tbuckley/cabot-search huggingface dataset:
Abstract 273: Molecular markers promoting metastases to the brain via EMT: Genes, proteins, and functional analysis.
Authors: Dhruve S. Jeevan, Sudeepta Sridhara, Alex Braun, Raj Murali, Meena Jhanwar-Uniyal
Journal: Cancer Research (2013)

Abstract Brain metastasis is the most common cause of mortality and morbidity of many cancers and occurs in more than 40% of patients. The metastatic cascade entails an orderly sequence of steps enabling tumor cells to migrate from the primary tumor and colonize at secondary locations. The underlying mechanisms of metastatic dissemination to the brain remain to be defined. However, In order to achieve this metastatic potential a cancer cell may go through a cellular reprogramming process, namely epithelial-to-mesenchymal transition (EMT), and its counterpart mesenchymal-to-epithelial transition (MET), by acquiring multiple genetic alterations and a stem cell like phenotype. We hypothesized that EMT would play a crucial role in brain metastasis. In order to achieve our goal we studied the expression of markers of EMT, MET, and stem cells in metastatic brain tumor samples. Microarray analysis of metastatic tumors was also done using a plate form of 17,000 genes. Furthermore, functional analysis establishing the metastatic phenotype of cancer cells towards a cerebral environment was also demonstrated using metastatic cell lines. Our results demonstrated that the expressions of EMT markers (Snail, TWIST, pSTAT3, NFkB), as well as the mesenchymal marker Vimentin, were present in metastatic tumor samples. The stem cell marker CD44 was also highly expressed. Gene expression analysis established the high presence of transcriptional factors associated with differentiation and reprogramming. Lastly, Immunofluorescence analysis demonstrated the presence of the mesenchymal marker Vimentin in brain tumor specimens. Tumor cells grown in astrocytic media displayed an increased cell proliferation, as well as enhanced S-phase cell cycle entry using an EDU incorporation technique. Migration of primary tumor cells was significantly enhanced in astrocytic media as evidenced by scratch wound migration. Furthermore, the tumor cells have a greater affinity for astrocytic media as demonstrated by chemotatic migratory tests. Moreover, co-culture analysis of primary tumor cells with astrocytic cells shows amicable mutual growth with Immunofluorescence demonstrating cell-to-cell interaction via E-Cadherin. In conclusion results of this study suggests that reprogramming via EMT/MET plays a crucial step in brain metastasis, and that the cerebral milieu provides a suitable microenvironment for metastatic cells to grow and disseminate. Citation Format: Dhruve S. Jeevan, Sudeepta Sridhara, Alex Braun, Raj Murali, Meena Jhanwar-Uniyal. Molecular markers promoting metastases to the brain via EMT: Genes, proteins, and functional analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 273. doi:10.1158/1538-7445.AM2013-273
Serious Fraud Office launches criminal inquiry into GlaxoSmithKline
Authors: A. O'Dowd
Journal: BMJ (2014)

The United Kingdom’s major fraud body has launched a criminal investigation into the drug company GlaxoSmithKline (GSK). The Serious Fraud Office inquiry, announced on 27 May, will focus on the commercial practices of GSK and its subsidiaries and comes just weeks after the company was accused of bribery in China.1

The BMJ understands that the new investigation will look at …
Adherent Platelets Recruit and Induce Differentiation of Murine Embryonic Endothelial Progenitor Cells to Mature Endothelial Cells In Vitro
Authors: Harald Langer, Andreas Eberhard May, Karin Daub, Ulrich Heinzmann, Peter Lang, Michael Schumm, Dietmar Vestweber, Steffen Massberg, Tanja Schönberger, Iris Pfisterer, Antonis K. Hatzopoulos, Meinrad Gawaz
Journal: Circulation Research (2005)

