tbuckley/cabot-search huggingface dataset:
p190RhoGEF (Rgnef) Promotes Colon Carcinoma Tumor Progression via Interaction with Focal Adhesion Kinase
Authors: Hong-Gang Yu, Ju-Ock Nam, Nichol L. G. Miller, Isabelle Tanjoni, Colin Walsh, Lei Shi, Linda Kim, Xiao Lei Chen, Alok Tomar, Ssang-Taek Lim, David D. Schlaepfer
Journal: Cancer Research (2011)

Focal adhesion kinase (FAK) functions downstream of integrins and growth factor receptors to promote tumor cell motility and invasion. In colorectal cancer, FAK is activated by amidated gastrin, a protumorigenic hormone. However, it is unclear how FAK receives signals from the gastrin receptor or other G-protein-coupled receptors that can promote cell motility and invasion. The Rho guanine-nucleotide exchange factor p190RhoGEF (Rgnef) binds FAK and facilitates fibroblast focal adhesion formation on fibronectin. Here we report that Rgnef mRNA and protein expression are significantly increased during colorectal tumor progression. In human colon carcinoma cells, Rgnef forms a complex with FAK and upon gastrin stimulation, FAK translocates to newly-forming focal adhesions where it facilitates tyrosine phosphorylation of paxillin. short hairpin (shRNA)-mediated knockdown of Rgnef or FAK, or pharmacological inhibition of FAK activity, is sufficient to block gastrin-stimulated paxillin phosphorylation, cell motility, and invadopodia formation in a manner dependent upon upstream cholecystokinin-2 receptor expression. Overexpression of the C-terminal region of Rgnef (Rgnef-C, amino acid 1,279-1,582) but not Rgnef-CΔFAK (amino acid 1,302-1,582 lacking the FAK binding site) disrupted endogenous Rgnef-FAK interaction and prevented paxillin phosphorylation and cell motility stimulated by gastrin. Rgnef-C-expressing cells formed smaller, less invasive tumors with reduced tyrosine phosphorylation of paxillin upon orthotopic implantation, compared with Rgnef-CΔFAK-expressing cells. Our studies identify Rgnef as a novel regulator of colon carcinoma motility and invasion, and they show that a Rgnef-FAK linkage promotes colon carcinoma progression in vivo.
Superior Efficacy of a Combined Epigenetic Therapy against Human Mantle Cell Lymphoma Cells
Authors: Warren Fiskus, Rekha Rao, Ramesh Balusu, Siddhartha Ganguly, Jianguo Tao, Eduardo Sotomayor, Uma Mudunuru, Jacqueline E. Smith, Stacey L. Hembruff, Peter Atadja, Victor E. Marquez, Kapil Bhalla
Journal: Clinical Cancer Research (2012)

Abstract Purpose: A deregulated epigenome contributes to the transformed phenotype of mantle cell lymphoma (MCL). This involves activity of the polycomb repressive complex (PRC) 2, containing three core proteins, EZH2, SUZ12, and EED, in which the SET domain of EZH2 mediates the histone methyltransferase activity. We determined the effects of 3-deazaneplanocin A (DZNep), an S-adenosylhomocysteine hydrolase inhibitor, and/or pan-histone deacetylase inhibitor panobinostat (PS) on cultured and primary MCL cells. Experimental Design: Following treatment with DZNep and/or PS, apoptosis and the levels and activity of EZH2 and PRC2 proteins in cultured and primary MCL cells were determined. Results: Treatment with DZNep depleted EZH2, SUZ12, and 3MeK27H3 in the cultured human MCL cells. DZNep also increased expression of p21, p27, and FBXO32, whereas it depleted Cyclin D1 and Cyclin E1 levels in MCL cells. In addition, DZNep treatment induced cell-cycle arrest and apoptosis in cultured and primary MCL cells. Furthermore, as compared with treatment with each agent alone, cotreatment with DZNep and PS caused greater depletion of EZH2, SUZ12, 3MeK27H3, and Cyclin D1 levels, whereas it induced greater expression of FBXO32, p16, p21, and p27. Combined treatment with DZNep and PS synergistically induced apoptosis of cultured and primary MCL cells while relatively sparing normal CD34 + cells. Cotreatment with DZNep and PS also caused significantly greater inhibition of tumor growth of JeKo-1 xenografts in NOD/SCID mice. Conclusions: These preclinical in vitro and in vivo findings show that cotreatment with DZNep and PS is an active combined epigenetic therapy worthy of further in vivo testing against MCL. Clin Cancer Res; 18(22); 6227–38. ©2012 AACR.
The development of experimental autoimmune encephalomyelitis in the mouse requires alpha4-integrin but not alpha4beta7-integrin.
Authors: B Engelhardt, M Laschinger, M Schulz, U Samulowitz, D Vestweber, G Hoch
Journal: Journal of Clinical Investigation (1998)

