Miracle-dz/UniFAR-FTUs huggingface dataset:
Obesity and pancreatic cancer: Overview of epidemiologic evidence and biologic mechanisms

In the United States, pancreatic cancer is characterized by a low 5‐yr survival rate of approximately 6%, fewer than 10% of patients diagnosed with localized disease and thus candidates for “curative” surgical resection, increasing incidence and few established risk factors. Similar statistics are observed for other industrialized nations. With new evidence to suggest that pancreatic cancer develops over a number of years, markers that can better identify high risk patients and are applicable to earlier diagnosis hold promise for improving these dire statistics. Obesity is one of the few modifiable risk factors that has been associated with increased risk of pancreatic cancer and also is related to increased risk of diabetes, a condition that in turn has been associated with pancreatic cancer development. Given recent data that nearly 70% of United States adults are overweight or obese, a clarification of the complex association between obesity and pancreatic cancer may disclose targets for prevention and intervention to decrease incidence and improve prognosis of this highly fatal disease. An overview of the current epidemiology and hypothesized biological mechanisms involved in the obesity‐pancreatic cancer association are presented. © 2011 Wiley Periodicals, Inc.
TRIM59 is up-regulated in gastric tumors, promoting ubiquitination and degradation of p53.

BACKGROUND & AIMS Little is known about factors that promote gastric carcinogenesis. We analyzed multiple microarray data sets for messenger RNAs (mRNAs) that were increased significantly in human gastric tumor samples, compared with the adjacent normal gastric tissue. We found expression of tripartite motif 59 (TRIM59), which encodes a putative ubiquitin ligase, to be increased, and investigated its effects in gastric cancer cell lines. METHODS We analyzed microarray data sets from the Oncomine database. We used quantitative polymerase chain reaction and immunoblotting to measure levels of TRIM59 mRNA and protein in 50 human gastric cancer and paired normal tissues, obtained from Renji Hospital and the First Affiliated Hospital of Nanchang University, in China. We also measured protein levels in the gastric epithelial cell line GES-1; the cancer cell lines MKN45, AGS, SGC7901, BGC823, Snu5, N87, and Snu1; and in tissue arrays of 108 human gastric tumors. TRIM59 was knocked down and overexpressed in gastric cancer cell lines, and the effects on proliferation, clone formation, migration, and growth of xenograft tumors in nude mice were assessed. TRIM59-related signaling pathways were examined by immunoblotting and quantitative polymerase chain reaction. We analyzed interactions among TRIM59, P53, and ubiquitin in immunoprecipitation studies. RESULTS Levels of TRIM59 mRNA and protein were increased significantly in gastric tumors compared with nontumor tissues; increased levels were associated with advanced tumor stage and shorter patient survival times. TRIM59 knockdown reduced proliferation, clone formation, and migration of gastric cancer cell lines, as well as growth of xenograft tumors in nude mice; overexpression of TRIM59 had the opposite effects. TRIM59 interacted physically with P53, increasing its ubiquitination and degradation. Increased levels of TRIM59 in human gastric tumors correlated with reduced expression of P53 target genes. CONCLUSIONS The putative ubiquitin ligase TRIM59 is up-regulated in human gastric tumors compared with nontumor tissues. Levels of TRIM59 correlate with tumor progression and patient survival times. TRIM59 interacts with P53, promoting its ubiquitination and degradation, and TRIM59 might promote gastric carcinogenesis via this mechanism.
C. elegans whole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency

Mutation is associated with developmental and hereditary disorders, aging, and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used Caenorhabditis elegans whole-genome sequencing to model mutational signatures, analyzing 183 worm populations across 17 DNA repair-deficient backgrounds propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in C. elegans was approximately one per genome per generation, not overtly altered across several DNA repair deficiencies over 20 generations. Telomere erosion led to complex chromosomal rearrangements initiated by breakage–fusion–bridge cycles and completed by simultaneously acquired, localized clusters of breakpoints. Aflatoxin B1 induced substitutions of guanines in a GpC context, as observed in aflatoxin-induced liver cancers. Mutational burden increased with impaired nucleotide excision repair. Cisplatin and mechlorethamine, DNA crosslinking agents, caused dose- and genotype-dependent signatures among indels, substitutions, and rearrangements. Strikingly, both agents induced clustered rearrangements resembling “chromoanasynthesis,” a replication-based mutational signature seen in constitutional genomic disorders, suggesting that interstrand crosslinks may play a pathogenic role in such events. Cisplatin mutagenicity was most pronounced in xpf-1 mutants, suggesting that this gene critically protects cells against platinum chemotherapy. Thus, experimental model systems combined with genome sequencing can recapture and mechanistically explain mutational signatures associated with human disease.
Functional NBS1 polymorphism is associated with occurrence and advanced disease status of nasopharyngeal carcinoma

