tbuckley/cabot-search huggingface dataset:
Abstract 5698: Next generation sequencing of circulating-free DNA from advanced non small cell lung cancer patients using Gene Reader®
Authors: Clara Mayo de las Casas, Mónica Garzón, Nuria Jordana Ariza, Ariadna Balada, Jordi Bertran-Alamillo, Beatriz García, Sergio Villatoro, Erika Aldeguer, Sonia Rodriguez, Raquel Campos, Santiago Viteri Ramirez, Maria Gonzalez-Cao, Niki Karachaliou, Rafael Rosell Costa, Miguel Angel Molina-Vila
Journal: Cancer Research (2017)

Abstract Background: Stand alone tests such as PCR-derived techniques, FISH or IHC are usually employed to determine clinically relevant alterations in non-small cell lung cancer (NSCLC). However, they target single genes and proteins. Mutiplex techniques can reduce the turnaround time and quantity of sample in this setting, but require a careful validation. Methods: A total of 41 cfDNA samples from serum and plasma from advanced NSCLC p were analyzed with the Actionable Insights Tumor Panel, which covers mutations in 15 clinically relevant genes, using the Gene Reader platform (Qiagen). The samples had been previously genotyped for EGFR, KRAS and BRAF mutations by stand alone, PNA-Taqman assays. Paired biopsies were available in 37 cases. The remaining 4 corresponded to p.T790M-positive blood samples of p progressing to EGFR TKIs. Results: Of the 41 samples taken into the GeneReader workflow, some had a DNA input concentration below specifications, in spite of this limitation, good results were obtained. 14 mutations were fully concordant between tissue, Taqman and GeneReader and the four p.T790M mutations were concordant between Taqman and GeneReader. Five mutations present in tissue were detected by GeneReader and not by Taqman and 11 mutations detected by Taqman were below the 1% detection threshold of GeneReader. Finally, 12 mutations present in tissue were not detected in cfDNA by any of the assays. Concordance between the stand alone tests and the Gene Reader in cfDNA was 64%, raising to 84% if mutations &amp;lt;1% allelic fraction were excluded. Conclusions: Application of NGS to liquid biopsies is challenging and requires a careful validation. However, once fully validated, NGS will probably become the methodology of choice for cfDNA analysis in NSCLC patients at presentation and at progression. Citation Format: Clara Mayo de las Casas, Mónica Garzón, Nuria Jordana Ariza, Ariadna Balada, Jordi Bertran-Alamillo, Beatriz García, Sergio Villatoro, Erika Aldeguer, Sonia Rodriguez, Raquel Campos, Santiago Viteri Ramirez, Maria Gonzalez-Cao, Niki Karachaliou, Rafael Rosell Costa, Miguel Angel Molina-Vila. Next generation sequencing of circulating-free DNA from advanced non small cell lung cancer patients using Gene Reader® [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5698. doi:10.1158/1538-7445.AM2017-5698
New somatic BRAF splicing mutation in Langerhans cell histiocytosis
Authors: Sébastien Héritier, Zofia Hélias-Rodzewicz, Rikhia Chakraborty, Amel G. Sengal, Christine Bellanné-Chantelot, Caroline Thomas, Anne Moreau, Sylvie Fraitag, Carl E. Allen, Jean Donadieu, Jean-François Emile
Journal: Molecular Cancer (2017)

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with constitutive activation of the MAPKinase RAS-RAF-MEK-ERK cell signaling pathway. We analyzed 9 LCH cases without BRAF V600 and MAP2K1 mutations by whole exome sequencing. We identified a new somatic BRAF splicing mutation in 2 cases. Both cases were childhood single system (SS) LCH cases, with self-healing outcome of the bone lesions. This mutant consisted in a 9 base pair duplication (c.1511_1517 + 2 duplication), encoding for a predicted mutant protein with insertion of 3 amino acids (p.Arg506_Lys507insLeuLeuArg) in the N-terminal lobe of the kinase domain of BRAF. Transient expression of the c.1511_1517 + 2dup BRAF mutant in HEK293 cells enhanced MAPKinase pathway activation, and was not inhibited by vemurafenib but was inhibited by PLX8394, a second-generation BRAF inhibitor able to inhibit signaling of BRAF monomers and dimers. Future LCH molecular screening panel should include this new mutation to better define its prevalence in LCH and its restriction to autoregressive bone SS LCH.
Do we Publish on Ethical Concepts in Abstracts Presented in Major Gastroenterology Congresses?
Authors: E Archavlis, T Emmanuel, C Tzathas, K Triantafyllou, SD Ladas
Journal: Endoscopy (2006)