Because monoclonal antibodies (mAbs) directed against alpha4-integrin and VCAM-1 inhibit the development of experimental autoimmune encephalomyelitis (EAE) in vivo, it has been concluded that the successful therapeutic effect is due to interference with alpha4beta1/VCAM-1-mediated interaction of autoaggressive T cells with the blood-brain barrier. A possible role for alpha4beta7-integrin, or interference with other T cell mediated events during the pathogenesis of EAE, has not been considered. We have compared the effects of mAb therapy on the development of EAE in the SJL/N mouse, using a large panel of mAbs directed against alpha4, beta7, the alpha4beta7-heterodimer, and against VCAM-1. Although encephalitogenic T cells express both alpha4-integrins, mAbs directed against the alpha4beta7-heterodimer or against the beta7-subunit did not interfere with the development of EAE. In contrast, mAbs directed against alpha4 and VCAM-1 inhibited or diminished clinical or histopathological signs of EAE. Our data demonstrate for the first time that alpha4beta7 is not essential for the development of EAE. Furthermore, our in vitro studies suggest that the therapeutic effect of anti-alpha4-treatment of EAE might also be caused by inhibition of antigen-specific T cell proliferation.
Effects of nilotinib on regulatory T cells: the dose matters
Authors: Fei Fei, Yingzhe Yu, Anita Schmitt, Markus T Rojewski, Baoan Chen, Jochen Greiner, Marlies Götz, Donald Bunjes, Michael Schmitt
Journal: Molecular Cancer (2010)

Abstract Background Nilotinib is a tyrosine kinase inhibitor with high target specificity. Here, we characterized the effects of nilotinib for the first time on CD4 + CD25 + regulatory T cells (Tregs) which regulate anti-tumor/leukemia immune responses. Design and Methods Carboxyfluorescein diacetate succinimidyl ester (CFSE) and 5-bromo-2-deoxy -uridine (BrdU) were used to assess the proliferation and cell cycle distribution of Tregs. The expression of the transcription factor forkhead box P3 (FoxP3) and the glucocorticoid-induced tumor necrosis factor receptor (GITR) were measured by flow cytometry. Western blotting analysis was used to detect the effects of nilotinib on the signal transduction cascade of T-cell receptor (TCR) in Tregs. Results Nilotinib inhibited the proliferation and suppressive capacity of Tregs in a dose-dependent manner. However, the production of cytokines secreted by Tregs and CD4 + CD25 - T cells was only inhibited at high concentrations of nilotinib exceeding the mean therapeutic serum concentrations of the drug in patients. Only high doses of nilotinib arrested both Tregs and CD4 + CD25 - T cells in the G 0 /G 1 phase and down-regulated the expression of FoxP3 and GITR. In western blotting analysis, nilotinib did not show significant inhibitory effects on TCR signaling events in Tregs and CD4 + CD25 - T cells. Conclusions These findings indicate that nilotinib does not hamper the function of Tregs at clinical relevant doses, while long-term administration of nilotinib still needs to be investigated.
Increased Rho-kinase expression and activity and pulmonary endothelial dysfunction in smokers with normal lung function
Authors: S. Duong-Quy, P. Dao, T. Hua-Huy, C. Guilluy, P. Pacaud, A.T. Dinh-Xuan
Journal: European Respiratory Journal (2010)

