tbuckley/cabot-search huggingface dataset:
Association study of a polymorphism of the CTGF gene and susceptibility to systemic sclerosis in the Japanese population
Authors: Y Kawaguchi, Y Ota, M Kawamoto, I Ito, N Tsuchiya, T Sugiura, Y Katsumata, M Soejima, S Sato, M Hasegawa, M Fujimoto, K Takehara, M Kuwana, H Yamanaka, M Hara
Journal: Annals of the Rheumatic Diseases (2008)

To validate the association of a single nucleotide polymorphism (SNP) of the connective tissue growth factor gene (CTGF) with susceptibility to systemic sclerosis (SSc) in the Japanese population.395 Japanese patients with SSc, 115 patients with rheumatoid arthritis and 269 healthy Japanese volunteers were enrolled in the study. An SNP (rs6918698) at -945 bp from the start codon in the promoter region of the CTGF gene was determined by allelic discrimination with the use of a specific TaqMan probe.The G allele showed a significantly higher frequency in patients with SSc than in controls (p<0.001; odds ratio 1.5; 95% confidence interval 1.2 to 1.9). In particular, the clinical subsets of SSc showed a more significant association between the G allele and diffuse cutaneous SSc (p<0.001) and the presence of interstitial lung disease (p<0.001), the presence of anti-topoisomerase I antibody (p<0.001) and anti-U1RNP antibody (p = 0.010). Association analyses using the genotype of the SNP yielded results similar to those of analyses using the allele.This study confirms the association between an SNP in the CTGF gene and susceptibility to SSc, especially in the presence of diffuse cutaneous SSc, interstitial lung disease and anti-topoisomerase I antibody. The results strongly suggest that this SNP may be a powerful indicator of severe skin and lung involvement in patients with SSc.
Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome–like skeletal defects induced by Pdk1 or Cbp mutations in mice
Authors: Jae-Hyuck Shim, Matthew B. Greenblatt, Anju Singh, Nicholas Brady, Dorothy Hu, Rebecca Drapp, Wataru Ogawa, Masato Kasuga, Tetsuo Noda, Sang-Hwa Yang, Sang-Kyou Lee, Vivienne I. Rebel, Laurie H. Glimcher
Journal: Journal of Clinical Investigation (2011)

Mutations in the coactivator CREB-binding protein (CBP) are a major cause of the human skeletal dysplasia Rubinstein-Taybi syndrome (RTS); however, the mechanism by which these mutations affect skeletal mineralization and patterning is unknown. Here, we report the identification of 3-phosphoinositide-dependent kinase 1 (PDK1) as a key regulator of CBP activity and demonstrate that its functions map to both osteoprogenitor cells and mature osteoblasts. In osteoblasts, PDK1 activated the CREB/CBP complex, which in turn controlled runt-related transcription factor 2 (RUNX2) activation and expression of bone morphogenetic protein 2 (BMP2). These pathways also operated in vivo, as evidenced by recapitulation of RTS spectrum phenotypes with osteoblast-specific Pdk1 deletion in mice (Pdk1osx mice) and by the genetic interactions observed in mice heterozygous for both osteoblast-specific Pdk1 deletion and either Runx2 or Creb deletion. Finally, treatment of Pdk1osx and Cbp+/- embryos with BMPs in utero partially reversed their skeletal anomalies at birth. These findings illustrate the in vivo function of the PDK1-AKT-CREB/CBP pathway in bone formation and provide proof of principle for in utero growth factor supplementation as a potential therapy for skeletal dysplasias.
Identification of a novel class of human adherent CD34− stem cells that give rise to SCID-repopulating cells
Authors: Selim Kuçi, Johannes T. Wessels, Hans-Jörg Bühring, Karin Schilbach, Michael Schumm, Gabriele Seitz, Jürgen Löffler, Peter Bader, Paul G. Schlegel, Dietrich Niethammer, Rupert Handgretinger
Journal: Blood (2003)
STUDIES BASED ON A MALIGNANT TUMOR OF THE RABBIT
Authors: Wade H. Brown, Louise Pearce
Journal: The Journal of Experimental Medicine (1923)

