tbuckley/cabot-search huggingface dataset:
Loss of Heterozygosity at the <i>BRCA2</i> Locus Detected by Multiplex Ligation-Dependent Probe Amplification is Common in Prostate Cancers from Men with a Germline <i>BRCA2</i> Mutation
Authors: Amber J. Willems, Sarah-Jane Dawson, Hema Samaratunga, Alessandro De Luca, Yoland C. Antill, John L. Hopper, Heather J. Thorne
Journal: Clinical Cancer Research (2008)

Prostate cancer risk is increased for men carrying a pathogenic germline mutation in BRCA2, and perhaps BRCA1. Our primary aim was to test for loss of heterozygosity (LOH) at the locus of the mutation in prostate cancers from men who a carry pathogenic germline mutation in BRCA1 or BRCA2, and to assess clinical and pathologic features of these tumors.From 1,243 kConFab families: (a) 215 families carried a pathogenic BRCA1 mutation, whereas 188 families carried a pathogenic BRCA2 mutation; (b) of the 158 men diagnosed with prostate cancer (from 137 families), 8 were confirmed to carry the family-specific BRCA1 mutation, whereas 20 were confirmed to carry the family-specific BRCA2 mutation; and (c) 10 cases were eliminated from analysis because no archival material was available. The final cohort comprised 4 and 14 men with a BRCA1 and BRCA2 mutation, respectively. We examined LOH at the BRCA1 and BRCA2 genes using multiplex ligation-dependent probe amplification of DNA from microdissected tumor.LOH at BRCA2 was observed in 10 of 14 tumors from BRCA2 mutation carriers (71%), whereas no LOH at BRCA1 was observed in four tumors from BRCA1 mutation carriers (P = 0.02). Under the assumption that LOH occurs only because the cancer was caused by the germline mutation, carriers of BRCA2 mutations are at 3.5-fold (95% confidence interval, 1.8-12) increased risk of prostate cancer. A high Gleason was the only distinct clinical feature.These observations are consistent with the idea that BRCA2, but not BRCA1, is a tumor suppressor of prostate cancer.
Methionine and Glucose Metabolism of Central Neurocytoma: A PET Study
Authors: Hidemasa Takao, Toshimitsu Momose, Kuni Ohtomo
Journal: Clinical Nuclear Medicine (2004)

Central neurocytoma is a rare, benign tumor of the central nervous system that was first described by Hassoun et al in 1982. The tumor is usually located in the ventricular system. Although most reported cases are histologically and clinically benign, several cases with recurrence have been previously reported. A few cases using carbon-11-methyl-L-methionine (C-11 MET) PET and/or F-18 FDG PET have been described in the literature. The authors report 2 cases of central neurocytoma that were studied with C-11 MET PET and F-18 FDG PET.
Delivering healthcare in situations of conflict or violence
Authors: V. Nathanson
Journal: BMJ (2011)

Since the recent publication of data showing favorable outcomes for patients with HIV-1 and ESRD, kidney transplantation has become a therapeutic option in this population. However, reports have documented unexplained reduced allograft survival in these patients. We hypothesized that the unrecognized infection of the transplanted kidney by HIV-1 can compromise long-term allograft function. Using electron microscopy and molecular biology, we examined protocol renal transplant biopsies from 19 recipients with HIV-1 who did not have detectable levels of plasma HIV-1 RNA at transplantation. We found that HIV-1 infected the kidney allograft in 68% of these patients. Notably, HIV-1 infection was detected in either podocytes predominately (38% of recipients) or tubular cells only (62% of recipients). Podocyte infection associated with podocyte apoptosis and loss of differentiation markers as well as a faster decline in allograft function compared with tubular cell infection. In allografts with tubular cell infection, epithelial cells of the proximal convoluted tubules frequently contained abnormal mitochondria, and both patients who developed features of subclinical acute cellular rejection had allografts with tubular cell infection. Finally, we provide a novel noninvasive test for determining HIV-1 infection of the kidney allograft by measuring HIV-1 DNA and RNA levels in patients’ urine. In conclusion, HIV-1 can infect kidney allografts after transplantation despite undetectable viremia, and this infection might influence graft outcome.
Abstract 3493: ON 01910. Na, a clinical trial stage multi-kinase inhibitor, induces apoptosis in chronic lymphocytic leukemia (CLL) cells through inhibition of PI3K/AKT and activation of the JNK pathway resulting in NOXA and BIM upregulation
Authors: Patricia Perez-Galan, Colby M. Chapman, Xiameng Sun, Federica Gibellini, Poching Liu, Nalini Raghavachari, Adrian Wiestner
Journal: Cancer Research (2010)