Endothelial dysfunction is one of the main consequences of the toxic effects of cigarette smoke on the vascular system. Increasing evidence suggests that the small G-protein RhoA and its downstream effectors, the Rho-kinases (ROCKs), are involved in systemic endothelial dysfunction induced by cigarette smoke. This study aimed to evaluate the role of the RhoA/ROCKs pathway in pulmonary artery endothelial function in current smokers with normal lung function. Lung tissues were obtained from nonsmokers and smokers who underwent lobectomy for lung carcinoma. Arterial relaxation in response to acetylcholine (ACh) was assessed in isolated pulmonary arterial rings. Protein expressions and activities of endothelial nitric oxide synthase (eNOS), ROCKs and the myosin phosphatase subunit 1 (MYPT-1) were sought. Relaxation in response to ACh was significantly lower in smokers as compared with nonsmokers (n = 8 in each group), consistent with reduced eNOS activity in the former compared with the latter. eNOS protein expression remained, however, the same in both groups. Expression of ROCKs, guanosine triphosphate-RhoA and phosphorylated MYPT-1 were significantly increased in smokers compared with controls. Pulmonary endothelial dysfunction is present in smokers whose lung function has not yet been impaired. Reduced activity of eNOS accounts at least in part for this endothelial dysfunction. Increased expression and activity of ROCKs accounts for another part through direct or indirect inhibition of the Rho-A/ROCKs pathway on nitric oxide synthesis and sustained pulmonary vasoconstriction through inhibition of myosin phosphatase.
Transcriptional regulation of human osteopontin promoter by histone deacetylase inhibitor, trichostatin A in cervical cancer cells
Authors: Priyanka Sharma, Santosh Kumar, Gopal C Kundu
Journal: Molecular Cancer (2010)

Abstract Background Trichostatin A (TSA), a potent inhibitor of histone deacetylases exhibits strong anti-tumor and growth inhibitory activities, but its mechanism(s) of action is not completely understood. Osteopontin (OPN) is a secreted glycoprotein which has long been associated with tumor metastasis. Elevated OPN expression in various metastatic cancer cells and the surrounding stromal cells often correlates with enhanced tumor formation and metastasis. To investigate the effects of TSA on OPN transcription, we analyzed a proximal segment of OPN promoter in cervical carcinoma cells. Results In this paper, we for the first time report that TSA suppresses PMA-induced OPN gene expression in human cervical carcinoma cells and previously unidentified AP-1 transcription factor is involved in this event. Deletion and mutagenesis analyses of OPN promoter led to the characterization of a proximal sequence (-127 to -70) that contain AP-1 binding site. This was further confirmed by gel shift and chromatin immunoprecipitation (ChIP) assays. Western blot and reverse transcription-PCR analyses revealed that TSA suppresses c-jun recruitment to the OPN promoter by inhibiting c-jun levels while c-fos expression was unaffected. Silencing HDAC1 followed by stimulation with PMA resulted in significant decrease in OPN promoter activity suggesting that HDAC1 but not HDAC3 or HDAC4 was required for AP-1-mediated OPN transcription. TSA reduces the PMA-induced hyperacetylation of histones H3 and H4 and recruitment of RNA pol II and TFIIB, components of preinitiation complex to the OPN promoter. The PMA-induced expression of other AP-1 regulated genes like cyclin D1 and uPA was also altered by TSA. Interestingly, PMA promoted cervical tumor growth in mice xenograft model was significantly suppressed by TSA. Conclusions In conclusion, these findings provide new insights into mechanisms underlying anticancer activity of TSA and blocking OPN expression at transcriptional level by TSA may act as novel therapeutic strategy for the management of cervical cancer.
Chondrocyte IGF-1 receptor expression and responsiveness to IGF-1 stimulation in mouse articular cartilage during various phases of experimentally induced arthritis.
Authors: P J Verschure, J van Marle, L A Joosten, W B van den Berg
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVE--To examine the distribution of insulin like growth factor-1 (IGF-1) receptors and the biological response to IGF-1 stimulation in articular cartilage of normal mouse knee joints and arthritic joints taken at various stages of experimentally induced arthritis. METHODS--In situ IGF-1 receptor expression and responsiveness to IGF-1 stimulation were examined in murine articular cartilage at different phases in two models of experimentally induced arthritis. IGF-1 receptor expression was visualised in joint sections with the use of anti-IGF-1 receptor antibodies and quantified by confocal laser scanning microscopy. Chondrocyte proteoglycan (PG) synthesis was measured by incorporation of 35S-sulphate. RESULTS--In control cartilage, the majority of IGF-1 receptors were found on chondrocytes localised in the middle and deeper zones of the cartilage, whereas receptor expression in surface zone chondrocytes was very low. During culture of normal articular cartilage, IGF-1 was able to maintain chondrocyte PG synthesis at the in vivo level. Concurrently with the development of arthritis, cartilage lost its capacity to react to IGF-1, but IGF-1 stimulation recovered when the inflammatory response waned. Shortly after induction of arthritis, IGF-1 receptor expression initially declined, but it had returned to normal levels by day 1 and remained increased thereafter. CONCLUSION--The distribution of IGF-1 receptor expression in the different zones of normal articular cartilage reflects IGF-1 stimulation and metabolic activity of chondrocytes in these layers. This correlation is disturbed in arthritic cartilage, suggesting inadequate or overruled signalling.
Comparative properties of the Charcot-Leyden crystal protein and the major basic protein from human eosinophils.
Authors: G J Gleich, D A Loegering, K G Mann, J E Maldonado
Journal: Journal of Clinical Investigation (1976)

