, Robert J Mentz, Neha J Pagidipati, Juliana C Chan, Stephanie M Gustavson, Nayyar Iqbal, Aldo P Maggioni, Peter Öhman, Neil R Poulter, Ambady Ramachandran, Bernard Zinman, Adrian F Hernandez, Rury R Holman
Journal: The Lancet Diabetes & Endocrinology (2017)
Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital Malformations
Authors: Krista F. Huybrechts, Gabriella Bröms, Lotte Brix Christensen, Kristjana Einarsdóttir, Anders Engeland, Kari Furu, Mika Gissler, Sonia Hernandez-Diaz, Pär Karlsson, Øystein Karlstad, Helle Kieler, Anna-Maria Lahesmaa-Korpinen, Helen Mogun, Mette Nørgaard, Johan Reutfors, Henrik Toft Sørensen, Helga Zoega, Brian T. Bateman
Journal: JAMA Psychiatry (2017)

Given the rapidly increasing use of stimulant medications during pregnancy and among women of reproductive age who may become pregnant inadvertently, there is a need to better understand their safety.To examine the risk of congenital malformations associated with intrauterine exposure to stimulants.Cohort study of the Medicaid-insured population in the United States nested in the 2000-2013 US Medicaid Analytic eXtract, with follow-up of safety signals detected in the Medicaid Analytic eXtract data using the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden). A total of 1 813 894 publicly insured pregnancies in the United States and 2 560 069 singleton pregnancies in the 5 Nordic countries ending in live births were included. Relative risks were estimated accounting for underlying psychiatric disorders and other potential confounders. Relative risk estimates for the US and Nordic data were pooled using a fixed-effects meta-analytic approach. The study was conducted from July 1, 2015, to March 31, 2017.Methylphenidate and amphetamines dispensed during the first trimester.Major congenital malformations and subgroup of cardiac malformations.In the US data, of the 1 813 894 pregnancies evaluated, 35.0 per 1000 infants not exposed to stimulants were diagnosed as having congenital malformations, compared with 45.9 per 1000 infants for methylphenidate and 45.4 for amphetamines. For cardiac malformations, the risks were 12.7 (95% CI, 12.6-12.9), 18.8 (95% CI, 13.8-25.6), and 15.4 (95% CI, 12.5-19.0) per 1000 infants, respectively. The adjusted relative risks for methylphenidate were 1.11 (95% CI, 0.91-1.35) for any malformation and 1.28 (95% CI, 0.94-1.74) for cardiac malformations. No increased risks were observed for amphetamines: 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. Findings were confirmed in sensitivity analyses accounting for proxies of unmeasured confounders and increasing the specificity of the exposure and outcome definitions. Replication of the analyses for methylphenidate using the Nordic data including 2 560 069 pregnancies yielded a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations, resulting in a pooled estimate of 1.28 (95% CI, 1.00-1.64).These findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy.
Estimating Cost-effectiveness of a Multimodal Ovarian Cancer Screening Program in the United States
Authors: Haley A. Moss, Andrew Berchuck, Megan L. Neely, Evan R. Myers, Laura J. Havrilesky
Journal: JAMA Oncology (2017)

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is the largest randomized clinical trial to evaluate screening's impact on ovarian cancer mortality, assigning women to multimodal screening (MMS) with serum cancer antigen 125 (CA-125) interpreted using a risk algorithm. If the MMS screening method is eventually shown to reduce mortality and be cost-effective, then it may be accepted by the medical community as a feasible screening tool.To estimate the cost-effectiveness of an MMS screening program in the United States.A Markov simulation model was constructed using data from UKCTOCS to compare MMS with no screening in the United States. Screening would begin at the age of 50 years for women in the general population. Published estimates of the long-term effect of MMS screening on ovarian cancer mortality and the trial's published hazard ratios were used to simulate mortality estimates up to 40 years from start of screening. Base-case costs included CA-125, ultrasound, and false-positive work-up results, in addition to a risk algorithm cost estimate of $100. The utility and costs of ovarian cancer treatment were incorporated into the model.Screening strategies varied by costs of the algorithm and treatment for advanced ovarian cancer, rates of screening compliance, ovarian cancer incidence, and extrapolation of ovarian cancer mortality.Costs, quality-adjusted life-years (QALYs), and mortality reduction of ovarian cancer screening.Multimodal screening is both more expensive and more effective in reducing ovarian cancer mortality over a lifetime than no screening. After accounting for uncertainty in the underlying parameters, screening women starting at age 50 years with MMS is cost-effective 70% of the time, when decision makers are willing to pay $150 000 per QALY. Screening reduced mortality by 15%, with an incremental cost-effectiveness ratio (ICER) ranging from $106 187 (95% CI, $97 496-$127 793) to $155 256 (95% CI, $150 369-$198 567).Ovarian cancer screening is potentially cost-effective in the United States depending on final significance of mortality reduction and cost of the CA-125 risk algorithm. These results are limited by uncertainty around the effect of screening on ovarian cancer mortality beyond the 11 years of UKCTOCS.
Case 38-2017
Authors: Florian S. Eichler, Kathryn J. Swoboda, Ann L. Hunt, Dean M. Cestari, Otto Rapalino
Journal: New England Journal of Medicine (2017)

A 20-year-old woman was evaluated for seizures and progressive dystonia, which she had had since she was 3 years of age. Her younger sister had a similar illness. Imaging studies showed areas of abnormal hyperintensity in the basal ganglia. A diagnostic test was performed.
Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines
Authors: F Maura, M Petljak, M Lionetti, I Cifola, W Liang, E Pinatel, L B Alexandrov, A Fullam, I Martincorena, K J Dawson, N Angelopoulos, M K Samur, R Szalat, J Zamora, P Tarpey, H Davies, P Corradini, K C Anderson, S Minvielle, A Neri, H Avet-Loiseau, J Keats, P J Campbell, N C Munshi, N Bolli
Journal: Leukemia (2017)

Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines