tbuckley/cabot-search huggingface dataset:
Lung Adenocarcinoma with <i>EGFR</i> Amplification Has Distinct Clinicopathologic and Molecular Features in Never-Smokers
Authors: Lynette M. Sholl, Beow Y. Yeap, A. John Iafrate, Alison J. Holmes-Tisch, Yi-Ping Chou, Ming-Tsang Wu, Yih-Gang Goan, Li Su, Elisa Benedettini, Jian Yu, Massimo Loda, Pasi A. Jänne, David C. Christiani, Lucian R. Chirieac
Journal: Cancer Research (2009)

In a subset of lung adenocarcinomas, the epidermal growth factor receptor (EGFR) is activated by kinase domain mutations and/or gene amplification, but the interaction between the two types of abnormalities is complex and unclear. For this study, we selected 99 consecutive never-smoking women of East Asian origin with lung adenocarcinomas that were characterized by histologic subtype. We analyzed EGFR mutations by PCR-capillary sequencing, EGFR copy number abnormalities by fluorescence and chromogenic in situ hybridization and quantitative PCR, and EGFR expression by immunohistochemistry with both specific antibodies against exon 19 deletion-mutated EGFR and total EGFR. We compared molecular and clinicopathologic features with disease-free survival. Lung adenocarcinomas with EGFR amplification had significantly more EGFR exon 19 deletion mutations than adenocarcinomas with disomy, and low and high polysomy (100% versus 54%, P = 0.009). EGFR amplification occurred invariably on the mutated and not the wild-type allele (median mutated/wild-type ratios 14.0 versus 0.33, P = 0.003), was associated with solid histology (P = 0.008), and advanced clinical stage (P = 0.009). EGFR amplification was focally distributed in lung cancer specimens, mostly in regions with solid histology. Patients with EGFR amplification had a significantly worse outcome in univariate analysis (median disease-free survival, 16 versus 31 months, P = 0.01) and when adjusted for stage (P = 0.027). Lung adenocarcinomas with EGFR amplification have a unique association with exon 19 deletion mutations and show distinct clinicopathologic features associated with a significantly worsened prognosis. In these cases, EGFR amplification is heterogeneously distributed, mostly in areas with a solid histology.
Use of home non-invasive ventilation (NIV) in patients with ankylosing spondylitis (AS)
Authors: Martina Mason, Rebecca Chadwick, Ian Smith
Journal: European Respiratory Journal (2012)

Background 

Ventilatory impairment is a recognised extra-articular manifestation of AS. To our knowledge there are no published data describing home NIV in this condition.

Aims and objectives 

Retrospective assessment of home NIV in AS patients at a tertiary UK ventilatory support centre to determine i) indications for NIV, ii) physiological response to treatment and iii) compliance and survival.

Methods 

Case records of patients referred for consideration of NIV between 1993 and 2011 were retrospectively reviewed and information regarding the indication for NIV, demographics, co-morbidities, arterial blood gas analysis, pulmonary function, mean overnight oxygen saturation (SpO2), compliance and survival recorded.

Results 

The case notes of 18 patients (15 male, 64±9.2 yrs) were reviewed. Most commenced NIV in the context of acute respiratory decompensation (n=11; 61%). The most frequent indication for NIV was hypercapnia (PaCO2≥6.5, n=14; 78%). NIV led to a sustained decrease in PaCO2 from the baseline (p<0.05) and rise in the mean overnight oxygen saturation (p<0.05). Twelve patients have died (68%) with the median time to death from starting NIV of 31 months (range 1-98). The median duration of treatment was 33 months (range 1-99).

