tbuckley/cabot-search huggingface dataset:
Obligate Progression Precedes Lung Adenocarcinoma Dissemination
Authors: Deborah R. Caswell, Chen-Hua Chuang, Dian Yang, Shin-Heng Chiou, Shashank Cheemalavagu, Caroline Kim-Kiselak, Andrew Connolly, Monte M. Winslow
Journal: Cancer Discovery (2014)

Abstract Despite its clinical importance, very little is known about the natural history and molecular underpinnings of lung cancer dissemination and metastasis. Here, we used a genetically engineered mouse model of metastatic lung adenocarcinoma in which cancer cells are fluorescently marked to determine whether dissemination is an inherent ability or a major acquired phenotype during lung adenocarcinoma metastasis. We find very little evidence for dissemination from oncogenic KRAS-driven hyperplasias or most adenocarcinomas. p53 loss is insufficient to drive dissemination but rather enables rare cancer cells in a small fraction of primary adenocarcinomas to gain alterations that drive dissemination. Molecular characterization of disseminated tumor cells indicates that downregulation of the transcription factor Nkx2-1 precedes dissemination. Finally, we show that metastatic primary tumors possess a highly proliferative subpopulation of cells with characteristics matching those of disseminating cells. We propose that dissemination is a major hurdle during the natural course of lung adenocarcinoma metastasis. Significance: Because of its aggressively metastatic nature, lung cancer is the top cancer killer of both men and women in the United States. We show that, unlike in other cancer types, lung cancer dissemination is a major initial barrier to metastasis. Our findings provide insight into the effect of p53 deficiency and downregulation of Nkx2-1 during lung adenocarcinoma progression. Cancer Discov; 4(7); 781–9. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 745
Hypermethylation of the GATA Genes in Lung Cancer
Authors: Mingzhou Guo, Yoshimitsu Akiyama, Michael G. House, Craig M. Hooker, Elizabeth Heath, Edward Gabrielson, Stephen C. Yang, Yu Han, Stephen B. Baylin, James G. Herman, Malcolm V. Brock
Journal: Clinical Cancer Research (2004)

Abstract Purpose: In lung cancer, DNA hypermethylation is known to be a common event. Experimental Design: Gene expression and methylation status of GATA-4, GATA-5, and GATA-6 were analyzed with cell lines and primary human lung cancers. Methylation profiles of primary lung cancers were analyzed and correlated with clinical as well as histopathological data. Results: Complete methylation was detected by methylation-specific PCR for both GATA-4 and GATA-5 in four cell lines (H358, DMS-53, A549, and H1299), all of which had no expression by reverse transcription-PCR analysis. Demethylation with 5-aza-2′deoxycytidine restored expression in each case. GATA-6 was ubiquitously expressed in all of the six cell lines. GATA-4 bisulfite sequencing revealed complete methylation of the GATA-4 promoter in H358 cells, correlating well with its lack of expression at the mRNA level. Only a few CpG sites showed methylation by bisulfite sequencing within the GATA-4 promoter in a cell line that expressed the gene. In 63 cases of primary lung cancers, GATA-4 and GATA-5 promoter methylation was detected in (42 of 63) 67% and (26 of 63) 41%, respectively. GATA-6 remained unmethylated both in cell lines and primary tumors. Six autopsy specimens of normal lung tissue showed no aberrant promoter hypermethylation for the GATA genes. Correlation of concomitant GATA-4 and GATA-5 methylation with clinicopathological parameters only found a statistically significant increase in methylation frequency with increasing patient age (P &amp;lt; 0.001). Conclusions: These epigenetic changes in the GATA genes in lung cancer are tumor-specific, relate to the loss of GATA gene expression, and occur increasingly in the elderly.
Efficacy and safety of NVA237<i>versus</i>placebo and tiotropium in patients with COPD: the GLOW2 study
Authors: Edward Kerwin, Jacques Hébert, Nicola Gallagher, Carmen Martin, Tim Overend, Vijay K.T. Alagappan, Yimeng Lu, Donald Banerji
Journal: European Respiratory Journal (2012)