Introduction: In the era of the new millennium, characterized by an increasing confrontation with administrative rules, budget restrictions and litigations, clinical research in gastroenterology involving powerful medications and invasive endoscopic procedures should be adhered to research ethics.
The Diagnosis and Treatment of Prostate Cancer
Authors: Mark S. Litwin, Hung-Jui Tan
Journal: JAMA (2017)

<h3>Importance</h3> Prostate cancer is the most common cancer diagnosis made in men with more than 160 000 new cases each year in the United States. Although it often has an indolent course, prostate cancer remains the third-leading cause of cancer death in men. <h3>Observations</h3> When prostate cancer is suspected, tissue biopsy remains the standard of care for diagnosis. However, the identification and characterization of the disease have become increasingly precise through improved risk stratification and advances in magnetic resonance and functional imaging, as well as from the emergence of biomarkers. Multiple management options now exist for men diagnosed with prostate cancer. Active surveillance (the serial monitoring for disease progression with the intent to cure) appears to be safe and has become the preferred approach for men with less-aggressive prostate cancer, particularly those with a prostate-specific antigen level of less than 10 ng/mL and Gleason score 3 + 3 tumors. Surgery and radiation continue to be curative treatments for localized disease but have adverse effects such as urinary symptoms and sexual dysfunction that can negatively affect quality of life. For metastatic disease, chemotherapy as initial treatment now appears to extend survival compared with androgen deprivation therapy alone. New vaccines, hormonal therapeutics, and bone-targeting agents have demonstrated efficacy in men with metastatic prostate cancer resistant to traditional hormonal therapy. <h3>Conclusions and Relevance</h3> Advances in the diagnosis and treatment of prostate cancer have improved the ability to stratify patients by risk and allowed clinicians to recommend therapy based on cancer prognosis and patient preference. Initial treatment with chemotherapy can improve survival compared with androgen deprivation therapy. Abiraterone, enzalutamide, and other agents can improve outcomes in men with metastatic prostate cancer resistant to traditional hormonal therapy.
Global funding trends for malaria research in sub-Saharan Africa: a systematic analysis
Authors: Michael G Head, Sian Goss, Yann Gelister, Victor Alegana, Rebecca J Brown, Stuart C Clarke, Joseph R A Fitchett, Rifat Atun, J Anthony G Scott, Marie-Louise Newell, Sabu S Padmadas, Andrew J Tatem
Journal: The Lancet Global Health (2017)

BackgroundTotal domestic and international funding for malaria is inadequate to achieve WHO global targets in burden reduction by 2030. We describe the trends of investments in malaria-related research in sub-Saharan Africa and compare investment with national disease burden to identify areas of funding strength and potentially neglected populations. We also considered funding for malaria control.MethodsResearch funding data related to malaria for 1997–2013 were sourced from existing datasets, from 13 major public and philanthropic global health funders, and from funding databases. Investments (reported in US$) were considered by geographical area and compared with data on parasite prevalence and populations at risk in sub-Saharan Africa. 45 sub-Saharan African countries were ranked by amount of research funding received.FindingsWe found 333 research awards totalling US$814·4 million. Public health research covered $308·1 million (37·8%) and clinical trials covered $275·2 million (33·8%). Tanzania ($107·8 million [13·2%]), Uganda ($97·9 million [12·0%]), and Kenya ($92·9 million [11·4%]) received the highest sum of research investment and the most research awards. Malawi, Tanzania, and Uganda remained highly ranked after adjusting for national gross domestic product. Countries with a reasonably high malaria burden that received little research investment or funding for malaria control included Central African Republic (ranked 40th) and Sierra Leone (ranked 35th). Congo (Brazzaville) and Guinea had reasonably high malaria mortality, yet Congo (Brazzaville) ranked 38th and Guinea ranked 25th, thus receiving little investment.InterpretationSome countries receive reasonably large investments in malaria-related research (Tanzania, Kenya, Uganda), whereas others receive little or no investments (Sierra Leone, Central African Republic). Research investments are typically highest in countries where funding for malaria control is also high. Investment strategies should consider more equitable research and operational investments across countries to include currently neglected and susceptible populations.FundingRoyal Society of Tropical Medicine and Hygiene and Bill & Melinda Gates Foundation.
Evaluation of the current guidelines for resection of hepatocellular carcinoma using the Appraisal of Guidelines for Research and Evaluation II instrument
Authors: Pascal Gavriilidis, Keith J. Roberts, Alan Askari, Robert P. Sutcliffe, Teh-la Huo, Po-Hong Liu, Ernest Hidalgo, Philippe Compagnon, Chetana Lim, Daniel Azoulay
Journal: Journal of Hepatology (2017)
Abstract P173: Targeting α-1-Adrenergic Receptors for Heart Failure Therapy
Authors: Megan D Montgomery, Bat-Erdene Myagmar, Paul C Simpson
Journal: Circulation Research (2011)