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Conclusion 

AS patients demonstrated good compliance with NIV, which was associated with a sustained improvement in physiological parameters.
Gastroesophageal Reflux in Infants
Authors: Rachel Rosen
Journal: JAMA Pediatrics (2013)

<h3>Importance</h3> Rarely have the best methods of diagnosis or the treatment of a disease engendered more controversy than gastroesophageal reflux (GER), a highly prevalent condition in infants. <h3>Objective</h3> To discuss the latest controversies in the diagnosis and treatment of GER in infants. <h3>Evidence Review</h3> All articles related to the diagnosis and treatment of GER were reviewed and, whenever possible, literature about infants was weighted with greater importance than literature about older children and adults. <h3>Findings</h3> Although as many as 60% of infants have signs of GER, the role of GER in causing disease is difficult to elucidate. Despite new diagnostic tools to detect acid and nonacid reflux, our understanding of the relationship between reflux events and symptoms is complex. Furthermore, acid suppression, the mainstay of therapy for GER, increases the burden of nonacid reflux, which is already much higher in infants than in older children and which may worsen symptoms. Therefore, more conservative therapies are recommended for symptomatic infants. <h3>Conclusions and Relevance</h3> Although GER is a common reason for visits to primary care providers and specialists, few data suggest that GER results in many of the symptoms to which it has been attributed. A strong shift away from acid-suppression therapy in infants has occurred because of the adverse effects, lack of efficacy, and increase of nonacid reflux burden relative to acid burden. Nonpharmacologic measures should be used whenever possible because most infant GER will resolve without intervention.
Epidemiology, Pathophysiology, and Prognostic Implications of Cystic Fibrosis–Related Diabetes
Authors: Antoinette Moran, Dorothy Becker, Samuel J. Casella, Peter A. Gottlieb, M. Sue Kirkman, Bruce C. Marshall, Bonnie Slovis
Journal: Diabetes Care (2010)

Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in subjects with cystic fibrosis (CF).A consensus conference on CFRD was cosponsored by the Cystic Fibrosis Foundation (CFF), the American Diabetes Association (ADA), and the Pediatric Endocrine Society (PES) in September 2009.The committee's evidencebased recommendations for clinical management of CFRD are published in this issue of Diabetes Care.This review article describes the epidemiology, pathogenesis, and prognostic implications of CFRD.
GATA1, Cytidine Deaminase, and the High Cure Rate of Down Syndrome Children With Acute Megakaryocytic Leukemia
Authors: Y. Ge, M. L. Stout, D. A. Tatman, T. L. Jensen, S. Buck, R. L. Thomas, Y. Ravindranath, L. H. Matherly, J. W. Taub
Journal: JNCI Journal of the National Cancer Institute (2005)