The homing and differentiation mechanisms of endothelial progenitor cells (EPCs) at sites of vascular lesions are unclear. To investigate whether platelets play a role in the recruitment and differentiation of EPCs, we made use of a robust mouse embryonic EPC (eEPC) line that reliably differentiates to a mature endothelial phenotype. We found that platelets stimulate chemotaxis and migration of these murine eEPCs. Further, the substantial adhesion of murine eEPCs on immobilized platelets that occurs under dynamic flow conditions is inhibited by neutralizing anti-P-selectin glycoprotein ligand-1 and anti-VLA-4 (beta1-integrin) monoclonal antibodies but not by anti-CD11b (aM-integrin; macrophage antigen-1). Coincubation of murine eEPCs with platelets for 5 days induced differentiation of EPCs to mature endothelial cells as verified by positive von Willebrand factor immunofluorescence and detection of Weibel Palade bodies through electron microscopy. We conclude that platelets may play a critical part in the capture and subsequent differentiation of murine eEPCs at sites of vascular lesions, revealing a possible new role of platelets in neoendothelization after vascular injury.
Radiological articular involvement in the dominant hand in rheumatoid arthritis.
Authors: W D Owsianik, A Kundi, J N Whitehead, G R Kraag, C Goldsmith
Journal: Annals of the Rheumatic Diseases (1980)

Scoring the severity of joint involvement in the x-rays of hands of patients with rheumatoid arthritis showed significantly greater joint destruction in the dominant hand. The difference was seen in all the joints, and especially in the wrists, but with the exception of the metacarpophalangeal joint of the thumb. The grip strength was not, however, different in the 2 hands.
Response to radiation incidents and radionuclear threats
Authors: John R Buscombe
Journal: BMJ (2004)

EDITOR—I agree with Turai et al that radiation injury could occur by accident in countries where disintegrating political entities such as the former Soviet Union leave the debris of their nuclear programmes lying around for an unsuspecting public to pick up.1 2 However, I am less sure of the real, as against hysterical, threat in Western …
Risk of Bladder Cancer Among Diabetic Patients Treated With Pioglitazone
Authors: James D. Lewis, Assiamira Ferrara, Tiffany Peng, Monique Hedderson, Warren B. Bilker, Charles P. Quesenberry, David J. Vaughn, Lisa Nessel, Joseph Selby, Brian L. Strom
Journal: Diabetes Care (2011)

OBJECTIVE Some preclinical in vivo studies and limited human data suggest a possible increased risk of bladder cancer with pioglitazone therapy. This is an interim report of an ongoing cohort study examining the association between pioglitazone therapy and the risk of bladder cancer in patients with diabetes. RESEARCH DESIGN AND METHODS This study includes 193,099 patients in the Kaiser Permanente Northern California diabetes registry who were ≥40 years of age between 1997 and 2002. Those with prior bladder cancer were excluded. Ever use of each diabetes medication (defined as two or more prescriptions within 6 months) was treated as a time-dependent variable. Cox regression–generated hazard ratios (HRs) compared pioglitazone use with nonpioglitazone use adjusted for age, sex, race/ethnicity, diabetes medications, A1C, heart failure, household income, renal function, other bladder conditions, and smoking. RESULTS The group treated with pioglitazone comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among nonpioglitazone users. Overall, ever use of pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI 0.9–1.5]), with similar results in men and women (test for interaction P = 0.8). However, in the a priori category of &amp;gt;24 months of therapy, there was an increased risk (1.4 [1.03–2.0]). Ninety-five percent of cancers diagnosed among pioglitazone users were detected at early stage. CONCLUSIONS In this cohort of patients with diabetes, short-term use of pioglitazone was not associated with an increased incidence of bladder cancer, but use for more than 2 years was weakly associated with increased risk.
The regulation of plasma 18-hydroxy 11-deoxycorticosterone in man.
Authors: G H Williams, L M Braley, R H Underwood
Journal: Journal of Clinical Investigation (1976)

