tbuckley/cabot-search huggingface dataset:
Lack of efficacy of etanercept in Sjogren syndrome correlates with failed suppression of tumour necrosis factor and systemic immune activation
Authors: N M Moutsopoulos, G E Katsifis, N Angelov, R A Leakan, V Sankar, S Pillemer, S M Wahl
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To provide insight into the clinical failure of the tumour necrosis factor α (TNFα) inhibitor, etanercept, in primary Sjögren syndrome (pSS), an extensive analysis of the systemic immune profile of patients with pSS was carried out and the effect of etanercept treatment on these immune parameters monitored. <h3>Methods:</h3> Peripheral blood mononuclear cells of patients with pSS and healthy controls were compared by flow cytometry to determine differences in distribution of specific cell populations (T cells, B cells, monocytes), and to determine their expression of activation markers (CD25, HLA-DR), TNF receptors and chemokine receptors (CXCR1, 2) before and after treatment. Systemic cytokine levels were measured by multiplex ELISA assay in plasma and in lipopolysaccharide-stimulated whole blood from healthy controls and from patients with pSS before and after etanercept treatment. Baseline cytokine levels were correlated with clinical markers of disease. <h3>Results:</h3> Before treatment, salivary gland inflammatory focus scores did not correlate with circulating TNF levels. Furthermore, consistent with the lack of evidence of significant clinical benefit, enhanced markers of immune activation, frequency of cell subpopulations and aberrant cytokine profiles were not restored to normal levels by etanercept treatment. Remarkably, the levels of circulating TNFα were significantly increased after treatment. <h3>Conclusion:</h3> Etanercept is an ineffective therapeutic agent in pSS consistent with the absence of suppression of TNFα and other indicators of immune activation in this patient population. These data suggest that TNFα may not be a pivotal cytokine in the pathogenesis of pSS, impelling continued molecular characterisation of disease parameters to define appropriate intervention targets.
A Chemically Induced Model for Squamous Cell Carcinoma of the Lung in Mice
Authors: Yian Wang, Zhongqiu Zhang, Ying Yan, William J. Lemon, Marie LaRegina, Carl Morrison, Ronald Lubet, Ming You
Journal: Cancer Research (2004)

Lung cancer, primarily associated with tobacco use, is the leading cause of cancer morbidity and mortality in the United States. Squamous cell carcinoma (SCC) is one of the four major histological types of lung cancer. Although there are several established models for lung adenoma and adenocarcinomas, there is no well-established mouse model for lung SCC. We treated eight different inbred strains of mice with N-nitroso-tris-chloroethylurea by skin painting and found that this regimen induced lung SCCs in five strains of mouse (SWR/J, NIH Swiss, A/J, BALB/cJ, and FVB/J) but not in the others (AKR/J, 129/svJ, and C57BL/6J). Mouse lung SCCs have similar histopathological features and keratin staining to human SCC. Moreover, a wide spectrum of abnormal lung squamous phenotypes including hyperplasia, metaplasia, carcinoma in situ, and invasive carcinoma, were observed. There are strain-specific differences in susceptibility to Lscc induction by N-nitroso-tris-chloroethylurea with NIH Swiss, A/J, and SWR/J mice developing scores of SCCs whereas the resistant strains AKR/J, 129/svJ, and C57BL/6J failed to develop any SCCs. FVB/J and BALB/cJ mice had an intermediate response. We conducted whole-genome linkage disequilibrium analysis in seven strains of mice, divided into three phenotype categories of susceptibility, using Fisher's exact test applied to 6,128 markers in publically available databases. Three markers were found significantly associated with susceptibility to SCC with the P < 0.05. They were D1Mit169, D3Mit178, and D18Mit91. Interestingly, none of these sites overlap with the major susceptibility loci associated with lung adenoma/adenocarcinoma development in mice. The mouse SCC described here is highly significant for preclinical studies of lung cancer chemopreventive agents because most human trials have been conducted against precancerous lesions for SCC. Furthermore, this model can be used in determining genetic modifiers that contribute to susceptibility or resistance to lung SCC development.
Cooperating Mechanisms of CXCR5 and CCR7 in Development and Organization of Secondary Lymphoid Organs
Authors: Lars Ohl, Golo Henning, Stefan Krautwald, Martin Lipp, Svenja Hardtke, Günter Bernhardt, Oliver Pabst, Reinhold Förster
Journal: The Journal of Experimental Medicine (2003)

