tbuckley/cabot-search huggingface dataset:
Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific Death
Authors: Sreenivasa Rao Kondapally Seshasai, Stephen Kaptoge, Alexander Thompson, Emanuele Di Angelantonio, Pei Gao, Nadeem Sarwar, Peter H. Whincup, Kenneth J. Mukamal, Richard F. Gillum, Ingar Holme, Inger Njolstad, Astrid Fletcher, Peter Nilsson, Sarah Lewington, Rory Collins, Vilmundur Gudnason, Simon G. Thompson, Naveed Sattar, Elizabeth Selvin, Frank B. Hu, John Danesh
Journal: New England Journal of Medicine (2011)

The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.
A Missense Mutation in KIT Kinase Domain 1 Correlates with Imatinib Resistance in Gastrointestinal Stromal Tumors
Authors: Lei L. Chen, Jonathan C. Trent, Elsie F. Wu, Gregory N. Fuller, Latha Ramdas, Wei Zhang, Austin K. Raymond, Victor G. Prieto, Caroline O. Oyedeji, Kelly K. Hunt, Raphael E. Pollock, Barry W. Feig, Kimberly J. Hayes, Haesun Choi, Homer A. Macapinlac, Walter Hittelman, Marco A. Velasco, Shreyaskumar Patel, Michael A. Burgess, Robert S. Benjamin, Marsha L. Frazier
Journal: Cancer Research (2004)

Abstract KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T→C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT.
Some Misconceptions about Understanding Autoimmunity through Experiments with Knockouts
Authors: Lawrence Steinman
Journal: The Journal of Experimental Medicine (1997)

Experimental autoimmune encephalomyelitis (EAE) has served as a prototypic model of T cell–mediated, organspecific autoimmune disease, and as a useful model for the human disease, multiple sclerosis (MS) (1). Frei et al. (2) demonstrate that in two strains of mice with a double knockout, where both TNF-α and LT-α are inactivated, that EAE may develop. The disease in these double knockout mice progresses in an apparently typical fashion, concordant with what is observed in the usual inbred strains of mice where EAE is induced: there is clinical paralysis, and histopathology reveals intense perivascular and parenchymal infiltration with CD4+ T cells and demyelination. They conclude, and I agree, that the results are surprising, given the large body of information suggesting that TNF-α and LT-α are important in the pathogenesis of EAE and MS. However, before accepting their ultimate conclusion that, “these results indicate that TNFα and LT-α are not essential for the development of EAE,” it is worthwhile to consider the limitations of the first-generation knockouts that have been employed in their study. Certain misconceptions have arisen concerning the interpretation of experiments with these contemporary knockouts. This is especially true when trying to understand the role of critical effector molecules like cytokines, in the development of complex phenotypes, like the paralysis and inflammation seen in EAE. Many of these cytokine molecules have diverse biological activities, and many of the functions of these molecules can be duplicated by other cytokines. Thus, in animals with disrupted or “knocked out” cytokine genes, one may expect many diverse changes in several physiological processes, and one might find that after all is done, that another gene and its product can replace the function of the gene that was disrupted.
Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer
Authors: C V A Wynter
Journal: Gut (2004)