18-hydroxy 11-deoxycorticosterone (18-OH DOC), a weak mineralocorticoid, was estimated by a radioimmunoassay procedure after purification in 49 patients with hypertension and 38 normal control subjects. The sensitivity of the method was 2-4 pg; there was no detectable blank, and the precision was 9-10%. In normal subjects the absolute plasma levels were similar to those of aldosterone. ACTH administration produced a 23-fold increase, and sodium restriction resulted in a 4-fold increase (5.4+/-0.7-20.5+/-3.0 ng/dl). On the other hand, the plasma levels of 18-OH DOC declined by nearly 50% with upright posture or angiotensin II infusion. During both of these procedures, plasma aldosterone levels significantly increased. Patients with normal and low renin hypertension had similar changes in plasma 18-OH DOC levels with sodium restriction. However, the mean high sodium level in the normal renin essential hypertension group (11.6+/-1.6 ng/dl) was significantly greater (P is less than 0.001) than in the control group (5.4+/-0.7 ng/dl). In addition, at least 22% and perhaps as high as 37% of the hypertensive subjects had levels greater than the upper limits of normal on a high sodium intake. Differences between the groups were less impressive in the sodium-restricted studies. There were no significant differences in age, duration of hypertension, sodium balance, serum sodium, potassium, or blood urea nitrogen in those patients who had elevated levels of plasma 18-OH DOC. Patients with primary aldosteronism had levels within the normal range on both dietary intake. However, in contrast to the other groups there were no significant changes in the plasma levels with sodium restriction. Thus, a significant number of patients with essential hypertension presumably have an alteration in 18-OH DOC secretion.
Hypertension Caused by Salt Loading in the Dog
Authors: THOMAS G. COLEMAN, ARTHUR C. GUYTON
Journal: Circulation Research (1969)

Experimental hypertension was produced in dogs by salt loading after renal mass had been surgically reduced to an estimated one-third normal. Salt loading was accomplished in one group of five dogs by administering isotonic saline in lieu of drinking water and in another group of six dogs by continuously infusing isotonic saline. Arterial pressure, cardiac output, heart rate, stroke volume, and total peripheral resistance were determined at frequent intervals during a 1-week control period and a 2-week salt-loading period in both groups. In addition, right atrial pressure, blood urea nitrogen, serum sodium, and serum potassium were determined in the group that was continuously infused. Both groups demonstrated an increase in mean arterial pressure to hypertensive levels, transiently increased cardiac output and stroke volume, initially depressed then subsequently increased total peripheral resistance, and initially depressed and variable heart rate. It is concluded that salt loading in a partially nephrectomized dog causes elevated arterial pressure that is initially induced by increased cardiac output but that is eventually sustained by increased peripheral resistance. Possible mechanisms are discussed.
Evolution of Plant MADS Box Transcription Factors: Evidence for Shifts in Selection Associated with Early Angiosperm Diversification and Concerted Gene Duplications
Authors: H. Shan, L. Zahn, S. Guindon, P. K. Wall, H. Kong, H. Ma, C. W. dePamphilis, J. Leebens-Mack
Journal: Molecular Biology and Evolution (2009)

Phylogenomic analyses show that gene and genome duplication events have led to the diversification of transcription factor gene families throughout the evolutionary history of land plants and that gene duplications have played an important role in shaping regulatory networks influencing key phenotypic characters including floral development and flowering time. A molecular evolutionary investigation of the mode and tempo of selection acting on the angiosperm MADS box AP1/SQUA, AP3/PI, AG/AGL11, and SEP gene subfamilies revealed site-specific patterns of shifting evolutionary constraint throughout angiosperm history. Specific positions in the four canonical MADS box gene regions, especially K domains and C-terminal regions of all four of these MADS box gene subfamilies exhibited clade-specific shifts in selective constraint following concerted duplication events. Moreover, the frequency of site-specific shifts in constraint was correlated with gene duplications and early angiosperm diversification. We hypothesize that coevolution among interacting MADS box proteins may be responsible for simultaneous increases in the ratio of nonsynonymous to synonymous substitutions (dN/dS = ω) early in angiosperm history and following concerted duplication events.
Royal British Nurses' Association
Authors: F. Nightingale, None Westminster, J. G. Wainwright, H. B. Carter, J. S. Bristowe, S. J. Sharkey, L. M. Gordon, E. H. Lushington, T. Bryant, E. C. Perry, F. C. N. Bower, R. Alcock, J. Troutbeck, M. E. Thynne, W. H. Allchin, T. Bond, M. J. Pyne, J. H. Hale, F. Treves, A. E. Sansom, E. C. E. Luckes, H. Wace, J. Curnow, C. A. Leigh, K. H. Monk, J. B. Martin, F. Wilcocks, H. A. C. Gordon, W. A. Mackinnon, J. R. Lunn, E. Vincent, W. Rathbone, A. Marsden
Journal: BMJ (1893)
Effects of hemopexin on heme-mediated repression of 5-aminolevulinate synthase and induction of heme oxygenase in cultured hepatocytes
Authors: Peter R. Sinclair, William J. Bement, John F. Healey, Nadia Gorman, Jacqueline F. Sinclair, Herbert L. Bonkovsky, Heng H. Liem, Ursula Muller-Eberhard
Journal: Hepatology (1994)

