tbuckley/cabot-search huggingface dataset:
Mutations in the Nijmegen Breakage Syndrome Gene in Medulloblastomas
Authors: Jian Huang, Michael A. Grotzer, Takuya Watanabe, Ekkehard Hewer, Torsten Pietsch, Stefan Rutkowski, Hiroko Ohgaki
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Cerebellar medulloblastoma is a highly malignant, invasive embryonal tumor with preferential manifestation in children. Nijmegen breakage syndrome (NBS) with NBS1 germ-line mutations is a rare autosomal recessive disease with clinical features that include microcephaly, mental and growth retardation, immunodeficiency, increased radiosensitivity, and predisposition to cancer. There may be functional interactions between NBS1 and the TP53 pathways. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of sporadic medulloblastomas. Experimental Design: Forty-two cases of medulloblastomas were screened for mutations in the NBS1 gene (all 16 exons) and the TP53 gene (exons 5-8) by single-stranded conformational polymorphism followed by direct DNA sequencing. Results: Seven of 42 (17%) medulloblastomas carried a total of 15 NBS1 mutations. Of these, 10 were missense point mutations and 5 were intronic splicing mutations. None of these were reported previously as germ-line mutations in NBS patients. No NBS1 mutations were detected in peritumoral brain tissues available in two patients. Of 5 medulloblastomas with TP53 mutations, 4 (80%) contained NBS1 mutations, and there was a significant association between TP53 mutations and NBS1 mutations (P = 0.001). Conclusions: We provide evidence of medulloblastomas characterized by NBS1 mutations typically associated with mutational inactivation of the TP53 gene.
The chemoattractant chemerin suppresses melanoma by recruiting natural killer cell antitumor defenses
Authors: Russell K. Pachynski, Brian A. Zabel, Holbrook E. Kohrt, Nicole M. Tejeda, Justin Monnier, Christina D. Swanson, Alison K. Holzer, Andrew J. Gentles, Gizette V. Sperinde, Abdolhossein Edalati, Husein A. Hadeiba, Ash A. Alizadeh, Eugene C. Butcher
Journal: The Journal of Experimental Medicine (2012)

Infiltration of specialized immune cells regulates the growth and survival of neoplasia. Here, in a survey of public whole genome expression datasets we found that the gene for chemerin, a widely expressed endogenous chemoattractant protein, is down-regulated in melanoma as well as other human tumors. Moreover, high chemerin messenger RNA expression in tumors correlated with improved outcome in human melanoma. In experiments using the B16 transplantable mouse melanoma, tumor-expressed chemerin inhibited in vivo tumor growth without altering in vitro proliferation. Growth inhibition was associated with an altered profile of tumor-infiltrating cells with an increase in natural killer (NK) cells and a relative reduction in myeloid-derived suppressor cells and putative immune inhibitory plasmacytoid dendritic cells. Tumor inhibition required host expression of CMKLR1 (chemokine-like receptor 1), the chemoattractant receptor for chemerin, and was abrogated by NK cell depletion. Intratumoral injection of chemerin also inhibited tumor growth, suggesting the potential for therapeutic application. These results show that chemerin, whether expressed by tumor cells or within the tumor environment, can recruit host immune defenses that inhibit tumorigenesis and suggest that down-regulation of chemerin may be an important mechanism of tumor immune evasion.
Gestational Diabetes Mellitus: NICE for the U.S.?
Authors: David Simmons, Aidan McElduff, Harold David McIntyre, Mohamed Elrishi
Journal: Diabetes Care (2009)

