tbuckley/cabot-search huggingface dataset:
TNF -induced GM-CSF release from human airway smooth muscle cells depends on activation of an ET-1 autoregulatory positive feedback mechanism
Authors: J Knobloch, H Peters, D Jungck, K Muller, J Strauch, A Koch
Journal: Thorax (2009)

<h3>Background:</h3> There is an urgent need to inhibit endothelin-1 (ET-1) induced chronic inflammatory processes in early stages of lung diseases in order to prevent untreatable irreversible stages often accompanied by lung fibrosis and pulmonary hypertension. Nothing is known about the airway inflammation-inducing and/or maintaining role of ET-1 in human airway smooth muscle cells (HASMCs). <h3>Objective:</h3> ET-1 and granulocyte–macrophage colony-stimulating factor (GM-CSF) expression in response to tumour necrosis factor α (TNFα) and ET-1 stimulation was investigated, and the impact of mitogen-activated protein kinase (MAPK) pathways in this context was studied. To elucidate the anti-inflammatory properties of the dual endothelin receptor antagonist bosentan that targets both endothelin receptor subtypes A (ET<sub>A</sub>R) and B (ET<sub>B</sub>R), its effect on the TNFα/ET-1/GM-CSF network was investigated. <h3>Methods:</h3> ET-1 and GM-CSF expression and activation of MAPKs were investigated via quantitative reverse transcription-PCR (RT-PCR), western blotting and ELISA. <h3>Main results:</h3> Both TNFα and ET-1 activated p38<sup>MAPK</sup> and extracellular signal-regulated kinase (ERK)-1/-2 signalling. ET-1 expression was induced by TNFα and by ET-1 itself. Both effects were inhibited by bosentan and by specific ET<sub>A</sub>R or p38<sup>MAPK</sup> blockade. ET-1- and TNFα-induced GM-CSF expression were both reduced by bosentan as well as by specific inhibition of either ET<sub>A</sub>R, ET<sub>B</sub>R, p38<sup>MAPK</sup> or ERK-1/-2. <h3>Conclusion:</h3> TNFα activates an ET<sub>A</sub>R- and p38<sup>MAPK</sup>-dependent ET-1 autoregulatory positive feedback loop to maintain GM-CSF release from HASMCs. Since bosentan impairs ET-1 autoregulation and TNFα-induced ET-1 release, as well as TNFα- and ET-1-induced GM-CSF release, the present data suggest therapeutic utility for bosentan in treating particularly the early stages of chronic inflammatory airway diseases.
205 COMBINED IMMUNOTHERAPY WITH IL12-EXPRESSING DENDRITIC CELLS AND AFP-PULSED DC TOWARDS ESTABLISHED HEPATOCELLULAR CARCINOMA
Authors: G. Decker, A. Vogt, E. Raskopf, V. Schmitz, W.H. Caselmann, T. Sauerbruch, M.A. Gonzalez-Carmona
Journal: Journal of Hepatology (2011)
Alliteration in medicine: a puzzling profusion of p's
Authors: G. F Hayden
Journal: BMJ (1999)

Puzzling, progressive profusion of alliterative "p's" in published papers.To depict this particular "p" predominance with pinpoint precision. PLAN: Periodic, painstaking perusal of periodicals by a professor of paediatrics.The "p" plethora is positively perplexing and potentially perturbing.
Renal Phenotypes Related to Hepatocyte Nuclear Factor-1β (TCF2) Mutations in a Pediatric Cohort
Authors: Tim Ulinski, Sandra Lescure, Sandrine Beaufils, Vincent Guigonis, Stéphane Decramer, Denis Morin, Séverine Clauin, Georges Desche[Combining Circumflex Accent]nes, Franc[COMBINING CEDILLA]ois Bouissou, Albert Bensman, Christine Bellanné-Chantelot
Journal: Journal of the American Society of Nephrology (2005)