The serum protein hemopexin is considered to have a major role in the mechanism of the uptake of heme by hepatocytes by means of a heme-hemopexin receptor. Therefore, we examined in primary cultures of adult rat and embryonic chick hepatocytes whether the presence of hemopexin would affect the heme-mediated repression of 5-aminolevulinate synthase activity (the rate-limiting enzyme of heme biosynthesis) and the heme-induced increase of heme oxygenase activity (the rate-limiting step of heme degradation). Both of these heme-mediated effects were partly or entirely prevented by the presence of hemopexin. We conclude that homologous hemopexin, at molar concentrations exceeding that of heme, inhibited the uptake of heme into hepatocytes. These results suggest that heme, in amounts sufficient to affect the rate-limiting steps of heme synthesis and degradation, can only enter hepatocytes in primary culture when the binding capacity of hemopexin for heme has been exceeded or altered.
Response to: "Rescuing the NIH before it is too late" from the Deputy Director for Extramural Research
Authors: N. Ruiz Bravo
Journal: Journal of Clinical Investigation (2006)

For a number of reasons, the NIH and the biomedical research community are facing a period of fiscal constraint after pronounced growth. In these difficult times, it is important that we all speak from the facts and work together to do a better job of explaining the importance of the nation's investment in biomedical research.
Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7
Authors: Benjamin J. Thompson, Vladimir Jankovic, Jie Gao, Silvia Buonamici, Alan Vest, Jennifer May Lee, Jiri Zavadil, Stephen D. Nimer, Iannis Aifantis
Journal: The Journal of Experimental Medicine (2008)

Ubiquitination is a posttranslational mechanism that controls diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes, including Notch1, c-Myc, and cyclin E. We have generated conditional Fbw7 knockout animals and inactivated the gene in hematopoietic stem cells (HSCs), progenitors, and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects hematopoiesis in a cell-autonomous manner. Fbw7−/− HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7−/− progenitors are unable to colonize the thymus, leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow (BM) stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E is visibly stabilized in the BM of Fbw7-deficient mice. Gene expression studies of Fbw7−/− HSCs and hematopoietic progenitors indicate that Fbw7 regulates, through the regulation of HSC cycle entry, the transcriptional “signature” that is associated with the quiescent, self-renewing HSC phenotype.
The Biology of the (Pro)Renin Receptor
Authors: Genevieve Nguyen, Dominik N. Muller
Journal: Journal of the American Society of Nephrology (2009)

The (pro)renin receptor (PRR) binds renin and prorenin, its proenzyme inactive form. Receptor-bound prorenin becomes enzymatically active and binding then activates the MAP kinases ERK1/2 and p38 pathways, leading to upregulation of profibrotic and cyclooxygenase-2 genes independent of angiotensin II generation. These characteristics explain the interest in the potential role of PRR in organ damage in diseases associated with activation of the renin-angiotensin system (RAS), in particular hypertension and diabetes. Although identification of PRR has improved our understanding of the physiology of the tissue RAS, its role in pathology is far from clear. Transgenic animals overexpressing PRR ubiquitously or selectively in smooth-muscle cells develop high BP or glomerulosclerosis, and increased expression of PRR is reported in models of hypertension or kidney damage. However, definitive proof is still lacking for a role for PRR in disease, or by showing improvement of disease by tissue-specific ablation of PRR or by administration of a specific PRR antagonist. Furthermore, the early embryonic lethality seen in PRR-null mice suggests PRR has additional essential cellular functions we do not understand.
Ligands for L-Selectin: Homing, Inflammation, and Beyond
Authors: Steven D. Rosen
Journal: Annual Review of Immunology (2003)

