tbuckley/cabot-search huggingface dataset:
Promoter hypermethylation of the SFRP2 gene is a high-frequent alteration and tumor-specific epigenetic marker in human breast cancer
Authors: Jürgen Veeck, Erik Noetzel, Nuran Bektas, Edgar Jost, Arndt Hartmann, Ruth Knüchel, Edgar Dahl
Journal: Molecular Cancer (2008)

Abstract Background We have previously reported that expression of the Wnt antagonist genes SFRP1 and SFRP5 is frequently silenced by promoter hypermethylation in breast cancer. SFRP2 is a further Wnt inhibitor whose expression was recently found being downregulated in various malignancies. Here we investigated whether SFRP2 is also implicated in human breast cancer, and if so whether SFRP2 promoter methylation might serve as a potential tumor biomarker. Methods We analyzed SFRP2 mRNA expression and SFRP2 promoter methylation in 10 breast cell lines, 199 primary breast carcinomas, 20 matched normal breast tissues and 17 cancer-unrelated normal breast tissues using RT-PCR, realtime PCR, methylation-specific PCR and Pyrosequencing, respectively. SFRP2 protein expression was assessed by immunohistochemistry on a tissue microarray. Proliferation assays after transfection with an SFRP2 expression vector were performed with mammary MCF10A cells. Statistical evaluations were accomplished with SPSS 14.0 software. Results Of the cancerous breast cell lines, 7/8 (88%) lacked SFRP2 mRNA expression due to SFRP2 promoter methylation ( P &lt; 0.001). SFRP2 expression was substantially restored in most breast cell lines after treatment with 5-aza-2'-deoxycytidine and trichostatin A. In primary breast carcinomas SFRP2 protein expression was strongly reduced in 93 of 125 specimens (74%). SFRP2 promoter methylation was detected in 165/199 primary carcinomas (83%) whereas all cancer-related and unrelated normal breast tissues were not affected by SFRP2 methylation. SFRP2 methylation was not associated with clinicopathological factors or clinical patient outcome. However, loss of SFRP2 protein expression showed a weak association with unfavorable patient overall survival ( P = 0.071). Forced expression of SFRP2 in mammary MCF10A cells substantially inhibited proliferation rates ( P = 0.045). Conclusion The SFRP2 gene is a high-frequent target of epigenetic inactivation in human breast cancer. Its methylation leads to abrogation of SFRP2 expression, conferring a growth advantage to epithelial mammary cells. This altogether supports a tumor suppressive function of SFRP2 . Although clinical patient outcome was not associated with SFRP2 methylation, the high frequency of this epimutation and its putative specificity to neoplastic cells may qualify SFRP2 promoter methylation as a potential candidate screening marker helping to improve early breast cancer detection.
Diagnosis of Hyperglycemia in a Cohort of Brazilian Subjects
Authors: Carolina S.V. Oliveira, José Gilberto H. Vieira, Maria Teresa Ghiringhello, Omar M. Hauache, Cláudia Helena M. Oliveira, Cristina Khawali, Claúdia Ferrer, Teresinha T. Tachibana, Rui M.B. Maciel, Gilberto Velho, André F. Reis
Journal: Diabetes Care (2007)

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) represent intermediate states between normal fasting glucose (NFG) or normal glucose tolerance (NGT), respectively, and diabetes (1). The regulation of fasting and glucose concentrations after an oral glucose load is dependent on different physiological mechanisms (2), and current evidence suggests that IFG and IGT have different pathophysiologies (3,4). Measurement of fasting plasma glucose (FPG) is the most frequently used screening test for diabetes. However, the oral glucose tolerance test (OGTT) might be a preferable test because FPG underestimates the severity of glucose intolerance (5,6) and because IFG and IGT define two distinct populations with only partial overlap (5,7,8). The present study was undertaken to compare insulin sensitivity and insulin secretion profiles associated with different stages of hyperglycemia as assessed by FPG only or by FPG and 2-h plasma glucose during an OGTT.