OBJECTIVE To compare recent U.S. and U.K. guidelines on gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS The guidelines from the American Diabetes Association, the American College of Obstetricians and Gynecologists, and the National Institute for Health and Clinical Excellence (NICE) in the U.K. were collated and compared using a general inductive approach. RESULTS There are substantial differences in the recommendations between the U.K. and the U.S. guidelines. Of particular note are the reduced sensitivities of the early and later antenatal and postnatal screening and diagnostic criteria. NICE undertook a cost-effectiveness analysis using lower prevalence estimates and limited outcomes and still showed screening for GDM to be cost-effective. CONCLUSIONS The latest NICE recommendations appear to reduce access to proven, cost-effective management of GDM, an issue relevant in the current U.S. health care policy debate.
P90 Osteoporosis in Non-Cystic Fibrosis Bronchiectasis (NCFBr) Adults: Abstract P90 Table 1
Authors: SS Sunny, A Burns, H Jary, T Aspray, A De Soyza
Journal: Thorax (2012)

<h3>Introduction</h3> Whilst osteoporosis is associated with COPD, little is known on its prevalence in non-cystic fibrosis bronchiectasis (NCFBr). We assessed the impact of factors associated with NCFBr disease severity on bone mineral density (BMD) and DEXA referral patterns in NCFBr. <h3>Methods</h3> BMD reports from DEXA scanners were collected for all NCFBr patients from our specialist clinic database and T-scores for lumbar spine (LS), total left hip (TLH) and neck of femur (NOF) were recorded. Osteoporosis was defined as T-scores ≤–2.5, osteopenia between –1 and –2.5 and normal BMD ≥–1. FEV1 values, exacerbation frequency and <i>Pseudomonas aeruginosa</i> chronic infection (defined as &gt;1 positive sputum result in past 12 months) were recorded. <h3>Results</h3> 336 NCFBr patients were identified attending the specialist clinic. 101 patients had DEXA scans performed (30%); 96 reports were retrievable. The male:female ratio was significantly different between scanned patients (29%:71%) and the entire NCFBr patient cohort (41%:59%): p&lt;0.01 (two-tailed chi-squared test). Osteoporosis was detected in the same percentage of scanned males as females (32%, any site). The prevalence of osteoporosis identified was similar across different scan sites (see table). Mean FEV<sub>1</sub> (% predicted) for DEXA-scanned patients was 58.2 (±28.4), 24% were colonised with <i>P</i>.<i> aeruginosa</i> and mean number of exacerbations was 4.7/year (±3.0; n=44). No significant correlation was found between T-scores (any site) and FEV<sub>1</sub>% pred values, <i>P</i>.<i> aeruginosa</i> colonisation or number of exacerbations. <h3>Conclusion</h3> More than 40% of NCFBr patients have osteopenia and more than 25% have osteoporosis; this is higher than seen in COPD (e.g. NHANES, Schnell <i>et al</i>, 2012). Male patients had lower DEXA scanning rates suggesting referral bias favouring females. Low BMD is not predictable based on NCFBr “disease severity parameters”. Greater emphasis on investigating NCFBr patients for osteoporosis, particularly males, may improve the incidence rate of fragility fractures in this patient population. Future studies on steroid use and osteoporosis incidence rates in this population would also be beneficial.
Comprehensive Pathway-Based Association Study of DNA Repair Gene Variants and the Risk of Nasopharyngeal Carcinoma
Authors: Hai-De Qin, Yin Yao Shugart, Jin-Xin Bei, Qing-Hua Pan, Lina Chen, Qi-Sheng Feng, Li-Zhen Chen, Wei Huang, Jian Jun Liu, Timothy J. Jorgensen, Yi-Xin Zeng, Wei-Hua Jia
Journal: Cancer Research (2011)