Homeostatic chemokines participate in the development of secondary lymphoid organs and later on in the functional organization of these tissues. The development of lymph nodes (LNs) and Peyer's patches depends on the recruitment of CD3− CD4+ interleukin (IL)-7Rαhi cells to sites of future organ development. CD3− CD4+ IL-7Rαhi cells express the chemokine receptor CXCR5 and might be attracted by its ligand CXCL13, which is secreted by mesenchymal cells. Mesenchymal cells also secrete CCL19, a ligand for CCR7, yet it is not clear whether CCR7 and CCL19 are important for secondary lymphoid organ development. Analyzing CXCR5−/− CCR7−/− double deficient mice we now show that these mice lack all examined peripheral LNs suggesting a profound role for both receptors in secondary lymphoid organ development. We demonstrate that CD3− CD4+ IL-7Rαhi cells express CXCR5 as well as CCR7 indicating that both receptors cooperate during an early step of secondary lymphoid organ development. Furthermore, CXCR5−/− CCR7−/− mice display a severely disturbed architecture of mesenteric LN and spleen. Due to an impaired migration of B cells into the white pulp, CXCR5−/− CCR7−/− mice fail to develop B cell follicles but show small clusters of unorganized lymphocytes in the spleen. These data demonstrate a cooperative function of CXCR5 and CCR7 in lymphoid organ organogenesis and organization.
Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial
Authors: Hansjochen Wilke, Kei Muro, Eric Van Cutsem, Sang-Cheul Oh, György Bodoky, Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, Oleg Lipatov, Tae-You Kim, David Cunningham, Philippe Rougier, Yoshito Komatsu, Jaffer Ajani, Michael Emig, Roberto Carlesi, David Ferry, Kumari Chandrawansa, Jonathan D Schwartz, Atsushi Ohtsu
Journal: The Lancet Oncology (2014)
Quantification of serum hepatitis C virus core protein level in patients chronically infected with different hepatitis C virus genotypes.
Authors: E Orito, M Mizokami, T Tanaka, J Y Lau, K Suzuki, M Yamauchi, Y Ohta, A Hasegawa, S Tanaka, M Kohara
Journal: Gut (1996)

BACKGROUND/AIM: A novel fluorescent enzyme immunoassay (FEIA) for the detection and quantification of serum hepatitis C virus (HCV) core protein was developed. The aim of this study was to evaluate the relation among serum HCV core protein level, HCV RNA level, and HCV genotype in patients with chronic HCV infection. PATIENTS AND METHODS: Serum HCV core protein, HCV RNA, HCV genotype were determined in 175 patients using the FEIA, branched DNA assay (Quantiplex HCV RNA ver 1.0), and serologically defined genotyping assay, respectively. For the specificity, all 13 patients seronegative for anti-HCV were negative for serum core antigen and HCV RNA by FEIA and bDNA, respectively. RESULTS: FEIA assay seems to be more sensitive than bDNA for patients with HCV type 2 infection (detection: 83.4% v 63.4%, p &lt; 0.01). There was a good overall correlation between the FEIA and bDNA results. However, when the patients were stratified into their HCV types, a correlation was observed in HCV type 1 but not in type 2 infection. Patients with HCV type 2 infection had a lower serum HCV core protein level (median 56 RFI) compared with type 1 infection (median 149 RFI, p &lt; 0.01). Thirty seven patients subsequently received interferon alpha therapy, patients who showed a complete and sustained response had a lower pretreatment serum HCV core protein level compared with patients who had a relapse and nonresponders (36 v 338 RFI, p &lt; 0.01). CONCLUSIONS: This study showed that FEIA (1) is a good assay for the detection and quantification of serum HCV core protein level, (2) is also very sensitive in detecting HCV core protein in patients with HCV type 2 infection, and (3) may have a role as a predictor of subsequent response to interferon therapy.
LFA-1–specific therapy prolongs allograft survival in rhesus macaques
Authors: Idelberto R. Badell, Maria C. Russell, Peter W. Thompson, Alexandra P. Turner, Tim A. Weaver, Jennifer M. Robertson, Jose G. Avila, Jose A. Cano, Brandi E. Johnson, Mingqing Song, Frank V. Leopardi, Sarah Swygert, Elizabeth A. Strobert, Mandy L. Ford, Allan D. Kirk, Christian P. Larsen
Journal: Journal of Clinical Investigation (2010)