The results obtained by intratesticular inoculation of a malignant tumor of the rabbit are presented in the form of a general summary covering the phenomena of growth and spontaneous regression of the tumor and the clinical evidence of disease in tumor animals. Under ordinary circumstances, growth is obtained by this method of inoculation in practically all animals, and the majority of them show metastases. The ultimate fate of tumor animals is variable. Spontaneous regression is of frequent occurrence, and apparent recovery may take place even after extensive metastases have developed. More often, the disease terminates fatally. The course of the disease may be fulminating in character with death occurring 6 to 7 weeks after inoculation, or it may be prolonged over a period of more than 6 months, but death usually occurs between 7 weeks and 3 months after inoculation. The symptomatology varies with the course of tumor growth but is in general that of a debilitating disease of an acute or chronic character in which the picture is frequently complicated by symptoms referable to mechanical causes or to one or more of the glands of internal secretion. The most prominent of these are due to the presence of metastases in the suprarenals or pituitary body, in which case symptoms of Addison's disease or diseases of the pituitary may be superimposed upon those attributable to the presence of extensive tumor growths. In the absence of such growths, however, the symptoms of suprarenal or pituitary involvement may dominate the picture.
Death Receptor Agonists as a Targeted Therapy for Cancer
Authors: Jeffrey Wiezorek, Pamela Holland, Jonathan Graves
Journal: Clinical Cancer Research (2010)

Apoptosis is integral to normal, physiologic processes that regulate cell number and results in the removal of unnecessary or damaged cells. Apoptosis is frequently dysregulated in human cancers, and recent advancements in our understanding of the regulation of programmed cell death pathways has led to the development of novel agents to reactivate apoptosis in malignant cells. The activation of cell surface death receptors by tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and death receptor agonists represent an attractive therapeutic strategy to promote apoptosis of tumor cells through the activation of the extrinsic pathway. The observation that Apo2L/TRAIL can eliminate tumor cells preferentially over normal cells has resulted in several potential therapeutics that exploit the extrinsic pathway, in particular, the soluble recombinant human (rh)Apo2L/TRAIL protein and agonist monoclonal antibodies that target death receptors 4 or 5. Many of these agents are currently being evaluated in phase 1 or 2 trials, either as a single agent or in combination with cytotoxic chemotherapy or other targeted agents. The opportunities and challenges associated with the development of death receptor agonists as cancer therapeutics, the status of ongoing clinical evaluations, and the progress toward identifying predictive biomarkers for patient selection and pharmacodynamic markers of response are reviewed.
17β-Estradiol modulates endothelin-1 expression and release in human endothelial cells
Authors: A Bilsel
Journal: Cardiovascular Research (2000)

Objective: In this study the role of 17β-estradiol (E2) in the regulation of endothelin-1 (ET-1) mRNA expression and secretion was investigated in cultured human umbilical vein endothelial cells (HUVECs). Methods: Endothelial cells were either deprived of or treated with 17β-estradiol (10−9, 10−7 M) for 48 h. After the incubation, the effect of E2 on ET-1 gene expression was evaluated by Northern blot analysis. ET-1 release into the media was measured by radioimmunoassay after 6 h of incubation under basal conditions and upon stimulation with thrombin (4 U/ml). In addition, the cyclic guanosine 5′-monophosphate (cGMP) content of cells was assayed by immunoassay. In order to exclude the role of nitric oxide (NO) in E2-induced effects on endothelin-1 gene expression and secretion, nitric oxide synthase (NOS) inhibitor, N-nitro l-arginine methyl ester (1 mM) (l-NAME) was added to the media of some cultures. Results: Incubation of HUVECs with 10−9 and 10−7 M E2 for 48 h resulted in a 30 and 47% inhibition of ET-1 mRNA expression, respectively. Incubation with E2 also decreased the basal and thrombin-stimulated ET-1 release while increasing the cGMP content of cells significantly. NOS inhibitor l-NAME increased the release of ET-1 from E2-incubated cells but did not alter the ET-1 release from hormone-deprived cells. However, ET-1 secretion of E2-treated cells were significantly less than the deprived ones. Northern blot analyses also demonstrated that inhibition of NOS only partly attenuated the effect of E2 on ET-1 gene expression. In the presence of l-NAME, treatment with 10−7 M E2 caused a 12% decrease in ET-1 gene expression. Conclusion: The results demonstrate that E2 may play both direct and indirect role in regulation of ET-1 gene expression and production in human endothelial cells. E2-induced increase in NO but decrease in ET-1 production may partly explain the mechanism of the protective effects of the hormone on the cardiovascular system.
Essential Role of Extracellular SOD in Reparative Neovascularization Induced by Hindlimb Ischemia
Authors: Ha Won Kim, Angela Lin, Robert E. Guldberg, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation Research (2007)