Guinea pig eosinophil granules contain a protein, the major basic protein (MBP), which accounts for more than half of the total granule protein, has a high content of arginine, and displays a remarkable tendency to form disulfide-linked aggregates. In this study we have purified a similar protein from human eosinophil granules and have compared the human MBP to the protein comprising the Charcot-Leyden crystal (CLC). Eosinophils from patients with various diseases were purified and disrupted, and the granule fraction was obtained. Examination of the granule fraction by transmission electron microscopy showed numerous typical eosinophil granules. Analyses of granule lysates by gel filtration and by polyacrylamide gel electrophoresis revealed the presence of peroxidase and MBP with properties similar to that previously found in guinea pig eosinophil granules. The human MBP had a molecular weight of 9,200, contained less than 1% carbohydrate, was rich in arginine, and readily formed disulfide-bonded aggregates. CLC were prepared from eosinophil-rich cell suspensions by homogenization in hypotonic saline. The supernates following centrifugation of cell debris spontaneously formed CLC. Analysis of CLC revealed the presence of a protein with a molecular weight of 13,000 containing 1.2% carbohydrate. The protein displayed a remarkable tendency to aggregate even in the presence of 0.2 M acetic acid. Human MBP and CLC protein differed in their molecular weights, carbohydrate compositions, and amino acid analyses. Mixtures of the MBP and the CLC protein yielded two bands in polyacrylamide gel electrophoresis. Neither eosinophil protein increased vascular permeability in the guinea pig skin or contracted the guinea pig ileum. The results indicate that the human MBP and the CLC are distinct substances with properties such that one cannot be derived from the other.
James Curtis Hepburn, M.D., 1815–1911 (Hepburn of Japan)
Authors: Herbert Wohl
Journal: New England Journal of Medicine (1970)

THE mutual "discovery" of Japan and the West began in the middle of the 16th century, when Europeans, three Portuguese sailors from a ship blown off course, landed in Japan. The first Western ships entered the Japanese islands a year or two later, bringing traders and missionaries.1 By 1570, there were 20 missionaries in Japan, the most famous being Francis Xavier, earlier cofounder of the Jesuits, who had arrived in 1549 for a two-year stay. Although these early visitors were well received, being learned and well bred, later arrivals engaged in slaving and other brutalities, which the Japanese soon found . . .
Validity of three accelerometers during treadmill walking and motor vehicle travel
Authors: Matthew Maddocks, Andrea Petrou, Lindsay Skipper, Andrew Wilcock
Journal: British Journal of Sports Medicine (2008)

To determine the relative accuracy during treadmill walking and motor vehicle travel of the ActivPAL, PALlite and Digi-Walker accelerometers.Forty healthy volunteers wearing all accelerometers undertook either five treadmill walks (n=20) at speeds ranging between 0.6 and 1.4 m/s or a 15 min motor vehicle journey (n=20). Step counts recorded by each accelerometer were compared with the actual step count determined by video analysis (treadmill walking) or with an actual step count of zero (motor vehicle). Mean percentage measurement error was calculated and compared between devices by one-way ANOVA and Student t test.For treadmill walking, the measurement error was lowest for the ActivPAL, with no significant differences between the ActivPAL and the PALlite monitors. The measurement error was significantly higher for the Digi-Walker at speeds of < or =1 m/s. During vehicle travel erroneous steps were recorded by the PALlite (254 steps) and Digi-Walker (25 steps), but not the ActivPAL monitor (0 steps).The ActivPAL accelerometer accurately measures step count over a range of walking speeds and, unlike the other accelerometers tested, is not falsely triggered by motor vehicle travel.
Natural History of CNS Relapse in Patients With Aggressive Non-Hodgkin's Lymphoma: A 20-Year Follow-Up Analysis of SWOG 8516—The Southwest Oncology Group
Authors: Steven H. Bernstein, Joseph M. Unger, Michael LeBlanc, Jonathan Friedberg, Thomas P. Miller, Richard I. Fisher
Journal: Journal of Clinical Oncology (2008)