Abstract Chronic Lymphocytic leukemia (CLL), the most common leukemia in Western countries, is a clinically heterogeneous disease characterized by the accumulation of mature B lymphocytes, where disease progression is driven by survival and proliferation signals provided by the tumor microenvironment. ON 01910. Na (Onconova Therapeutics) belongs to the family of styryl benzyl sulfones, a novel family of non-ATP competitive kinase inhibitors. ON 01910. Na is under clinical development in hematologic and solid tumors. Here we show that ON 01910. Na induced apoptosis in CLL samples (n=28) in vitro, without showing significant toxicity against T-cells or normal B-cells. Twenty four CLL samples were highly sensitive to ON 01910. Na (mean IC50=0.89 μM) a concentration readily achieved in phase I clinical trials, three showed moderate sensitivity (mean IC50=4.26 μM) and one was resistant (IC50 &amp;gt;8 μM). There were no significant differences in ON01910. Na cytotoxicity against CLL cells expressing mutated (mean IC50=1.33 μM) or unmutated (mean IC50 =1.22μM) IgVH sequences. ON 01910. Na was similarly effective against tumor cells carrying 17p or 11q deletions. ON 01910. Na activated Bax and Bak, leading to mitochondrial depolarization. To delineate the upstream pathways underlying ON 01910. Na induced apoptosis, we performed Gene Expression Profiling (GEP) in CLL cells treated in vitro for 4 and 10 hours with ON 01910. Na. Gene Set Enrichment Analysis (GSEA) identified gene sets indicating BCR and PI3K inhibition (FDR&amp;lt;0.2). In keeping with PI3K inhibition, we found that ON 19010. Na inhibited phosphorylation of Akt and Foxo3a, and FOXO3 target genes, including Bim, were upregulated. In addition, GSEA identified induction of AP-1 gene sets (FDR&amp;lt;0.01) suggesting the generation of reactive oxygen species (ROS) by ON 01910. Na. Consistently, we found a rapid increase in ROS in cells treated with ON 01910. Na and ROS scavengers protected cells from its cytotoxic effect. ROS upregulated the proapoptotic BH3-only protein Noxa, and knockdown of Noxa by shRNA decreased the sensitivity to the drug by 60%. Our results identify ON 01910. Na as a promising agent in the treatment of CLL with an interesting dual mechanism of action: inhibition of the PI3K/AKT survival pathway with Foxo mediated upregulation of BIM and the induction of oxidative stress resulting in Noxa upregulation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3493.
Children With Newly Diagnosed IDDM Have Increased Levels of Antibodies to Bovine Serum Albumin But Not to Ovalbumin
Authors: Tero Saukkonen, Erkki Savilahti, Outi Vaarala, Esa T Virtala, Jaakko Tuomilehto, Hans K Åkerblom
Journal: Diabetes Care (1994)

OBJECTIVE To study the humoral immune response to bovine serum albumin (BSA) and ovalbumin (OA) in children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS We examined serum samples from 505 children 0.8–14.9 years of age with newly diagnosed IDDM for antibodies to BSA and OA by enzyme-linked immunosorbent assay (ELISA). We also had two control groups: 85 unrelated control children (0.8–7.1 years of age) and 395 nondiabetic siblings (3.0–14.9 years of age). The specificity of antibodies detected in ELISA was confirmed by immunoblotting in a subset of sera with varying levels of antibodies. RESULTS Diabetic children &amp;lt;7 years of age had a significantly higher level of IgG (immunoglobulin) antibodies to BSA than did unrelated control children (P &amp;lt; 0.0001). The difference was greatest in the youngest group of children, 0.8–2.9 years of age. IgA antibodies to BSA were detected more frequently among diabetic than control children (P = 0.0009). Levels of IgG and IgA antibodies to ovalbumin did not differ between diabetic and control children. Diabetic children 3.0–14.9 years of age also had higher levels of IgG and IgA antibodies to BSA than did their age- and sex-matched nondiabetic siblings (P = 0.02 and P &amp;lt; 0.0001, respectively). Those siblings who contracted IDDM during the follow-up period (n = 15) had a measurable level of IgA antibodies to BSA more often than did those who remained nondiabetic (60 and 34%, respectively; P = 0.04). Neither before nor after diagnosis of IDDM was there any significant trend in antibody levels. CONCLUSIONS A high level of antibodies to BSA commonly associates with IDDM, whereas the humoral immune response to OA is similar in diabetic and nondiabetic children.
Invasive or non-invasive methods for the diagnosis of subclinical coeliac disease?
Authors: A Tursi
Journal: Gut (2002)

