tbuckley/cabot-search huggingface dataset:
HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL
Authors: Anita Pathil, Sorin Armeanu, Sascha Venturelli, Paolo Mascagni, Thomas S. Weiss, Michael Gregor, Ulrich M. Lauer, Michael Bitzer
Journal: Hepatology (2006)

Hepatocellular carcinoma (HCC) displays a striking resistance to chemotherapeutic drugs or innovative tumor cell apoptosis–inducing agents such as tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Recently, we found 2 histone deacetylase inhibitors (HDAC-I), valproic acid and ITF2357, exhibiting inherent therapeutic activity against HCC. In TRAIL-sensitive cancer cells, the mechanism of HDAC-I–induced cell death has been identified to be TRAIL-dependent by inducing apoptosis in an autocrine fashion. In contrast, in HCC-derived cells, a prototype of TRAIL-resistant tumor cells, we found a HDAC-I-mediated apoptosis that works independently of TRAIL and upregulation of death receptors or their cognate ligands. Interestingly, TRAIL resistance could be overcome by a combinatorial application of HDAC-I and TRAIL, increasing the fraction of apoptotic cells two- to threefold compared with HDAC-I treatment alone, whereas any premature HDAC-I withdrawal rapidly restored TRAIL resistance. Furthermore, a tumor cell–specific downregulation of the FLICE inhibitory protein (FLIP) was observed, constituting a new mechanism of TRAIL sensitivity restoration by HDAC-I. In contrast, FLIP levels in primary human hepatocytes (PHH) from different donors were upregulated by HDAC-I. Importantly, combination HDAC-I/TRAIL treatment did not induce any cytotoxicity in nonmalignant PHH. In conclusion , HDAC-I compounds, exhibiting a favorable in vivo profile and inherent activity against HCC cells, are able to selectively overcome the resistance of HCC cells toward TRAIL. Specific upregulation of intracellular FLIP protein levels in nonmalignant hepatocytes could enhance the therapeutic window for clinical applications of TRAIL, opening up a highly specific new treatment option for advanced HCC. (Hepatology 2006;43:425–434.)
Small cell variant of CD30+ primary cutaneous T-cell lymphoma with epidermotropism that completely regressed after incisional skin biopsy
Authors: T. Kamiya, K. Saga, K. Yanagisawa, R. Kaneko, T. Yamashita, O. Ishida, K. Jimbow
Journal: British Journal of Dermatology (2006)

Conflicts of interest: none declared. Sir, CD30+ primary cutaneous T‐cell lymphomas (CTCLs) without anaplastic large lymphoid cytology are extremely rare, especially with epidermotropism.1 In the literature we found few reports of primary CTCL predominantly composed of CD30+ small‐ to medium‐sized lymphoma cells.1, 2 We report on two patients with small cell CD30+ primary CTCL without anaplastic large cell phenotype. CD30+ atypical lymphoid cells showed epidermotropism, i.e. these cells were present not only in the dermis but also in the epidermis singly and in clusters. These tumours regressed completely after incisional skin biopsy. These two cases indicate that even primary CTCLs without anaplastic large cell cytology should be immunohistochemically examined for the expression of CD30 because CD30+ lymphomas have a significantly favourable prognosis when they are confined to the skin. Patient 1. In July 2003, a 32‐year‐old woman presented with an asymptomatic erythematous nodule on her right cheek (Fig. 1a). It had progressively enlarged over 1·5 months. The diameter of the nodule was 1·5 cm at presentation. No other similar lesions were noticed on other areas of the skin, and lymph nodes were not palpable.
RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway–Dependent Tumors
Authors: Xuesong Zhao, Tatyana Ponomaryov, Kimberly J. Ornell, Pengcheng Zhou, Sukriti K. Dabral, Ekaterina Pak, Wei Li, Scott X. Atwood, Ramon J. Whitson, Anne Lynn S. Chang, Jiang Li, Anthony E. Oro, Jennifer A. Chan, Joseph F. Kelleher, Rosalind A. Segal
Journal: Cancer Research (2015)