As a component of the MRN (MRE11/RAD50/NBS1) complex, NBS1 plays an important role in cellular response to DNA damage and the maintenance of chromosomal integrity. The NBS1 E185Q polymorphism (8360G>C, rs1805794) has been frequently studied in some cancers with discordant results, but its association with nasopharyngeal carcinoma (NPC) in Chinese population has not been investigated. Moreover, there is no report about the association between NBS1 3′UTR variant rs2735383 and the risk of NPC. A multiple center case–control analysis was performed to assess the association between NBS1 polymorphisms and NPC risk in Eastern and Southern Chinese population. The genotypes and haplotypes were determined in 1052 cases and 1168 controls and the associations with risk of NPC were estimated by logistic regression. Cell migration assays were performed in 24‐well transwell chambers to detect the effects of NBS1 E185Q SNP on cell migration. We observed significant difference in genotype frequencies at the rs1805794 C/G site between cases and controls (Ptrend < 0.0001). The C allele increases the risk for invasive disease or metastatic disease, compared with G allele. More over, CNE‐2 cells (NPC cell line) transfected with pcDNA‐NBS1‐185Q (8360CC) had significantly higher migration levels than those transfected with pcDNA‐NBS1‐185E (8360GG) (P = 0.024). These findings suggest that E185Q polymorphism in NBS1 may be a genetic modifier for the occurrence and aggression of NPC. © 2011 Wiley‐Liss, Inc.
Large transcription units unify copy number variants and common fragile sites arising under replication stress

Copy number variants (CNVs) resulting from genomic deletions and duplications and common fragile sites (CFSs) seen as breaks on metaphase chromosomes are distinct forms of structural chromosome instability precipitated by replication inhibition. Although they share a common induction mechanism, it is not known how CNVs and CFSs are related or why some genomic loci are much more prone to their occurrence. Here we compare large sets of de novo CNVs and CFSs in several experimental cell systems to each other and to overlapping genomic features. We first show that CNV hotpots and CFSs occurred at the same human loci within a given cultured cell line. Bru-seq nascent RNA sequencing further demonstrated that although genomic regions with low CNV frequencies were enriched in transcribed genes, the CNV hotpots that matched CFSs specifically corresponded to the largest active transcription units in both human and mouse cells. Consistently, active transcription units >1 Mb were robust cell-type-specific predictors of induced CNV hotspots and CFS loci. Unlike most transcribed genes, these very large transcription units replicated late and organized deletion and duplication CNVs into their transcribed and flanking regions, respectively, supporting a role for transcription in replication-dependent lesion formation. These results indicate that active large transcription units drive extreme locus- and cell-type-specific genomic instability under replication stress, resulting in both CNVs and CFSs as different manifestations of perturbed replication dynamics.
Pancreatic cancer: Helicobacter pylori colonization, N‐Nitrosamine exposures, and ABO blood group