Alpha-1 adrenergic receptors (α1-ARs) have beneficial effects in the heart and cardiac myocytes. In pilot studies in vivo , a sub-hypertensive dose of the α1A subtype-selective agonist A61603 has cardioprotective signaling and prevents and rescues cardiomyopathy in mouse models. These studies give a possible explanation for adverse cardiac effects of α1-antagonists in clinical trials and are a rationale to test α1-agonists in heart failure. Our objective was to establish models to screen α1-agonists for beneficial cardiac signaling. We tested the hypothesis that different α1-AR agonists have distinct beneficial cardiac effects at very low doses. To test this, we studied α1-AR-mediated cardioprotective and adaptive hypertrophic signaling in isolated neonatal rat ventricular myocytes (NRVM) and adult mouse ventricular myocytes (AMVM). We compared A61603 to all clinically approved α1-agonists: epinephrine (EPI), norepinephrine (NE), phenylephrine (PE), dobutamine (DOB), methoxamine (MET), and midodrine (MID) at 5 doses, all in the presence of the beta-blocker propranolol (200 nM). Cardioprotective signaling was measured by α1-AR-ERK survival pathway activation and cell viability by MTT assay after doxorubicin (20 μM)-induced toxicity. Cellular adaptive hypertrophy was measured by protein synthesis in NRVM and fetal gene protein expression in AMVM. In NRVM, A61603 was the most potent (EC 50 = 4 nM) and efficacious agonist for ERK activation. The rank-order potency was: A61603 &gt; NE &gt; EPI &gt; PE &gt; MET &gt; DOB &gt; MID. For protein synthesis, A61603 had high efficacy and potency (EC 50 = 12 nM). The rank-order potency was: A61603 &gt; NE &gt; DOB &gt; PE &gt; EPI &gt; MET &gt; MID. In AMVM, A61603 was potent for ERK (EC 50 = 58 nM) and increased cell viability 48% (1.48 vs. 1.00 control) with doxorubicin toxicity. A61603 (200 nM) increased the number of myocytes expressing beta-myosin heavy chain and atrial natriuretic factor by immunocytochemistry. We conclude that myocyte culture models are predictive of α1-agonist efficacy and potency in adaptive and protective cardiac effects. A61603 , an imidazoline with high affinity for the α1A-AR, is more potent and efficacious in myocyte models than are clinically available α1-agonists, and is a promising candidate for therapeutic testing in vivo .
Maturation of the Infant Respiratory Microbiota, Environmental Drivers, and Health Consequences. A Prospective Cohort Study
Authors: Astrid A. T. M. Bosch, Wouter A. A. de Steenhuijsen Piters, Marlies A. van Houten, Mei Ling J. N. Chu, Giske Biesbroek, Jolanda Kool, Paula Pernet, Pieter-Kees C. M. de Groot, Marinus J. C. Eijkemans, Bart J. F. Keijser, Elisabeth A. M. Sanders, Debby Bogaert
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Perinatal and postnatal influences are presumed important drivers of the early-life respiratory microbiota composition. We hypothesized that the respiratory microbiota composition and development in infancy is affecting microbiota stability and thereby resistance against respiratory tract infections (RTIs) over time.Objectives: To investigate common environmental drivers, including birth mode, feeding type, antibiotic exposure, and crowding conditions, in relation to respiratory tract microbiota maturation and stability, and consecutive risk of RTIs over the first year of life.Methods: In a prospectively followed cohort of 112 infants, we characterized the nasopharyngeal microbiota longitudinally from birth on (11 consecutive sample moments and the maximum three RTI samples per subject; in total, n = 1,121 samples) by 16S-rRNA gene amplicon sequencing.Measurements and Main Results: Using a microbiota-based machine-learning algorithm, we found that children experiencing a higher number of RTIs in the first year of life already demonstrate an aberrant microbial developmental trajectory from the first month of life on as compared with the reference group (0–2 RTIs/yr). The altered microbiota maturation process coincided with decreased microbial community stability, prolonged reduction of Corynebacterium and Dolosigranulum, enrichment of Moraxella very early in life, followed by later enrichment of Neisseria and Prevotella spp. Independent drivers of these aberrant developmental trajectories of respiratory microbiota members were mode of delivery, infant feeding, crowding, and recent antibiotic use.Conclusions: Our results suggest that environmental drivers impact microbiota development and, consequently, resistance against development of RTIs. This supports the idea that microbiota form the mediator between early-life environmental risk factors for and susceptibility to RTIs over the first year of life.
PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation
Authors: Candani S. A. Tutuka, Miles C. Andrews, John M. Mariadason, Paul Ioannidis, Christopher Hudson, Jonathan Cebon, Andreas Behren
Journal: Molecular Cancer (2017)