The hepatocyte nuclear factor-1beta encoded by the TCF2 gene plays a role for the specific regulation of gene expression in various tissues such as liver, kidney, intestine, and pancreatic islets and is involved in the embryonic development of these organs. TCF2 mutations are known to be responsible for the maturity-onset diabetes of the young type 5 associated with renal manifestations. Several observations have suggested that TCF2 mutations may be involved in restricted renal phenotypes. Eighty children (median age at diagnosis 0.2 yr) with renal cysts, hyperechogenicity, hypoplasia, or single kidneys were studied. Quantitative multiplex PCR amplification of short fluorescence fragments for the search of large genomic rearrangements and sequencing for the detection of point mutations were performed. TCF2 anomalies were detected in one third of patients (25 of 80). The main alteration was the complete deletion of the TCF2 gene detected in 16 patients. Family screening revealed de novo TCF2 anomalies in nine of 17 probands with a high prevalence of deletions (seven of nine). TCF2 anomalies were associated with bilateral renal anomalies (P < 0.001) and bilateral cortical cysts (P < 0.001). However, abnormal renal function, detected in 40% of patients, was independent of the TCF2 genotype. No difference in renal function or severity of renal morphologic lesions was observed between patients with a TCF2 deletion and those with point mutations. In conclusion, TCF2 molecular anomalies are involved in restricted renal phenotype in childhood without alteration of glucose metabolism. These findings have important implications in the diagnosis of patients with renal dysplasia with cysts and their follow-up.
Identifying and Overcoming Immune Resistance Mechanisms in the Melanoma Tumor Microenvironment
Authors: Thomas F. Gajewski
Journal: Clinical Cancer Research (2006)

Abstract The continually growing list of defined tumor antigens is broadening the potential applicability of tumor antigen-targeted cancer therapies. Although cancer vaccines and adoptive T-cell transfer have been shown to increase the frequency of circulating tumor antigen-specific T cells, these approaches cause clinical responses in a few patients. In melanoma, approximately one third of metastatic lesions contain activated T cells, including those specific for tumor antigens, arguing that the priming phase has occurred already in such individuals even without vaccination. These observations indicate that tumor resistance to immune destruction may dominate in many instances, arguing for a thorough analysis of the melanoma tumor microenvironment in individual patients. Recent work has suggested that T-cell anergy, the influence of CD4+CD25+ regulatory T cells, the expression of inhibitory ligands, such as PD-L1, and the activity of nutrient-catabolizing enzymes, such as indoleamine 2,3-dioxygenase, may be involved. Preclinical murine models have shown that interfering with each of these processes can translate into T-cell–mediated tumor control. Importantly, each of these targets is amenable to clinical manipulation. Clinical translation of these approaches to counter negative regulation of antitumor immunity should receive high priority.
Abstract IA12: Conducting hypothesis testing trials for the treatment of advanced prostate cancer
Authors: Johann S. de Bono
Journal: Cancer Research (2012)

Abstract There are multiple challenges to the successful development of novel therapeutics for advanced prostate cancer. These include: 1) The identification of novel targets for drug discovery for treating this disease; 2) Intraand inter-patient molecular heterogeneity; 3) The pattern of disease metastases resulting in largely bone disease that is not readily measurable radiologically by standard imaging methods; 4) Difficulty accessing metastatic disease that can be interrogated to elucidate mechanisms of resistance; 5) The widespread use of PSA changes to drive therapeutic decisions; 6) The lack of a proven intermediate endpoint of overall survival to accelerate drug development. Nevertheless, major progress has been made with five novel agents being shown to improve overall survival in this patient population including abiraterone acetate, alpharadin, cabazitaxel, MDV3100 and Sipuleucel T. Citation Format: Johann S. de Bono. Conducting hypothesis testing trials for the treatment of advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA12.
Long-Acting Risperidone and Oral Antipsychotics in Unstable Schizophrenia
Authors: Robert A. Rosenheck, John H. Krystal, Robert Lew, Paul G. Barnett, Louis Fiore, Danielle Valley, Soe Soe Thwin, Julia E. Vertrees, Matthew H. Liang
Journal: New England Journal of Medicine (2011)

Long-acting injectable risperidone, a second-generation antipsychotic agent, may improve adherence to treatment and outcomes in schizophrenia, but it has not been tested in a long-term randomized trial involving patients with unstable disease.
Virus-host interactomics: new insights and opportunities for antiviral drug discovery
Authors: Benoît de Chassey, Laurène Meyniel-Schicklin, Jacky Vonderscher, Patrice André, Vincent Lotteau
Journal: Genome Medicine (2014)