I read with great interest the letters published in Gut on the role of small bowel biopsies and antiendomysial antibodies (EMA) as methods for diagnosing coeliac disease in patients with iron deficiency anaemia (IDA) ( Gut 2001; 49 :595). In particular, Pearce et al seem to prefer EMA instead of histological evaluation because of the considerable resource implications for histology departments, and Scott seems to agree with Pearce's affirmation even if he takes into consideration the important role of histological evaluation. However, I do not completely agree with the conclusions of these authors.

Firstly, I would debate the role of non-invasive methods in diagnosing subclinical/silent coeliac disease. In my experience, IDA is the main indication of subclinical forms of coeliac disease1 and thus it should be taken into consideration in clinical practice. Although EMA are a well known hallmark of coeliac disease and the prevalence is more than 90% in classical forms of coeliac disease, our study and other recent studies clearly showed that the prevalence of EMA (as well as AGA) is lower than expected in clinical practice,2–4 probably due to the high prevalence of slight histological lesions in these patients (Marsh I-IIIa lesions according to the Marsh classification5). In contrast, the sorbitol H2-breath test (H2-BT) seems to be more effective than EMA in diagnosing this form of coeliac disease, probably because of a better correlation with slight histological lesions.6 In the light of these experiences, sorbitol H2-BT may be a good alternative to small bowel biopsy in identifying coeliac disease in patients with IDA but unfortunately this is not always true. In fact, in clinical practice, it is easy to observe patients with IDA EMA− and a negative sorbitol H2-BT test who show slight histological lesions …
Abstract 4155: Comprehensive glucan profile exploration of mutated K-ras knockdown in colorectal cancer
Authors: Hiroshi Kawamata, Keishi Yamashita, Atsushi Kuno, Seiji Shirasawa, Hisashi Narimatsu, Masahiko Watanabe
Journal: Cancer Research (2012)

Abstract (Background) In colorectal cancer (CRC), K-ras mutation is found in nearly 40% of the patients, and it is of prognostic significance (Onozato W et al, J Surg Oncol, 2010). Moreover, its knockdown in CRC cell lines with mutated K-ras gene results in robust reduction of ability of cell proliferation and anchorage independent growth (Shirasawa S, Science, 1993), both of which reflect metastatic ability. On the other hand, robust alterations of glycan structures have been reported in CRC promotion steps, accompanied by remarkable phenotypic changes, however there is no report that mentions the relationship of K-ras mutation and glycan change. (Materials and Methods) We examined glycan change of CRC cell lines (DLD1 and HCT116) somatically knocked out for K-ras gene by lectin array including 41 lectins to elucidate whether K-ras mutation-induced glycan changes play a critical role in CRC promotion. (Result) (1) In DLD1, we compared DLD1 wild type genotype cells (DLD1, DKS-5) with those that were knocked out for mutated K-ras gene (DKO-3, DKS-8), and the signals of MAL, MPA, UEA-I, and TJA-II were remarkably decreased in the knockdown cells. (2) In HCT116, we compared HCT116 wild type genotypic cells (HCT116, Hk2-10) with those that were knocked out for the mutated K-ras gene (Hke-3), and both MAL and MPA were remarkably declined. (3) In both cell lines, expression changes of glycans which can bind with MAL and MPA were consistent with the results of the lectin blotting, and both lectin signals were confirmed to be commonly altered by removing the mutated K-ras gene. (Conclusion) Mutated K-ras may be involved in critical phenotype change of CRC, accompanied by abnormal sialic acid recognition. 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 4155. doi:1538-7445.AM2012-4155
Numbers needed to treat derived from meta-analyses---sometimes informative, usually misleading
Authors: L. Smeeth, A. Haines, S. Ebrahim
Journal: BMJ (1999)

The number needed to treat—the number of patients who must be treated to prevent one adverse outcome—is a widely used measure. 1 2 It is increasingly being calculated by pooling absolute risk differences in trials included in meta-analyses. 3 4 This option is available in statistical software and the Cochrane Database of Systematic Reviews . 5 6 In this paper, we examine pooled numbers needed to treat derived from trials and meta-analyses of interventions to prevent cardiovascular disease. We show that a pooled number needed to treat may be misleading because of variation in the event rates in trials, differences in the outcomes considered, effects of secular trends on disease risk, and differences in clinical setting. The number needed to treat should be derived by applying the relative risk reductions from treatment which have been estimated by trials or meta-analysis to relevant baseline risks for different types of patients. This provides a range of possible numbers needed to treat in different patient groups.