Down syndrome children with acute megakaryocytic leukemia (AMkL) have higher cure rates than non-Down syndrome acute myeloid leukemia (AML) patients treated with cytosine arabinoside (ara-C). Megakaryoblasts from Down syndrome AML patients are more sensitive in vitro to ara-C than cells from non-Down syndrome AML patients. Somatic mutations in the GATA1 transcription factor have been detected exclusively and almost uniformly in Down syndrome AMkL patients, suggesting a potential linkage to the chemotherapy sensitivity of Down syndrome megakaryoblasts. Stable transfection of wild-type GATA1 cDNA into the Down syndrome AMkL cell line CMK resulted in decreased (8- to 17-fold) ara-C sensitivity and a threefold-lower generation of the active ara-C metabolite ara-CTP compared with that for mock-transfected CMK cells. High intracellular levels of uridine arabinoside (ara-U) (an inactive ara-C catabolite generated by cytidine deaminase) and cytidine deaminase transcripts were detected in GATA1-transfected CMK sublines, whereas no ara-U was detected in mock-transfected cells. Cytidine deaminase transcripts were a median 5.1-fold ( P = .002) lower in Down syndrome megakaryoblasts (n = 16) than in blast cells from non-Down syndrome patients (n = 56). These results suggest that GATA1 transcriptionally upregulates cytidine deaminase and that the presence or absence of GATA1 mutations in AML blasts likely confers differences in ara-C sensitivities due to effects on cytidine deaminase gene expression, which, in turn, contributes to the high cure rate of Down syndrome AMkL patients.
Curcumin Inhibits Tumor Growth and Angiogenesis in Ovarian Carcinoma by Targeting the Nuclear Factor-κB Pathway
Authors: Yvonne G. Lin, Ajaikumar B. Kunnumakkara, Asha Nair, William M. Merritt, Liz Y. Han, Guillermo N. Armaiz-Pena, Aparna A. Kamat, Whitney A. Spannuth, David M. Gershenson, Susan K. Lutgendorf, Bharat B. Aggarwal, Anil K. Sood
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Curcumin, a component of turmeric, has been shown to suppress inflammation and angiogenesis largely by inhibiting the transcription factor nuclear factor-κB (NF-κB). This study evaluates the effects of curcumin on ovarian cancer growth using an orthotopic murine model of ovarian cancer. Experimental Design: In vitro and in vivo experiments of curcumin with and without docetaxel were done using human ovarian cancer cell lines SKOV3ip1, HeyA8, and HeyA8-MDR in athymic mice. NF-κB modulation was ascertained using electrophoretic mobility shift assay. Evaluation of angiogenic cytokines, cellular proliferation (proliferating cell nuclear antigen), angiogenesis (CD31), and apoptosis (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling) was done using immunohistochemical analyses. Results: Curcumin inhibited inducible NF-κB activation and suppressed proliferation in vitro. In vivo dose-finding experiments revealed that 500 mg/kg orally was the optimal dose needed to suppress NF-κB and signal transducers and activators of transcription 3 activation and decrease angiogenic cytokine expression. In the SKOV3ip1 and HeyA8 in vivo models, curcumin alone resulted in 49% (P = 0.08) and 55% (P = 0.01) reductions in mean tumor growth compared with controls, whereas when combined with docetaxel elicited 96% (P &amp;lt; 0.001) and 77% reductions in mean tumor growth compared with controls. In mice with multidrug-resistant HeyA8-MDR tumors, treatment with curcumin alone and combined with docetaxel resulted in significant 47% and 58% reductions in tumor growth, respectively (P = 0.05). In SKOV3ip1 and HeyA8 tumors, curcumin alone and with docetaxel decreased both proliferation (P &amp;lt; 0.001) and microvessel density (P &amp;lt; 0.001) and increased tumor cell apoptosis (P &amp;lt; 0.05). Conclusions: Based on significant efficacy in preclinical models, curcumin-based therapies may be attractive in patients with ovarian carcinoma.
Effects of Different Insulin Regimes on Postprandial Myocardial Perfusion Defects in Type 2 Diabetic Patients
Authors: Roldano Scognamiglio, Christian Negut, Saula Vigili de Kreutzenberg, Antonio Tiengo, Angelo Avogaro
Journal: Diabetes Care (2006)