Hyperplastic polyps (HP) of the colorectum have traditionally been regarded as non-neoplastic lesions. Recent data implicate HP in the pathogenesis of colorectal cancers (CRC) characterised by extensive DNA methylation and microsatellite instability. The aim of this study was to identify morphological and molecular features that may characterise subtypes of HP with potential for neoplastic progression.HP (22) clustering around distal CRC (group I) were compared with HP (58) in subjects with hyperplastic polyposis (group II). DNA methylation was tested in methylated in tumour (MINT) loci (1, 2, 12, 31) and genes HPP1, MGMT, p14ARF, p16INK4a, and hMLH1.Group II HP showed significantly more methylation than group I HP at all loci except MINT1 and MGMT. Group I showed the lowest frequency of DNA methylation but the highest frequency of K-ras mutation. Group II HP (termed HP variant) had the morphological features of the recently described "sessile serrated adenomas". Methylation of hMLH1 was found most frequently in group II polyps that included foci of dysplasia (7/10) and in no group I lesions.The findings support the existence of morphological and molecular heterogeneity among HP and highlight a subset that is likely to have significant malignant potential.
908 NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN BRAZIL: CLINICAL AND HISTOLOGICAL PROFILE
Authors: H.P. Cotrim, E.R. Parise, N. Leite, C. Oliveira, A. Martinelli, J. Galizzi, R.C. Silva, A. Mattos, L. Pereira, W. Amorim, C. Ivantes, F. Souza, M. Costa, L. Maia, M. Pessoa, F. Oliveira
Journal: Journal of Hepatology (2008)
Candidate genes for COPD in two large data sets
Authors: P. S. Bakke, G. Zhu, A. Gulsvik, X. Kong, A. G. N. Agusti, P. M. A. Calverley, C. F. Donner, R. D. Levy, B. J. Make, P. D. Pare, S. I. Rennard, J. Vestbo, E. F. M. Wouters, W. Anderson, D. A. Lomas, E. K. Silverman, S. G. Pillai
Journal: European Respiratory Journal (2010)

Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV₁) % predicted and FEV₁/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV₁ % predicted and FEV₁/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.
Narrative Review: Effect of Bariatric Surgery on Type 2 Diabetes Mellitus
Authors: Marion L. Vetter
Journal: Annals of Internal Medicine (2009)

Bariatric surgery leads to substantial and durable weight reduction. Nearly 30% of patients who undergo bariatric surgery have type 2 diabetes, and for many of them, diabetes resolves after surgery (84% to 98% for bypass procedures and 48% to 68% for restrictive procedures). Glycemic control improves in part because of caloric restriction but also because gut peptide secretion changes. Gut peptides, which mediate the enteroinsular axis, include the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, as well as ghrelin and peptide YY. Bariatric surgery (particularly bypass procedures) alters secretion of these gut hormones, which results in enhanced insulin secretion and sensitivity. This review discusses the various bariatric procedures and how they alter the enteroinsular axis. Familiarity with these effects can help physicians decide among the different surgical procedures and avoid postoperative hypoglycemia.
Ovarian influences on female development: Revolutionary or evolutionary?
Authors: Kim Wallen
Journal: Behavioral and Brain Sciences (1998)

The Fitch &amp; Denenberg target article focuses almost exclusively on short gestation mammals, which differ substantially from long-gestation mammals in the timing and type of hormonal contribution to their sexual differentiation. Conclusions regarding the role of ovaries in female sexual differentiation may accordingly apply to only a limited number of species. Specific criticisms of the organizational effects of hormones stem from an incomplete reading of the original literature. The mechanisms proposed in this target article reflect an extension of the principle of hormonal organization, not a revolutionary restructuring.
Novel Agents on the Horizon for Cancer Therapy
Authors: W. W. Ma, A. A. Adjei
Journal: CA A Cancer Journal for Clinicians (2009)

Although cancer remains a devastating diagnosis, several decades of preclinical progress in cancer biology and biotechnology have recently led to successful development of several biological agents that substantially improve survival and quality of life for some patients. There is now a rich pipeline of novel anticancer agents in early phase clinical trials. The specific tumor and stromal aberrancies targeted can be conceptualized as membrane-bound receptor kinases (HGF/c-Met, human epidermal growth factor receptor and insulin growth factor receptor pathways), intracellular signaling kinases (Src, PI3k/Akt/mTOR, and mitogen-activated protein kinase pathways), epigenetic abnormalities (DNA methyltransferase and histyone deacetylase), protein dynamics (heat shock protein 90, ubiquitin-proteasome system), and tumor vasculature and microenvironment (angiogenesis, HIF, endothelium, integrins). Several technologies are available to target these abnormalities. Of these, monoclonal antibodies and small-molecule inhibitors have been the more successful, and often complementary, approaches so far in clinical settings. The success of this target-based cancer drug development approach is discussed with examples of recently approved agents, such as bevacizumab, erlotinib, trastuzumab, sorafenib, and bortezomib. This review also highlights the pipeline of rationally designed drugs in clinical development that have the potential to impact clinical care in the near future.
Chronic Kidney Disease, Dialysis, and Transplantation: A Companion to &lt;emph type="ital"&gt;Brenner and Rector’s The Kidney&lt;/emph&gt;
Authors: Edgar V. Lerma
Journal: JAMA (2012)

