tbuckley/cabot-search huggingface dataset:
Frequency and types of EGFR mutation in Moroccan patients with non-small cell lung cancer
Authors: M.L. Sow, H. El Yacoubi, B. Moukafih, S. Balde, G. Akimana, S. Elkhoyaali, H. Abahssain, H. Mrabti, I. Elghissassi, H. Errihani
Journal: Annals of Oncology (2019)

Background: Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC), particularly in adenocarcinoma histology (aNSCLC). The frequency of EGFR mutations is ethnicity-dependent, with a higher proportion in Asian populations than Caucasian populations. Yet there is a lack of data of these mutations among North African patients. The aim of this study was to report the frequency and types of EGFR mutations in a group of NSCLC Moroccan patients. Methods: Tumor specimens from Moroccan patients with NSCLC were collected, between November 2010 and December 2017 to determine frequency and types of EGFR mutations. Tumors were tested for EGFR by polymerase chain reaction and sequencing of exons 18, 19, 20, and 21. Results: A total of 334 patients were consequently enrolled: 242 (72.5%) males and 92 females (27.5%), with a mean age of 61.9 years. 56.9% had a history of smoking, and only the adenocarcinoma histology are considered. EGFR testing of 334 (100%) demonstrated wild typein 261 (78.1%) and mutated EGFR in 73 (21.9%).Mutations were mainly detected in the exon 19 (65.8%), followed by exon 21 L858 (17.8%),exon 21codon (5.5%) and exon 18 (6.8%), whereas mutations in the exon 20 were less frequent(4.1%). In patients with aNSCLC, the detection of EGFR mutation was independently associated with gender (41,3% females Vs.14,5% males; p < 0.001) and smoking status (34.8% non-smokers Vs. 12.9%, p < 0.001). Conclusions: Our findings confirm the genetic heterogeneity of NSCLC worldwide, reporting frequency of EGFR mutations in NSCLC Moroccan patients intermediate between Asian (50%) and Caucasian (15%) populations. The substantial lack of data from several large geographic regions of the world, notably our region, highlights a potential lack of routine mutation testing and consequent access to EGFR targeted agents, suggesting the need for further research implementations in Morocco. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Genome Evolution of the Obligate Endosymbiont Buchnera aphidicola
Authors: Rebecca A Chong, Hyunjin Park, Nancy A Moran
Journal: Molecular Biology and Evolution (2019)

Abstract An evolutionary consequence of uniparentally transmitted symbiosis is degradation of symbiont genomes. We use the system of aphids and their maternally inherited obligate endosymbiont, Buchnera aphidicola, to explore the evolutionary process of genome degradation. We compared complete genome sequences for 39 Buchnera strains, including 23 newly sequenced symbiont genomes from diverse aphid hosts. We reconstructed the genome of the most recent shared Buchnera ancestor, which contained 616 protein-coding genes, and 39 RNA genes. The extent of subsequent gene loss varied across lineages, resulting in modern genomes ranging from 412 to 646 kb and containing 354–587 protein-coding genes. Loss events were highly nonrandom across loci. Genes involved in replication, transcription, translation, and amino acid biosynthesis are largely retained, whereas genes underlying ornithine biosynthesis, stress responses, and transcriptional regulation were lost repeatedly. Aside from losses, gene order is almost completely stable. The main exceptions involve movement between plasmid and chromosome locations of genes underlying tryptophan and leucine biosynthesis and supporting nutrition of aphid hosts. This set of complete genomes enabled tests for signatures of positive diversifying selection. Of 371 Buchnera genes tested, 29 genes show strong support for ongoing positive selection. These include genes encoding outer membrane porins that are expected to be involved in direct interactions with hosts. Collectively, these results indicate that extensive genome reduction occurred in the ancestral Buchnera prior to aphid diversification and that reduction has continued since, with losses greater in some lineages and for some loci.
Novel qPCR screen for efficient and reliable identification of RET fusion-positive non-small cell lung cancer.
Authors: Brock Lloyd Schweitzer, Rebecca B Smith, Rachel Skelton, Ryan Vincent, Frank McMahon, John Handshoe, Stephan Wade Morris, David Richard Hout
Journal: Journal of Clinical Oncology (2015)