Abstract The current therapeutic arsenal against viral infections remains limited, with often poor efficacy and incomplete coverage, and appears inadequate to face the emergence of drug resistance. Our understanding of viral biology and pathophysiology and our ability to develop a more effective antiviral arsenal would greatly benefit from a more comprehensive picture of the events that lead to viral replication and associated symptoms. Towards this goal, the construction of virus-host interactomes is instrumental, mainly relying on the assumption that a viral infection at the cellular level can be viewed as a number of perturbations introduced into the host protein network when viral proteins make new connections and disrupt existing ones. Here, we review advances in interactomic approaches for viral infections, focusing on high-throughput screening (HTS) technologies and on the generation of high-quality datasets. We show how these are already beginning to offer intriguing perspectives in terms of virus-host cell biology and the control of cellular functions, and we conclude by offering a summary of the current situation regarding the potential development of host-oriented antiviral therapeutics.
Nonpharmaceutical Interventions Implemented by US Cities During the 1918-1919 Influenza Pandemic
Authors: Howard Markel, Harvey B. Lipman, J. Alexander Navarro, Alexandra Sloan, Joseph R. Michalsen, Alexandra Minna Stern, Martin S. Cetron
Journal: JAMA (2007)

A critical question in pandemic influenza planning is the role nonpharmaceutical interventions might play in delaying the temporal effects of a pandemic, reducing the overall and peak attack rate, and reducing the number of cumulative deaths. Such measures could potentially provide valuable time for pandemic-strain vaccine and antiviral medication production and distribution. Optimally, appropriate implementation of nonpharmaceutical interventions would decrease the burden on health care services and critical infrastructure.To examine the implementation of nonpharmaceutical interventions for epidemic mitigation in 43 cities in the continental United States from September 8, 1918, through February 22, 1919, and to determine whether city-to-city variation in mortality was associated with the timing, duration, and combination of nonpharmaceutical interventions; altered population susceptibility associated with prior pandemic waves; age and sex distribution; and population size and density.Historical archival research, and statistical and epidemiological analyses. Nonpharmaceutical interventions were grouped into 3 major categories: school closure; cancellation of public gatherings; and isolation and quarantine.Weekly excess death rate (EDR); time from the activation of nonpharmaceutical interventions to the first peak EDR; the first peak weekly EDR; and cumulative EDR during the entire 24-week study period.There were 115,340 excess pneumonia and influenza deaths (EDR, 500/100,000 population) in the 43 cities during the 24 weeks analyzed. Every city adopted at least 1 of the 3 major categories of nonpharmaceutical interventions. School closure and public gathering bans activated concurrently represented the most common combination implemented in 34 cities (79%); this combination had a median duration of 4 weeks (range, 1-10 weeks) and was significantly associated with reductions in weekly EDR. The cities that implemented nonpharmaceutical interventions earlier had greater delays in reaching peak mortality (Spearman r = -0.74, P < .001), lower peak mortality rates (Spearman r = 0.31, P = .02), and lower total mortality (Spearman r = 0.37, P = .008). There was a statistically significant association between increased duration of nonpharmaceutical interventions and a reduced total mortality burden (Spearman r = -0.39, P = .005).These findings demonstrate a strong association between early, sustained, and layered application of nonpharmaceutical interventions and mitigating the consequences of the 1918-1919 influenza pandemic in the United States. In planning for future severe influenza pandemics, nonpharmaceutical interventions should be considered for inclusion as companion measures to developing effective vaccines and medications for prophylaxis and treatment.
Synaptic Vesicles and Exocytosis
Authors: R Jahn, T C Sudhof
Journal: Annual Review of Neuroscience (1994)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Increased Expression of Metallothionein Is Associated with Irinotecan Resistance in Gastric Cancer
Authors: Jong Ho Chun, Hark Kyun Kim, Eugene Kim, In-Hoo Kim, Ju Han Kim, Hee Jin Chang, Il Ju Choi, Hyeong-Seok Lim, Il-Jin Kim, Hio Chung Kang, Jae-Hyun Park, Jae-Moon Bae, Jae-Gahb Park
Journal: Cancer Research (2004)

Abstract To gain insight into clinically relevant mechanisms of irinotecan resistance, we undertook oligonucleotide microarray analyses on paired malignant effusion samples obtained from eight gastric cancer patients treated with weekly irinotecan. Pretreatment and posttreatment (48 h) effusion samples were obtained for each patient, and the change in expression profile was compared between clinical responders and nonresponders. When differences in the expression of genes were examined using SAM (Significance Analysis of Microarrays) software, five isoforms of the metallothionein family were identified to have significantly higher signal log ratios in five nonresponders, compared with three responders. Compared with control cells, metallothionein 1X (MT1X)-transfected AGS cells showed a 1.4-fold higher irinotecan IC50 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and tended to form more colonies. These findings collectively suggest that irinotecan-induced up-regulation of metallothionein might be associated with irinotecan resistance in patients with gastric cancer, although it remains to be confirmed in a larger data set.
Endoscopic tri-modal imaging for detection of early neoplasia in Barrett's oesophagus: a multi-centre feasibility study using high-resolution endoscopy, autofluorescence imaging and narrow band imaging incorporated in one endoscopy system
Authors: W L Curvers, R Singh, L-M W.-K. Song, H C Wolfsen, K Ragunath, K Wang, M B Wallace, P Fockens, J J G H M Bergman
Journal: Gut (2007)