NVA237 (glycopyrronium bromide) is a once-daily long-acting muscarinic antagonist (LAMA) in development for chronic obstructive pulmonary disease (COPD). The GLycopyrronium bromide in COPD airWays clinical Study 2 (GLOW2) evaluated the efficacy and safety of NVA237 in moderate-to-severe COPD over 52 weeks. Patients were randomised 2:1:1 to NVA237 50 μg, placebo or open-label tiotropium 18 μg for 52 weeks. Primary end-point was trough forced expiratory volume in 1 s (FEV 1 ) at 12 weeks. 1,066 patients were randomised, 810 completed the study. At week 12, trough FEV 1 increased significantly by 97 mL with NVA237 (95% CI 64.6–130.2; p&lt;0.001) and 83 mL with tiotropium (95% CI 45.6–121.4; p&lt;0.001). Compared with placebo, NVA237 produced significant improvements in dyspnoea (Transition Dyspnoea Index at week 26; p=0.002) and health status (St George's Respiratory Questionnaire at week 52; p&lt;0.001). NVA237 significantly reduced the risk of moderate-to-severe COPD exacerbations by 34% (p=0.001) and the use of rescue medication (p=0.039), versus placebo. NVA237-placebo and tiotropium-placebo differences were comparable for all outcomes. Safety profiles were similar across groups. NVA237 50 μg provided significant improvements in lung function, dyspnoea, health status, exacerbations and rescue medication use, versus placebo, and was comparable to tiotropium. NVA237 can potentially be an alternative choice of LAMA for COPD patients.
Expression of EphA2 is Prognostic of Disease-Free Interval and Overall Survival in Surgically Treated Patients with Renal Cell Carcinoma
Authors: Christopher J. Herrem, Tomohide Tatsumi, Kathleen S. Olson, Keisuke Shirai, James H. Finke, Ronald M. Bukowski, Ming Zhou, Amy L. Richmond, Ithaar Derweesh, Michael S. Kinch, Walter J. Storkus
Journal: Clinical Cancer Research (2005)

Abstract Whereas normally expressed at sites of cell-to-cell contact in adult epithelial tissues, recent studies have shown that the receptor tyrosine kinase EphA2 is overexpressed in numerous epithelial-type carcinomas, with the greatest level of EphA2 expression observed in metastatic lesions. In the current study, we have assessed EphA2 expression in archived renal cell carcinoma (RCC) tissues as it relates to patient disease course. Using specific anti-EphA2 monoclonal antibody 208 and immunohistochemistry, we evaluated EphA2 protein expression levels in RCC specimens surgically resected from 34 patients (including 30 conventional clear-cell RCC, 3 papillary, and 1 chromophobic RCC cases) resulting in clinical cures. Regardless of histopathologic subtype, RCC lesions expressing higher levels of EphA2 tended to be of a higher grade (P &amp;lt; 0.05) and larger (P = 0.093), more-highly-vascularized tumors (P = 0.005). Perhaps most notable, the degree of EphA2 overexpression (versus normal matched autologous kidney tissue) seemed predictive of short-term (&amp;lt;1 year) versus longer-term (≥1 year) disease-free interval (P &amp;lt; 0.001) and of overall survival (P &amp;lt; 0.001) among the RCC patients evaluated. These data suggest that EphA2 expression level may serve as a useful prognostic tool in the clinical management of patients who have been successfully treated with surgery, but who are at greater risk for accelerated disease recurrence and who have a poorer prognosis.
Lung function decline in asthma
Authors: M. R. Sears
Journal: European Respiratory Journal (2007)

Progressive decline in lung function in asthma has been well recognised but not fully explained. For example, in a Danish population study (the Copenhagen City Heart Study), three measurements of forced expiratory volume in one second (FEV1) were made over 15 yrs in 17,506 subjects, including 1,095 with asthma 1. Asthmatics showed a decline in FEV1 of 38 mL·yr−1 compared with 22 mL·yr−1 in normal individuals. However, accelerated decline is not invariable. Many asthmatics retain normal or close to normal lung function throughout life, showing reversibility from acute worsenings and return to previous function. Conversely, some patients develop “irreversible” asthma, as seen in population-based studies 2 and in specialist-treated patients whose obstruction persisted despite bronchodilators and oral corticosteroids 3. In the latter patients, lung function decreased with age, and with duration and severity of asthma. Progressive loss of function can be inexorable despite aggressive therapy, resulting in end-stage respiratory failure that occasionally justifies lung transplantation 4.