Aberrant Shh signaling promotes tumor growth in diverse cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy, and the mechanisms of resistance remain poorly understood. Using new medulloblastoma models, we identify two distinct paradigms of resistance to Smo inhibition. Sufu mutations lead to maintenance of the Shh pathway in the presence of Smo inhibitors. Alternatively activation of the RAS-MAPK pathway circumvents Shh pathway dependency, drives tumor growth, and enhances metastatic behavior. Strikingly, in BCC patients treated with Smo inhibitor, squamous cell cancers with RAS/MAPK activation emerged from the antecedent BCC tumors. Together, these findings reveal a critical role of the RAS-MAPK pathway in drug resistance and tumor evolution of Shh pathway-dependent tumors.
Signal transduction networks in rheumatoid arthritis
Authors: D Hammaker, S Sweeney, G S Firestein
Journal: Annals of the Rheumatic Diseases (2003)

<b>Background:</b> Severe asthma patients with a significant smoking history have airflow obstruction with reported neutrophilia. We hypothesise that multi-omic analysis will enable the definition of smoking and ex-smoking severe asthma molecular phenotypes. <b>Methods:</b> The U-BIOPRED severe asthma patients containing current-smokers (CSA), ex-smokers (ESA), non-smokers (NSA) and healthy non-smokers (NH) was examined. Blood and sputum cell counts, fractional exhaled nitric oxide and spirometry were obtained. Exploratory proteomic analysis of sputum supernatants and transcriptomic analysis of bronchial brushings, biopsies and sputum cells was performed. <b>Results:</b> Colony stimulating factor (CSF)2 protein levels were increased in CSA sputum supernatants with azurocidin 1, neutrophil elastase and CXCL8 upregulated in ESA. Phagocytosis and innate immune pathways were associated with neutrophilic inflammation in ESA. Gene Set Variation Analysis of bronchial epithelial cell transcriptome from CSA showed enrichment of xenobiotic metabolism, oxidative stress and endoplasmic reticulum stress compared to other groups. CXCL5 and matrix metallopeptidase 12 genes were upregulated in ESA and the epithelial protective genes, mucin 2 and cystatin SN, were downregulated. <b>Conclusion:</b> Despite little difference in clinical characteristics, CSA were distinguishable from ESA subjects at the sputum proteomic level with CSA having increased CSF2 expression and ESA patients showed sustained loss of epithelial barrier processes.
Prevalence of graphite related lung diseases amongst graphite miners
Authors: Rajaratnam Manivasakan, Chandimani Undugodage, Wathsala Gunasinghe, Kirthi Gunasekera, Asha Samaranayake, Judeson Gnanapragasam
Journal: European Respiratory Journal (2013)

Background 

Bogala is one of the largest graphite mines in Sri Lanka where graphite pneumoconiosis(GP) was first described1. Strict dust control measures and protective legislation had been introduced since 1972.

Objectives 

To evaluate graphite related lung diseases amongst the miner population at the Bogala graphite mine.

Method 

All miners were screened for symptoms of respiratory disease with a questionnaire followed by physical examination, chest radiography, sputum AFB and spirometry.

Results 

There were 183 workers. Out of which 171(93.4%) were males. There were 66 (36%) underground workers and 117 (64%) surface workers. 20.5% males were smokers

The majority (33.3%) had worked for a period of 10-14 years. 15.2% had worked for fewer than 5 years, 27.5% for 5-9 years and 10.5% for 15-19 years. 13.5% had worked for more than 20 years.

Majority was asymptomatic. 2 had non-specific cough, 1 had dyspnea, and 1 had both. All 4 had normal spirometry and chest radiography. Examination was normal in all.

None had chest radiographic evidence of GP. Radiological abnormalities were noted in 4.3%; emphysematous changes in 2, hilar prominence in 2, apical pleural thickening in 1, nonspecific inflammatory shadows in 3, and left lower zone bronchiectasis in 1.

Sputum AFB was negative in all.

Spirometry was normal in the majority. Restrictive pattern on spirometry was seen in 9% (n=17). However all were asymptomatic with normal chest radiography.

Conclusion 

GP and related diseases have become a rarity in the exposed probably related to the introduction of protective equipment and safer environment.