Outcomes in transplantation have been limited by suboptimal long-term graft survival and toxicities associated with current immunosuppressive approaches. T cell costimulation blockade has shown promise as an alternative strategy to avoid the side effects of conventional immunosuppressive therapies, but targeting CD28-mediated costimulation alone has proven insufficient to prevent graft rejection in primates. Donor-specific memory T (TM) cells have been implicated in costimulation blockade-resistant transplant rejection, due to their enhanced effector function and decreased reliance on costimulatory signaling. Thus, we have tested a potential strategy to overcome TM cell-driven rejection by targeting molecules preferentially expressed on these cells, such as the adhesion molecule lymphocyte function-associated antigen 1 (LFA-1). Here, we show that short-term treatment (i.e., induction therapy) with the LFA-1-specific antibody TS-1/22 in combination with either basiliximab (an IL-2Rα-specific mAb) and sirolimus (a mammalian target of rapamycin inhibitor) or belatacept (a high-affinity variant of the CD28 costimulation-blocker CTLA4Ig) prolonged islet allograft survival in nonhuman primates relative to control treatments. Moreover, TS-1/22 masked LFA-1 on TM cells in vivo and inhibited the generation of alloproliferative and cytokine-producing effector T cells that expressed high levels of LFA-1 in vitro. These results support the use of LFA-1-specific induction therapy to neutralize costimulation blockade-resistant populations of T cells and further evaluation of LFA-1-specific therapeutics for use in transplantation.
The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis
Authors: Gwon-Soo Jung, Mi-Kyung Kim, Mi Sun Choe, Kyeong-Min Lee, Hye-Soon Kim, Young Joo Park, Hueng-Sik Choi, Ki-Up Lee, Keun-Gyu Park, In-Kyu Lee
Journal: Journal of the American Society of Nephrology (2009)

The accumulation of extracellular matrix proteins is a common feature of fibrotic kidney diseases. Accumulating evidence suggests that TGF-beta and plasminogen activator inhibitor type 1 (PAI-1) promote the development of renal fibrosis by stimulating the generation and inhibiting the removal of matrix proteins. The small heterodimer partner (SHP) represses PAI-1 expression in the liver by inhibiting TGF-beta signaling, but whether SHP inhibits renal fibrosis is unknown. Here, unilateral ureteral obstruction (UUO) markedly increased the expression of PAI-1, type I collagen, and fibronectin but decreased SHP gene expression. Moreover, in kidneys of SHP-/- mice, the expression of PAI-1, type I collagen, fibronectin and alpha-smooth muscle actin (alpha-SMA) were higher compared with those in kidneys of wild-type mice. In addition, loss of SHP accelerated renal fibrosis after UUO. Adenovirus-mediated overexpression of SHP in cultured rat mesangial cells and renal tubular epithelial cells inhibited TGF-beta-stimulated expression of PAI-1, type I collagen, and fibronectin. SHP inhibited TGF-beta- and Smad3-stimulated PAI-1 promoter activities as well as TGF-beta-stimulated binding of Smad3 to its consensus response element on the PAI-1 promoter. Similarly, in vivo, adenovirus-mediated overexpression of SHP in the kidney inhibited the expression of UUO-induced PAI-1, type I collagen, fibronectin, and alpha-SMA. In summary, SHP attenuates renal fibrosis in obstructive nephropathy, making its pathway a possible therapeutic target for chronic kidney disease.
DC-STAMP is essential for cell–cell fusion in osteoclasts and foreign body giant cells
Authors: Mitsuru Yagi, Takeshi Miyamoto, Yumi Sawatani, Katsuya Iwamoto, Naobumi Hosogane, Nobuyuki Fujita, Kozo Morita, Ken Ninomiya, Toru Suzuki, Kana Miyamoto, Yuichi Oike, Motohiro Takeya, Yoshiaki Toyama, Toshio Suda
Journal: The Journal of Experimental Medicine (2005)