We analyzed data from 900 subjects without previously known diabetes who underwent an OGTT for diagnostic purposes at Fleury Institute, Sao Paulo, Brazil. A double-glycemic status was determined for each subject. A first set was based on FPG only as follows: NFG (FPG …
GLUCOCORTICOID SUPPRESSION OF MACROPHAGE MIGRATION INHIBITORY FACTOR
Authors: James E. Balow, Alan S. Rosenthal
Journal: The Journal of Experimental Medicine (1973)

The ability of hydrocortisone to modify antigen-mediated inhibition of macrophage migration, an in vitro correlate of cellular immunity in the guinea pig, was investigated. Only the glucocorticoids, hydrocortisone and dexamethasone, significantly blocked migration inhibitory factor (MIF) activity in pharmacologic concentrations. Hydrocortisone had no effect on antigen "processing" by macrophages, nor on the ability of antigen-stimulated peritoneal exudate lymphocytes to produce MIF. Rather, hydrocortisone antagonized directly the inhibitory effect of MIF on the macrophage.
Long term NSAID treatment inhibits COX-2 synthesis in the knee synovial membrane of patients with osteoarthritis: differential proinflammatory cytokine profile between celecoxib and aceclofenac
Authors: M A Alvarez-Soria
Journal: Annals of the Rheumatic Diseases (2006)

To compare the effect of celecoxib with that of a classic non-steroidal anti-inflammatory drug (NSAID) on synovial inflammation and on the synovial expression of proinflammatory genes in patients with knee osteoarthritis (OA).30 patients with severe knee OA scheduled for total knee replacement surgery were included in a 3 month clinical trial. They were randomised to two groups: patients treated with celecoxib (CBX) (200 mg/24 h) and patients treated with aceclofenac (ACF) (100 mg/12 h). Those patients with OA who did not want to be treated with NSAIDs served as a control group. During knee surgery, synovial fluid (SF) and synovial membrane (SM) were collected. A SM specimen was fixed and embedded in paraffin and another part was frozen for molecular biology studies.At the end of study both CBX and ACF treated patients showed a significant improvement in pain and knee function compared with controls. Both drugs significantly reduced prostaglandin E(2) (PGE(2)) SF concentration and down regulated COX-2 mRNA and protein expression at the SM. However, synovial macrophage infiltration (CD68 antigen staining) and expression of proinflammatory mediators, such as interleukin 1beta and tumour necrosis factor alpha, were decreased only by CBX treatment.Both drugs improved joint pain and function, inhibited SF PGE(2) concentration, and induced a decrease in synovial COX-2 expression and synthesis not related to the tissue inflammatory status. These data suggest that PGE(2) blocking agents may decrease PGE(2) production not only by direct COX-2 inhibition but also by down regulating COX-2 expression and synthesis. However, CBX and ACF appear to have different anti-inflammatory profiles in controlling OA synovial macrophage infiltration and proinflammatory expression.
Diverticular disease of the large intestine in Northern Norway.
Authors: T J Eide, H Stalsberg
Journal: Gut (1979)

In 280 unselected necropsies on patients over 20 years of age in Northern Norway, diverticular disease was present in 25% of the males and 43% of the females. The frequency of diverticular disease increased in both sexes by age. Both the frequency of diverticular disease and the average number of diverticula per case with diverticular disease were higher in females than in males in all age groups. The sigmoid was the most frequent site of diverticula in both sexes and for all ages, and the average number of diverticula per diverticulum-bearing segment was also highest in the sigmoid for all ages and in both sexes. The average number of diverticula in the sigmoid of affected individuals increased with age and with the number of segments involved. Diverticular disease was not associated with adenomas of the large intestine or with malignant or benign neoplasms elsewhere in the body or with any of the common diseases thought to be related to a Western type of diet, except with cerebrovascular disease.
Lung abscess complicating chondromas in Carney's syndrome
Authors: RP Convery, AJ Grainger, NK Bhatnagar, D Scott, SJ Bourke
Journal: European Respiratory Journal (1998)

Carney's syndrome consists of a combination of three rare tumours: gastric leiomyosarcoma, pulmonary chondroma and catecholamine-secreting paraganglioma. We describe a young woman with Carney's syndrome, who developed a lung abscess, due to obstruction of a bronchus by a chondroma, 11 yrs after having had a partial gastrectomy for a leiomyosarcoma.
Rescue of TRAF3-null mice by p100 NF-κB deficiency
Authors: Jeannie Q. He, Brian Zarnegar, Gagik Oganesyan, Supriya K. Saha, Soh Yamazaki, Sean E. Doyle, Paul W. Dempsey, Genhong Cheng
Journal: The Journal of Experimental Medicine (2006)