Thirty years of research with animal models has shown that pancreatic adenocarcinoma is induced by N‐nitrosamine carcinogens, which damage DNA through adduct formation. Human risk factors for pancreatic cancer include gastric colonization by Helicobacter pylori, as well as dietary intake of those same N‐nitrosamines or of nitrite which forms those N‐nitrosamines in the stomach, and cigarette smoking which also contains those N‐nitrosamines. Physiologic actions of H. pylori colonization enhance the carcinogenic effect of N‐nitrosamines delivered by smoking or dietary sources. This effect is modulated by host inflammatory response to the organism, by various virulence and other properties of the Helicobacter itself, and by host‐organism interactions. A recent genome‐wide association study identified SNPs within the ABO 9q34 locus as statistically significantly associated with risk of pancreatic cancer. A number of recent and older studies going back 40 yr also support the ABO association. ABO‐product antigens are expressed on gastrointestinal epithelium on which H. pylori binds, and ABO genotype is known to be associated with risks of duodenal and gastric ulcer and with risk of gastric cancer, conditions definitively related to Helicobacter colonization. We suspect that ABO genotype/phenotype status influences the behavior of H. pylori which in turn affects gastric and pancreatic secretory function, and these ultimately influence the pancreatic carcinogenicity of dietary‐ and smoking‐related N‐nitrosamine exposures, and thus risk of pancreatic cancer. Our study results on the interaction of ABO and H. pylori significantly confirm this hypothesis and together with other existing studies strongly implicate this organism in the disease etiology. © 2011 Wiley Periodicals, Inc.
Cortical mastoidectomy in quiescent, tubotympanic, chronic otitis media: is it routinely necessary?

OBJECTIVE This study aimed to compare outcomes for mastoidotympanoplasty and for tympanoplasty alone in cases of quiescent, tubotympanic, chronic, suppurative otitis media. STUDY DESIGN Single-blinded, randomised, controlled study within a tertiary referral hospital. METHODS Sixty-eight cases were randomly allocated into two groups. In group one, 35 ears underwent type one tympanoplasty along with cortical mastoidectomy. In group two, 33 ears underwent type one tympanoplasty alone. Outcome measures were as follows: perforation closure and graft uptake, hearing improvement, disease eradication, and post-operative complications. RESULTS There were no statistically significant differences in hearing improvement, tympanic perforation closure, graft uptake or disease eradication, comparing the two groups at three and six months post-operatively. CONCLUSION Mastoidotympanoplasty was not found to be superior to tympanoplasty alone over a short term follow-up period. Hence, it may not be necessary to undertake routine mastoid exploration at this stage of disease.
Urinary incontinence in adolescent females with cystic fibrosis in Poland

ObjectivesThere have been many studies regarding urinary incontinence in cystic fibrosis females. However, no data concerning that issue was yet investigated in Poland.MethodsAn anonymous questionnaire was sent by mail to all Polish cystic fibrosis females 16 years of age and older.Results64 patients responded to the questionnaire, 44% reported having urinary incontinence. Median age of onset of incontinence was 14.5 years. There were no differences in age, Body Mass Index (BMI), Forced expiratory volume in 1 second (FEV1), Cystic Fibrosis-Related Diabetes and Percutaneous Endoscopic Gastrostomy between continent and incontinent respondents. Significant correlations between urinary incontinence and number of respiratory exacerbations, sexual activity, and constipation were observed. No relationships between frequency and severity of urinary incontinence and form of chest physiotherapy, BMI and FEV1 were identified. Most respondents declared that urinary incontinence affected their daily life and prevented them from chest physiotherapy.ConclusionsUrinary incontinence should be identified and regarded with high priority in cystic fibrosis; health professionals should be aware that it is their responsibility to actively initiate discussion with patients of that subject in early adolescence.
Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study.

BACKGROUND & AIMS Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points. METHODS We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death). RESULTS Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤ 2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels >2.0 times the ULN (P < .0001). Absolute levels of alkaline phosphatase 1 year after study enrollment predicted patient outcomes better than percentage change in level. One year after study enrollment, a bilirubin level 1.0 times the ULN best predicted patient transplant-free survival (C statistic, 0.79). Of patients with bilirubin levels ≤ 1.0 times the ULN, 86% survived for 10 years after study enrollment compared with 41% of those with levels >1.0 times the ULN (P < .0001). Combining levels of alkaline phosphatase and bilirubin increased the ability to predict patient survival times. We confirmed the predictive value of alkaline phosphatase and bilirubin levels in multiple subgroups, such as patients who had not received treatment with ursodeoxycholic acid, and at different time points after study enrollment. CONCLUSIONS Levels of alkaline phosphatase and bilirubin can predict outcomes (liver transplantation or death) of patients with PBC and might be used as surrogate end points in therapy trials.
Role of epigenetic and miR‐22 and miR‐29b alterations in the downregulation of Mat1a and Mthfr genes in early preneoplastic livers in rats induced by 2‐acetylaminofluorene