Neovascularization is an important physiological repair mechanism in response to ischemic injury, and its process is dependent on reactive oxygen species (ROS). Overproduction of superoxide anion (O 2 ·− ) rather contributes to various cardiovascular diseases. The extracellular superoxide dismutase (ecSOD) is one of the major antioxidant enzymes against O 2 ·− in blood vessels; however, its role in neovascularization induced by tissue ischemia is unknown. Here we show that hindlimb ischemia of mice stimulates a significant increase in ecSOD activity in ischemic tissues where ecSOD protein is highly expressed at arterioles. In mice lacking ecSOD, ischemia-induced increase in blood flow recovery, collateral vessel formation, and capillary density are significantly inhibited. Impaired neovascularization in ecSOD −/− mice is associated with enhanced O 2 ·− production, TUNEL-positive apoptotic cells and decreased levels of NO 2 − /NO 3 − and cGMP in ischemic tissues as compared with wild-type mice, and it is rescued by infusion of the SOD mimetic tempol. Recruitment of inflammatory cells into ischemic tissues as well as numbers of inflammatory cells and endothelial progenitor cells (c-kit + /CD31 + cells) in both peripheral blood and bone marrow (BM) are significantly reduced in these knockout mice. Of note, ecSOD expression is markedly increased in BM after ischemia. NO 2 − /NO 3 − and cGMP levels are decreased in ecSOD −/− BM. Transplantation of wild-type BM into ecSOD −/− mice rescues the defective neovascularization. Thus, ecSOD in BM and ischemic tissues induced by hindlimb ischemia may represent an important compensatory mechanism that blunts the overproduction of O 2 ·− , which may contribute to reparative neovascularization in response to ischemic injury.
Loss of Methylthioadenosine Phosphorylase and Elevated Ornithine Decarboxylase Is Common in Pancreatic Cancer
Authors: Ahmad L. Subhi, Baiqing Tang, Binaifer R. Balsara, Deborah A. Altomare, Joseph R. Testa, Harry S. Cooper, John P. Hoffman, Neal J. Meropol, Warren D. Kruger
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Loss of the methylthioadenosine phosphorylase (MTAP) gene at 9p21 is observed frequently in a variety of human cancers. We have shown previously that MTAP can act as a tumor suppressor gene and that its tumor suppressor function is related to its effect on polyamine homeostasis. Ornithine decarboxylase is a key enzyme in the regulation of polyamine metabolism. The aim of this study is to analyze MTAP and ornithine decarboxylase (ODC) expression in primary pancreatic tumor specimens. Experimental Design: We measured MTAP and ODC activity in protein extracts derived from 30 surgically resected tumor samples and eight normal pancreas samples. In a subset of six samples, we also examined MTAP DNA using interphase fluorescence in situ hybridization. In addition, we examined the effect of the ODC inhibitor difluoromethylornithine on two pancreatic adenocarcinoma-derived cell lines. Result: MTAP activity was 2.8-fold reduced in adenocarcinomas and 6.3-fold reduced in neuroendocrine tumors compared with control pancreas. Conversely, ODC activity was 3.6-fold elevated in adenocarcinomas and 3.9-fold elevated in neuroendocrine tumors compared