tbuckley/cabot-search huggingface dataset:
Anti-inflammatory and Upper Gastrointestinal Effects of Celecoxib in Rheumatoid Arthritis
Authors: Lee S. Simon, Arthur L. Weaver, David Y. Graham, Alan J. Kivitz, Peter E. Lipsky, Richard C. Hubbard, Peter C. Isakson, Kenneth M. Verburg, Shawn S. Yu, William W. Zhao, G. Steven Geis
Journal: JAMA (1999)

In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 (COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal (GI) tract effects that result from COX-1 inhibition.To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis.Randomized, multicenter, placebo-controlled, double-blind trial lasting 12 weeks, with follow-up at weeks 2, 6, and 12, from September 1996 thorugh February 1998.Seventy-nine clinical sites in the United States and Canada.A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were randomized; 688 (60%) of these completed the study.Patients were randomized to receive celecoxib, 100 mg, 200 mg, or 400 mg twice per day (n = 240, 235, and 218, respectively); naproxen, 500 mg twice per day (n = 225); or placebo (n = 231).Improvement in signs and symptoms of rheumatoid arthritis as assessed using standard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment, compared among treatment groups.All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo. Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks. The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 (4%) of 99, and the incidences across all dosages of celecoxib were not significantly different (P>.40): 9 (6%) of 148 with 100 mg twice per day, 6 (4%) of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400 mg twice per day. In contrast, the incidence with naproxen was 36 (26%) of 137, significantly greater than either placebo or celecoxib (P<.001). The overall incidences of GI tract adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg twice per day, respectively; and 31 % for naproxen.In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.
Vitamin D2 Analog 19-nor-1,25-Dihydroxyvitamin D2: Antitumor Activity Against Leukemia, Myeloma, and Colon Cancer Cells
Authors: Takashi Kumagai, James O'Kelly, Jonathan W Said, H Phillip Koeffler
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: 1,25-Dihydroxyvitamin D3 inhibits growth of several types of human cancer cells in vitro, but its therapeutic use is hampered because it causes hypercalcemia. 19-nor-1,25-Dihydroxyvitamin D2 (paricalcitol) is a noncalcemic vitamin D analog that is approved by the Food and Drug Administration for the treatment of secondary hyperparathyroidism. We investigated the antitumor activity and mechanism of action of paricalcitol in vitro and in vivo. Methods: Effects of paricalcitol on proliferation, the cell cycle, differentiation, and apoptosis were examined in cancer cell lines. Effects on tumor growth were examined with colon cancer cell xenografts in nude mice (five in the experimental group and five in the control group). The interaction of paricalcitol with the vitamin D receptor (VDR) in mononuclear spleen cells and myeloid stem cells from wild-type and VDR knockout mice was examined. All statistical tests were two-sided. Results: Paricalcitol inhibited the proliferation of myeloid leukemia cell lines HL-60, NB-4, and THP-1 cells at an effective dose that inhibited growth 50% (ED50) of 2.4–5.8 × 10−9M by inducing cell cycle arrest and differentiation. Paricalcitol inhibited the proliferation of NCI-H929 myeloma cells at an ED50 of 2.0 × 10−10M by inducing cell cycle arrest and apoptosis. Paricalcitol also inhibited the proliferation of colon cancer cell lines HT-29 (ED50 = 1.7 × 10−8M) and SW837 (ED50 = 3.2 × 10−8M). HT-29 colon cancer xenografts in paricalcitol-treated nude mice were smaller (1044 mm3 and 1752 mm3, difference = 708 mm3, 95% confidence interval = 311 to 1104 mm3; P = .03) and weighed less (1487 mg and 4162 mg, difference = 2675 mg, 95% confidence interval = 2103 to 3248 mg; P<.001) than those in vehicle-treated mice. Paricalcitol induced committed myeloid hematopoietic stem cells from wild-type but not from VDR knockout mice to differentiate as macrophages. Conclusion: Paricalcitol has anticancer activity against myeloid leukemia, myeloma, and colon cancer cells that may be mediated through the VDR. Because it has been approved by the Food and Drug Administration, clinical trials of this agent in certain cancers are reasonable.
Unilateral multiple plaque-like syringomas
Authors: F. RONGIOLETTI, M.T. SEMINO, A. REBORA
Journal: British Journal of Dermatology (1996)

