tbuckley/cabot-search huggingface dataset:
Phase II Trial of Interleukin 1 and Indomethacin in Treatment of Metastatic Melanoma
Authors: J. E. Janik, L. L. Miller, D. L. Longo, G. C. Powers, W. J. Urba, W. C. Kopp, B. L. Gause, B. D. Curti, R. G. Fenton, J. J. Oppenheim, K. C. Conlon, J. T. Holmlund, M. Sznol, W. H. Sharfman, R. G. Steis, S. P. Creekmore, W. G. Alvord, A. E. Beauchamp, J. W. Smith
Journal: JNCI Journal of the National Cancer Institute (1996)

The rising incidence of malignant melanoma and the lack of curative therapies for metastatic disease represent a therapeutic challenge. New agents effective in treating this disease are needed. Because of the additive antitumor effects of interleukin 1α (IL-1α) and indomethacin in vivo, we conducted a phase II trial of this combination in patients with melanoma. We used the recommended dose determined from our phase I trial to ascertain the antitumor activity of the combination. From August 1, 1990, through July 28, 1992, 49 patients entered the study. They were stratified into two groups based on the presence of visceral (n = 14) and nonvisceral (n = 35) metastases. The patients received 7 days of both IL-1α (0.1μg/kg per day by intravenous bolus infusion) and indomethacin (50 mg orally every 8 hours). At least two cycles of therapy, repeated at 21-day intervals, were planned. Additional treatment was given to those patients who had stable or responding lesions. A chi-squared test for homogeneity of proportions was used to compare groups on several measures. All P values resulted from two-sided tests. Fever, chills, and hypotension were among the most common side effects. None of the 14 patients with visceral metastases responded to the treatment. Of the 35 patients with nonvisceral metastases, three showed a partial response for 6 months each and one showed a complete response for more than 34 months; the response rate was 11% (95% confidence interval [CI] = 5%-26%). All responding patients required phenylephrine for treatment of IL-1α-induced hypotension, whereas six (19%) of 31 of the nonresponding patients with nonvisceral metastases required phenylephrine ( P =.0008). The response rate in women was higher; three of 10 women (30%; 95% CI =11%-60%) responded, whereas one of 25 men (4%; 95% CI = 0%-20%) responded ( P =.029). All three women were positive for human leukocyte antigen (HLA) B7 expression ( P =.011). The combination of IL-1α and indomethacin has minimal antitumor activity in melanoma patients. All responses were confined to patients with nonvisceral metastases. IL-1α-induced hypotension, gender, and HLA B7 expression were positively associated with response. Administration of higher doses of IL-1α alone has been shown to produce hypotension in a large proportion of patients but can be given safely with phenylephrine support. Because of the association of hypotension with antitumor activity, treatment with higher IL-1α doses alone may be a strategy for attaining better response rates. [J Natl Cancer Inst 1996;88:44–9]
Bosentan does not improve pulmonary hypertension and lung remodeling in heart failure
Authors: B.H. Jiang, J-C. Tardif, Y. Shi, J. Dupuis
Journal: European Respiratory Journal (2010)

Pulmonary hypertension (PH) and right ventricular (RV) dysfunction associated with heart failure (HF) carry a poor prognosis. Although endothelin receptor antagonists (ERAs) demonstrated benefits in pulmonary arterial hypertension, their efficacy in PH associated with HF was not specifically evaluated. 2 weeks after myocardial infarction (MI) rats received bosentan (100 or 200 mg·kg −1 ·day −1 ) or no treatment for 3 weeks. PH, RV hypertrophy and function as well as lung remodeling and function were evaluated. LV echocardiographic wall motion abnormality and function measured before treatment (2 weeks after MI) and after treatment (5 weeks after MI) were similar in MI control and MI treatment groups. HF induced PH and RV hypertrophy compared with sham: RV systolic pressure 39±5 versus 23±0.8 mmHg and RV/left ventricular+septum weight 52±7 versus 24±0.5% (all p&lt;0.01). Bosentan did not significantly modify these parameters. In addition, bosentan did not improve depressed RV function measured by echocardiograph from the RV myocardial performance index and tricuspid annular plane systolic excursion. The respiratory pressure–volume relationship revealed that HF caused a restrictive lung syndrome with histological lung remodeling and fibrosis, also not improved by bosentan. Dual ERA therapy with bosentan does not reduce PH, RV hypertrophy and lung remodeling and dysfunction associated with ischaemic HF.
Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP)
Authors: Koichi Watashi, Ann Sluder, Takuji Daito, Satoko Matsunaga, Akihide Ryo, Shushi Nagamori, Masashi Iwamoto, Syo Nakajima, Senko Tsukuda, Katyna Borroto-Esoda, Masaya Sugiyama, Yasuhito Tanaka, Yoshikatsu Kanai, Hiroyuki Kusuhara, Masashi Mizokami, Takaji Wakita
Journal: Hepatology (2013)

Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. Although nucleos(t)ide analogs inhibiting viral reverse transcriptase are clinically available as anti-HBV agents, emergence of drug-resistant viruses highlights the need for new anti-HBV agents interfering with other targets. Here we report that cyclosporin A (CsA) can inhibit HBV entry into cultured hepatocytes. The anti-HBV effect of CsA was independent of binding to cyclophilin and calcineurin. Rather, blockade of HBV infection correlated with the ability to inhibit the transporter activity of sodium taurocholate cotransporting polypeptide (NTCP). We also found that HBV infection-susceptible cells, differentiated HepaRG cells and primary human hepatocytes expressed NTCP, while nonsusceptible cell lines did not. A series of compounds targeting NTCP could inhibit HBV infection. CsA inhibited the binding between NTCP and large envelope protein in vitro . Evaluation of CsA analogs identified a compound with higher anti-HBV potency, having a median inhibitory concentration &lt;0.2 μM. Conclusion : This study provides a proof of concept for the novel strategy to identify anti-HBV agents by targeting the candidate HBV receptor, NTCP, using CsA as a structural platform. (Hepatology 2014;59:1726–1737)
Disappointment with triethers as markers for measuring triglyceride absorption in man
Authors: D. R. Saunders, T. K. O'Brien
Journal: Gut (1972)

Glycerol triethers were tried as non-absorbable, oil-phase markers for indirectly measuring triglyceride absorption in the human proximal jejunum. Tritium labelled 1-hexadecyl-2, 3-didodecyl glycerol, or 1,2,3-trioleyl glycerol, or 1,2,3-tridecyl glycerol was dissolved in linseed oil and egg yolk lipids; an aqueous emulsion of the lipid mixture was infused into the stomach. Unexpectedly, postprandial jejunal contents contained proportionately less triether than triglyceride compared with the test meals. These triethers were found to separate from an aqueous phase at a faster rate than the triglyceride. This dissociation occurred in the stomach and thwarted quantification of triglyceride absorption by this test system.
In vitro and in vivo comparative study of chimeric liver-specific promoters
Authors: M.Gabriela Kramer, Miguel Barajas, Nerea Razquin, Pedro Berraondo, Manuel Rodrigo, Catherine Wu, Cheng Qian, Puri Fortes, Jesus Prieto
Journal: Molecular Therapy (2003)

Targeting therapeutic genes to the liver is essential to improve gene therapy protocols of hepatic diseases and of some hereditary disorders. Transcriptional targeting can be achieved using liver-specific promoters. In this study we have made chimeric constructs combining promoter and enhancer regions of the albumin, α1-antitrypsin, hepatitis B virus core protein, and hemopexin genes. Tissue specificity, activity, and length of gene expression driven from these chimeric regulatory sequences have been analyzed in cultured cells from hepatic and nonhepatic origin as well as in mice livers and other organs. We have identified a collection of liver-specific promoters whose activities range from twofold to less than 1% of the CMV promoter in human hepatoma cells. We found that the best liver specificity was attained when both enhancer and promoter sequences of hepatic genes were combined. In vivo studies were performed to analyze promoter function during a period of 50 days after gene transfer to the mouse liver. We found that among the various chimeric constructs tested in this work, the α1-antitrypsin promoter alone or linked to the albumin or hepatitis B enhancers is the most potent in directing stable gene expression in liver cells.
Role of the CXCL12/CXCR4 Axis in Peritoneal Carcinomatosis of Gastric Cancer
Authors: Kazuo Yasumoto, Keiichi Koizumi, Atsuhiro Kawashima, Yurika Saitoh, Yoshihisa Arita, Kanna Shinohara, Takayuki Minami, Takashi Nakayama, Hiroaki Sakurai, Yutaka Takahashi, Osamu Yoshie, Ikuo Saiki
Journal: Cancer Research (2006)