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Arterial stiffness is increased in subjects with COPD stage 3-4
Authors: Ulf Nilsson, Linnea Quist, Kjell Larsson, Bo Lundbäck, Viktor Johansson, Eva Rönmark, Anders Blomberg, Anne Lindberg
Journal: European Respiratory Journal (2014)

Introduction:  Cardiovascular disease (CVD) is common in COPD, and is related to increased mortality. Arterial stiffness is a marker of early atherosclerosis but the association between COPD and arterial stiffness as an indicator of CVD is still unclear.   Aim:  To evaluate the relationship between arterial stiffness, CVD and COPD in a population-based study.   Methods:  A population-based COPD-cohort recruited from the OLIN (Obstructive Lung Disease in Northern Sweden) studies has together with age- and sex-matched subjects without obstructive lung function impairment been invited to annual examinations since 2005. In 2010, 947 subjects, whereof 416 with COPD, participated in a structured interview, spirometry and measurements of pulse wave velocity (PWV).   Results:  PWV was higher among those with COPD stage 3-4, 10.52 m/s compared to the non-COPD, 9.13 m/s (p=0.042). Subjects≥60 years of age had higher mean PWV then those l60 years of age, and so did also subjects with CVD and/or reported hypertension compared to those without in both COPD and non-COPD groups (pl0.001 respectively). In a multivariate model, COPD stage 3-4 was associated with higher PWV, also when adjusted for sex, age group, smoking habits, measured blood pressure and reported CVD and/or reported hypertension.   Conclusion:  Arterial stiffness, assessed as PWV, was increased among subjects with COPD stage 3-4 compared to non-COPD subjects, and remained significantly associated to increased arterial stiffness also when adjusted for common confounders. This suggests a relationship between COPD severity and arterial stiffness not simplistically associated with other common CVD risk factors.
Dectin-1 Mediates the Biological Effects of β-Glucans
Authors: Gordon D. Brown, Jurgen Herre, David L. Williams, Janet A. Willment, Andrew S. J. Marshall, Siamon Gordon
Journal: The Journal of Experimental Medicine (2003)

The ability of fungal-derived β-glucan particles to induce leukocyte activation and the production of inflammatory mediators, such as tumor necrosis factor (TNF)-α, is a well characterized phenomenon. Although efforts have been made to understand how these carbohydrate polymers exert their immunomodulatory effects, the receptors involved in generating these responses are unknown. Here we show that Dectin-1 mediates the production of TNF-α in response to zymosan and live fungal pathogens, an activity that occurs at the cell surface and requires the cytoplasmic tail and immunoreceptor tyrosine activation motif of Dectin-1 as well as Toll-like receptor (TLR)-2 and Myd88. This is the first demonstration that the inflammatory response to pathogens requires recognition by a specific receptor in addition to the TLRs. Furthermore, these studies implicate Dectin-1 in the production of TNF-α in response to fungi, a critical step required for the successful control of these pathogens.
Lack of Coreceptor Allows Survival of Chronically Stimulated Double-Negative α/β T Cells
Authors: Abdel Rahim A. Hamad, Ananth Srikrishnan, Paria Mirmonsef, Chris P.M. Broeren, Carl H. June, Drew Pardoll, Jonathan P. Schneck
Journal: The Journal of Experimental Medicine (2001)