### Summary points

Numbers needed to treat are often used to summarise treatment effects in a clinically relevant way

They are derived from the baseline risk without treatment and the reduction in risk achieved with treatment

Numbers needed to treat are sensitive to factors that change the baseline risk such as the outcome considered, patients' characteristics, secular trends in incidence and case fatality, and the clinical setting

Pooled numbers needed to treat derived from meta-analyses can be seriously misleading because the baseline risk often varies appreciably between the trials

Applying the pooled relative risk reductions calculated from meta-analyses or individual trials to the baseline risk relevant to specific patient group produces a useful number needed to treat

The interventions selected for study were use of statins for lowering cholesterol concentrations in primary and secondary prevention of coronary heart disease.7 …
Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease
Authors: Zhentao Zhang, Mingke Song, Xia Liu, Seong Su Kang, Il-Sun Kwon, Duc M Duong, Nicholas T Seyfried, William T Hu, Zhixue Liu, Jian-Zhi Wang, Liming Cheng, Yi E Sun, Shan Ping Yu, Allan I Levey, Keqiang Ye
Journal: Nature Medicine (2014)
Clinical evaluation of liver structure and function in humans exposed to halogenated hydrocarbons.
Authors: P S Guzelian
Journal: Environmental Health Perspectives (1985)

An unresolved question is whether humans exposed to comparatively low doses of persistent environmental chemicals such as polyhalogenated biphenyls or organochlorine pesticides are at risk for injury to the liver. Cross-sectional epidemiologic studies suggest that these chemicals may produce statistically significant but clinically mild abnormalities in the commonly employed chemical tests of liver function. The few reports of human liver morphology reveal nonspecific changes reflecting effects of lipophilic chemicals. There is evidence that chemicals of this category in at least some doses cause induction of liver microsomal enzymes involved in biotransformation of foreign substances. This finding has been documented by measurements of the clearance of model drugs or the appearance in the urine of steroid metabolites or glucaric acid. Although a positive statistical correlation between the concentrations of these chemicals in serum and the serum gamma-glutamyltranspeptidase activity has been reported, the non-specificity of the latter enzyme precludes conclusion that this change is indicative of induction of liver microsomal enzymes. Although the effects of this type of environmental chemical are not indicative of progressive liver disease, only prospective clinical trials can resolve the issue of the risk for future development of liver malignancy.
Carboxyl-terminal and central regions of human immunodeficiency virus-1 NEF recognized by cytotoxic T lymphocytes from lymphoid organs. An in vitro limiting dilution analysis.
Authors: F Hadida, A Parrot, M P Kieny, B Sadat-Sowti, C Mayaud, P Debre, B Autran
Journal: Journal of Clinical Investigation (1992)

Cytotoxic T lymphocytes (CTL) specific for human immunodeficiency virus (HIV) proteins have been analyzed in lymphoid organs from seropositive patients. Indeed, an active HIV replication coexists with a major CD8+ lymphocytic infiltration in these organs. We have shown in a previous report that HIV-seropositive patients lungs were infiltrated by HIV specific CD8+ lymphocytes. In the present report, we show that HIV-specific CTL responses can also be detected in lymph nodes and spleens, and were mainly directed against the ENV, GAG, and NEF HIV-1 proteins. The primary NEF-specific CTL responses were further characterized by epitope mapping. Determination of epitope-specific CTL frequencies were performed by limiting dilution analysis. Our results indicated that, in addition to the central region of NEF (AA66-148), a new immunodominant region is recognized by CTL. This region corresponds to the carboxyl-terminal domain of NEF (amino acids 182-206). AA182-206 is recognized in association with at least two common human histocompatibility leukocyte antigen (HLA) molecules (HLA-A1 and B8), with clonal frequencies of one CTL per 10(-5) to 10(-6) splenic lymphocytes. Our data indicate that lymphoid organs may represent a major reservoir for in vivo activated HIV-specific CTL. Furthermore, the carboxyl-terminal domain of NEF was found to be conserved among several HIV strains. Therefore, our finding is of interest for further HIV vaccines development.
Influence of Bile Duct Diameter on the Therapeutic Quality of Endoscopic Balloon Sphincteroplasty
Authors: A. Ohashi, K. Tamada, T. Tomiyama, T. Aizawa, S. Wada, T. Miyata, T. Nishizono, S. Tano, Y. Sato, N. Ueno, K. Ido, K. Kimura
Journal: Endoscopy (1999)