e22154 Background: The REarranged during Transfection (RET) protein is a cell surface receptor tyrosine kinase (RTK) critical for normal cell growth and differentiation; however, genetic alterations including chromosomal translocations that create RET fusions can drive various forms of cancer. To date, several RET fusion partners (including KIF5B, CCDC6/PTC/H4, NCO4/PTC3/ELE1 and TRIM33/PTC7) with numerous subtypes have been identified in different malignancies. Two of these RET fusions, KIF5B-RET and CCDC6-RET, have been found recurrently in 1-2% of non-small cell lung cancer (NSCLC) while the additional RET fusions have been observed largely in papillary thyroid cancer. Clinical trials are underway to test the efficacy of a number of tyrosine kinase inhibitor (TKI) therapies that target oncogenic RET kinase activity. Thus, there is a strong clinical demand for the contemporaneous development of a robust RET fusion detection assay together with RET-targeted therapies for the efficient and routine screening of NSCLC and other cancers. Methods: We have developed a sensitive and streamlined qPCR-based assay to identify RET fusion-positive tumors by monitoring RET mRNA. A cohort of over 800 archival FFPE NSCLC patient samples was tested using the RET qPCR assay and compared to RET status as determined by fusion-specific RNA qPCR and sequencing of cDNA. Results: Analytical performance studies of this assay have demonstrated an estimated sensitivity and specificity of ≥ 97% in formalin-fixed paraffin-embedded (FFPE) cell lines. A head-to-head comparison between the RET qPCR assay and RET breakapart FISH using a subset of the NSCLC cohort demonstrated an estimated accuracy of 95% for the RET qPCR assay (70% lower confidence bound) and estimated accuracy of only 55% for RET FISH (30% lower confidence bound). Conclusions: This RET qPCR assay is therefore capable of reliably detecting RET fusion-positive tumors and could be used in routine clinical testing, either alone or in larger multiplexed NSCLC gene panels.
Prevalence and Prognosis of Unrecognized Myocardial Infarction in Asymptomatic Patients With Diabetes: A Two-Center Study With Up to 5 Years of Follow-up
Authors: Michael D. Elliott, John F. Heitner, Han Kim, Edwin Wu, Michele A. Parker, Daniel C. Lee, Dixon B. Kaufman, Robert O. Bonow, Robert Judd, Raymond J. Kim
Journal: Diabetes Care (2019)

To determine the prevalence and prognostic significance of unrecognized myocardial infarction (MI) by delayed-enhancement MRI (DE-MRI) in asymptomatic patients with diabetes.In this prospective, two-center study of asymptomatic patients without known cardiac disease (n = 120), two prespecified cohorts underwent a research MRI: 1) a high-risk group with type 1 diabetes and chronic renal insufficiency (n = 50) and 2) an average-risk group with type 2 diabetes (n = 70). The primary end point was a composite of all-cause mortality and clinical MI.Overall, the prevalence of unrecognized MI was 19% by DE-MRI (28% high-risk group and 13% average-risk group) and 5% by electrocardiography. During up to 5 years of follow-up with a total of 460 patient-years of follow-up, the rate of death/MI was markedly higher in patients with diabetes with (vs. without) unrecognized MI (all 44% vs. 7%, high-risk group 43% vs. 6%, and average-risk group 44% vs. 8%; all P < 0.01). After adjustment for Framingham risk score, left ventricular ejection fraction, and diabetes type, the presence of unrecognized MI by DE-MRI conferred an eightfold increase in risk of death/MI (95% CI 3.0-21.1, P < 0.0001). Addition of unrecognized MI to clinical indices significantly improved model discrimination for adverse events (integrated discrimination improvement = 0.156, P = 0.001).Unrecognized MI is prevalent in asymptomatic patients with diabetes without a history of cardiac disease and confers a markedly increased risk of death and clinical MI.
Islet Plotting: 3D Bioprinting of Functional Islets of Langerhans in an Alginate/Methylcellulose Hydrogel Blend (Adv. Healthcare Mater. 7/2019)
Authors: Sarah Duin, Kathleen Schütz, Tilman Ahlfeld, Susann Lehmann, Anja Lode, Barbara Ludwig, Michael Gelinsky
Journal: Advanced Healthcare Materials (2019)