Proper activation of nuclear factor (NF)–κB transcription factors is critical in regulating fundamental biological processes such as cell survival and proliferation, as well as in inflammatory and immune responses. Recently, the NF-κB signaling pathways have been categorized into the canonical pathway, which results in the nuclear translocation of NF-κB complexes containing p50, and the noncanonical pathway, which involves the induced processing of p100 to p52 and the formation of NF-κB complexes containing p52 (Bonizzi, G., and M. Karin. 2004. Trends Immunol. 25:280–288). We demonstrate that loss of tumor necrosis factor (TNF) receptor–associated factor 3 (TRAF3) results in constitutive noncanonical NF-κB activity. Importantly, TRAF3−/− B cells show ligand-independent up-regulation of intracellular adhesion molecule 1 and protection from spontaneous apoptosis during in vitro culture. In addition, we demonstrate that loss of TRAF3 results in profound accumulation of NF-κB–inducing kinase in TRAF3−/− cells. Finally, we show that the early postnatal lethality observed in TRAF3-deficient mice is rescued by compound loss of the noncanonical NF-κB p100 gene. Thus, these genetic data clearly demonstrate that TRAF3 is a critical negative modulator of the noncanonical NF-κB pathway and that constitutive activation of the noncanonical NF-κB pathway causes the lethal phenotype of TRAF3-deficient mice.
Serum immunoreactive gastrin: specificity for rheumatoid arthritis, bimodality of distribution, and failure of effect of anti-inflammatory drugs.
Authors: P J Rooney, D M Grennan, R D Sturrock, P M Brooks, W C Dick
Journal: Annals of the Rheumatic Diseases (1976)

A significant rise in immunoreactive gastrin in a proportion of patients with rheumatoid arthritis is confirmed. Such a rise does not seem to occur in other inflammatory or tissue destructive diseases. The patients with raised immunoreactive gastrin appear to form a separate population but the factors determining this separation remain obscure. Anti-inflammatory drugs, at least during short-term administration have no influence on immunoreactive gastrin concentrations.
A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver disease
Authors: Taichiro Nishikawa, Nadège Bellance, Aaron Damm, Han Bing, Zhen Zhu, Kan Handa, Mladen I. Yovchev, Vasudha Sehgal, Tyler J. Moss, Michael Oertel, Prahlad T. Ram, Iraklis I. Pipinos, Alejandro Soto-Gutierrez, Ira J. Fox, Deepak Nagrath
Journal: Journal of Hepatology (2014)
Roles of Mitogen-Activated Protein Kinases and Protein Kinase C in α <sub>1A</sub> -Adrenoceptor–Mediated Stimulation of the Sarcolemmal Na <sup>+</sup> -H <sup>+</sup> Exchanger
Authors: Andrew K. Snabaitis, Hiroyuki Yokoyama, Metin Avkiran
Journal: Circulation Research (2000)

Abstract —Activation of the sarcolemmal Na + -H + exchanger (NHE) has been implicated as a mechanism of inotropic, arrhythmogenic, antiacidotic, and hypertrophic effects of α 1 -adrenoceptor (AR) stimulation. Although such regulation of sarcolemmal NHE activity has been shown to be selectively mediated through the α 1A -AR subtype, distal signaling mechanisms remain poorly defined. We investigated the roles of various kinase pathways in α 1A -AR–mediated stimulation of sarcolemmal NHE activity in adult rat ventricular myocytes. As an index of NHE activity, trans -sarcolemmal acid efflux rate ( J H ) was determined through microepifluorescence in single cells, during recovery from intracellular acidosis in bicarbonate-free conditions. Extracellular signal-regulated kinase (ERK), p38-mitogen-activated protein kinase (MAPK), and p90 rsk activities were indexed on the basis of analysis of their phosphorylation status. In control cells, there was no change in J H in response to vehicle. Phenylephrine and A61603, an α 1A -AR subtype–selective agonist, increased J H , as well as cellular ERK and p90 rsk activities. Neither agonist affected p38 activity, which was increased with sorbitol. The MAPK kinase inhibitor PD98059 abolished phenylephrine- and A61603-induced increases in J H and cellular ERK and p90 rsk activities. In contrast, the PKC inhibitor GF109203X abolished phenylephrine- and A61603-induced increases in J H but failed to prevent the increases in ERK and p90 rsk activities. Our findings suggest that α 1A -AR–mediated stimulation of sarcolemmal NHE activity in rat ventricular myocytes requires activation of the ERK (but not the p38) pathway of the MAPK cascade and that the ERK-mediated effect may occur via p90 rsk . Activation of PKC is also required for α 1A -AR–mediated NHE stimulation, but such regulation occurs through an ERK-independent pathway.
Enhancement of lung tumorigenesis in a Gprc5a Knockout mouse by chronic extrinsic airway inflammation
Authors: Peter Barta, Carolyn Van Pelt, Taoyan Men, Burton F Dickey, Reuben Lotan, Seyed Javad Moghaddam
Journal: Molecular Cancer (2012)