Postprandial glycemia is an independent risk factor for cardiovascular disease that is more powerful than fasting glycemia and determines myocardial perfusion defects in type 2 diabetes. We examined the efficacy of two different insulin regimes (regular insulin and insulin analog) in controlling postprandial hyperglycemia and in preventing myocardial perfusion abnormalities.A total of 20 consecutive type 2 diabetic patients and 20 control subjects were enrolled in this randomized, three-way, cross-over, placebo-controlled study. Myocardial perfusion was assessed by myocardial contrast echocardiography (MCE) in fasting and postprandial (120 min) state.Insulin analog was associated with lower, but not statistically significant, postprandial glycemia than regular insulin (glucose increase: 116 +/- 8 vs. 136 +/- 5%, P = NS). However, the area under the curve following insulin analog was significantly lower than regular insulin (18,354 +/- 702 vs. 20,757 +/- 738 mg per 120 min, P = 0.032). Fasting myocardial flow velocity (beta), myocardial blood volume (MBV), and myocardial blood flow (MBF) did not differ between control and type 2 diabetic subjects. Postprandial beta (0.67 +/- 0.24 vs. 0.92 +/- 0.25, P < 0.01), MBV (8.4 +/- 2 vs. 10.9 +/- 1.2, P < 0.01), and MBF (5.6 +/- 2 vs. 9.9 +/- 2.8, P < 0.01) increased significantly in control subjects. In type 2 diabetes, during placebo in the postprandial state, beta increased (0.65 +/- 0.27 vs. 0.89 +/- 0.24, P < 0.01), while MBV (8.34 +/- 1.2 vs. 4.3 +/- 1.3, P < 0.01) and MBF (5.4 +/- 1.5 vs. 3.4 +/- 0.9, P < 0.01) decreased. Similar changes in MCE variables were observed after regular insulin: beta increased (0.65 +/- 0.22 vs. 0.92 +/- 0.12, P < 0.01) and MBV (8.2 +/- 2 vs. 5.2 +/- 1.16, P < 0.01) and MBF (5.4 +/- 1.9 vs. 4.2 +/- 0.86, P < 0.01) were reduced. After insulin analog, postprandial beta (0.66 +/- 0.18 vs. 0.9 +/- 0.18, P < 0.01), MBV (8.2 +/- 1.6 vs. 9.6 +/- 1.2, P < 0.01), and MBF (5.4 +/- 2 vs. 7.2 +/- 1.9, P < 0.01) increased. Values of postprandial MBV and MBF were higher after insulin analog than regular insulin treatment.Insulin analog partially reversed myocardial perfusion abnormalities observed in postprandial state by improving glucose control.
The two faces of Alba: the evolutionary connection between proteins participating in chromatin structure and RNA metabolism
Authors: L Aravind, Lakshminarayan M Iyer, Vivek Anantharaman
Journal: Genome biology (2003)

There is considerable heterogeneity in the phyletic patterns of major chromosomal DNA-binding proteins in archaea. Alba is a well-characterized chromosomal protein from the crenarchaeal genus Sulfolobus. While Alba has been detected in most archaea and some eukaryotic taxa, its exact functions in these taxa are not clear. Here we use comparative genomics and sequence profile analysis to predict potential alternative functions of the Alba proteins.Using sequence-profile searches, we were able to unify the Alba proteins with RNase P/MRP subunit Rpp20/Pop7, human RNase P subunit Rpp25, and the ciliate Mdp2 protein, which is implicated in macronuclear development. The Alba superfamily contains two eukaryote-specific families and one archaeal family. We present different lines of evidence to show that both eukaryotic families perform functions related to RNA metabolism. Several members of one of the eukaryotic families, typified by Mdp2, are combined in the same polypeptide with RNA-binding RGG repeats. We also investigated the relationships of the unified Alba superfamily within the ancient RNA-binding IF3-C fold, and show that it is most closely related to other RNA-binding members of this fold, such as the YhbY and IF3-C superfamilies. Based on phyletic patterns and the principle of phylogenetic bracketing, we predict that at least some of the archaeal members may also possess a role in RNA metabolism.The Alba superfamily proteins appear to have originated as RNA-binding proteins which formed various ribonucleoprotein complexes, probably including RNase P. It was recruited as a chromosomal protein possibly only within the crenarchaeal lineage. The evolutionary connections reported here suggest how a diversity of functions based on a common biochemical basis emerged in proteins of the Alba superfamily.
Angiogenic Potential of Prostate Carcinoma Cells Overexpressing bcl-2
Authors: A Fernandez, T Udagawa, C Schwesinger, W Beecken, E Achilles-Gerte, T McDonnell, R D'Amato
Journal: JNCI Journal of the National Cancer Institute (2001)