We describe a unique presentation of multiple unilateral syringomas characterized by indurated plaques. Histologically, in addition to typical eccrine duct proliferation, desmoplasia exceeding by far that usually observed in syringoma, accounted for the hard consistency of the plaques. This unusual presentation should be added to the numerous clinical variants of syringoma.
Effect of an Aggressive Lipid-Lowering Strategy on Progression of Atherosclerosis in the Left Main Coronary Artery From Patients in the Post Coronary Artery Bypass Graft Trial
Authors: Carl W. White, Fredarick L. Gobel, Lucien Campeau, Genell L. Knatterud, Sandra A. Forman, James S. Forrester, Nancy L. Geller, J. Alan Herd, Ann Hickey, Byron J. Hoogwerf, Donald B. Hunninghake, Yves Rosenberg, Michael L. Terrin
Journal: Circulation (2001)

Background The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of two lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol levels to a mean yearly cholesterol level from 93 to 97 mg/dL compared with a moderate reduction to a level of 132 to 136 mg/dL decreased the progression of atherosclerosis in saphenous vein grafts. Low-dose anticoagulation did not affect progression. This secondary analysis tested the hypothesis that a similar decrease in progression of atherosclerosis would also be present in native coronary arteries as measured in the left main coronary artery (LMCA). Methods and Results A sample of 402 patients was randomly selected from 1102 patients who had baseline and follow-up views of the LMCA suitable for analysis. Patients treated with the aggressive lipid-lowering strategy had less progression of atherosclerosis in the LMCA as measured by changes in minimum ( P =0.0003) lumen diameter or the maximum percent stenosis ( P =0.001), or the presence of substantial progression ( P =0.008), or vascular occlusion ( P =0.005) when compared with the moderate strategy. Conclusions A strategy of aggressive lipid lowering results in significantly less atherosclerosis progression than a moderate approach in LMCAs.
Fra-2 mediates oxygen-sensitive induction of transforming growth factor β in cardiac fibroblasts
Authors: Sashwati Roy, Savita Khanna, Ali Azad, Rebecca Schnitt, Guanglong He, Cora Weigert, Hidenori Ichijo, Chandan K. Sen
Journal: Cardiovascular Research (2010)

In the ischaemia-reperfused heart, transforming growth factor beta (TGFbeta) proteins trigger the differentiation of cardiac fibroblasts (CFs) contributing to fibrosis. Reoxygenation of the heart, in addition to being a trigger for reperfusion injury, induces tissue remodelling by hyperoxia-sensitive signalling processes involving TGFbeta. Here, we sought to characterize the molecular mechanisms responsible for the O(2)-sensitive transcriptional induction of TGFbeta in murine CF and to test the significance of such findings in the infarcted myocardium in vivo using laser capture microdissection.All three isoforms of TGFbeta were induced in the CF-rich peri-infarct tissue as well as in CF exposed to hyperoxic challenge. Reporter studies demonstrated that TGFbeta transcription is hyperoxia inducible. Deletion of any one or both of the activating protein-1 (AP-1) binding sites in the TGFbeta reporter construct resulted in loss of O(2) sensitivity, demonstrating that AP-1 confers O(2) sensitivity to TGFbeta transcription. Fos-related AP-1 transcription factor (Fra-2) and Ask-1 (apoptosis signal-regulating kinase-1) were identified as key mediators of AP-1-dependent O(2)-sensitive TGFbeta transcription. Knockdown of Fra-2 significantly blunted O(2)-induced expression of TGFbeta1 as well as TGFbeta3 in CF. Knockdown of Ask-1 blunted hyperoxia-induced Fra-2 gene expression and nuclear localization in CF. Collectively, these observations point towards a central role of Ask-1 and Fra-2 in O(2)-inducible AP-1 activation and induction of TGFbeta.Taken together with the observation that Fra-2-regulated genes are implicated in fibrosis, identification of Fra-2 as an O(2)-sensitive transcriptional regulator of inducible TGFbeta expression positions Fra-2 as an important player in reoxygenation-induced fibrosis.
Genomics and Perinatal Care
Authors: Joann Bodurtha, Jerome F. Strauss
Journal: New England Journal of Medicine (2012)