Abstract Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Because chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may be involved in the development of peritoneal carcinomatosis by gastric carcinoma. Human gastric carcinoma cell lines, which were all highly efficient in generating malignant ascites in nude mice upon i.p. inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells expressed CXCR4 mRNA at high levels and showed vigorous migratory responses to its ligand CXCL12. CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase of NUGC4 cells. We also showed that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. Additionally, we examined human clinical samples. Malignant ascitic fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (4.67 ng/mL). Moreover, immunohistochemical analysis showed that 22 of 33 primary gastric tumors with peritoneal metastasis were positive for CXCR4 expression (67%), whereas only 4 of 16 with other distant metastasis were positive (25%). Notably, 22 of 26 CXCR4-expressing primary tumors developed peritoneal metastases (85%). CXCR4 positivity of primary gastric carcinomas significantly correlated with the development of peritoneal carcinomatosis (P &amp;lt; 0.001). Collectively, our results strongly suggest that the CXCR4/CXC12 axis plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. Thus, CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma. (Cancer Res 2006; 66(4): 2181-7)
Prevalence of tuberculosis, hepatitis C virus, and HIV in homeless people: a systematic review and meta-analysis
Authors: Ulla Beijer, Achim Wolf, Seena Fazel
Journal: The Lancet Infectious Diseases (2012)

100 million people worldwide are homeless; rates of mortality and morbidity are high in this population. The contribution of infectious diseases to these adverse outcomes is uncertain. Accurate estimates of prevalence data are important for public policy and planning and development of clinical services tailored to homeless people. We aimed to establish the prevalence of tuberculosis, hepatitis C virus, and HIV in homeless people.We searched PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature for studies of the prevalence of tuberculosis, hepatitis C virus, and HIV in homeless populations. We also searched bibliographic indices, scanned reference lists, and corresponded with authors. We explored potential sources of heterogeneity in the estimates by metaregression analysis and calculated prevalence ratios to compare prevalence estimates for homeless people with those for the general population.We identified 43 eligible surveys with a total population of 63,812 (59 736 homeless individuals when duplication due to overlapping samples was accounted for). Prevalences ranged from 0·2% to 7·7% for tuberculosis, 3·9% to 36·2% for hepatitis C virus infection, and 0·3% to 21·1% for HIV infection. We noted substantial heterogeneity in prevalence estimates for tuberculosis, hepatitis C virus infection, and HIV infection (all Cochran's χ(2) significant at p<0·0001; I(2)=83%, 95% CI 76-89; 95%, 94-96; and 94%, 93-95; respectively). Prevalence ratios ranged from 34 to 452 for tuberculosis, 4 to 70 for hepatitis C virus infection, and 1 to 77 for HIV infection. Tuberculosis prevalence was higher in studies in which diagnosis was by chest radiography than in those which used other diagnostic methods and in countries with a higher general population prevalence than in those with a lower general prevalence. Prevalence of HIV infection was lower in newer studies than in older ones and was higher in the USA than in the rest of the world.Heterogeneity in prevalence estimates for tuberculosis, hepatitis C virus, and HIV suggests the need for local surveys to inform development of health services for homeless people. The role of targeted and population-based measures in the reduction of risks of infectious diseases, premature mortality, and other adverse outcomes needs further examination. Guidelines for screening and treatment of infectious diseases in homeless people might need to be reviewed.The Wellcome Trust.
Cardiac gap junctions and connexins: their role in atrial fibrillation and potential as therapeutic targets
Authors: H van der Velden
Journal: Cardiovascular Research (2002)