with control pancreas. Using interphase fluorescence in situ hybridization, we found in tumor samples that 43 to 75% of the nuclei had lost at least one copy of MTAP locus, indicating that loss of MTAP activity was at least partially because of deletion of the MTAP locus. We also show that inhibition of ODC by difluoromethylornithine caused decreased cell growth and increased apoptosis in two MTAP-deleted pancreatic adenocarcinoma-derived cell lines. Conclusions: MTAP activity is frequently lost, and ODC activity is frequently elevated in both pancreatic adenocarcinoma and neuroendocrine tumors. Inhibition of ODC activity caused decreased cell growth and increased apoptosis in pancreatic tumor-derived cell lines. These findings suggest that MTAP and polyamine metabolism could be potential therapeutic targets in the treatment of pancreatic cancer.
Increased mortality in ankylosing spondylitis is related to disease activity
Authors: G. Bakland, J. T. Gran, J. C. Nossent
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> The onset of disease in ankylosing spondylitis (AS) is generally earlier than in other joint diseases, exposing patients to a prolonged burden of disease. Whether this is associated with excess mortality is still uncertain. Radiation therapy for AS has previously been shown to increase mortality. The present study investigated standardised mortality ratios, causes of death and survival predictors in a large regional cohort of patients with AS. <h3>Method</h3> A total of 677 patients with AS followed at our hospital since 1977 were matched by gender, age and postal area to three controls from the general population and standardised mortality rates (SMRs) were calculated. Cause of death was established using patients9 hospital records. In a subset of 360 patients, clinical and demographic data collected during an earlier research visit (1998–2000) were used in a prospective multivariate analysis of predictors for mortality in AS. <h3>Results</h3> The crude mortality among patients with AS in this study was 14.5% (98 patients); SMR was only significantly increased among male patients compared with female patients (1.63 vs 1.38, p&lt;0.001). Circulatory disease was the most frequent cause of death (40.0%), followed by malignant (26.8%) and infectious (23.2%) diseases. Factors independently associated with reduced survival were diagnostic delay (OR 1.05), increasing levels of C-reactive protein (OR 2.68), work disability (OR 3.65) and not using any non-steroidal anti-inflammatory drugs (OR 4.35). <h3>Conclusions</h3> Mortality is increased in patients with AS and circulatory disease is the most frequent cause of death. Parameters reflecting the duration and intensity of inflammation are associated with reduced survival. These results indicate that, to improve long-term survival in AS, there is a need for early detection and anti-inflammatory treatment as well as a vigilant approach for cardiovascular risk factors.
Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice
Authors: Yuli Liu, Lingfei Xu, Anne K. Hennig, Attila Kovacs, Annabel Fu, Sarah Chung, David Lee, Bin Wang, Ramin S. Herati, Judith Mosinger Ogilvie, Shi-Rong Cai, Katherine Parker Ponder
Journal: Molecular Therapy (2004)

Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program liver to secrete enzyme with mannose 6-phosphate (M6P), and enzyme in blood could be taken up by other cells via the M6P receptor. Newborn MPS I mice were injected with 10(9) (high dose) or 10(8) (low dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA. Most animals achieved stable expression of IDUA in serum at 1240 +/- 147 and 110 +/- 31 units/ml, respectively. At 8 months, untreated MPS I mice had aortic insufficiency, increased bone mineral density (BMD), and reduced responses to sound and light. In contrast, MPS I mice that received high-dose RV had normal echocardiograms, BMD, auditory-evoked brain-stem responses, and electroretinograms. This is the first report of complete correction of these clinical manifestations in any model of mucopolysaccharidosis. Biochemical and pathologic evaluation confirmed that storage was reduced in these organs. Mice that received low-dose RV and achieved 30 units/ml of serum IDUA activity had no or only partial improvement. We conclude that high-dose neonatal gene therapy with an RV reduces some major clinical manifestations of MPS I in mice, but low dose is less effective.
Water and sodium regulation in chronic heart failure: the role of natriuretic peptides and vasopressin
Authors: P Kalra
Journal: Cardiovascular Research (2001)

Time for primary review 28 days. 

Chronic heart failure (CHF) is a complex syndrome characterised by objective evidence of ventricular dysfunction and associated clinical symptoms [1]. Activated neurohormonal mechanisms play an important role in the maintenance of circulatory homeostasis. They can be divided into the vasoconstrictive, sodium retaining and the opposing vasodilatory, natriuretic systems. Vasoconstrictive and sodium retentive actions are provided by the renin–angiotensin–aldosterone system, the sympathetic nervous system, vasopressin, thromboxane and endothelin [2–5]. Initially, in patients with heart failure, these act as important compensatory mechanisms maintaining blood pressure and adequate tissue perfusion. However, prolonged activation of these systems has deleterious effects on haemodynamics and directly on the heart itself. Enhanced vasoconstriction and fluid retention result in adverse loading conditions in the failing ventricle, whilst high levels of angiotensin II directly induce cardiac myocyte necrosis and adversely alter the myocardial matrix structure [6–9]. Angiotensin II also potentiates sympathetic drive by direct stimulation and by impairing its control by the baroreceptors [10].

In view of these adverse effects, it might be anticipated that measurement of plasma levels of neurohormones would be a helpful adjunct during prognostic assessment and even in the tailoring of therapy in CHF. Several studies have demonstrated an impaired prognosis in patients with CHF who have elevated plasma levels of norepinephrine and endothelin-1 [11,12]. Cardiac cachexia is a wasting condition that occurs in a significant percentage of patients with CHF, and is associated with a particularly poor prognosis [13]. This group appears to have marked neurohormonal abnormalities, with patients demonstrating elevated levels of norepinephrine and a reduction in plasma sodium concentration [14]. However, drugs that reduce plasma catecholamine levels are not necessarily associated with an improved prognosis, suggesting that the mechanisms involved in blunting the effects of the sympathetic nervous system … 

*Corresponding author. Tel.: +44-207-351-8127; fax: +44-207-351-8733 p.kalra{at}ic.ac.uk
Emerging cardiovascular risk factors in subclinical hypothyroidism: Lack of change after restoration of euthyroidism
Authors: A. Pérez, J.M. Cubero, N. Sucunza, E. Ortega, R. Arcelús, J. Rodriguez-Espinosa, J. Ordoñez-Llanos, F. Blanco-Vaca
Journal: Metabolism (2004)
Abstract 3998: The role of serum amyloid A1 (SAA1) in nasopharyngeal carcinoma (NPC)
Authors: Hong Lok Lung, Arthur Kwok Leung Cheung, Yeung Man Chung, Edison Tak-Bun Liu, Daniel Chua, Maria Li Lung
Journal: Cancer Research (2012)

Abstract Background and aims: Nasopharyngeal carcinoma (NPC) is a cancer which occurs in high frequency in Southern China. The identification of diagnostic and prognostic markers will be highly beneficial for early stage NPC detection. Previous microcell-mediated chromosome transfer (MMCT) studies showed that the transfer of an intact human chromosome 11 suppresses the in vivo tumor growth of a NPC cell line (HONE1) in nude mouse tumorigenicity assays. We aim to identify candidate genes which are associated with tumor suppression in NPC. Methods: Differential expression analysis of 19K genes was performed in oligonucleotide microarray hybridization for the chromosome 11 microcell hybrids (MCHs)/ tumor segregants (TSs) pairs to hunt for some other unknown NPC genes. The gene expression of the candidate gene was examined in the NPC cell lines and tumor tissues. Functional analysis of restoration of the candidate gene expression was studied. Results: Using oligonucleotide microarray analysis, Serum Amyloid A 1 (SAA1), mapping close to 11p15.1, was identified as showing consistent down-regulated expression in the TSs, as compared to their parental tumor-suppressing MCHs. Gene expression and protein analyses show that SAA1 was not expressed in the NPC HONE1 recipient cells, tumor segregants, and other NPC cell lines; SAA1 was exclusively expressed in the non-tumorigenic MCHs. The mechanism of SAA1 gene inactivation in these NPC cell lines was attributed to hypermethylation. The clinical relevance of SAA1 in NPC was examined by RT-PCR; 54.8% (23/42) of NPC specimens showed either down-regulation or loss of SAA1 gene expression. After transfection of SAA1 gene into HONE1 cells, a dramatic reduction of colony formation ability was observed. Conclusions: These findings suggest that SAA1 is a candidate tumor suppressor gene in NPC. Acknowledgments Grant support: Research Grants Council of the Hong Kong Special Administrative Region, People's Republic of China grant HKU772309 (H.L. Lung) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3998. doi:1538-7445.AM2012-3998