Carcinogenesis is a multistep sequential process of clonal expansion of initiated cells associated with the accumulation of multiple cancer‐specific heritable phenotypes. The acquisition of these heritable cancer‐specific alterations may be triggered by mutational and/or non‐mutational changes in the genome that affect the regulation of gene expression. Currently, cancer‐specific epigenetically mediated changes in gene expression are regarded as driving events in tumorigenesis. In the present study, we investigated the role of gene‐specific expression changes in the mechanism of rat hepatocarcinogenesis induced by the complete hepatocarcinogen 2‐acetylaminofluorene (2‐AAF). The results of the present study demonstrate significant alterations in gene expression, especially of Mat1a and Mthfr genes, during early stages of rat 2‐AAF‐induced liver carcinogenesis. Both of these genes were downregulated in the livers of 2‐AAF‐treated male rats. Inhibition of Mat1a expression was associated with an increase in histone H3 lysine 27 trimethylation and a decrease in histone H3 lysine 18 acetylation at the gene promoter/first exon region. Additionally, we demonstrate for the first time a critical contribution of miR‐22 and miR‐29b microRNAs in the inhibition of Mat1a and Mthfr gene expression during 2‐AAF‐induced rat hepatocarcinogenesis. The downregulation of Mat1a and Mthfr genes was accompanied by marked functional alterations in one‐carbon metabolism. The results of the present study suggest that downregulation of the Mat1a and Mthfr genes may be one of the main driver events that promote liver carcinogenesis by causing a profound accumulation of subsequent epigenetic abnormalities during progression of the carcinogenic process. © 2011 Wiley Periodicals, Inc.
Diverse alternative back-splicing and alternative splicing landscape of circular RNAs

Circular RNAs (circRNAs) derived from back-spliced exons have been widely identified as being co-expressed with their linear counterparts. A single gene locus can produce multiple circRNAs through alternative back-splice site selection and/or alternative splice site selection; however, a detailed map of alternative back-splicing/splicing in circRNAs is lacking. Here, with the upgraded CIRCexplorer2 pipeline, we systematically annotated different types of alternative back-splicing and alternative splicing events in circRNAs from various cell lines. Compared with their linear cognate RNAs, circRNAs exhibited distinct patterns of alternative back-splicing and alternative splicing. Alternative back-splice site selection was correlated with the competition of putative RNA pairs across introns that bracket alternative back-splice sites. In addition, all four basic types of alternative splicing that have been identified in the (linear) mRNA process were found within circRNAs, and many exons were predominantly spliced in circRNAs. Unexpectedly, thousands of previously unannotated exons were detected in circRNAs from the examined cell lines. Although these novel exons had similar splice site strength, they were much less conserved than known exons in sequences. Finally, both alternative back-splicing and circRNA-predominant alternative splicing were highly diverse among the examined cell lines. All of the identified alternative back-splicing and alternative splicing in circRNAs are available in the CIRCpedia database (http://www.picb.ac.cn/rnomics/circpedia). Collectively, the annotation of alternative back-splicing and alternative splicing in circRNAs provides a valuable resource for depicting the complexity of circRNA biogenesis and for studying the potential functions of circRNAs in different cells.
A flexible method for estimating the fraction of fitness influencing mutations from large sequencing data sets

A continuing challenge in the analysis of massively large sequencing data sets is quantifying and interpreting non-neutrally evolving mutations. Here, we describe a flexible and robust approach based on the site frequency spectrum to estimate the fraction of deleterious and adaptive variants from large-scale sequencing data sets. We applied our method to approximately 1 million single nucleotide variants (SNVs) identified in high-coverage exome sequences of 6515 individuals. We estimate that the fraction of deleterious nonsynonymous SNVs is higher than previously reported; quantify the effects of genomic context, codon bias, chromatin accessibility, and number of protein–protein interactions on deleterious protein-coding SNVs; and identify pathways and networks that have likely been influenced by positive selection. Furthermore, we show that the fraction of deleterious nonsynonymous SNVs is significantly higher for Mendelian versus complex disease loci and in exons harboring dominant versus recessive Mendelian mutations. In summary, as genome-scale sequencing data accumulate in progressively larger sample sizes, our method will enable increasingly high-resolution inferences into the characteristics and determinants of non-neutral variation.
The hepatobiliary paracellular pathway: a paradigm revisited.

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