Abstract DNA repair plays a central role in protecting against environmental carcinogenesis, and genetic variants of DNA repair genes have been reported to be associated with several human malignancies. To assess whether DNA gene variants were associated with nasopharyngeal carcinoma (NPC) risk, a candidate gene association study was conducted among the Cantonese population within the Guangdong Province, China, the ethnic group with the highest risk for NPC. A 2-stage study design was utilized. In the discovery stage, 676 tagging SNPs covering 88 DNA repair genes were genotyped in a matched case-control study (cases/controls = 755/755). Eleven SNPs with Ptrend &amp;lt; 0.01 were identified. Seven of these SNPs were located within 3 genes, RAD51L1, BRCA2, and TP53BP1. In the validation stage, these 11 SNPs were genotyped in a separate Cantonese population (cases/controls = 1,568/1,297). Two of the SNPs (rs927220 and rs11158728), both in RAD51L1, remained strongly associated with NPC. The SNP rs927220 had a significant Pcombined of 5.55 × 10−5, with OR = 1.20 (95% CI = 1.10–1.30), Bonferroni corrected P = 0.0381. The other SNP (rs11158728), which is in strong linkage disequilibrium with rs927220 (r2 = 0.7), had a significant Pcombined of 2.0 × 10−4, Bonferroni corrected P = 0.1372. Gene–environment interaction analysis suggested that the exposures of salted fish consumption and cigarette smoking had potential interactions with DNA repair gene variations, but need to be further investigated. Our findings support the notion that DNA repair genes, in particular RAD51L1, play a role in NPC etiology and development. Cancer Res; 71(8); 3000–8. ©2011 AACR.
The Kaposi's Sarcoma–related Herpesvirus (KSHV)-encoded Chemokine vMIP-I is a Specific Agonist for the CC Chemokine Receptor (CCR)8
Authors: Michael J. Endres, Charles G. Garlisi, Hong Xiao, LiXin Shan, Joseph A. Hedrick
Journal: The Journal of Experimental Medicine (1999)

The Kaposi's sarcoma-related herpesvirus (KSHV), also designated human herpesvirus 8, is the presumed etiologic agent of Kaposi's sarcoma and certain lymphomas. Although KSHV encodes several chemokine homologues (viral macrophage inflammatory protein [vMIP]-I, -II, and -III), only vMIP-II has been functionally characterized. We report here that vMIP-I is a specific agonist for the CC chemokine receptor (CCR)8 that is preferentially expressed on Th2 T cells. Y3 cells transfected with CCR8 produced a calcium flux in response to vMIP-I and responded vigorously in in vitro chemotaxis assays. In competition binding experiments, the interaction of vMIP-I with CCR8 was shown to be specific and of high affinity. In contrast to its agonist activity at CCR8, vMIP-I did not interact with CCR5 or any of 11 other receptors examined. Furthermore, vMIP-I was unable to inhibit CCR5-mediated HIV infection. These findings suggest that expression of vMIP-I by KSHV may influence the Th1/Th2 balance of the host immune response.
Allergic disease may increase the risk of atherosclerosis
Authors: E Suh
Journal: Thorax (2006)

▴ Knoflach M, Kiechl S, Mayr A, et al. Allergic rhinitis, asthma, and atherosclerosis in the Bruneck and ARMY studies. Arch Intern Med2005;165:2521–6 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] This paper describes two studies investigating the association between common allergic conditions (allergic rhinitis and asthma) and atherosclerotic disease. In the Bruneck study of 826 middle aged and elderly Italian subjects, 32 (3.9%) had a diagnosis of allergic disease. The 5 year development and … [1]: {openurl}?query=rft.jtitle%253DArchives%2Bof%2BInternal%2BMedicine%26rft.stitle%253DArch%2BIntern%2BMed%26rft.issn%253D0003-9926%26rft.aulast%253DKnoflach%26rft.auinit1%253DM.%26rft.volume%253D165%26rft.issue%253D21%26rft.spage%253D2521%26rft.epage%253D2526%26rft.atitle%253DAllergic%2BRhinitis%252C%2BAsthma%252C%2Band%2BAtherosclerosis%2Bin%2Bthe%2BBruneck%2Band%2BARMY%2BStudies%26rft_id%253Dinfo%253Adoi%252F10.1001%252Farchinte.165.21.2521%26rft_id%253Dinfo%253Apmid%252F16314550%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1001/archinte.165.21.2521&link_type=DOI [3]: /lookup/external-ref?access_num=16314550&link_type=MED&atom=%2Fthoraxjnl%2F61%2F4%2F299.atom [4]: /lookup/external-ref?access_num=000233510200013&link_type=ISI
Clonality and Prognostic Implications of <i>p53</i> and Epidermal Growth Factor Receptor Somatic Aberrations in Multiple Primary Lung Cancers
Authors: Yih-Leong Chang, Chen-Tu Wu, Shu-Chen Lin, Chin-Fu Hsiao, Yuh-Shan Jou, Yung-Chie Lee
Journal: Clinical Cancer Research (2007)