A mong both prospective parents and providers of medical care, genetic and social concerns peak during the perinatal period.Advances in genomics and assisted reproductive technology have created new opportunities to detect genetic disorders and susceptibilities at multiple times during perinatal care and thus are relevant to these concerns.Emerging therapies for single-gene disorders may reshape these discussions.Practitioners working with persons wishing to be parents are encouraged to inquire about their genetic backgrounds and family histories, to counsel them about tests for disease-carrier status that are based on known population-specific risks, 1 and to refer them, when appropriate, to specialists in high-risk pregnancy and genetics.Nonetheless, there are major differences across the world in the adoption and implementation of genetic education and screening practices by providers, women and their partners, and health payment systems. 2,3Such differences are to be expected because access to health care, along with the availability of genetic counseling and testing, varies.Even in the best-case scenario, patients, practitioners, and policymakers face complicated choices when selecting which genomic techniques to use broadly or individually in assessing risk and in determining how laboratory findings should inform decision making as the options for genetic testing expand. 4For example, it is not always possible to predict a priori the severity of a clinical condition on the basis of a genotype.A laboratory result may be flawless, but the identified genetic variation may not be known to cause a disease (i.e., it is a variant of uncertain significance).Or the discovered mutation or variant in a known disease gene may not reliably correlate with phenotype because of the influence of modifiers, which can be genetic, epigenetic, or environmental. Pr ec oncep t ion Gene t ic Scr eening a nd Te s t ingGenetic risk, especially of known genetic conditions in the family or a previous pregnancy, should ideally be assessed before conception or the establishment of a pregnancy in the context of assisted reproductive technology.Genetic screening is offered for a particular condition (or group of conditions) in individuals, groups, or populations.A family history of the condition is not required for genetic screening.Genetic testing is generally carried out when there is suspicion that an individual is at increased risk because of family history or because of a positive result on a biochemical screening test.][7][8][9][10] The American College of
Favorable Outcome of Severe, Extensive, Granulocyte Colony-Stimulating Factor–Induced, Corticosteroid-Resistant Sweet's Syndrome Treated With High-Dose Intravenous Immunoglobulin
Authors: Rodolfo Calixto, Yara Menezes, Maurício Ostronoff, Alexandre Sucupira, Luis Fábio Botelho, Rodrigo Florencio, Monique Martins, Ana Patrícia Souto Maior
Journal: Journal of Clinical Oncology (2014)
Putative Predictive Biomarkers of Survival in Patients with Metastatic Pancreatic Adenocarcinoma Treated with Gemcitabine and Ganitumab, an IGF1R Inhibitor
Authors: Ian McCaffery, Yanyan Tudor, Hongjie Deng, Rui Tang, Samuel Suzuki, Sunita Badola, Hedy L. Kindler, Charles S. Fuchs, Elwyn Loh, Scott D. Patterson, Li Chen, Jennifer L. Gansert
Journal: Clinical Cancer Research (2013)

This planned exploratory analysis assessed the predictive nature of baseline circulating factors of the insulin-like growth factor (IGF) axis on the treatment effect of ganitumab (monoclonal antibody inhibitor of IGF-1 receptor) plus gemcitabine in a randomized phase II study in metastatic pancreatic adenocarcinoma.Baseline levels of IGFs/IGF binding proteins (IGFBP) were analyzed in serum or plasma. Mutations and gene expression were analyzed in archival samples. Treatment effects between biomarker subgroups were compared for overall survival (OS). Associations of tumor markers with OS were evaluated.For patients with evaluable samples, ganitumab was associated with improved OS versus placebo (HR, 0.49; 95% CI: 0.28-0.87). The treatment effect on improved OS was strong in the patient subset with higher levels of IGF-1, IGF-2, or IGFBP-3, or lower levels of IGFBP-2, but not so on the other corresponding subset. Median OS of ganitumab versus placebo in patients with higher levels of IGF-1, IGF-2, and IGFBP-3 was 16 versus 6.8 months (HR, 0.25; 95% CI: 0.09-0.67), 16 versus 5.9 months (HR, 0.24; 95% CI: 0.09-0.68), and 16 versus 6.8 months (HR, 0.28; 95% CI: 0.11-0.73), and in patients with lower IGFBP-2 levels was 12.7 versus 6.6 months (HR, 0.19; 95% CI: 0.07-0.55). Interaction between treatment and IGFs/IGFBPs in multivariate analyses suggested predictive potential for IGF-2 (P = 0.002) and IGFBP-2 (P = 0.02). KRAS mutation status and PTEN expression were not associated with OS.Baseline circulating factors of the IGF axis may predict OS benefit from ganitumab plus gemcitabine in metastatic pancreatic adenocarcinoma.
STUDIES ON MENINGOCOCCUS INFECTION
Authors: Geoffrey Rake, Henry W. Scherp
Journal: The Journal of Experimental Medicine (1933)