In article number 1801631 by Michael Gelinsky and co-workers, primary islets of Langerhans from rats are bioprinted into microporous 3D structures using an alginate/methylcellulose blend as bioink. The hydrogel blend is comparable to plain alginate in terms of diffusion of glucose and insulin. Plotted islets retain their viability and morphology, continue to produce insulin and glucagon over time in culture, and release insulin in response to glucose stimulation.
A qualitative analysis of the attitudes of Irish patients towards participation in genetic-based research.
Authors: Terri Patricia McVeigh, Karl J Sweeney, Michael J. Kerin, David James Gallagher
Journal: Journal of Clinical Oncology (2015)

e20564 Background: Progress in diagnostic and therapeutic strategies in cancer care is fundamentally dependent upon high-quality biomedical research. Recent technological advances have facilitated considerable gains in our understanding of disease aetiology, and rapidly emerging data promises further progress. Translating this potential into the clinic is dependent upon participant recruitment into innovative clinical trials. Our aim was to identify factors influencing Irish patient participation in genetic research, in particular with respect to commercial and financial implications. Methods: A multi-centre cross-sectional survey study was performed. Consecutive patients attending four out-patient clinics were asked to complete paper-based questionnaires. An electronic version of the same questionnaire was created on Survey Monkey with a link made public on a social media website for a period of 24 hours. Data was analysed using SPSS. Results: 351 questionnaires were completed (99 paper, 252 electronic). The majority of respondents were female (n = 288, 82%), and highly educated, with 244 (70%) attending college/university. Most participants supported genetic research (267, 76%), more frequently for common diseases (274, 78%) than rare disorders (204, 58%, p < 0.001, X2). 103(29%) had participated in scientific research, and 57(16%) had donated material to a biobank. The majority (n = 213, 61%) would not support research with potential financial/commercial gain. 106(30%) would decline to participate in research if researchers would benefit financially, compared to 49(14%) if the research was supported by a pharmaceutical company, (p < 0.001, X2). Respondents would provide buccal samples (258,74%) more readily than tissue (225,64%) or blood (222,63%). Conclusions: A high level of support for genetic research exists among the Irish patient population, but active participation is dependent upon a number of factors, notably, type of biological material to be utilised, frequency of the disease in question, and commercial interest of the researchers. The commercial interest of industry had a lesser impact possibly reflecting a positive association with developments in therapy.
Injectable polypeptide hydrogel-based co-delivery of vaccine and immune checkpoint inhibitors improves tumor immunotherapy
Authors: Huijuan Song, Pengxiang Yang, Pingsheng Huang, Chuangnian Zhang, Deling Kong, Weiwei Wang
Journal: Theranostics (2019)

Immunotherapy, an attractive option for cancer treatment, necessitates the direct stimulation of immune cells in vivo and the simultaneous effective inhibition of immunosuppressive tumor microenvironments. Methods:In the present study, we developed an injectable PEG-b-poly(L-alanine) hydrogel for co-delivery of a tumor vaccine and dual immune checkpoint inhibitors to increase tumor immunotherapy efficacy.Tumor cell lysates, granulocyte-macrophage colony stimulating factor (GM-CSF), and immune checkpoint inhibitors (anti-CTLA-4/PD-1 antibody) were readily encapsulated in the porous hydrogel during the spontaneous self-assembly of polypeptide in aqueous solution.Results: Sustained release of tumor antigens and GM-CSF persistently recruited and activated dendritic cells (DCs) and induced a strong T-cell response in vivo, which was further enhanced by the immune checkpoint therapy.The hydrogel vaccine also upregulated the production of IgG and the secretion of cytokines including IFN-γ, IL-4, and TNF-α.Importantly, the hydrogel-based combination therapy had superior immunotherapy effects against melanoma and 4T-1 tumor in comparison with the vaccine alone or in addition with a single immune checkpoint blockade.In studying the underlying mechanism, we found that the hydrogel-based combinatorial immunotherapy not only significantly increased the activated effector CD8 + T cells within the spleens and tumors of vaccinated mice, but also reduced the ratio of Tregs. Conclusion:Our findings indicate that the polypeptide hydrogel can be used as an effective sustained delivery platform for vaccines and immune checkpoint inhibitors, providing an advanced combinatorial immunotherapy approach for cancer treatment.
TCTAP A-045 Manual Thrombus Aspiration Reduces Myocardial Necrosis During Primary Percutaneous Coronary Intervention (PPCI) in Patients with ST-Elevation Myocardial Infarction (STEMI).
Authors: A.P.M. Sohrabuzzaman, S. Mokaddas Hossain, Fahmida Zaman
Journal: Journal of the American College of Cardiology (2019)
SAT-357-Tropifexor, a farnesoid X receptor agonist for the treatment of non-alcoholic steatohepatitis: Interim results based on baseline body mass index from first two parts of Phase 2b study FLIGHT-FXR
Authors: Arun Sanyal, Patricia Lopez, Eric Lawitz, Won Kim, Jee-Fu Huang, Pietro Andreone, George Boon Bee Goh, Yi-Cheng Chen, Vlad Ratziu, Yoon Jun Kim, Marno Ryan, Martin Weltman, Andreas Geier, Juergen Loeffler, Felicity Schaefer, Sujata Vaidyanathan, Miljen Martic, Clifford Brass
Journal: Journal of Hepatology (2019)
Abstract 18134: Time to Recovery in Individual Domains of the Cerebral Performance Category-Extended
Authors: Katharyn L Flickinger, Melissa J Repine, Allison C Koller, Margo B Holm, Elizabeth R Skidmore, Clifton W Callaway, Jon C Rittenberger
Journal: Circulation (2017)