Abstract Purpose: For treatment decision and prognostic applications, we evaluated p53/epidermal growth factor receptor (EGFR) somatic aberrations in multiple primary lung cancers to differentiate multifocal tumors from intrapulmonary metastasis. Experimental Design: Fifty-eight multiple primary lung cancers of 1,037 patients in a 10-year period were identified to investigate somatic mutations and altered expression of p53 and EGFR for clonality assessment. Genomic DNA was extracted from microdissected cells of paraffin-embedded multiple primary lung cancer tissues. Overexpression and somatic mutations in exons of p53 (exons 5-8) and tyrosine kinase domain of EGFR (exons 18-22) were examined by immunohistochemical staining and DNA sequencing, respectively. Results: High frequency of somatic mutations in p53 (33 of 58, 56.9%) and/or EGFR (44 of 58, 75.9%) resulted in high discrimination rate of tumor clonality (50 of 58, 86.2%) of multiple primary lung cancers. Twenty-two cases (37.9%) were assessed as having the same clonality and 28 cases (48.3%) were determined as having different clonality, which further supported the carcinogenic theory of field cancerization. Notably, the occurrence of lymph node metastasis was more commonly observed in tumors with the same clonality (P = 0.045) and was associated with poor patient 5-year survival rate (P = 0.001). However, no correlation was found between tumor clonality and patient survival (P = 0.630). The EGFR somatic aberrations in 58 multiple primary lung cancers, including vascular invasion associated with EGFR overexpression (P = 0.012) and mutation (P = 0.025), further suggested the potential benefits of target therapy of inoperable multiple primary lung cancers. Conclusions: Our results suggest that analysis of somatic alterations in p53 and EGFR can significantly improve the clonality assessment and impact management of multiple primary lung cancer patients.
24 A new developed self-expanding metal stent as a treatment of acute esophageal variceal bleeding
Authors: R. Hubmann, G. Bodlaj, M. Czompo, L. Benkö, P. Pichler, A. Al-Kathib, P. Kiblböck, A. Shamiyeh, M. Sedlak, G. Biesenbach
Journal: Journal of Hepatology (2006)
Peripheral insulin resistance accounts for impaired glucose tolerance and is associated with systemic inflammation in COPD
Authors: John Archer, Emma Baker
Journal: European Respiratory Journal (2011)

Introduction:  Impaired glucose tolerance is common in COPD [Archer & Baker, Resp Med: COPD Update 2009;5:67-74]. We assessed pancreatic function, hepatic and peripheral insulin resistance and determined the relationship of these with systemic inflammation.   Methods:  Participants were 8 stable COPD patients (C) (4 male, 66±8yrs, FEV 1  44±16%predicted, body mass index (BMI) 23±6kg/m 2 ) and 8 healthy volunteers (V) (8m, 24±5yrs, FEV 1  89±12%, BMI 22±2kg/m 2 ) without diabetes mellitus and with fasting glucose    Results:  Fasting glucose (p=0.038), HbA 1C  (p=0.013) and C peptide (p=0.028) were higher in COPD than in volunteers, but insulin was not different (p=0.234). HOMA2-%B was: C 126 [81-182], V 91 [86-113], p=0.279, HOMA2-IR was: C 1.3 [0.8-1.8], V 1.0 [0.7-1.2], p=0.161, Matsuda Index was: C 3 [3-5], V (8 [6-10], p=0.002. In COPD, but not volunteers, ln(CRP) was inversely correlated with ln(Matsuda) (R=-0.760, p=0.047) but not with other homeostatic measures after controlling for BMI.   Conclusion:  Non-obese COPD patients without diabetes had increased composite, but not hepatic, insulin resistance compared to volunteers, indicating skeletal muscle insulin resistance. Possible mechanisms underlying the correlation between peripheral insulin resistance and inflammation include inhibition of insulin receptor signalling by inflammatory mediators or pro-inflammatory effects of elevated glucose.
Classification Algorithms Based on Anterior Segment Optical Coherence Tomography Measurements for Detection of Angle Closure
Authors: Monisha E. Nongpiur, Benjamin A. Haaland, David S. Friedman, Shamira A. Perera, Mingguang He, Li-Lian Foo, Mani Baskaran, Lisandro M. Sakata, Tien Y. Wong, Tin Aung
Journal: Ophthalmology (2012)
Intracellular Na+ activity and positive inotropic effect of sulmazole in guinea pig ventricular myocardium. Comparison with a cardioactive steroid.
Authors: R Schmied, G X Wang, M Korth
Journal: Circulation Research (1991)