BRAF inhibitors (BRAFi) are standard of care for the treatment of BRAF V600 mutation-driven metastatic melanoma, but can lead to paradoxical activation of the mitogen-activated protein kinase (MAPK) signalling pathway. This can result in the promotion of precancerous lesions and secondary neoplasms, mainly (but not exclusively) associated with pre-existing mutations in RAS genes. We previously reported a patient with synchronous BRAF-mutated metastatic melanoma and BRAF wt /KRAS G12D-metastatic colorectal cancer (CRC), whose CRC relapsed and progressed when treated with the BRAF inhibitor dabrafenib (GSK2118436). We used tissue from the resected CRC metastasis to derive a cell line, LM-COL-1, which directly and reliably mimicked the clinical scenario including paradoxical activation of the MAPK signalling pathway resulting in increased cell proliferation upon dabrafenib treatment. Novel BRAF inhibitors (PLX8394 and PLX7904), dubbed as "paradox breakers", were developed to inhibit V600 mutated oncogenic BRAF without causing paradoxical MAPK pathway activation. In this study we used our LM-COL-1 model alongside multiple other CRC cell lines with varying mutational backgrounds to demonstrate and confirm that the paradox breaker PLX8394 retains on-target inhibition of mutated BRAF V600 without paradoxically promoting MAPK signalling.
At what age should patients with AML be termed elderly?: Results of a population-based study of the impact of age on treatment outcome and its modification by karyotype
Authors: K. Schmidt, Gitte Birk Kerndrup, L.S. Mortensen, Birgitte Strange Preiss, N.T. Pedersen, P. Gram-Hansen, L. Friis, T.M. Andersen
Journal: Blood (2001)
The Montreux definition of neonatal ARDS: biological and clinical background behind the description of a new entity
Authors: Daniele De Luca, Anton H van Kaam, David G Tingay, Sherry E Courtney, Olivier Danhaive, Virgilio P Carnielli, Luc J Zimmermann, Martin C J Kneyber, Pierre Tissieres, Joe Brierley, Giorgio Conti, Jane J Pillow, Peter C Rimensberger
Journal: The Lancet Respiratory Medicine (2017)
The Role of Chest Computed Tomography in the Evaluation and Management of the Patient with Chronic Obstructive Pulmonary Disease
Authors: Wassim W. Labaki, Carlos H. Martinez, Fernando J. Martinez, Craig J. Galbán, Brian D. Ross, George R. Washko, R. Graham Barr, Elizabeth A. Regan, Harvey O. Coxson, Eric A. Hoffman, John D. Newell, Douglas Curran-Everett, James C. Hogg, James D. Crapo, David A. Lynch, Ella A. Kazerooni, MeiLan K. Han
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation minimal residual disease of AML patients as determined by multiparameter flow cytometry: a retrospective and prospective analysis
Authors: Ying-Jun Chang, Yu Wang, Yan-Rong Liu, Lan-Ping Xu, Xiao-Hui Zhang, Huan Chen, Yu-Hong Chen, Feng-Rong Wang, Wei Han, Yu-Qian Sun, Chen-Hua Yan, Fei-Fei Tang, Xiao-Dong Mo, Kai-Yan Liu, Xiao-Jun Huang
Journal: Journal of Hematology & Oncology (2017)