Tumors commonly outgrow their blood supply, thereby creating hypoxic conditions, which induce apoptosis and increase expression of angiogenic growth factors. The bcl-2 oncogene inhibits apoptosis induced by a variety of stimuli, including hypoxia. On the basis of bcl-2's role in regulating apoptosis in response to hypoxia, we hypothesized that this oncogene might affect other responses to hypoxia, such as the expression of angiogenic growth factors.Three prostate carcinoma cell lines, PC3, LNCaP, and DU-145, were stably transfected with a bcl-2 complementary DNA (cDNA), and transfectants were analyzed in vitro for the expression of angiogenic factors after exposure to either normoxic (19% O(2)) or hypoxic (1% O(2)) conditions. The in vivo angiogenic potential of the transfected cells was determined by analyzing vessel density in xenografts derived from them and by measuring the ability of these xenografts to induce neovascularization when implanted in mouse corneal micropockets. Statistical tests were two-sided.When exposed to hypoxic conditions, prostate carcinoma cells overexpressing bcl-2 expressed statistically significantly higher levels of vascular endothelial growth factor (VEGF), an angiogenic factor, than control-transfected cells (P = .001 for PC3, P = .04 for DU-145 after 48 hours). This effect of bcl-2 was independent of its antiapoptotic activity because increased expression of VEGF was detected in PC3 cells overexpressing bcl-2 even though PC3 cells are inherently resistant to hypoxia-induced apoptosis. In vivo, xenograft tumors derived from the bcl-2-overexpressing prostate carcinoma cell lines displayed increased angiogenic potential and grew more aggressively than tumors derived from the control cell lines (P =.03 for PC3). Treatment of bcl-2-overexpressing and control tumors with the antiangiogenic drug TNP-470 neutralized the aggressive angiogenesis in bcl-2-overexpressing tumors (P = .04 for PC3, P = .004 for DU-145) and the moderate angiogenesis in control tumors (P = .01 for PC3, P = .05 for DU-145), resulting in similar growth rates for both tumors.bcl-2 may play a dual role in tumorigenesis by suppressing apoptosis and by stimulating angiogenesis.
Mapping the Risk of Mesothelioma Due to Neighborhood Asbestos Exposure
Authors: Norio Kurumatani, Shinji Kumagai
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Little is known about neighborhood exposure to asbestos and mesothelioma risk among residents around an industrial source of asbestos.To investigate the magnitude of the risk among residents by asbestos exposure levels and to determine the range of the area affected by asbestos.We calculated standardized mortality ratios of mesothelioma from 1995 to 2006 among the estimated population at risk that lived around a former large asbestos cement pipe plant in Amagasaki City, Japan, between 1957 and 1975, the time when the plant had used crocidolite and chrysotile. The distance between the plant and homes and relative asbestos concentrations obtained by diffusion equations involving meteorological conditions were used to determine asbestos exposure levels among residents.We identified 73 mesothelioma deaths of 35 men and 38 women who had no occupational exposure to asbestos. Among persons who had lived within a 300-m radius of the plant, the standardized mortality ratio of mesothelioma was 13.9 (95% confidence interval, 5.6-28.7) for men and 41.1 (95% confidence interval, 15.2-90.1) for women. When the study area was divided into five regions by relative asbestos concentration, standardized mortality ratios of mesothelioma declined, for both sexes, in a linear dose-dependent manner with concentration. The regions with a significantly elevated standardized mortality ratio reached 2,200 m from the plant in the same direction in which the wind predominantly blew.Neighborhood exposure to asbestos can pose a serious risk to residents across a wide area.
The IL23 axis plays a key role in the pathogenesis of IBD
Authors: D. McGovern, F. Powrie
Journal: Gut (2007)

Exciting new results from a genetic study in humans and functional studies in mice have pinpointed interleukin 23 (IL23) and its receptor as a key pathway in the pathogenesis of inflammatory bowel disease (IBD). These findings reveal a hitherto unappreciated role for the IL23 axis in intestinal inflammation and may open new avenues for development of therapeutic strategies in IBD.
Progranulin regulates neuronal outgrowth independent of Sortilin
Authors: Jennifer Gass, Wing C Lee, Casey Cook, Nicole Finch, Caroline Stetler, Karen Jansen-West, Jada Lewis, Christopher D Link, Rosa Rademakers, Anders Nykjær, Leonard Petrucelli
Journal: Molecular Neurodegeneration (2012)