Purpose To investigate the incidence, natural history, and risk factors predictive of CNS relapse in patients with de novo aggressive lymphomas and to evaluate the efficacy of CNS prophylaxis in patients with initial bone marrow (BM) involvement. Patients and Methods We conducted an analysis of CNS events from 20-year follow-up data on 899 eligible patients with aggressive lymphoma treated on Southwest Oncology Group protocol 8516, a randomized trial of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), ProMACE (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide)-CytaBOM (cytarabine, bleomycin, vincristine, methotrexate), and m-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide). Patients with BM involvement randomly assigned to receive ProMACE-CytaBOM (63 patients) or m-BACOD (58 patients) were to receive CNS prophylaxis, whereas those randomly assigned to receive CHOP or MACOP-B did not. Results CNS relapse is uncommon (25 of 899 patients), with a cumulative incidence of 2.8%. CNS relapse occurs early (median time to relapse, 5.4 months from diagnosis). Indeed, 20 of 25 patients with CNS relapse relapsed during chemotherapy, or within 6 months of completion. The number of extranodal sites and the International Prognostic Index were predictive of CNS relapse. There was no significant benefit of CNS prophylaxis in patients with BM involvement at diagnosis; however, given the small number of events, the power of this analysis is limited. Conclusion The early occurrence of CNS events suggests that these patients had subclinical disease at initial diagnosis. As such, strategies to better detect and treat patients with subclinical CNS disease at diagnosis would be anticipated to result in a decrease in the incidence of CNS relapse, without subjecting those patients not destined for CNS relapse to unnecessary and potentially toxic prophylaxis strategies.
Suicide and Newspapers: A Replicated Study
Authors: SOL BLUMENTHAL, LAWRENCE BERGNER
Journal: American Journal of Psychiatry (1973)

To determine the importance of imitation in the act of suicide, the authors replicated a study by Motto that dealt with the relationship of suicide rates to the cessation of newspaper publication caused by a strike. Using the population of New York City during a partial newspaper strike, they compared the rates of suicide during this period with the rates during identical periods of three preceding years and two subsequent years. They found that while the overall suicide rate was not significantly reduced, the suicide rate of young women under age 35 was lower.
Review body reports in PM's in tray
Authors: W. Russell
Journal: BMJ (1985)

This is the time of year when the chickens-in other words, the reports of the pay review bodies-come home to roost.First to arrive was the one on nurses' pay with a recommendation said to be 9%, which is way beyond the 3% figure that ministers have been talking about for public sector pay.The report from the doctors' and dentists' review body should have arrived by now, and there again there seems every indication of an award that simply cannot be given in full.But the nurses present a special problem.Last year was the first year of their pay body and as a result its report was
Preventing Obesity Across Generations: Evidence for Early Life Intervention
Authors: Debra Haire-Joshu, Rachel Tabak
Journal: Annual Review of Public Health (2015)

To prevent the intergenerational transfer of obesity and end the current epidemic, interventions are needed across the early life stages, from preconception to prenatal to infancy through the age of 2 years. The foundation for obesity is laid in early life by actions and interactions passed from parent to child that have long-lasting biologic and behavioral consequences. The purpose of this paper is to examine the best evidence about (a) factors in parents and offspring that promote obesity during the early life stages, (b) the social determinants and dimensions of obesity in early life, (c) promising and effective interventions for preventing obesity in early life, and (d) opportunities for future research into strategies to disrupt the intergenerational cycle of obesity that begins early in life. The pathway for halting the intergenerational obesity epidemic requires the discovery and development of evidence-based interventions that can act across multiple dimensions of influence on early life.