In the heart, changes in velocity and in patterns of conduction of myocardial electrical activity can affect cardiac rhythm and the coordination of contraction. Abnormal electrical coupling between cardiomyocytes through gap junctions is, therefore, considered an important factor in various pathophysiologic conditions. In the present report we summarize the literature on gap junctions and their structural proteins, the connexins, in the normal and fibrillating atrium. Putative implications of the recently reported remodelling of atrial gap junctions for stability of the arrhythmia will be discussed. Also the reversibility of the remodelling process will be addressed in the light of a potentially new therapeutic target for controlling the progression of atrial fibrillation (AF).
Second-line anti-tuberculosis drug concentrations for susceptibility testing in the MODS assay
Authors: Sean Patrick Fitzwater, G. Andrew Sechler, Oswaldo Jave, Jorge Coronel, Alberto Mendoza, Robert H. Gilman, Jon S. Friedland, David A.J. Moore
Journal: European Respiratory Journal (2012)

Multidrug-resistant tuberculosis (TB) threatens TB control worldwide. The microscopic observation drug susceptibility (MODS) assay is a low-cost, high-performance TB diagnostic tool for rapid liquid culture and direct isoniazid and rifampicin drug susceptibility testing (DST). The objective of this study was to explore the potential for extending the MODS assay to rapid second-line DST and to identify critical concentrations of candidate drugs for prospective testing. Sputum samples from 94 TB culture-positive patients receiving second-line TB agents were cultured following standardised MODS protocols, with a range of titrations of antimicrobial drugs added. Critical concentrations were determined using a modified Kaplan–Meier survival curve analysis. Candidate critical concentrations were determined for capreomycin (10 μg·mL −1 ), ciprofloxacin (1.25 μg·mL −1 ), cycloserine (40 μg·mL −1 ), ethambutol (10 μg·mL −1 ), ethionamide (5 μg·mL −1 ), kanamycin (5 μg·mL −1 ), para-aminosalicylic acid (10 μg·mL −1 ) and streptomycin (10 μg·mL −1 ). No cut-off point was identified for the other second-line drugs or for pyrazinamide. At particular concentrations of some second-line TB drugs this novel Kaplan–Meier analysis clearly differentiated populations that were susceptible or resistant. These candidate critical concentrations should now be tested in a range of epidemiological settings to define the performance of direct, second-line TB DST with MODS, offering potential low-cost second-line TB DST capacity.
Genome2D: a visualization tool for the rapid analysis of bacterial transcriptome data
Authors: Richard JS Baerends, Wiep Klaas Smits, Anne de Jong, Leendert W Hamoen, Jan Kok, Oscar P Kuipers
Journal: Genome biology (2004)

Genome2D is a Windows-based software tool for visualization of bacterial transcriptome and customized datasets on linear chromosome maps constructed from annotated genome sequences. Genome2D facilitates the analysis of transcriptome data by using different color ranges to depict differences in gene-expression levels on a genome map. Such output format enables visual inspection of the transcriptome data, and will quickly reveal transcriptional units, without prior knowledge of expression level cutoff values. The compiled version of Genome2D is freely available for academic or non-profit use from http://molgen.biol.rug.nl/molgen/research/molgensoftware.php.
Wavelet Transformations of Tumor Expression Profiles Reveals a Pervasive Genome-Wide Imprinting of Aneuploidy on the Cancer Transcriptome
Authors: Amit Aggarwal, Siew Hong Leong, Cheryl Lee, Oi Lian Kon, Patrick Tan
Journal: Cancer Research (2005)

Aneuploidy is frequently observed in many human cancers, but its global effects on the cancer transcriptome are controversial. We did a systematic and unbiased genome-wide survey to determine the extent a tumor's abnormal karyotype (chromosomal amplifications and deletions) is detectably "imprinted" onto that tumor's gene expression profile. By using a novel methodology employing wavelet transform signal-processing algorithms to identify genomic regions of coordinated gene expression (wavelet variance scanning), we analyzed a series of gastric cancer cell lines and identified >100 genomic regions exhibiting distinct patterns of subtle but significant coordinated transcription, ranging from tens to hundreds of genes. A large majority (80%) of these regions could be specifically localized to a site of detectable genomic amplification or deletion; reciprocally, up to 47% of the total aneuploidy in each of the individual cell lines could be directly inferred from the gene expression data. Genome-wide portraits of tumor aneuploidy can thus be successfully reconstructed solely from gene expression data, implying that the effects of aneuploidy must be pervasively and globally imprinted within the cancer transcriptome. Aneuploidy may contribute to tumor behavior not just by affecting the expression of a few key oncogenes and tumor suppressor genes but also by subtly altering the expression levels of hundreds of genes in the oncogenome.
Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: relationship with synovitis and steroid treatment
Authors: Clio Ribbens, M. Martin y Porras, N. Franchimont, Marie-Joëlle Kaiser, J. M. Jaspar, Pierre Damas, F. A. Houssiau, Michel Malaise
Journal: Annals of the Rheumatic Diseases (2002)