Abstract Background Progranulin (PGRN), a widely secreted growth factor, is involved in multiple biological functions, and mutations located within the PGRN gene ( GRN ) are a major cause of frontotemporal lobar degeneration with TDP-43-positive inclusions (FLTD-TDP). In light of recent reports suggesting PGRN functions as a protective neurotrophic factor and that sortilin (SORT1) is a neuronal receptor for PGRN, we used a Sort1-deficient ( Sort1 −/− ) murine primary hippocampal neuron model to investigate whether PGRN’s neurotrophic effects are dependent on SORT1. We sought to elucidate this relationship to determine what role SORT1, as a regulator of PGRN levels, plays in modulating PGRN’s neurotrophic effects. Results As the first group to evaluate the effect of PGRN loss in Grn knockout primary neuronal cultures, we show neurite outgrowth and branching are significantly decreased in Grn −/− neurons compared to wild-type (WT) neurons. More importantly, we also demonstrate that PGRN overexpression can rescue this phenotype. However, the recovery in outgrowth is not observed following treatment with recombinant PGRN harboring missense mutations p.C139R, p.P248L or p.R432C, indicating that these mutations adversely affect the neurotrophic properties of PGRN. In addition, we also present evidence that cleavage of full-length PGRN into granulin peptides is required for increased neuronal outgrowth, suggesting that the neurotrophic functions of PGRN are contained within certain granulins. To further characterize the mechanism by which PGRN impacts neuronal morphology, we assessed the involvement of SORT1. We demonstrate that PGRN induced-outgrowth occurs in the absence of SORT1 in Sort1 −/− cultures. Conclusion We demonstrate that loss of PGRN impairs proper neurite outgrowth and branching, and that exogenous PGRN alleviates this impairment. Furthermore, we determined that exogenous PGRN induces outgrowth independent of SORT1, suggesting another receptor(s) is involved in PGRN induced neuronal outgrowth.
Polymorphisms in Chlamydia trachomatis tryptophan synthase genes differentiate between genital and ocular isolates
Authors: Harlan D. Caldwell, Heidi Wood, Debbie Crane, Robin Bailey, Robert B. Jones, David Mabey, Ian Maclean, Zeena Mohammed, Rosanna Peeling, Christine Roshick, Julius Schachter, Anthony W. Solomon, Walter E. Stamm, Robert J. Suchland, Lacey Taylor, Sheila K. West, Tom C. Quinn, Robert J. Belland, Grant McClarty
Journal: Journal of Clinical Investigation (2003)

We previously reported that laboratory reference strains of Chlamydia trachomatis differing in infection organotropism correlated with inactivating mutations in the pathogen's tryptophan synthase (trpBA) genes. Here, we have applied functional genomics to extend this work and find that the paradigm established for reference serovars also applies to clinical isolates — specifically, all ocular trachoma isolates tested have inactivating mutations in the synthase, whereas all genital isolates encode a functional enzyme. Moreover, functional enzyme activity was directly correlated to IFN-γ resistance through an indole rescue mechanism. Hence, a strong selective pressure exists for genital strains to maintain a functional synthase capable of using indole for tryptophan biosynthesis. The fact that ocular serovars (serovar B) isolated from the genital tract were found to possess a functional synthase provided further persuasive evidence of this association. These results argue that there is an important host-parasite relationship between chlamydial genital strains and the human host that determines organotropism of infection and the pathophysiology of disease. We speculate that this relationship involves the production of indole by components of the vaginal microbial flora, allowing chlamydiae to escape IFN-γ–mediated eradication and thus establish persistent infection.