The relationship between IFNL4 genotype and the rate of fibrosis in hepatitis C patients.

Introduction: IFNL4 rs12979860 genotype CC is associated with increased ALT activity and liver stiffness in hepatitis C virus (HCV) genotype (G) 3 infection but not in G1. The primary aim of this study is to assess an interaction between IFNL4 genotype, viral genotype and the stage of liver fibrosis. Secondary aims are to study the potential interactions between IFNL4 genotype, viral genotype and viral load as well as ALT levels. Methods: We performed a cross sectional study of patients with untreated chronic hepatitis C. Inflammation and liver fibrosis were scored using METAVIR. DNA was extracted from serum samples and the rs12979860 was genotyped using a custom made Taqman assay. Results: About 304 consecutive patients with chronic Hepatitis C were included. 52% had G1 infection and 48% had G3. Among patients with G3, advanced fibrosis or cirrhosis (F3F4) was present in 35% of the patients with IFNL4 CC and 28% with CT/TT (p = 0.24). Among patients with G1, F3F4 was present in 20% of the patients with IFNL4 CC and 19% with CT/TT (p = 0.52). IFNL4 CC was associated with higher mean value of normalized (n)ALT both in HCV G1 and G3 infection. Conclusions: IFNL4 genotype was not a predictor of advanced liver fibrosis in G3 or G1 infected patients. IFNL4 CC predicted a higher mean value of ALT among both G1 and G3 infected patients.

Telomere shortening correlates to dysplasia but not to DNA aneuploidy in longstanding ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic, inflammatory bowel disease which may lead to dysplasia and adenocarcinoma in patients when long-lasting. Short telomeres have been reported in mucosal cells of UC patients. Telomeres are repetitive base sequences capping the ends of linear chromosomes, and protect them from erosion and subsequent wrongful recombination and end-to-end joining during cell division. Short telomeres are associated with the development of chromosomal instability and aneuploidy, the latter being risk factors for development of dysplasia and cancer. Specifically, the abrupt shortening of one or more telomeres to a critical length, rather than bulk shortening of telomeres, seems to be associated with chromosomal instability. METHODS: We investigated possible associations between dysplasia, aneuploidy and telomere status in a total of eight lesions from each of ten progressors and four nonprogressors suffering from longstanding UC. We have analyzed mean telomere length by qPCR, as well as the amount of ultra-short telomeres by the Universal STELA method. RESULTS: An increased amount of ultra-short telomeres, as well as general shortening of mean telomere length are significantly associated with dysplasia in longstanding UC. Furthermore, levels of ultra-short telomeres are also significantly increased in progressors (colons harbouring cancer/dysplasia and/or aneuploidy) compared to nonprogressors (without cancer/dysplasia/aneuploidy), whereas general shortening of telomeres did not show such associations. CONCLUSIONS: Our data suggest that ultra-short telomeres may be more tightly linked to colorectal carcinogenesis through development of dysplasia in UC than general telomere shortening. Telomere status was not seen to associate with DNA aneuploidy.

Improved lymph node harvest from resected colon cancer specimens did not cause upstaging from TNM stage II to III.

BACKGROUND: The number of lymph nodes retrieved and examined from a resected colon cancer specimen may be crucial for correct staging. We examined if efforts to increase the lymph node harvest to more than 12 lymph nodes per specimen would upstage some patients from TNM stage II to III. METHODS: Three hospitals compared results from 2000 with those of 2007 in 421 resected patients with stage II and III colon cancer. Hospital A endeavored to improve the surgical procedure while the pathologists enhanced the quality of lymph node sampling. Hospital B did not make any marked changes, while hospital C introduced the GEWF lymph node solvent (glacial acetic acid, ethanol, distilled water, and formaldehyde) in their pathology method. RESULTS: In 2000, 12 or more lymph nodes were harvested in 39.6, 45.0, and 21.1% of the specimens from the three hospitals, while the figures for 2007 were 85.7, 42.0, and 90.3%, respectively. The significant increase in lymph node harvest in two of the hospitals in 2007 compared to 2000 (p < 0.001) did not affect the share of patients with stage III in 2007 (38.7%) compared to 2000 (44.1%) (p = 0.260). The number of positive lymph nodes and the lymph node ratio (LNR) decreased from 2000 to 2007. A lymph node yield of 12 or more was not associated with an increased probability of positive lymph nodes in a multivariable logistic regression analysis. CONCLUSION: More radical surgery and dedicated pathologists and the use of the GEWF solvent significantly increased the lymph node yield but did not upstage patients from TNM stage II to III.

Nondysplastic Ulcerative Colitis Has High Levels of the Homologous Recombination Repair Protein NUCKS1 and Low Levels of the DNA Damage Marker Gamma-H2AX.

Background: The colon and rectum are continuously exposed to oxidative stress that generates reactive oxygen species, which are a major cause of DNA double-strand breaks (DSB). Furthermore, chronic inflammatory diseases such as ulcerative colitis (UC) are characterized by an excess of reactive nitrogen species that can also lead to DNA double-strand breakage and genomic instability. We investigated the expression of the nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) protein in UC and sporadic colorectal cancer (CRC) due to its involvement in both DNA double-strand break repair and inflammatory signaling. Methods: NUCKS1 expression and expression of the DNA double-strand break marker gamma-H2AX (γH2AX) were assessed in formalin-fixed, paraffin-embedded UC and CRC patient biopsies using peroxidase immunohistochemistry. Expression levels for both proteins were evaluated together with previously published expression-level data for hTERT and TP53 proteins in the same material. Results: Nondysplastic UC lesions had 10-fold lower γH2AX expression and approximately 4-fold higher NUCKS1 expression compared with sporadic CRC, indicating minimal DNA DSB damage and heightened DNA DSB repair in these lesions, respectively. NUCKS1 expression in UC tended to decrease with increasing grades of dysplasia, whereas γH2AX, hTERT, and TP53 expression tended to increase with increasing grades of dysplasia. The highest γH2AX expression was seen in sporadic CRC, indicating considerable DNA DSB damage, whereas the highest NUCKS1 expression and hTERT expression were seen in nondysplastic UC. Conclusions: Overall, our data suggest that NUCKS1 may be involved in DNA DSB repair and/or inflammatory signaling in UC, but a more thorough investigation of both pathways in UC is warranted.