Introduction: Cardiac arrest survivors often experience cognitive and physical impairments. Global measures of recovery such as the Modified Rankin Scale (mRS) and Cerebral Performance Category (CPC) improve over 9-12 months. Individual domains of function may recover at different rates, and can be evaluated separately using the 10 domain Cerebral Performance Category Extended (CPC-E). CPC-E domains include alertness, logical thinking, attention, motor skills, short-term memory, basic and complex activities of daily living (ADL), mood, fatigue, and return to work. Hypothesis: We tested whether the proportion of patients with recovery for individual functional domains of the CPC-E varied at hospital discharge, 3 months and 6 months after cardiac arrest. Methods: Chart review occurred between 2/1/16 and 5/31/17 for baseline demographic data and Post Cardiac Arrest Category (PCAC). We recorded clinical outcome measures including mRS, CPC, and CPC-E scores at discharge, 3 months, and 6 months. We defined reco...
Polyploidy spectrum: a new marker in HCC classification
Authors: Myriam Bou-Nader, Stefano Caruso, Romain Donne, Séverine Celton-Morizur, Julien Calderaro, Géraldine Gentric, Mathilde Cadoux, Antoine L’Hermitte, Christophe Klein, Thomas Guilbert, Miguel Albuquerque, Gabrielle Couchy, Valérie Paradis, Jean-Pierre Couty, Jessica Zucman-Rossi, Chantal Desdouets
Journal: Gut (2019)

Objectives Polyploidy is a fascinating characteristic of liver parenchyma. Hepatocyte polyploidy depends on the DNA content of each nucleus (nuclear ploidy) and the number of nuclei per cell (cellular ploidy). Which role can be assigned to polyploidy during human hepatocellular carcinoma (HCC) development is still an open question. Here, we investigated whether a specific ploidy spectrum is associated with clinical and molecular features of HCC. Design Ploidy spectra were determined on surgically resected tissues from patients with HCC as well as healthy control tissues. To define ploidy profiles, a quantitative and qualitative in situ imaging approach was used on paraffin tissue liver sections. Results We first demonstrated that polyploid hepatocytes are the major components of human liver parenchyma, polyploidy being mainly cellular (binuclear hepatocytes). Across liver lobules, polyploid hepatocytes do not exhibit a specific zonation pattern. During liver tumorigenesis, cellular ploidy is drastically reduced; binuclear polyploid hepatocytes are barely present in HCC tumours. Remarkably, nuclear ploidy is specifically amplified in HCC tumours. In fact, nuclear ploidy is amplified in HCCs harbouring a low degree of differentiation and TP53 mutations. Finally, our results demonstrated that highly polyploid tumours are associated with a poor prognosis. Conclusions Our results underline the importance of quantification of cellular and nuclear ploidy spectra during HCC tumorigenesis.
Abstract 18756: The Association Between Residual Non-Infarct Related Coronary Stenoses in ST-Elevation Myocardial Infarction and Adverse Outcomes
Authors: Ameen Basha, Todd J Anderson, Diane Galbraith, Merril L Knudtson, Stephen B Wilton, Kevin Bainey, David W Allen, Robert Welsh, Bryan J Har
Journal: Circulation (2017)