Among 228 adults followed up after 21–33 yrs in a clinic in Groningen, the Netherlands, 16% had irreversible airway obstruction, which was defined as FEV1 <80% predicted with reversibility <9% pred 5. Irreversible disease was predicted by a lower FEV1, less reversibility and less (rather than greater, as one might have expected) airway hyperresponsiveness (AHR) at initial screening. Patients using regular treatment developed irreversible obstruction less frequently. Loss of lung function has serious consequences. In 89 asthmatics followed over 17 yrs in Perth, Australia, lower lung function, but not initial symptom severity, predicted mortality 6. The risk of death was higher with decreased FEV1 and increased FEV1 variability, age and treatment requirements.

Both the Melbourne (Australia) 7 and Dunedin (New Zealand) 8 longitudinal studies of the natural history of asthma show that impaired lung function …
Intestinal permeability in coeliac disease: the response to gluten withdrawal and single-dose gluten challenge.
Authors: I Hamilton, I Cobden, J Rothwell, A T Axon
Journal: Gut (1982)

Intestinal permeability has been studied in 21 patients with coeliac disease in relapse and after gluten withdrawal using an oral test of intestinal permeability based on the simultaneous oral administration of two probe molecules. The increased absorption of the larger molecule (cellobiose) and the decreased absorption of the smaller (mannitol) found in untreated coeliac disease both returned to normal within five months of starting treatment, the abnormality in cellobiose absorption correcting more rapidly than that of mannitol. After exposure to a single oral dose of gluten, the intestinal permeability of six patients with treated coeliac disease became transiently abnormal with an increased absorption of cellobiose, returning to normal within one week. The possible structural and functional implications of these findings are discussed. The cellobiose/mannitol ratio appears to be of value in assessing the response to gluten withdrawal in coeliac disease, and also in monitoring patients who are already established on a gluten free diet by detecting dietary lapses and 'non-responding coeliac disease'. It may also offer an alternative to jejunal biopsy in patients subjected to gluten challenge.
990 USEFULNESS OF DIFFUSION WEIGHTED IMAGES FROM MAGNETIC RESONANCE IMAGING IN THE DETECTION OF HYPERVASCULAR HEPATOCELLULAR CARCINOMA
Authors: Y. Mori, H. Tamai, N. Shingaki, K. Moribata, T. Shiraki, H. Deguchi, K. Ueda, I. Inoue, T. Maekita, M. Iguchi, M. Ichinose
Journal: Journal of Hepatology (2011)
DNA ploidy in early gastric carcinoma (T1): a flow cytometric study of 100 European cases.
Authors: M J Brito, M I Filipe, G T Williams, H Thompson, M G Ormerod, J Titley
Journal: Gut (1993)

DNA ploidy of 100 early gastric carcinomas (T1) was analysed by flow cytometry on archival material from five European centres and was correlated to morphological features and clinical behaviour. Tumours were classified according to the macroscopic appearance, histological type, and growth pattern. Aneuploidy was observed in 39% of tumours. Aneuploidy was more frequent in submucosal than in mucosal tumours (p = 0.04), in raised than in flat or ulcerated lesions (p = 0.001), and in the intestinal histological than in the diffuse types (p = 0.016). The presence of lymph node metastasis in 10 cases had no obvious relation to DNA ploidy. Five related deaths occurred during the follow up (6 months--16 years) of 84 patients. These results are similar to those reported in a large Japanese series suggesting no major differences between the two populations. Although follow up data were insufficient to relate DNA ploidy to tumour behaviour in this study, the Japanese experience shows that particular attention should be paid to early direction and complete surgical excision of raised intestinal type T1 carcinomas that have a Pen A growth pattern and are aneuploid.
Transporting silence: Design of carriers for siRNA to angiogenic endothelium
Authors: Raymond M. Schiffelers, Archibald J. Mixson, Aslam M. Ansari, Marcel H.A.M. Fens, Quingquan Tang, Qin Zhou, Jun Xu, Grietje Molema, Patrick Y. Lu, Puthupparampil V. Scaria, Gert Storm, Martin C. Woodle
Journal: Journal of Controlled Release (2005)
Identification of a Novel c-Myc Protein Interactor, JPO2, with Transforming Activity in Medulloblastoma Cells
Authors: Annie Huang, Cynthia S.W. Ho, Romina Ponzielli, Dalia Barsyte-Lovejoy, Eric Bouffet, Daniel Picard, Cynthia E. Hawkins, Linda Z. Penn
Journal: Cancer Research (2005)