Endoscopic balloon sphincteroplasty (EBS) has been reported to be a safe alternative to sphincterotomy for the treatment of bile duct stones. We evaluated the factors which influence the therapeutic efficacy of EBS.A total of 118 consecutive patients with bile duct stones were treated by EBS. After conventional endoscopic retrograde cholangiography (ERC), EBS was done using a biliary dilation catheter (balloon diameter, 8mm). The duct was then cleared using Dormia baskets or retrievel balloon catheters. When the stones were greater than 8 mm in diameter, mechanical lithotripsy was performed before extraction. Complete stone clearance was assessed by balloon-ERC and intraductal ultrasonography. Therapeutic efficacy was assessed using univariate and multivariate analysis. Patients were classified into three groups according to the bile duct diameter: nondilated (bile duct < or = 10 mm), mildly dilated (10 mm < bile duct < or = 15 mm), and severely dilated group (bile duct > 15 mm).In 113 of 118 (96%) patients, the stones were completely cleared with one to six endoscopic sessions (mean 1.6 sessions). In the nondilated group, 24 of 28 (85%) patients were cleared of stones in one session (mean 1.2 sessions), without the use of mechanical lithotripsy in 23 of 28 (82 %) patients. In the mildly dilated group, 23 of 38 (61 %) patients were cleared of stones in one session (mean 1.5 sessions). In contrast, in the severely dilated group, only 16 of 52 (31 %) patients were cleared of stones in one session (mean 2.0 sessions). Stone size, number of stones, and use of mechanical lithotripsy were independent variables which influenced the success of stone clearance in one session after EBS.When EBS is done in patients with bile duct stones, bile duct diameter may be a good indicator of therapeutic efficacy. In patients with severely dilated bile ducts (> 15 mm), EBS is of limited effectiveness.
Abstract 3362: Tyr-phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate pyruvate dehydrogenase complex and promote the Warburg effect
Authors: Jun Fan, Ting-Lei Gu, Titus Boggon, Sumin Kang, Jing Chen
Journal: Cancer Research (2014)

Abstract Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homoeostasis in mammalian cells. The current understanding of PDC regulation involves serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDHK), which inhibits PDH and subsequently PDC, whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here we report that lysine acetylation of PDHA1 and PDP1 is induced by EGF-stimulation in human cells, and is common in diverse human cancer cells. We found that K321 acetylation inhibits PDHA1 by recruiting PDHK1 and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important for the metabolic switch to glycolysis in cancer cells and promote tumor growth. Moreover, we identified mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) as the upstream acetyltransferase of PDHA1 and PDP1 using a novel shRNA library that targets the majority of acetyltransferases in the human genome, and SIRT3 as the deacetylase. Knockdown of ACAT1 results in decreased cancer cell proliferation and tumor growth. Furthermore, we found that EGFR and other tyrosine kinases including FGFR1 that are frequently dysregulated in human cancers phosphorylate PDP1 at Y381, which dissociates SIRT3 and recruits ACAT1 to PDC. Our findings suggest a novel mechanism where lysine acetylation of PDHA1 and PDP occurs in both normal and cancer cells, and contributes to inhibitory regulation of PDC, providing complementary insight into the current understanding of PDHA1 regulation. We also demonstrate that hierarchical, distinct post-translational modifications crosstalk to regulate PDC by controlling its molecular composition. Moreover, our findings for the first time link a mitochondrial acetyltransferase, ACAT1, to the Warburg effect and tumor growth, suggesting that the ACAT1-PDP1-PDHA axis represents a promising anti-cancer target. Citation Format: Jun Fan, Ting-Lei Gu, Titus Boggon, Sumin Kang, Jing Chen. Tyr-phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate pyruvate dehydrogenase complex and promote the Warburg effect. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3362. doi:10.1158/1538-7445.AM2014-3362