<h3>Objective:</h3> To investigate the diagnostic potential of endoscopic tri-modal imaging and the relative contribution of each imaging modality (i.e. high-resolution endoscopy (HRE), autofluorescence imaging (AFI) and narrow-band imaging (NBI)) for the detection of early neoplasia in Barrett’s oesophagus. <h3>Design:</h3> Prospective multi-centre study. <h3>Setting:</h3> Tertiary referral centres. <h3>Patients:</h3> 84 Patients with Barrett’s oesophagus. <h3>Interventions:</h3> The Barrett’s oesophagus was inspected with HRE followed by AFI. All lesions detected with HRE and/or AFI were subsequently inspected in detail by NBI for the presence of abnormal mucosal and/or microvascular patterns. Biopsies were obtained from all suspicious lesions for blinded histopathological assessment followed by random biopsies. <h3>Main outcome measures:</h3> (1) Number of patients with early neoplasia diagnosed by HRE and AFI; (2) number of lesions with early neoplasia detected with HRE and AFI; and (3) reduction of false positive AFI findings after NBI. <h3>Results:</h3> Per patient analysis: AFI identified all 16 patients with early neoplasia identified with HRE and detected an additional 11 patients with early neoplasia that were not identified with HRE. In three patients no abnormalities were seen but random biopsies revealed HGIN. After HRE inspection, AFI detected an additional 102 lesions; 19 contained HGIN/EC (false positive rate of AFI after HRE: 81%). Detailed inspection with NBI reduced this false positive rate to 26%. <h3>Conclusions:</h3> In this international multi-centre study, the addition of AFI to HRE increased the detection of both the number of patients and the number of lesions with early neoplasia in patients with Barrett’s oesophagus. The false positive rate of AFI was reduced after detailed inspection with NBI.
Identification of a gene encoding a melanoma tumor antigen recognized by HLA-A31-restricted tumor-infiltrating lymphocytes.
Authors: R F Wang, P F Robbins, Y Kawakami, X Q Kang, S A Rosenberg
Journal: The Journal of Experimental Medicine (1995)

The availability of antitumor cytotoxic T lymphocytes which can be generated from either peripheral blood lymphocytes after stimulation in vitro or tumor infiltrating lymphocytes (TIL) has made it possible to identify a number of melanoma antigens presented by major histocompatibility complex class I molecules. The present and previous studies indicated that TIL586 recognized an antigen expressed on most melanoma and normal melanocytes in the context of the HLA-A31 molecule. We report here the cloning of a cDNA that directs the expression of the shared melanoma antigen recognized by this TIL. The DNA sequence analysis revealed that the cDNA was almost identical to the gene encoding tyrosinase-related protein 1 or glycoprotein gp75 which was originally identified by serum antibodies in a patient with melanoma. The gene was found to be expressed only in melanoma, normal melanocyte cell lines, and retina, but not in other normal tissues tested. The gp75 antigen presented by HLA-A31 may therefore constitute a useful immune target for specific treatment of patients with melanoma, since both antibody- and T cell-mediated immune responses can be generated against this antigen.
Characterization of Atrioventricular Nodal Reentry With Continuous Atrioventricular Node Conduction Curve by Double Atrial Extrastimulation
Authors: Chi-Tai Kuo, Kuo-Hung Lin, Nye-Jan Cheng, Po-Hsien Chu, Tsu-Shiu Hsu, Cheng-Wen Chiang, Ying-Shiung Lee
Journal: Circulation (1999)