1. Ranasinha, K. W. et al Brit. J. industr. Med.1972:29:178-183. Graphite pneumoconiosis.
Left Ventricular Myocardial Contractile Response to Aortic Constriction in the Hyperthyroid Guinea Pig
Authors: M. JAY GOODKIND
Journal: Circulation Research (1968)

Maximum left ventricular systolic pressure response to aortic constriction served as a measure of myocardial contractility in anesthetized euthyroid and hyperthyroid guinea pigs. This response in hyperthyroid guinea pigs (155.4 ± 1.40 mm Hg) was significantly greater than in euthyroid animals (147.3 ± 1.33 mm Hg) ( P &lt;.001) and developed at a lower end-diastolic pressure in hyperthyroid (11.27±0.418 mm Hg) than in euthyroid guinea pigs (14.15±0.521 mm Hg) ( P &lt;.001). Beta-adrenergic receptor blockade with propranolol decreased the heart rate in both groups of animals but did not alter the contractile response. After propranolol, the heart rate of the hyperthyroid animals, though decreased, was still greater than that of euthyroid controls. Cardiac stimulation at a rate similar to that of the hyperthyroid animals (430 beats/min) did not change the left ventricular contractile response of normal guinea pigs. It is concluded that myocardial contractility in hyperthyroid guinea pigs is greater than normal. Increased activity of the sympathetic nervous system is probably present in hyperthyroidism, is reflected in the tachycardia, but does not appear to increase myocardial contractility. The increased myocardial contractility therefore is probably due in large part to a direct effect of thyroid hormone on cardiac muscle.
Oligoclonal CD4<sup>+</sup>T Cells in the Lungs of Patients with Severe Emphysema
Authors: Andrew K. Sullivan, Philip L. Simonian, Michael T. Falta, John D. Mitchell, Gregory P. Cosgrove, Kevin K. Brown, Brian L. Kotzin, Norbert F. Voelkel, Andrew P. Fontenot
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Within the lungs of patients with severe emphysema, inflammation continues despite smoking cessation. Foci of T lymphocytes in the small airways of patients with emphysema have been associated with disease severity. Whether these T cells play an important role in this continued inflammatory response is unknown. Objective: The aim of this study was to determine if T cells recruited to the lungs of subjects with severe emphysema contain oligoclonal T-cell populations, suggesting their accumulation in response to antigenic stimuli. Methods: Lung T-cell receptor (TCR) Vβ repertoire from eight patients with severe emphysema and six control subjects was evaluated at the time of tissue procurement (ex vivo) and after 2 weeks of culture with interleukin 2 (in vitro). Junctional region nucleotide sequencing of expanded TCR-Vβ subsets was performed. Results: No significantly expanded TCR-Vβ subsets were identified in ex vivo samples. However, T cells grew from all emphysema (n = 8) but from only one of the control lung samples (n = 6) when exposed to interleukin 2 (p = 0.0013). Within the cultured cells, seven major CD4-expressing TCR-Vβ subset expansions were identified from five of the patients with emphysema. These expansions were composed of oligoclonal populations of T cells that had already been expanded in vivo. Conclusion: Severe emphysema is associated with inflammation involving T lymphocytes that are composed of oligoclonal CD4+ T cells. These T cells are accumulating in the lung secondary to conventional antigenic stimulation and are likely involved in the persistent pulmonary inflammation characteristic of severe emphysema.
Reclassification of 300 Primary Cutaneous B-Cell Lymphomas According to the New WHO–EORTC Classification for Cutaneous Lymphomas: Comparison With Previous Classifications and Identification of Prognostic Markers
Authors: Nancy J. Senff, Juliette J. Hoefnagel, Patty M. Jansen, Maarten H. Vermeer, Joop van Baarlen, Willeke A. Blokx, Marijke R. Canninga-van Dijk, Marie-Louise Geerts, Konnie M. Hebeda, Philip M. Kluin, King H. Lam, Chris J.L.M. Meijer, Rein Willemze
Journal: Journal of Clinical Oncology (2007)