Introduction: Approximately 40-60% of STEMI patients present with multivessel disease (MVD). Revascularization strategies include immediate percutaneous coronary intervention (PCI) in multiple dise...
Particle Depletion Does Not Remediate Acute Effects of Traffic-related Air Pollution and Allergen. A Randomized, Double-Blind Crossover Study
Authors: Denise J. Wooding, Min Hyung Ryu, Anke Hüls, Andrew D. Lee, David T. S. Lin, Christopher F. Rider, Agnes C. Y. Yuen, Chris Carlsten
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Diesel exhaust (DE), an established model of traffic-related air pollution, contributes significantly to the global burden of asthma and may augment the effects of allergen inhalation. Newer diesel particulate-filtering technologies may increase NO2 emissions, raising questions regarding their effectiveness in reducing harm from associated engine output.Objectives: To assess the effects of DE and allergen coexposure on lung function, airway responsiveness, and circulating leukocytes, and determine whether DE particle depletion remediates these effects.Methods: In this randomized, double-blind crossover study, 14 allergen-sensitized participants (9 with airway hyperresponsiveness) underwent inhaled allergen challenge after 2-hour exposures to DE, particle-depleted DE (PDDE), or filtered air. The control condition was inhaled saline after filtered air. Blood sampling and spirometry were performed before and up to 48 hours after exposures. Airway responsiveness was evaluated at 24 hours.Measurements and Main Results: PDDE plus allergen coexposure impaired lung function more than DE plus allergen, particularly in those genetically at risk. DE plus allergen and PDDE plus allergen each increased airway responsiveness in normally responsive participants. DE plus allergen increased blood neutrophils and was associated with persistent eosinophilia at 48 hours. DE and PDDE each increased total peripheral leukocyte counts in a manner affected by participant genotypes. Changes in peripheral leukocytes correlated with lung function decline.Conclusions: Coexposure to DE and allergen impaired lung function, which was worse after particle depletion (which increased NO2). Thus, particulates are not necessarily the sole or main culprit responsible for all harmful effects of DE. Policies and technologies aimed at protecting public health should be scrutinized in that regard.Clinical trial registered with www.clinicaltrials.gov (NCT02017431).
Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives
Authors: Xin Sun, Peiyi Yan, Chang Zou, Yin‐Kwan Wong, Yuhan Shu, Yew Mun Lee, Chongjing Zhang, Nai‐Di Yang, Jigang Wang, Jianbin Zhang
Journal: Medicinal Research Reviews (2019)

Artemisinin and its derivatives, with their outstanding clinical efficacy and safety, represent the most effective and impactful antimalarial drugs. Apart from its antimalarial effect, artemisinin has also been shown to exhibit selective anticancer properties against multiple cancer types both in vitro and in vivo. Specifically, our previous studies highlighted the therapeutic effects of artemisinin on autophagy regulation. Autophagy is a well-conserved degradative process that recycles cytoplasmic contents and organelles in lysosomes to maintain cellular homeostasis. The deregulation of autophagy is often observed in cancer cells, where it contributes to tumor adaptation to nutrient-deficient tumor microenvironments. This review discusses recent advances in the anticancer properties of artemisinin and its derivatives via their regulation of autophagy, mitophagy, and ferritinophagy. In particular, we will discuss the mechanisms of artemisinin activation in cancer and novel findings regarding the role of artemisinin in regulating autophagy, which involves changes in multiple signaling pathways. More importantly, with increasing failure rates and the high cost of the development of novel anticancer drugs, the strategy of repurposing traditional therapeutic Chinese medicinal agents such as artemisinin to treat cancer provides a more attractive alternative. We believe that the topics covered here will be important in demonstrating the potential of artemisinin and its derivatives as safe and potent anticancer agents.
Engineering Hydrogels beyond a Hydrated Network
Authors: Robert Wieduwild, Yong Xu, Serge Ostrovidov, Ali Khademhosseini, Yixin Zhang, Gorka Orive
Journal: Advanced Healthcare Materials (2019)

Abstract In recent years, many mechanical, physical, chemical, and biochemical features of biomatrices have emerged as important properties to dictate the fates of cells. To construct chemically defined biomaterials to recapitulate various biological niches for both cell biology research and therapeutic utilities, it has become increasingly clear that a simple hydrated polymer network would not be able to provide the complex cues and signaling required for many types of cells. The researchers are facing a growing list of mechanophysical and biochemical properties, while each of them could be an important cellular trigger. To include all these design parameters in screening and synthesis is practically difficult, if not impossible. Developing novel high throughput screening technology by combining assay miniaturization, computer simulations, and modeling can help researchers to tackle the challenge to identify the most relevant parameters to tailor materials for specific applications.