Background —Characterization of typical atrioventricular nodal reentrant tachycardia (AVNRT) with continuous AVN conduction (A 1 A 2 /A 2 H 2 ) curves by double atrial extrastimulation (A 1 A 2 A 3 ) has never been systematically studied. Methods and Results —This study was composed of 33 patients with typical AVNRT and continuous AVN conduction curves (group 1) and 103 patients with AVNRT and discontinuous AVN conduction curves (group 2). Using A 1 A 2 A 3 with predefined fast pathway–conducted A 2 , we examined the effects of slow pathway ablation on the A 2 A 3 /A 3 H 3 curves in both groups. In group 1, anterograde AVN effective refractory period (272±33 versus 277±47 ms, P &gt;0.05) and AVN Wenckebach block cycle length (320±45 versus 343±59 ms, P &gt;0.05) remained unchanged after ablation. A 2 H 2 max was shorter in group 1 than group 2 (237±89 versus 395±72 ms, P &lt;0.05) at baseline. It shortened in group 2 (395±72 versus 221±78 ms, P &lt;0.001) but remained unchanged in group 1 (237±89 versus 214±59 ms, P &gt;0.05) after ablation. A 1 A 2 A 3 could further disclose discontinuous A 2 A 3 /A 3 H 3 curves in 29 patients of group 1. A 3 H 3 max shortened in both groups (375±81 versus 238±82 ms, P &lt;0.001, and 419±104 versus 220±78 ms, P &lt;0.001, respectively) in a similar fashion. Successful ablation resulted in loss of the left portion of the A 2 A 3 /A 3 H 3 curves in the 4 patients of group 1 with continuous A 2 A 3 /A 3 H 3 curves. Conclusions —Use of A 1 A 2 A 3 could expose discontinuous A 2 A 3 /A 3 H 3 curves in most patients with continuous A 1 A 2 /A 2 H 2 curves. Significant shortening of A 3 H 3 max after ablation may be indicative of successful elimination of AVNRT.
<i>MUC5B</i>: a good target for future therapy in pulmonary fibrosis?
Authors: Rahul Mahida, Alice M Turner
Journal: Thorax (2013)

Idiopathic pulmonary fibrosis (IPF), sarcoidosis and systemic sclerosis can each cause diffuse parenchymal lung disease involving alveolar epithelial abnormalities, and manifest as interstitial lung fibrosis. Systemic sclerosis is an autoimmune connective tissue disease and sarcoidosis is a multisystem granulomatous disease; the development of lung fibrosis in both conditions generally indicates a poor prognosis. IPF is a progressive disease which is thought to occur after recurrent injury to the alveolar epithelium followed by dysregulation of cellular homoeostasis, abnormal repair and excessive deposition of extracellular matrix, ultimately leading to loss of lung function.1 Mortality 3–5 years after diagnosis of IPF is 50%, and treatment options are currently limited.

Seibold et al 2 have previously shown that a variant single-nucleotide polymorphism (SNP) in the promoter region of an airway mucin gene ( MUC5B ) is associated with greatly increased production of MUC5B, and with pulmonary fibrosis. This suggested that dysregulated MUC5B expression in the lung may be key to the pathogenesis of pulmonary fibrosis. One hypothesis is that an excess of MUC5B causes bronchiolar plugging and impairs mucosal host defence, reducing clearance …
Inhibition by somatostatin of carbamylcholine-induced gastrin and glucagon release from the isolated perfused canine stomach.
Authors: P J Lefebvre, A S Luyckx, A H Brassinne
Journal: Gut (1981)

At an arterial plasma concentration of 61 nmol/1 (100 ng/ml) synthetic cyclic somatostatin completely abolished basal glucagon and gastrin release as well as carbamylcholineinduced glucagon and gastrin release from the isolated perfused dog stomach.These obser- vations are compatible with the view that endogenous somatostatin previously reported to be released during vagal stimulation might be involved to explain the lack of gastric-glucagon response in this situation.They do not, however, rule out the alternative proposal that the dog fundic A-cell may simply be a non-innervated cell.We have previously reported that the electrical stimulation of both dorsal and ventral vagal trunks of the isolated perfused dog stomach does not elicit gastric-glucagon release, although gastrin release is markedly stimulated.'In contrast, the intra-arterial infusion of acetyl-(or carbamyl-) choline unequivocally stimulated the release of glucagon and gastrin from the isolated stomach.2'Among the possible explanations for this discrep- ancy, we have suggested that somatostatin, also released in our system by the electrical stimulation of the vagus nerves, might simultaneously inhibit gastric-glucagon release.' 4 The present experi- ments were performed in order to see if exogenous somatostatin intra-arterial infusion would modify glucagon and gastrin release from the isolated perfused canine stomach, in response to an intra-arterial infusion of carbamylcholine, an analogue of the physiological neurotransmitter, acetylcholine. Methods ISOLATION AND PERFUSION OF STOMACHStomachs from overnight-fasted normal 8-12 kg mongrel dogs of both sexes were isolated with