Osteoclasts are bone-resorbing cells that play a pivotal role in bone remodeling. Osteoclasts form large multinuclear giant cells by fusion of mononuclear osteoclasts. How cell fusion is mediated, however, is unclear. We identify the dendritic cell–specific transmembrane protein (DC-STAMP), a putative seven-transmembrane protein, by a DNA subtraction screen between multinuclear osteoclasts and mononuclear macrophages. DC-STAMP is highly expressed in osteoclasts but not in macrophages. DC-STAMP–deficient mice were generated, and osteoclast cell fusion was completely abrogated in homozygotes despite normal expression of osteoclast markers and cytoskeletal structure. As osteoclast multinucleation was restored by retroviral introduction of DC-STAMP, loss of cell fusion was directly attributable to a lack of DC-STAMP. Defects in osteoclast multinucleation reduce bone-resorbing activity, leading to osteopetrosis. Similar to osteoclasts, foreign body giant cell formation by macrophage cell fusion was also completely abrogated in DC-STAMP–deficient mice. We have thus identified an essential regulator of osteoclast and macrophage cell fusion, DC-STAMP, and an essential role of osteoclast multinucleation in bone homeostasis.
Antibodies as antigens. The use of mouse monoclonal antibodies to focus human T cells against selected targets.
Authors: A Lanzavecchia, S Abrignani, D Scheidegger, R Obrist, B Dörken, G Moldenhauer
Journal: The Journal of Experimental Medicine (1988)

We found that three tumor patients treated with mouse mAbs have T cells that recognize processed mouse Ig on autologous APC in a class II-restricted fashion, and we have shown that mouse mAbs directed against various cell surface molecules can be used as antigens to focus these T cells on an MHC class II-positive target of choice.
Effect of postal prompts to patients and general practitioners on the quality of primary care after a coronary event (POST): randomised controlled trial
Authors: G. Feder, C. Griffiths, S. Eldridge, M. Spence
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objectives:</b> To determine whether postal prompts to patients who have survived an acute coronary event and to their general practitioners improve secondary prevention of coronary heart disease. <b>Design:</b> Randomised controlled trial. <b>Setting:</b> 52 general practices in east London, 44 of which had received facilitation of local guidelines for coronary heart disease. <b>Participants:</b> 328 patients admitted to hospital for myocardial infarction or unstable angina. <b>Interventions:</b> Postal prompts sent 2 weeks and 3 months after discharge from hospital. The prompts contained recommendations for lowering the risk of another coronary event, including changes to lifestyle, drug treatment, and making an appointment to discuss these issues with the general practitioner or practice nurse. <b>Main outcome measures:</b> Proportion of patients in whom serum cholesterol concentrations were measured;proportion of patients prescribed β blockers (6 months after discharge); and proportion of patients prescribed cholesterol lowering drugs (1 year after discharge). <b>Results:</b>Prescribing of β bockers (odds ratio 1.7,95% confidence interval 0.8 to 3.0, P&gt;0.05) and cholesterol lowering drugs (1.7, 0.8 to 3.4, P&gt;0.05) did not differ between intervention and control groups. A higher proportion of patients in the intervention group (64%) than in the control group (38%) had their serum cholesterol concentrations measured (2.9, 1.5 to 5.5, P&lt;0.001). Secondary outcomes were significantly improved for consultations for coronary heart disease, the recording of risk factors, and advice given. There were no significant differences in patients9 self reported changes to lifestyle or to the belief that it is possible to modify the risk of another coronary event. <b>Conclusions:</b> Postal prompts to patients who had had acute coronary events and to their general practitioners in a locality where guidelines for coronary heart disease had been disseminated did not improve prescribing of effective drugs for secondary prevention or self reported changes to lifestyle. The prompts did increase consultation rates related to coronary heart disease and the recording of risk factors in the practices. Effective secondary prevention of coronary heart disease requires more than postal prompts and the dissemination of guidelines.
TREM-2 promotes macrophage survival and lung disease after respiratory viral infection
Authors: Kangyun Wu, Derek E. Byers, Xiaohua Jin, Eugene Agapov, Jennifer Alexander-Brett, Anand C. Patel, Marina Cella, Susan Gilfilan, Marco Colonna, Daniel L. Kober, Tom J. Brett, Michael J. Holtzman
Journal: The Journal of Experimental Medicine (2015)