Abstract Background Although cigarette smoking is the principal cause of lung carcinogenesis, chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, has been identified as an independent risk factor for lung cancer. Bacterial colonization, particularly with non-typeable Haemophilus influenzae (NTHi), has been implicated as a cause of airway inflammation in COPD besides cigarette smoke. Accordingly, we hypothesized that lung cancer promotion may occur in a chronic inflammatory environment in the absence of concurrent carcinogen exposure. Results Herein, we investigated the effects of bacterial-induced COPD-like inflammation and tobacco carcinogen-enhanced tumorigenesis/inflammation in the retinoic acid inducible G protein coupled receptor knock out mouse model (Gprc5a-/- mouse) characterized by late-onset, low multiplicity tumor formation. Three-month-old Gprc5a-/- mice received 4 intraperitoneal injections of the tobacco-specific carcinogen, NNK, followed by weekly exposure to aerosolized NTHi lysate for 6 months. The numbers of inflammatory cells in the lungs and levels of several inflammatory mediators were increased in Gprc5a-/- mice treated with NTHi alone, and even more so in mice pretreated with NNK followed by NTHi. The incidence of spontaneous lung lesions in the Gprc5a-/- mice was low, but NTHi exposure led to enhanced development of hyperplastic lesions. Gprc5a-/- mice exposed to NNK alone developed multiple lung tumors, while NTHi exposure increased the number of hyperplastic foci 6-fold and the tumor multiplicity 2-fold. This was associated with increased microvessel density and HIF-1α expression. Conclusion We conclude that chronic extrinsic lung inflammation induced by bacteria alone or in combination with NNK enhances lung tumorigenesis in Gprc5a-/- mice.
Use of Read codes in diabetes management in a south London primary care group: implications for establishing disease registers
Authors: J. Gray
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To establish current practice in the use of Read codes for diabetes. <b>Design</b> Cross sectional study. <b>Setting</b> 17 practices in the Battersea primary care group in southwest London. <b>Data sources</b> Computerised medical records. <b>Main outcome measures</b> Number of codes in use in all practices; variation in the use of codes between practices; and prevalence of Read code use in diabetic patients. <b>Results</b> At least 9 separate Read code groupings and 25 individual diabetes codes were in use in the 17 general practices. Only one Read code (C10, diabetes mellitus) and its subcodes was being used in all 17 practices, but its use varied from 14% to 98% of patients with diabetes. The use of other key Read codes for monitoring the care of patients with diabetes also varied widely between practices; for example, &lt; 20% of practices used the code for the location of care. Less than half of patients (45%) with diabetes had their type of diabetes coded, and even fewer (21%) had measures such as the examination of the retina coded. <b>Conclusions</b> The use of Read codes for diabetes needs to be standardised and coding levels improved if valid diabetic registers are to be constructed and the quality of care is to be monitored effectively. Until all patients with diabetes have the C10 Read code recorded, clinicians will have to use a wide range of Read codes and prescribing data to ensure that diabetes registers are complete.
What can mendelian randomisation tell us about modifiable behavioural and environmental exposures?
Authors: George Davey Smith, Shah Ebrahim
Journal: BMJ (2005)

Using genetic variants as a proxy for modifiable environmental factors that are associated with disease can circumvent some of the problems of observational studies 

Epidemiologists look for modifiable causes of common diseases to improve population health. However, epidemiological studies may identify spurious “causes.” For example, the epidemiological findings that hormone replacement therapy protects against coronary heart disease,w1β carotene prevents lung cancer,w2and vitamin E and vitamin C reduce risk of cardiovascular diseasew3have all been refuted by randomised controlled trials and have raised concerns about the value of epidemiological studies.1 The misleading findings were probably due to confounding by behavioural, physiological, and socioeconomic factors related both to exposures and to disease end points.2 3 One solution to these problems is mendelian randomisation.4 5

Mendelian randomisation is a recent development in genetic epidemiology6 7 based on Mendel's second law that inheritance of one trait is independent of inheritance of other traits. It uses common genetic polymorphisms that are known to influence exposure patterns (such as propensity to drink alcohol) or have effects equivalent to those produced by modifiable exposures (such as raised blood cholesterol concentration). Associations between genetic variants and outcome are not generally confounded by behavioural or environmental exposures. This means that observational studies of genetic variants have similar properties to intention to treat analyses in randomised controlled trials (fig 1).