Objective: To determine matrix metalloproteinase-3 (MMP-3) serum levels in patients with rheumatic diseases and to study the relation between MMP-3 and C reactive protein (CRP) levels. Methods: MMP-3 serum levels were determined by enzyme linked immunosorbent assay (ELISA) in (<i>a</i>) patients with active inflammatory rheumatic diseases: rheumatoid arthritis (RA), psoriatic arthritis, polymyalgia rheumatica, acute crystal arthritis, and ankylosing spondylitis; (<i>b</i>) patients with active inflammatory systemic diseases: cutaneo-articular or renal systemic lupus erythematosus (SLE), systemic sclerosis, and vasculitides; (<i>c</i>) patients with non-inflammatory rheumatic diseases: osteoarthritis and fibromyalgia; (<i>d</i>) critically ill patients without rheumatic diseases, representing an acute inflammatory control group; (<i>e</i>) healthy controls. Results: MMP-3 serum levels were significantly increased in patients with active RA, psoriatic arthritis, and polymyalgia rheumatica, whether treated or not by corticosteroids, and in female patients with acute crystal arthritis. MMP-3 serum levels were normal in steroid-free patients with active cutaneo-articular or renal SLE, systemic sclerosis, and vasculitides but were significantly increased in steroid treated patients. MMP-3 levels were normal in fibromyalgia, osteoarthritis, ankylosing spondylitis, and acute inflammatory controls. MMP-3 was significantly correlated with CRP in RA (<i>r</i>=0.5, p=0.0004) but not in any of the other disease groups. Conclusions: MMP-3 serum levels are increased in inflammatory rheumatic diseases characterised by joint synovitis, such as RA, polymyalgia rheumatica, psoriatic arthritis, and acute crystal arthritis—that is, whether the diseases are acute or chronic, erosive or not. They are normal in SLE, systemic sclerosis, and vasculitides as well as in non-rheumatic inflammatory controls, but are significantly increased by steroids. These data strongly suggest that serum MMP-3 reflects synovial inflammation.
Natural killer type 2 bias in remission of multiple sclerosis
Authors: Kazuya Takahashi, Sachiko Miyake, Takayuki Kondo, Keiji Terao, Megumi Hatakenaka, Shuji Hashimoto, Takashi Yamamura
Journal: Journal of Clinical Investigation (2001)

Multiple sclerosis (MS) is an autoimmune disease characterized by clinical relapse and remission. Because of the potential role of natural killer (NK) cells in the regulation of autoimmunity, we have examined cytokine profile and surface phenotype of NK cells in the peripheral blood of MS. Here we demonstrate that NK cells in the remission of MS are characterized by a remarkable elevation of IL-5 mRNA and a decreased expression of IL-12Rβ2 mRNA, as well as a higher expression of CD95. Moreover, the NK cells from MS in remission produced much larger amounts of IL-5 than did those from controls after stimulation with phorbol myristate acetate (PMA) and ionomycin. These features are reminiscent of those of NK type 2 (NK2) cells that can be induced in a condition favoring functional deviation of T cells toward Th2. Remarkably, the NK cells lose the NK2-like property when relapse of MS occurs, but regain it after recovery. We also found that NK2 cells induced in vitro inhibit induction of Th1 cells, suggesting that the NK2-like cells in vivo may also prohibit autoimmune effector T cells. Taken together, it is possible that NK cells play an active role in maintaining the remission of MS.