Viral infections and type 2 immune responses are thought to be critical for the development of chronic respiratory disease, but the link between these events needs to be better defined. Here, we study a mouse model in which infection with a mouse parainfluenza virus known as Sendai virus (SeV) leads to long-term activation of innate immune cells that drive IL-13–dependent lung disease. We find that chronic postviral disease (signified by formation of excess airway mucus and accumulation of M2-differentiating lung macrophages) requires macrophage expression of triggering receptor expressed on myeloid cells-2 (TREM-2). Analysis of mechanism shows that viral replication increases lung macrophage levels of intracellular and cell surface TREM-2, and this action prevents macrophage apoptosis that would otherwise occur during the acute illness (5–12 d after inoculation). However, the largest increases in TREM-2 levels are found as the soluble form (sTREM-2) long after clearance of infection (49 d after inoculation). At this time, IL-13 and the adapter protein DAP12 promote TREM-2 cleavage to sTREM-2 that is unexpectedly active in preventing macrophage apoptosis. The results thereby define an unprecedented mechanism for a feed-forward expansion of lung macrophages (with IL-13 production and consequent M2 differentiation) that further explains how acute infection leads to chronic inflammatory disease.
Study of the mechanism of cationic drug release increase coated with Surelease® after curing
Authors: Yanting Hou, Huiying Wang, Xuezhu Zhang, Meijuan Zou, Gang Cheng
Journal: Asian Journal of Pharmaceutical Sciences (2013)

This paper describes the investigation of the release mechanism of the cationic drug coated with Surelease® after curing compared with nonionic and anionic drug. The release rate of cured propafenone hydrochloride pellets coated with Surelease® was increased significantly compared with uncured ones. The changes in release rate after seal-coating proved the migration of drug into the polymer film. Based on a comparative study of ammonia permeation tests and the impact of ammonia on drug with different properties, it was shown that the change in release of the cationic drug after curing was related to the combination of cationic drug and ammonia in Surelease®. Also, the scanning electron microscopy results showed that curing and dissolution can both prevent polymer film coalescence. During coating, the evaporated ammonia combined with the cationic drug and the polymer film coalesced. However, the combined ammonia could be decomposed during curing and interrupt the coalescence of the polymer-coat, leading to increased release. In an optimized process, the ammonia in the Surelease® can be evaporated quickly and the ionization of the drug will be reduced. All these factors can contribute to the formation of the polymer film.
The Effects of Secretin, Pancreozymin, and Gastrin on Insulin and Glucagon Secretion in Anesthetized Dogs *
Authors: Roger H. Unger, Hermann Ketterer, John Dupré, Anna M. Eisentraut
Journal: Journal of Clinical Investigation (1967)

The effects upon islet hormone secretion of highly purified preparations of secretin and of pancreozymin-cholecystokinin and of a crude gastrin-containing extract of hog antrum have been studied in acutely operated dogs. All three preparations were shown to cause a striking increase in insulin concentration in the pancreaticoduodenal venous plasma after their rapid endoportal injection in anesthetized dogs. With each hormone preparation, the peak in insulin secretion occurred 1 minute after injection, and a rapid decline was observed immediately thereafter. Whereas secretin and gastrin failed to alter significantly the pancreaticoduodenal venous glucagon or arterial glucose concentration, pancreozymin caused a dramatic rise in pancreaticoduodenal venous glucagon concentration, which reached a peak 3 minutes after injection, and hyperglycemia was noted to occur soon thereafter. Endoportal infusion of secretin and pancreozymin for 20 minutes caused responses that were sustained but qualitatively identical to the responses noted after rapid injection of the hormones. The beta-cytotropic effect of secretin was abolished by the infusion of epinephrine. These results could not be attributed to the small degree of contamination of the enteric hormone preparations with insulin or glucagon, and it would appear that secretin, pancreozymin, and probably gastrin have insulin-releasing activity and that pancreozymin has, in addition, glucagon-releasing activity.The demonstration that these three hormones possess insulin-releasing activity suggests that there is in the gastrointestinal tract a chain of betacytotropic hormones from antrum to ileum that is capable of augmenting insulin secretion as required for disposal of substrate loads. It is suggested that the existence of this "entero-insular axis" prevents high substrate concentrations that would otherwise follow ingestion of large meals were the insular response entirely a function of arterial substrate concentration.
Preventing Graves' Ophthalmopathy
Authors: Wilmar M. Wiersinga
Journal: New England Journal of Medicine (1998)

Graves' ophthalmopathy and Graves' hyperthyroidism are closely linked, but the precise relation between these different expressions of the same disease is poorly understood. One much-debated issue is whether ophthalmopathy develops or becomes more severe as a result of the treatment of hyperthyroidism with antithyroid drugs, thyroidectomy, or radioiodine. The question must be considered in the context of the natural history of Graves' ophthalmopathy. In patients with Graves' hyperthyroidism, eye disease appears before the onset of hyperthyroidism in about 20 percent, at the same time as hyperthyroidism in about 40 percent, and after hyperthyroidism in about 40 percent. Furthermore, this eye . . .