Lymphoproliferative diseases are characterized by massive accumulation of CD4−CD8−B220+ (double-negative [DN]) T cells in peripheral organs. Although evidence indicates these cells are derived from mature autoreactive α/β T cells, the significance of coreceptor downregulation is not known. In this study, we examined the role CD4 coreceptor plays in the survival of repeatedly stimulated T cells. CD4+/+ and CD4−/− T cells from AND T cell receptor (TCR) transgenic mice exhibited similar phenotypes after antigenic stimulation, but the CD4−/− T cells survived in much larger numbers than the CD4+/+ cells upon primary and secondary major histocompatibility complex (MHC)/peptide stimulation. Enhanced survival of CD4−/− T cells was due to decreased apoptosis rather than enhanced proliferation. Similarly, circumvention of the CD4/MHC interaction by using a surrogate TCR ligand that does not engage CD4 led to significant enhancement of CD4+/+ cells than when stimulated with MHC/peptide. Finally, we generated DN B220+ T cells using an in vitro model system and showed they were more tolerant to chronic stimulation than CD4+/+ cells. Together, these results indicate that coreceptor engagement controls expansion of normal T cells. In the absence of coreceptor, T cells survive chronic stimulation and express B220 as seen in autoimmune lymphoproliferative diseases.
Protein Interactome Reveals Converging Molecular Pathways Among Autism Disorders
Authors: Yasunari Sakai, Chad A. Shaw, Brian C. Dawson, Diana V. Dugas, Zaina Al-Mohtaseb, David E. Hill, Huda Y. Zoghbi
Journal: Science Translational Medicine (2011)

We developed an autism protein interaction network that provides a framework for studying autism pathogenesis and reveals shared molecular pathways among distinct autism spectrum disorders.
Selection on Coding Regions Determined Hox7 Genes Evolution
Authors: M. A. Fares
Journal: Molecular Biology and Evolution (2003)

The important role of Hox genes in determining the regionalization of the body plan of the vertebrates makes them invaluable candidates for evolutionary analyses regarding functional and morphological innovation. Gene duplication and gene loss led to a variable number of Hox genes in different vertebrate lineages. The evolutionary forces determining the conservation or loss of Hox genes are poorly understood. In this study, we show that variable selective pressures acted on Hox7 genes in different evolutionary lineages, with episodes of positive selection occurring after gene duplications. Tests for functional divergence in paralogs detected significant differentiation in a region known to modulate HOX7 protein activity. Our results show that both positive and negative selection on coding regions are influencing Hox7 genes evolution.
Coagulation disorders and the IPF puzzle
Authors: David B Coultas
Journal: Thorax (2013)

While idiopathic pulmonary fibrosis (IPF) remains a frustrating mystery for patients and their physicians, growing evidence from a number of different sources provides potentially clinically relevant clues to the puzzle of this largely untreatable and highly fatal disorder.1 ,2 Answers to frequently asked questions from patients of ‘why me?’ ‘what is the cause?’ ‘what can be done?’ and ‘what can I expect?’ are gradually emerging from studies of pathogenesis, clinical trials and epidemiological investigations.

For over three decades, the majority of IPF research has focused on pathogenesis and clinical trials of various therapeutic agents.2 Available evidence on pathogenic mechanisms suggests that pulmonary fibrosis results from a number of exposures that cause alveolar epithelial injury (eg, cigarette smoke, asbestos fibres, viruses) followed by activation of a complex set of abnormal, genetically determined biological pathways that result in fibrosis.3 Altering the course of the disease remains a challenge partly because of the complexity of the pathogenesis of IPF, and time needed for discovery and clinical trials of new agents to determine efficacy. Moreover, despite the growing number of clinical trials among patients with symptomatic IPF the results have been disappointing. Therefore, parallel research approaches are needed on interventions to prevent the occurrence (ie, primary prevention) or progression of subclinical pulmonary fibrosis (ie, secondary prevention).