Understanding the molecular basis of lymphocyte homing to lymphoid organs was originally a problem of concern only to immunologists. With the discovery of L-selectin and its ligands, interested scientists have expanded to include glycobiologists, immunopathologists, cancer biologists, and developmental biologists. Going beyond its first discovered role in homing to lymph nodes, the L-selectin system is implicated in such diverse processes as inflammatory leukocyte trafficking in both acute and chronic settings, hematogenous metastasis of carcinoma cells, effector mechanisms for inflammatory demyelination of axons, and implantation of the early mammalian embryo. This review focuses on the ligands for L-selectin that are found on vascular endothelium, leukocytes, carcinoma cells, and at various extravascular sites. The discovery of selectins and their ligands has validated the long-predicted hypothesis that carbohydrate-directed cell adhesion is relevant in eukaryotic systems. Emphasis will be given to the carbohydrate and sulfation modifications of the ligands, which enable recognition by L-selectin. The rapid "homing" of labeled cells into the lymph nodes presumably had its basis in the special affinity of small lymphocytes for the endothelium of the postcapillary venules.
Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials
Authors: T Ninomiya, V Perkovic, F Turnbull, B Neal, F Barzi, A Cass, C Baigent, J Chalmers, N Li, M Woodward, S MacMahon
Journal: BMJ (2013)

<b>Objective</b> To define the cardiovascular effects of lowering blood pressure in people with chronic kidney disease. <b>Design</b> Collaborative prospective meta-analysis of randomised trials. <b>Data sources and eligibility</b> Participating randomised trials of drugs to lower blood pressure compared with placebo or each other or that compare different blood pressure targets, with at least 1000 patient years of follow-up per arm. <b>Main outcome measures</b> Major cardiovascular events (stroke, myocardial infarction, heart failure, or cardiovascular death) in composite and individually and all cause death. <b>Participants</b> 26 trials (152 290 participants), including 30 295 individuals with reduced estimated glomerular filtration rate (eGFR), which was defined as eGFR &lt;60 mL/min/1.73m<sup>2</sup>. <b>Data extraction</b> Individual participant data were available for 23 trials, with summary data from another three. Meta-analysis according to baseline kidney function was performed. Pooled hazard ratios per 5 mm Hg lower blood pressure were estimated with a random effects model. <b>Results</b> Compared with placebo, blood pressure lowering regimens reduced the risk of major cardiovascular events by about a sixth per 5 mm Hg reduction in systolic blood pressure in individuals with (hazard ratio 0.83, 95% confidence interval 0.76 to 0.90) and without reduced eGFR (0.83, 0.79 to 0.88), with no evidence for any difference in effect (P=1.00 for homogeneity). The results were similar irrespective of whether blood pressure was reduced by regimens based on angiotensin converting enzyme inhibitors, calcium antagonists, or diuretics/β blockers. There was no evidence that the effects of different drug classes on major cardiovascular events varied between patients with different eGFR (all P&gt;0.60 for homogeneity). <b>Conclusions</b> Blood pressure lowering is an effective strategy for preventing cardiovascular events among people with moderately reduced eGFR. There is little evidence from these overviews to support the preferential choice of particular drug classes for the prevention of cardiovascular events in chronic kidney disease.
Renal and liver functions and muscle injuries during training and after competition in Thai boxers.
Authors: V Saengsirisuwan, S Phadungkij, C Pholpramool
Journal: British Journal of Sports Medicine (1998)

To observe whether there are any injuries to muscle and deleterious effects on the liver and kidneys during training and after competition in Thai boxers.Serum levels of intracellular enzymes and specific markers in the urine were measured during training and after fighting in Thai boxers.During the training period, the activities of muscle enzymes were significantly increased whereas those of the liver enzymes and creatinine clearance were not changed. After a match, on the other hand, both liver and muscle enzyme activities were elevated but renal function was decreased.The training protocol for Thai boxers has virtually no deleterious effect on liver and renal function, but damage to skeletal muscle cells may occur. However, competition may cause muscle injury without any obvious damage to the liver and kidneys.
Routine invasive strategy within 24 hours of thrombolysis versus ischaemia-guided conservative approach for acute myocardial infarction with ST-segment elevation (GRACIA-1): a randomised controlled trial
Authors: Francisco Fernandez-Avilés, Joaquín J Alonso, Alfonso Castro-Beiras, Nicolás Vázquez, Jesús Blanco, Juan Alonso-Briales, Juan López-Mesa, Felipe Fernández-Vazquez, Isabel Calvo, Luis Martínez-Elbal, José A San Román, Benigo Ramos
Journal: The Lancet (2004)