Three fractions have been isolated from autolysates of the meningococcus. Of these, one, the type-specific substance, has been described in detail. The same type-specific substance appears to be present in Type I and Type III organisms, but a substance differing at least serologically has been obtained from Type II strains. Detailed chemical analysis of both of the type-specific substances thus far isolated is being carried out and will be the subject of a later paper.
Implications of Endocrine Gland–Derived Vascular Endothelial Growth Factor/Prokineticin-1 Signaling in Human Neuroblastoma Progression
Authors: Elly S.W. Ngan, Francesco Y.L. Sit, King Liu Lee, Xiaoping Miao, Zhengwei Yuan, Weilin Wang, John M. Nicholls, Kenneth K.Y. Wong, Mercè Garcia-Barcelo, Vincent C.H. Lui, Paul K.H. Tam
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Neuroblastoma is a common pediatric tumor that is derived from improperly differentiated neural crest cells (NCC). We recently revealed that endocrine gland–derived vascular endothelial growth factor/prokineticin-1 (EG-VEGF/Prok-1) is a key factor mediating the growth and differentiation of enteric NCCs during development. In this report, we further elucidate its role in neuroblastoma progression. Experimental Design: We studied the expression and copy number of EG-VEGF/Prok-1 receptors (PK-R1 and PK-R2) in 26 neuroblastoma tumors by real-time reverse transcription-PCR and immunohistochemical analysis. Implication of EG-VEGF/Prok-1 signaling in neuroblastoma progression was further shown in a neuroblastoma cell line (SK-N-SH). Results: We found that all neuroblastoma samples from stages II to IV expressed both PK-R1 and PK-R2. Kruskall-Wallis signed rank tests revealed that the expression level of PK-R1 transcript is associated with the stages and metastasis of the neuroblastoma (P &amp;lt; 0.05), and PK-R2 is persistently higher in advanced-stage neuroblastoma samples. About 38% of the neuroblastoma tumors (10:26) possessed MYCN amplification, whereas no PK-R1 and PK-R2 amplifications were detected, suggesting that the overexpression of the receptors was not due to gene amplification. Subsequent functional studies showed that EG-VEGF/Prok-1 activates the Akt pathway to induce the proliferation of neuroblastoma cells. Targeted down-regulation studies revealed that EG-VEGF/Prok-1–mediated proliferation requires the presence of these two receptors, and that PK-R2 is essential for inhibiting apoptosis. In vitro migration and invasion assays also indicated that EG-VEGF/Prok-1 significantly enhances the cell migration/invasion of SK-N-SH. Conclusions: Our study has shown for the first time that aberrant EG-VEGF/Prok-1 signaling favors neuroblastoma progression and could be a potential target for future neuroblastoma treatment.
Anti–Monocyte Chemoattractant Protein-1/Monocyte Chemotactic and Activating Factor Antibody Inhibits Neointimal Hyperplasia in Injured Rat Carotid Arteries
Authors: Yutaka Furukawa, Akira Matsumori, Naohiro Ohashi, Tetsuo Shioi, Koh Ono, Akihisa Harada, Kouji Matsushima, Shigetake Sasayama
Journal: Circulation Research (1999)

Abstract —Monocyte chemoattractant protein-1 (MCP-1)/monocyte chemotactic and activating factor (MCAF) has been suggested to promote atherogenesis. The effects of in vivo neutralization of MCP-1 in a rat model were examined in an effort to clarify the role of MCP-1 in the development of neointimal hyperplasia. Competitive polymerase chain reaction analysis revealed maximum MCP-1 mRNA expression at 4 hours after carotid arterial injury. Increased immunoreactivities of MCP-1 were also detected at 2 and 8 hours after injury. Either anti–MCP-1 antibody or nonimmunized goat IgG (10 mg/kg) was then administered every 12 hours to rats that had undergone carotid arterial injury. Treatment with 3 consecutive doses of anti–MCP-1 antibody within 24 hours (experiment 1) and every 12 hours for 5 days (experiment 2) significantly inhibited neointimal hyperplasia at day 14, resulting in a 27.8% reduction of the mean intima/media ratio ( P &lt;0.05) in experiment 1 and a 43.6% reduction ( P &lt;0.01) in experiment 2. This effect was still apparent at day 56 (55.6% inhibition; P &lt;0.05). The number of vascular smooth muscle cells in the neointima at day 4 was significantly reduced by anti–MCP-1 treatment, demonstrating the important role of MCP-1 in early neointimal lesion formation. However, recombinant MCP-1 did not stimulate chemotaxis of vascular smooth muscle cells in an in vitro migration assay. These results suggest that MCP-1 promotes neointimal hyperplasia in early neointimal lesion formation and that neutralization of MCP-1 before, and immediately after, arterial injury may be effective in preventing restenosis after angioplasty. Further studies are needed to clarify the mechanism underlying the promotion of neointimal hyperplasia by MCP-1.
Secretion of cytokines and growth factors into autosomal dominant polycystic kidney disease liver cyst fluid
Authors: Matthew T. Nichols, Elsa Gidey, Tom Matzakos, Rolf Dahl, Greg Stiegmann, Raj J. Shah, Jared J. Grantham, Gregory J. Fitz, R. Brian
Journal: Hepatology (2004)