Comparison of design of mendelian randomisation studies and randomised controlled trials



The simplest way of appreciating the potential of mendelian randomisation is to consider applications of the underlying principles. The inferences that can be drawn from mendelian randomisation studies depend on the different ways in which genetic variants can proxy for environmentally modifiable exposures.

### Understanding effects of health related behaviours

In observational studies, alcohol consumption is related to many known and unknown confounding factors; ill health …
Resolved
Authors: Ajay K. Singh
Journal: Journal of the American Society of Nephrology (2009)

Some time has passed since the torrent of discussion surrounding the cardiovascular risk of pushing up hemoglobin concentrations in dialysis patients with erythropoietin. The debate here reflects a look back on the tension produced by confusing data and outcomes. Is it the target hemoglobin per se or the high doses of erythropoietin in subsets of resistant patients that is the problem? You decide.
Angiokeratoma corporis diffusum in a Spanish patient with aspartylglucosaminuria
Authors: E. Vargas-Diez, A. Chabas, M.J. Coll, J. Sanchez-Perez, A. Garcia-Diez, J.M. Fernandez-Herrera
Journal: British Journal of Dermatology (2002)

Summary Angiokeratoma corporis diffusum (ACD), initially considered to be synonymous with Fabry's disease, represents a well-known cutaneous marker of some other lysosomal enzyme disorders. Aspartylglucosaminuria (AGU) is a rare hereditary disorder mostly affecting the Finnish population, with only a few sporadic patients of non-Finnish origin. To date, only three patients with AGU have been reported with cutaneous lesions of ACD. A 19-year-old Spanish woman presented with a 10-year history of progressive ACD affecting the limbs, buttocks and trunk. After the age of 6 years she had developed progressive mental deterioration, coarse facies and macroglossia with a scrotal appearance. Peripheral blood smears showed many vacuolated lymphocytes. Enzyme analysis in cultured fibroblasts revealed a decreased activity of aspartylglucosaminidase. By the age of 31 years the patient had developed a bipolar psychosis, polycystic ovarian disease and severe impairment of cognitive skills. This is the first case of AGU detected in a Spanish patient presenting with cutaneous lesions of ACD. To our knowledge, macroglossia with a scrotal appearance and polycystic ovarian disease have not been reported in previous cases of AGU.
NKT cells promote antibody-induced joint inflammation by suppressing transforming growth factor β1 production
Authors: Hye Young Kim, Hyun Jung Kim, Hye Sook Min, Sanghee Kim, Weon Seo Park, Seong Hoe Park, Doo Hyun Chung
Journal: The Journal of Experimental Medicine (2005)

Although NKT cells has been known to exert protective roles in the development of autoimmune diseases, the functional roles of NKT cells in the downstream events of antibody-induced joint inflammation remain unknown. Thus, we explored the functional roles of NKT cells in antibody-induced arthritis using the K/BxN serum transfer model. NKT cell–deficient mice were resistant to the development of arthritis, and wild-type mice administrated with α-galactosyl ceramide, a potent NKT cell activator, aggravated arthritis. In CD1d−/− mice, transforming growth factor (TGF)-β1 was found to be elevated in joint tissues, and the blockade of TGF-β1 using neutralizing monoclonal antibodies restored arthritis. The administration of recombinant TGF-β1 into C57BL/6 mice reduced joint inflammation. Moreover, the adoptive transfer of NKT cells into CD1d−/− mice restored arthritis and reduced TGF-β1 production. In vitro assay demonstrated that interleukin (IL)-4 and interferon (IFN)-γ were involved in suppressing TGF-β1 production in joint cells. The adoptive transfer of NKT cells from IL-4−/− or IFN-γ−/− mice did not reverse arthritis and TGF-β1 production in CD1d−/− mice. In conclusion, NKT cells producing IL-4 and IFN-γ play a role in immune complex–induced joint inflammation by regulating TGF-β1.