Recent studies suggest that inhibition of Na+,K(+)-ATPase may contribute to the positive inotropic action of the imidazopyridine sulmazole. Therefore, we investigated the effect of sulmazole and its stereoisomers and for comparison the effect of the cardioactive steroid dihydroouabain (DHO) on intracellular Na+ activity by means of Na(+)-sensitive microelectrodes. In the resting papillary muscle of the guinea pig, (+/-)-sulmazole increased intracellular Na+ activity (aiNa) within 15-20 minutes by 0.5 +/- 0.1 (n = 3), 1.3 +/- 0.1 (n = 7), 2.7 +/- 0.2 (n = 6), and 4.9 +/- 0.5 (n = 6) mM at 60, 100, 300, and 1,000 microM, respectively. (+)-Sulmazole was more effective than the racemate; aiNa was increased by 1.2 +/- 0.3, 2.1 +/- 0.3, and 4.0 +/- 0.2 mM at 60, 100, and 300 microM, respectively (n = 2 for each concentration). In the contracting papillary muscle (0.2 Hz), (+)- and (+/-)-sulmazole (600 and 1,000 microM) produced a maximum positive inotropic effect that exceeded that of DHO by 11% and 8%, respectively. As an inotropic agent, (+)-sulmazole was almost twice as potent as the racemate. The maximum direct inotropic effect of (-)-sulmazole (1,000 microM) amounted to only 14% of the DHO maximum and was, in contrast to the racemate and (+)-sulmazole, antagonized by 3 microM carbachol. (-)-Sulmazole did not affect aiNa.(ABSTRACT TRUNCATED AT 250 WORDS)
Histopathological study of intrahepatic aberrant vessels in cases of noncirrhotic portal hypertension
Authors: Makoto Ohbu, Masahiko Okudaira, Kiyoharu Watanabe, Satoshi Kaneko, Tomoko Takai
Journal: Hepatology (1994)