In the new WHO-European Organisation for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas three major groups of primary cutaneous B-cell lymphoma (CBCL) are distinguished: primary cutaneous marginal zone B-cell lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL) with a good prognosis, and primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT), with an intermediate-level prognosis. This study aimed to assess the clinical significance of the new classification compared with previous classification schemes (EORTC 1997; WHO 2001) and to define prognostic factors within the newly defined categories.In the present study clinical data and histologic sections of 300 patients with CBCL, formerly classified according to the EORTC classification, were reviewed and reclassified according to the WHO and the new WHO-EORTC classification schemes.After reclassification, the study comprised 71 patients with PCMZL, 171 patients with PCFCL, and 58 patients with PCLBCL-LT, showing 5-year disease-specific survivals of 98%, 95%, and 50%, respectively. When compared with the EORTC and WHO schemes, 5.3% and 36.3% of patients with CBCL were reclassified into another prognostic category. Multivariate analysis of PCFCL revealed localization on the leg and expression of FOXP1 as independent parameters associated with a poor prognosis. Expression of Bcl-2 or MUM-1 had no significant effect on survival in this group. In PCLBCL-LT, no independent prognostic parameters were found.These results emphasize the clinical significance of the WHO-EORTC classification, but suggest that within the group of PCFCL, distinction should be made between lymphomas presenting on the legs and lymphomas presenting at other sites.
Interplay of Selective Pressure and Stochastic Events Directs Evolution of the MEL172 Satellite DNA Library in Root-Knot Nematodes
Authors: Nevenka Meštrović, Philippe Castagnone-Sereno, Miroslav Plohl
Journal: Molecular Biology and Evolution (2006)

According to the library model, related species can have in common satellite DNA (satDNA) families amplified in differing abundances, but reasons for persistence of particular sequences in the library during long periods of time are poorly understood. In this paper, we characterize 3 related satDNAs coexisting in the form of a library in mitotic parthenogenetic root-knot nematodes of the genus Meloidogyne. Due to sequence similarity and conserved monomer length of 172 bp, this group of satDNAs is named MEL172. Analysis of sequence variability patterns among monomers of the 3 MEL172 satellites revealed 2 low-variable (LV) domains highly reluctant to sequence changes, 2 moderately variable (MV) domains characterized by limited number of mutations, and 1 highly variable (HV) domain. The latter domain is prone to rapid spread and homogenization of changes. Comparison of the 3 MEL172 consensus sequences shows that the LV domains have 6% changed nucleotide positions, the MV domains have 48%, whereas 78% divergence is concentrated in the HV domain. Conserved distribution of intersatellite variability might indicate a complex pattern of interactions in heterochromatin, which limits the range and phasing of allowed changes, implying a possible selection imposed on monomer sequences. The lack of fixed species-diagnostic mutations in each of the examined MEL172 satellites suggests that they existed in unaltered form in a common ancestor of extant species. Consequently, the evolution of these satellites seems to be driven by interplay of selective constraints and stochastic events. We propose that new satellites were derived from an ancestral progenitor sequence by nonrandom accumulation of mutations due to selective pressure on particular sequence segments. In the library of particular taxa, established satellites might be subject to differential amplification at chance due to stochastic mechanisms of concerted evolution.
Development of a quantitative assay for hepatic HBV ccc DNA levels in patients with chronic hepatitis B
Authors: Bettina Werle, Karsten Wursthorn, Jorg Petersen, Scott Bowden, Stephen Locarnini, Craig James, Carol Brosgart, Shelly Xiong, William Delaney, Craig Gibbs, Fabien Zoulim
Journal: Journal of Hepatology (2002)
Long-term epicardial ventricular pacing from endocardial bipolar pacemaker lead: perforation of right atrial wall.
Authors: D A Lees, G D Green
Journal: Thorax (1977)