Abstract c-myc oncogene activation is critical in the pathogenesis of a spectrum of human malignancies. The c-Myc NH2-terminal domain (MycNTD) is essential for cellular transformation, and mediates critical protein interactions that modulate c-Myc oncogenic properties. In medulloblastoma, the most common malignant pediatric brain tumor, deregulated c-myc expression is linked with poorer disease phenotypes and outcomes. The biological basis for these associations is, however, not well understood. To better understand mechanisms underlying Myc-mediated transformation of medulloblastoma, we sought to identify novel MycNTD protein interactors from a medulloblastoma cell line library using a unique two-hybrid system. We identified a novel MycNTD binding protein, JPO2, which shows nuclear colocalization with c-Myc, and interacts with c-Myc both in vitro and in mammalian cells. In Rat1a transformation assays, JPO2 potentiates c-Myc transforming activity, and can complement a transformation-defective Myc mutant. Immunohistochemical studies indicate tumor-specific JPO2 expression in human medulloblastoma, and an association of JPO2 expression with metastatic tumors. Significantly, JPO2 expression induces colony formation in UW228, a medulloblastoma cell line, whereas RNAi-mediated JPO2 knockdown impairs colony formation in UW228, and in Myc-transformed UW228 cells. These data provide evidence for biochemical and functional interaction between c-Myc and JPO2 in medulloblastoma transformation. JPO2 is closely related to JPO1, a Myc transcriptional target with transforming activity. As tumor-specific JPO1 expression in human and murine medulloblastoma has also been reported; these collective observations suggest important functional links between the novel JPO protein family and c-Myc in medulloblastoma transformation.
Proteomic and Metabolomic Analysis of Smooth Muscle Cells Derived From the Arterial Media and Adventitial Progenitors of Apolipoprotein E–Deficient Mice
Authors: Manuel Mayr, Anna Zampetaki, Anissa Sidibe, Ursula Mayr, Xiaoke Yin, Ayesha I. De Souza, Yuen-Li Chung, Basetti Madhu, Paul H. Quax, Yanhua Hu, John R. Griffiths, Qingbo Xu
Journal: Circulation Research (2008)

We have recently demonstrated that stem cell antigen 1-positive (Sca-1(+)) progenitors exist in the vascular adventitia of apolipoprotein E-deficient (apoE(-/-)) mice and contribute to smooth muscle cell (SMC) accumulation in vein graft atherosclerosis. Using a combined proteomic and metabolomic approach, we now characterize these local progenitors, which participate in the formation of native atherosclerotic lesions in chow-fed apoE(-/-) mice. Unlike Sca-1(+) progenitors from embryonic stem cells, the resident Sca-1(+) stem cell population from the vasculature acquired a mature aortic SMC phenotype after platelet-derived growth factor-BB stimulation. It shared proteomic and metabolomic characteristics of apoE(-/-) SMCs, which were clearly distinct from wild-type SMCs under normoxic and hypoxic conditions. Among the differentially expressed proteins were key enzymes in glucose metabolism, resulting in faster glucose consumption and a compensatory reduction in baseline interleukin-6 secretion. The latter was associated with a marked upregulation of insulin-like growth factor binding proteins (IGFBPs) 3 and 6. Notably, reconstitution of interleukin-6 to levels measured in the conditioned medium of wild-type SMCs attenuated the elevated IGFBP expression in apoE(-/-) SMCs and their vascular progenitors. This coregulation of apoE, interleukin-6, and IGFBPs was replicated in wild-type SMCs from hypercholesterolemic mice and confirmed by silencing apoE expression in SMCs from normocholesterolemic mice. In summary, we provide evidence that Sca-1(+) progenitors contribute to native atherosclerosis in apoE(-/-) mice, that apoE deficiency and hypercholesterolemia alter progenitor cell behavior, and that inflammatory cytokines such as interleukin-6 act as metabolic regulators in SMCs of hyperlipidemic mice.
Subcortical Correlates of Craving in Recently Abstinent Alcoholic Patients
Authors: F Schneider, U Habel, M Wagner, P Franke, J B Salloum, N J Shah, I Toni, C Sulzbach, K Hönig, W Maier, W Gaebel, K Zilles
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: This study investigated functional cerebral correlates of craving in alcoholic patients and examined the state/trait characteristics of the regional cerebral network implicated in craving. METHOD: Functional magnetic resonance imaging (fMRI) was used to map cerebral response elicited by ethanol odor in 10 male patients with alcohol dependence who had undergone detoxification and 10 matched nonpatients. After 3 weeks, during which the patients underwent standardized behavioral therapy with psychopharmacological intervention, all subjects were studied a second time with fMRI to evaluate the effects of therapy on the functional cerebral correlates of craving. RESULTS: In the alcoholic patients, cue-induced craving before treatment elicited activation primarily in the subcortical-limbic region of the right amygdala/hippocampal area and in the cerebellum. After treatment, activation was found in the superior temporal sulcus, while subcortical or cerebellar participation was no longer present. Comparison subjects showed no comparable amygdala or cerebellar activation during ethanol stimulation and demonstrated no change in activation pattern between measurements. CONCLUSIONS: This investigation points to state-dependent neurobiological correlates of cue-induced craving in alcoholic patients and suggests that these correlates can be influenced by therapeutic interventions. The presence of emotional aspects of craving is suggested by amygdala activation.
LINE dancing in the human genome: transposable elements and disease
Authors: Victoria P Belancio, Prescott L Deininger, Astrid M Roy-Engel
Journal: Genome Medicine (2009)