This study compared the effects of pre-transplantation minimal residual disease (pre-MRD) on outcomes in AML patients who underwent human leukocyte antigen-matched sibling donor transplantation (MSDT) or who received unmanipulated haploidentical allografts. A retrospective study (n = 339) and a prospective study (n = 340) were performed. MRD was determined using multiparameter flow cytometry. Either after retrospective or prospective analysis, patients with negative pre-MRD (pre-MRDneg) had a lower incidence of relapse than those with positive pre-MRD (pre-MRDpos) in MSDT settings (P < 0.001 for all), but relapse was comparable in Haplo-SCT settings for patients with pre-MRDneg versus pre-MRDpos (P = 0.866 and 0.161, respectively). In either the retrospective (n = 65) or the prospective study (n = 76), pre-MRDpos subjects receiving Haplo-SCT experienced a lower incidence of relapse than those who underwent MSDT (P < 0.001 and p = 0.017, respectively). Of the patients with pre-MRDpos in either the total (n = 141) or the subgroup excluding cases which received donor lymphocyte infusion (DLI; n = 105), those who underwent MSDT had a higher incidence of relapse than those receiving haplo-SCT (P < 0.01 for all). Multivariate analysis showed that, for pre-MRDpos cases, haplo-SCT was associated with a low incidence of relapse and with better LFS and OS in either retrospective group, prospective group, combination groups, or subgroup not including cases which received DLI. The results indicated that, for pre-MRD-positive AML patients, haplo-SCT was associated with lower incidence of relapse and better survival, suggesting a stronger anti-leukemia effect.
Depression links to physical health decline in cancer caregivers
Authors: Jacqui Wise
Journal: BMJ (2017)

People who care for a family member with cancer show a steady decline in their own physical health, a study in the journal Cancer has found.1

The researchers found that symptoms of depression were the only significant predictor of caregivers’ physical health decline, and they urged screening to identify the people most at risk.

The US study, funded …
Epigenomic analysis of DNMT3B-mediated cervical cancer invasion by methylated DNA immunoprecipitation identifies PTPRR as a metastasis suppressor gene
Authors: Po Hsuan Su, Rui-Lan Huang, Chin Yu Liu, Hui Chen Wang, Her Young Su, Ming Tzeung Chung, Ya Wen Lin, Hung-Cheng Lai
Journal: Cancer Research (2014)
New Therapeutic Approach for Central Nervous System Lymphoma By Intracerebroventricular Delivery of CD19CAR T Cells
Authors: Xiuli Wang, Ryan Urak, Walter Miriam, Laura Lim, Brenda Aguilar, Alfonso Brito, Aniee Sarkissian, Christine Brown, Sandra H. Thomas, Leslie Popplewell, Lihua E. Budde, Stephen J. Forman
Journal: Blood (2016)
PIK3CA mutation analysis in Chinese patients with solid tumors.
Authors: Ling Xu, Xiujuan Qu, Rui Ma, Yuee Teng, Jingdong Zhang, Bo Jin, Mingfang Zhao, Zhi Li, Tianshu Guo, Zichang Yang, Yunpeng Liu
Journal: Journal of Clinical Oncology (2016)

e23246 Background: PIK3CA mutation has been studied in various solid cancers. However, the impact of PI3KCA mutation on solid cancers is controversial. The aim of this study was to evaluate the clinicopathological and prognostic relevance of PIK3CA mutation in Chinese solid cancers patients. Methods: PIK3CA mutations were screened in various tumor specimens using next generation sequencing technology. Correlation between PIK3CA mutations and clinicopathological characteristics was analyzed by Spearman’s correlation. Overall survivals were analyzed by using the Kaplan–Meier method and compared by the log-rank test. Statistical data were obtained by using SPSS for Windows version 20.0. P values < 0.05 were considered to indicate statistically significant results. Results: In total, 13.69 % (36/263) of all patients harbored PIK3CA mutations. PIK3CA mutations were more commonly observed in ECOG PS 0 patients (P = 0.011). PIK3CA mutations were 19.05 % (4/21) in gastric cancer, 9.47 % (9/95) in colorectal cancer, 10.69 % (14 /131) in lung cancer, and 56.25 % (9/16) in breast cancer patients, respectively. PIK3CA mutations are common in ECOG PS 0 colorectal cancer patients (P = 0.005) and > = 60 years gastric cancer patients (P = 0.006). In PIK3CA mutations patients, exon 9 mutations (44.44%, 4/9) was higher in colorectal cancer, exon 13 mutations (64.29%, 9/14) was higher in lung cancer, and exon 20 mutations (44.44%, 4/9) was higher in breast cancer, P = 0.015. The overall survival of PIK3CA mutant-type patients was 26 (95% CI: 15.8-36.2) months, while PIK3CA wild-type patients was 15 (95% CI: 10.7-19.3) months. PIK3CA mutations were significantly associated with the longer survival time (P = 0.049). Conclusions: The patients with mutant PIK3CA had distinct characteristics in ECOG PS and have better survival in Chinese solid cancers.