One of the hazards of endocardial cardiac pacing is that the pacemaker lead may perforate the myocardial wall or interventricular septum although the incidence of such perforations is believed to be small. This paper describes what is believed to be a unique case in which a pacemaker lead perforated the atrial wall at implantation (or possibly shortly afterwards) and yet gave satisfactory right ventricular epicardial pacing for more than five years. The perforation was discovered during a routine postmortem examination but earlier lateral x-ray examinations would probably have identified the abnormal position of the electrodes. Moreover, the present implantation technique would not have allowed perforation of the atrial wall at implantation to go undetected.
Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials
Authors: Lesley Ann Saketkoo, Shikha Mittoo, Dörte Huscher, Dinesh Khanna, Paul F Dellaripa, Oliver Distler, Kevin R Flaherty, Sid Frankel, Chester V Oddis, Christopher P Denton, Aryeh Fischer, Otylia M Kowal-Bielecka, Daphne LeSage, Peter A Merkel, Kristine Phillips, David Pittrow, Jeffrey Swigris, Katerina Antoniou, Robert P Baughman, Flavia V Castelino, Romy B Christmann, Lisa Christopher-Stine, Harold R Collard, Vincent Cottin, Sonye Danoff, Kristin B Highland, Laura Hummers, Ami A Shah, Dong Soon Kim, David A Lynch, Frederick W Miller, Susanna M Proudman, Luca Richeldi, Jay H Ryu, Nora Sandorfi, Catherine Sarver, Athol U Wells, Vibeke Strand, Eric L Matteson, Kevin K Brown, James R Seibold
Journal: Thorax (2013)

Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities.The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF).A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed.Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.
Combined exposure to dog and indoor pollution: incident asthma in a high-risk birth cohort
Authors: C. Carlsten, M. Brauer, H. Dimich-Ward, A. Dybuncio, A. B. Becker, M. Chan-Yeung
Journal: European Respiratory Journal (2010)

The impact of single exposures on asthma development is better understood than the effect of multiple exposures. The objective of the present study was to evaluate the effect of combined early exposure to dog allergen (Can-f1) plus indoor nitrogen dioxide (NO₂) or environmental tobacco smoke (ETS) on asthma and bronchial hyperreactivity (BHR) in a high-risk birth cohort. We also aimed to assess atopy's impact on the effects of these exposures. Peri-birth ETS exposure was measured using cord blood cotinine (CCot). During year 1, atopy, NO₂, Can-f1, and urinary cotinine (UCot) were measured. At 7 yrs of age, 380 children were assessed for asthma and BHR. Exposure effects were determined using stepwise multiple linear regression. Co-exposure to elevated Can-f1 and NO₂, or Can-f1 and ETS (CCot), increased risk for asthma, relative to having neither such exposure (OR 4.8 (95% CI 1.1-21.5) and 2.7 (1.1-7.1), respectively); similar risks resulted when substituting dog ownership for allergen. Atopy increased asthma and BHR risk associated with several exposures; notably, atopy with elevated UCot, relative to atopy without such exposure, increased risk of BHR (OR 3.1 (95% CI 1.1-8.6)). In a high-risk birth cohort, early co-exposure to Can-f1 and NO₂ or ETS increased the risk of incident asthma. Atopy increased the risk of asthma and BHR associated with ETS.
Increased islet apoptosis in Pdx1+/– mice
Authors: James D. Johnson, Noreen T. Ahmed, Dan S. Luciani, Zhiqiang Han, Hung Tran, Jun Fujita, Stanley Misler, Helena Edlund, Kenneth S. Polonsky
Journal: Journal of Clinical Investigation (2003)

Mice with 50% Pdx1, a homeobox gene critical for pancreatic development, had worsening glucose tolerance with age and reduced insulin release in response to glucose, KCl, and arginine from the perfused pancreas. Surprisingly, insulin secretion in perifusion or static incubation experiments in response to glucose and other secretagogues was similar in islets isolated from Pdx1+/– mice compared with Pdx1+/+ littermate controls. Glucose sensing and islet Ca2+ responses were also normal. Depolarization-evoked exocytosis and Ca2+ currents in single Pdx1+/– cells were not different from controls, arguing against a ubiquitous β cell stimulus-secretion coupling defect. However, isolated Pdx1+/– islets and dispersed β cells were significantly more susceptible to apoptosis at basal glucose concentrations than Pdx1+/+ islets. BclXL and Bcl-2 expression were reduced in Pdx1+/– islets. In vivo, increased apoptosis was associated with abnormal islet architecture, positive TUNEL, active caspase-3, and lymphocyte infiltration. Although similar in young mice, both β cell mass and islet number failed to increase with age and were approximately 50% less than controls by one year. These results suggest that an increase in apoptosis, with abnormal regulation of islet number and β cell mass, represents a key mechanism whereby partial PDX1 deficiency leads to an organ-level defect in insulin secretion and diabetes.