The principal extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD) involves formation of liver cysts derived from intrahepatic bile ducts. Autocrine and paracrine factors secreted into the cyst would be positioned to modulate the rate of hepatic cyst growth. The aim of this study was to identify potential growth factors present in human ADPKD liver cyst fluid. Cytokine array and enzyme-linked immunosorbent assay analysis of human ADPKD liver cyst fluid detected epithelial neutrophil attractant 78, interleukin (IL)-6 (503 ± 121 pg/mL); and IL-8 (4,488 ± 355 pg/mL); and elevated levels of vascular endothelial growth factor compared with non-ADPKD bile (849 ± 144 pg/mL vs. 270 pg/mL maximum concentration). ADPKD liver cyst cell cultures also released IL-8 and vascular endothelial growth factor, suggesting that cystic epithelial cells themselves are capable of secreting these factors. Western blotting of cultured cyst cells and immunostaining of intact cysts demonstrate that cysteine-X-cysteine receptor 2, an epithelial neutrophil attractant 78 and IL-8 receptor, is expressed at the apical domain of cyst lining epithelial cells. Suggesting the cystic epithelial cells may exist in hypoxic conditions, electron microscopy of the ADPKD liver cyst epithelium revealed morphological features similar to those observed in ischemic bile ducts. These features include elongation, altered structure, and diminished abundance of apical microvilli. In conclusion, IL-8, epithelial neutrophil attractant 78, IL-6, and vascular endothelial growth factor may serve as autocrine and paracrine factors to direct errant growth of ADPKD liver cyst epithelia. Interruption of these signaling pathways may provide therapeutic targets for inhibiting liver cyst expansion. (Hepatology 2004;40:836-846).
Effect of recent antigen priming on adoptive immune responses. III. Antigen-induced selective recruitment of subsets of recirculating lymphocytes reactive to H-2 determinants.
Authors: J Sprent, J F Miller
Journal: The Journal of Experimental Medicine (1976)

Information was sought on the reactivity of thoracic duct lymphocytes (TDL) from parental strain mice injected intravenously with large numbers of irradiated semiallogeneic spleen cells. TDL collected at 1 day after spleen cell injection were almost totally depleted of lymphocytes able to produce cell-mediated lympholysis (CML), a graft-versus-host (GVH) reaction, and skin allograft rejection against the H-2 determinants on the injected spleen cells. Normal or near normal responses were observed against third-party determinants. In the case of CML, there was no evidence that the unresponsiveness was due to suppressor cells. In marked contrast, the capacity of TDL to exert a specific mixed lymphocyte reaction (MLR) against the injected determinants was reduced by no more than two to fourfold; this applied whether MLR were measured in vivo or in vitro. Injection of normal rather than irradiated semiallogeneic spleen cells gave similar results. Complete and specific removal of MLR-producing lymphocytes was achieved, however, in a different system in which parental strain T cells were filtered from blood to lymph through irradiated F1 hybrid mice. Since this system presumably provided a much higher concentration of H-2 determinants to the responding lymphocytes, it is suggested that the differing results obtained with these two systems may indicate that certain cells reactive to H-2 determinants are of low affinity, their reactivity being detected in the MLR, but not by other parameters. With both systems, MLR-producing lymphocytes reappeared in the lymph after 2-3 days; the cells collected at this stage gave an MLR of altered kinetics. The present data, in toto, suggest that under certain conditions of antigen presentation, virtually all recirculating lymphocytes reactive to a given set of H-2 determinants can be induced to leave the circulation for a period of 1-2 days. After responding to the injected determinants (presumably in organs such as the spleen), the cells re-enter the circulation in an activated state after 2-3 days.