Aberrant vessels, which are defined as dilated blood vessels immediately adjacent to the peripheral portal tract, appear under conditions of extrahepatic portal obstruction and nodular regenerative hyperplasia as well as idiopathic portal hypertension. Our study was undertaken to compare their morphological aspects in these three disease cases. Aberrant vessels were found in 84% of cases of idiopathic portal hypertension, 67% of cases of extrahepatic portal obstruction infantile type, 78% of cases of extrahepatic portal obstruction adult type and 83% of cases of nodular regenerative hyperplasia. They were divided into three types: type I–no communication with the portal vein, the lumen of which is normally open; type II–communication with the portal vein; and type III–no communication with the portal vein, which is occluded. The most common types of aberrant vessel were type III in idiopathic portal hypertension (51%), type I in extrahepatic portal obstruction infantile type (46%), type II in extrahepatic portal obstruction adult type (43%) and type III in nodular regenerative hyperplasia (45%). Serial sections revealed transition between types I, II and III, at frequencies between types II and III, types I and II, and types I and III of 35.7%, 33.7% and 30.6%, respectively. Aberrant vessels demonstrated the same immunoreactivity as portal veins for collagen type IV, laminin, factor VIII and ulex europaeus agglutinin-I. They were concluded to arise from the vasa septalis or inlet venules, which would be used as intrahepatic shunts draining portal blood flow blocked by stenosed portal veins. Increased portal pressure would be expected to enhance development of aberrant vessels. They open into sinusoids, and differ from portovenous shunts, which are observed in liver cirrhosis. Therefore, the hepatic parenchyma is supplied with portal blood through aberrant vessels and thereby escapes from collapse induced by blockage of portal blood flow in spite of marked stenosis of peripheral portal veins in idiopathic portal hypertension. (Hepatology 1994;20:302–308.)
Hydrolysis of human milk fat globules by pancreatic lipase: role of colipase, phospholipase A2, and bile salts.
Authors: L Bläckberg, O Hernell, T Olivecrona
Journal: Journal of Clinical Investigation (1981)

Human milk fat globules were used to explore how dietary triglycerides are hydrolyzed by pancreatic lipase. These triglycerides were hydrolyzed very slowly by lipase alone as if the surface layer of proteins and phospholipids impeded the action of the enzyme. The inhibition of lipase activity could be overcome by addition either of colipase or of pancreatic phospholipase A2. Colipase enhanced triglyceride hydrolysis in a dose-dependent manner whether bile salts were present or not. Bile salts had no effect on the activity of pancreatic lipase alone but further enhanced the activity at all concentrations of colipase tested. Bile salts were a prerequisite to relieve inhibition of lipase activity by phospholipase A2. Human milk fat globules exposed to phospholipase A2 should be representative of a physiological substrate for pancreatic lipase. A major new observation was that bile salts, even at high concentrations, stimulated triglyceride hydrolysis of such phospholipase-treated globules by pancreatic lipase also in the absence of colipase.
Dose-Dense Chemotherapy Improves Mechanisms of Antitumor Immune Response
Authors: Chih-Long Chang, Yun-Ting Hsu, Chao-Chih Wu, Yan-Zen Lai, Connie Wang, Yuh-Cheng Yang, T.-C. Wu, Chien-Fu Hung
Journal: Cancer Research (2012)

Dose-dense (DD) regimens of combination chemotherapy may produce superior clinical outcomes, but the basis for these effects are not completely clear. In this study, we assessed whether a DD combinatorial regimen of low-dose cisplatin and paclitaxel produces superior immune-mediated efficacy when compared with a maximum tolerated dose (MTD) regimen in treating platinum-resistant ovarian cancer as modeled in mice. Immune responses generated by the DD regimen were identified with regard to the immune cell subset responsible for the antitumor effects observed. The DD regimen was less toxic to the immune system, reduced immunosuppression by the tumor microenvironment, and triggered recruitment of macrophages and tumor-specific CD8(+) T-cell responses to tumors [as determined by interleukin (IL)-2 and IFN-γ secretion]. In this model, we found that the DD regimen exerted greater therapeutic effects than the MTD regimen, justifying its further clinical investigation. Fourteen patients with platinum-resistant relapse of ovarian cancer received DD chemotherapy consisting of weekly carboplatin (AUC2) and paclitaxel (60-80 mg/m(2)) as the third- or fourth-line treatment. Serum was collected over the course of treatment, and serial IFN-γ and IL-2 levels were used to determine CD8(+) T-cell activation. Of the four patients with disease control, three had serum levels of IL-2 and IFN-γ associated with cytotoxic CD8(+) T-cell activity. The therapeutic effect of the DD chemotherapy relied on the preservation of the immune system and the treatment-mediated promotion of tumor-specific immunity, especially the antitumor CD8(+) T-cell response. Because the DD regimen controlled drug-resistant disease through a novel immune mechanism, it may offer a fine strategy for salvage treatment.