For any disease, the ultimate goal is primary prevention through elimination of exposures that cause the disease. While epidemiological evidence suggests this may be a possible approach for IPF, there are also major challenges. Exposure to a number of environmental and occupational agents may cause IPF,4 and control of these exposures offers the potential to prevent the development of IPF. For example, based …
A Blood-Based Proteomic Classifier for the Molecular Characterization of Pulmonary Nodules
Authors: Xiao-jun Li, Clive Hayward, Pui-Yee Fong, Michel Dominguez, Stephen W. Hunsucker, Lik Wee Lee, Matthew McLean, Scott Law, Heather Butler, Michael Schirm, Olivier Gingras, Julie Lamontagne, Rene Allard, Daniel Chelsky, Nathan D. Price, Stephen Lam, Pierre P. Massion, Harvey Pass, William N. Rom, Anil Vachani, Kenneth C. Fang, Leroy Hood, Paul Kearney
Journal: Science Translational Medicine (2013)

Each year, millions of pulmonary nodules are discovered by computed tomography and subsequently biopsied. Because most of these nodules are benign, many patients undergo unnecessary and costly invasive procedures. We present a 13-protein blood-based classifier that differentiates malignant and benign nodules with high confidence, thereby providing a diagnostic tool to avoid invasive biopsy on benign nodules. Using a systems biology strategy, we identified 371 protein candidates and developed a multiple reaction monitoring (MRM) assay for each. The MRM assays were applied in a three-site discovery study (n = 143) on plasma samples from patients with benign and stage IA lung cancer matched for nodule size, age, gender, and clinical site, producing a 13-protein classifier. The classifier was validated on an independent set of plasma samples (n = 104), exhibiting a negative predictive value (NPV) of 90%. Validation performance on samples from a nondiscovery clinical site showed an NPV of 94%, indicating the general effectiveness of the classifier. A pathway analysis demonstrated that the classifier proteins are likely modulated by a few transcription regulators (NF2L2, AHR, MYC, and FOS) that are associated with lung cancer, lung inflammation, and oxidative stress networks. The classifier score was independent of patient nodule size, smoking history, and age, which are risk factors used for clinical management of pulmonary nodules. Thus, this molecular test provides a potential complementary tool to help physicians in lung cancer diagnosis.
The 23rd RSM Symposium on Cystic Fibrosis in Children and Adults
Authors: Tj David
Journal: Journal of the Royal Society of Medicine (2010)

This supplement arises out of the 23rd one-day meeting on cystic fibrosis (CF) organized by the Section of Paediatrics of the Royal Society of Medicine. The proceedings of the first 22 meetings, held between 1985 and 2008, were published as Supplements to the Journal of the Royal Society of Medicine.1–22 This most recent meeting, organized by Dr Ian Balfour-Lynn, was held at the Royal Society of Medicine in London on 3 November 2009. We are grateful to Forest Laboratories Europe for their support.

As in the past, the programme was designed to cover topical practical issues that face those who care for children and adults with CF. The audience comprised a mixture of paediatricians, adult chest physicians, physiotherapists, dietitians, CF specialist nurses, pharmacists, and community and primary care medical staff, reflecting the multidisciplinary approach to the modern management of CF.

Topics covered included how to minimize damage from the use of aminoglycosides (Alan Smyth), predicting mortality (Paul Aurora), the history of the development of the adult CF centre in Manchester (Kevin Webb), highlights from the 2009 North American CF Conference (Andy Jones and colleagues), selected CF papers published in 2009 (Ian Balfour-Lynn), a debate about the appropriateness or otherwise of intubation and artificial ventilation in CF (Ian Ketchell in favour, Mark Rosenthal against), and four presentations by trainees.

It is hoped that all these papers will be of immediate practical interest to all doctors who care for patients with CF. A further RSM CF meeting will be held on 2 November 2010.