Transposable elements (TEs) have been consistently underestimated in their contribution to genetic instability and human disease. TEs can cause human disease by creating insertional mutations in genes, and also contributing to genetic instability through non-allelic homologous recombination and introduction of sequences that evolve into various cis-acting signals that alter gene expression. Other outcomes of TE activity, such as their potential to cause DNA double-strand breaks or to modulate the epigenetic state of chromosomes, are less fully characterized. The currently active human transposable elements are members of the non-LTR retroelement families, LINE-1, Alu (SINE), and SVA. The impact of germline insertional mutagenesis by TEs is well established, whereas the rate of post-insertional TE-mediated germline mutations and all forms of somatic mutations remain less well quantified. The number of human diseases discovered to be associated with non-allelic homologous recombination between TEs, and particularly between Alu elements, is growing at an unprecedented rate. Improvement in the technology for detection of such events, as well as the mounting interest in the research and medical communities in resolving the underlying causes of the human diseases with unknown etiology, explain this increase. Here, we focus on the most recent advances in understanding of the impact of the active human TEs on the stability of the human genome and its relevance to human disease.
A Randomized Controlled Trial of a Smoking Cessation Intervention Among People With a Psychotic Disorder
Authors: Amanda Baker, Robyn Richmond, Melanie Haile, Terry J Lewin, Vaughan J Carr, Rachel L Taylor, Sylvia Jansons, Kay Wilhelm
Journal: American Journal of Psychiatry (2006)

Despite extremely high rates of smoking among individuals with psychotic disorders and the associated financial and health costs, few studies have investigated the efficacy of smoking cessation interventions among this group. The purpose of this study was to compare an integrated psychological and nicotine replacement therapy intervention for people with a psychotic disorder with routine care alone.The authors recruited 298 regular smokers with a psychotic disorder residing in the community and randomly assigned them to a routine care comparison condition (N=151) or an eight-session, individually administered smoking cessation intervention (N=147), which consisted of nicotine replacement therapy, motivational interviewing, and cognitive behavior therapy. Outcome variables included continuous and point-prevalence abstinence rates, smoking reduction status, and changes in symptoms and functioning.While there were no overall differences between the treatment group and comparison group in abstinence rates, a significantly higher proportion of smokers who completed all treatment sessions stopped smoking at each of the follow-up occasions (point-prevalence rates: 3 months, 30.0% versus 6.0%; 6 months, 18.6% versus 4.0%; and 12 months, 18.6% versus 6.6%). Smokers who completed all treatment sessions were also more likely to have achieved continuous abstinence at 3 months (21.4% versus 4.0%). There was a strong dose-response relationship between treatment session attendance and smoking reduction status, with one-half of those who completed the intervention program achieving a 50% or greater reduction in daily cigarette consumption across the follow-ups, relative to less than one-fifth of the comparison subjects. There was no evidence of any associated deterioration in symptoms or functioning.These findings demonstrate the utility of a nicotine replacement therapy plus motivational interviewing/cognitive behavior therapy smoking cessation intervention among individuals with a psychotic disorder. Further development of more efficacious interventions is required for those who do not respond to existing interventions.