Role of PTPN22 and CSK gene polymorphisms as predictors of susceptibility and clinical heterogeneity in patients with Henoch-Schönlein purpura (IgA vasculitis)

INTRODUCTION: To determine whether the PTPN22 (protein tyrosine phosphatase nonreceptor 22)/CSK (c-src tyrosine kinase) pathway is implicated in the susceptibility and clinical heterogeneity of Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies. METHODS: A set of 329 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria and 515 sex and ethnically matched controls were recruited in this study. Two well-known CSK (CSK rs34933034 and CSK rs1378942) and two functional PTPN22 (PTPN22 rs2476601 (R620W) and PTPN22 rs33996649 (R263Q)) polymorphisms, previously associated with autoimmunity, were genotyped with TaqMan single nucleotide polymorphism (SNP) genotyping assays. RESULTS: No significant differences in the genotype and allele frequencies between HSP patients and controls were observed when the CSK rs34933034, CSK rs1378942, PTPN22 rs2476601 (R620W) and PTPN22 rs33996649 (R263Q) polymorphisms were analyzed independently. In keeping with this observation, no significant differences were found when we assessed these polymorphisms combined conforming haplotypes. In addition, there were no differences in the allele or genotype frequencies when HSP patients were stratified according the age at disease onset, sex, presence of arthralgia/arthritis, nephritis or gastrointestinal manifestations. CONCLUSIONS: Our results do not support association between PTPN22/CSK and HSP

SOX2 expression correlates with lymph-node metastases and distant spread in right-sided colon cancer

<p>Abstract</p> <p>Background</p> <p>The transcription factor SOX2, which is involved in the induction of pluripotent stem cells and contributes to colorectal carcinogenesis, is associated with a poor prognosis in colon cancer (CC). Furthermore, SOX2 is a repressor of the transcriptional activity of β-catenin in vitro. Since the majority of CC develop via an activation of the Wnt/β-catenin signalling pathway, indicated by nuclear expression of β-catenin, we wanted to investigate the expression patterns of SOX2 and β-catenin and correlate them with the occurrence of lymph node and distant metastases as indicators of malignant progression.</p> <p>Methods</p> <p>The expression of SOX2 and β-catenin was investigated in a case control study utilizing a matched pair collection (N = 114) of right-sided CCs with either corresponding distant metastases (N = 57) or without distant spread (N = 57) by applying immunohistochemistry.</p> <p>Results</p> <p>Elevated protein expression of SOX2 significantly correlated with the presence of lymph node- (<it>p </it>= 0.006) and distant metastases (<it>p </it>= 0.022). Nuclear β-catenin expression correlated significantly only with distant metastases (<it>p </it>= 0.001). Less than 10% of cases showed a coexpression of high levels of β-catenin and SOX2. The positivity for both markers was also associated with a very high risk for lymph-node metastases (<it>p </it>= 0.007) and distant spread (<it>p </it>= 0.028).</p> <p>Conclusion</p> <p>We demonstrated that increased expression of either SOX2 or nuclear β-catenin are associated with distant metastases in right-sided CC. Additionally, SOX2 is also associated with lymph-node metastases. These data underline the importance of stemness-associated markers for the identification of CC with high risk for distant spread.</p

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

MUC5AC (mucin 5AC, oligomeric mucus/gel-forming)

Review on MUC5AC (mucin 5AC, oligomeric mucus/gel-forming), with data on DNA, on the protein encoded, and where the gene is implicated

Loss of RNF43 function contributes to gastric carcinogenesis by impairing DNA damage response.

BACKGROUND &amp; AIMS: RING finger protein 43 (RNF43) is a tumor suppressor that frequently is mutated in gastric tumors. The link between RNF43 and modulation of WNT signaling has not been shown clearly in the stomach. Because mutations in RNF43 are highly enriched in microsatellite-unstable gastric tumors, which show defects in DNA damage response (DDR), we investigated whether RNF43 is involved in DDR in the stomach. METHODS: DDR activation and cell viability upon γ-radiation was analyzed in gastric cells where expression of RNF43 was depleted. Response to chemotherapeutic agents 5-fluorouracil and cisplatin was analyzed in gastric cancer cell lines and xenograft tumors. In addition, involvement of RNF43 in DDR activation was analyzed upon Helicobacter pylori infection in wild-type and Rnf43ΔEx8 mice. Furthermore, a cohort of human gastric biopsy specimens was analyzed for RNF43 expression and mutation status as well as for activation of DDR. RESULTS: RNF43 depletion conferred resistance to γ-radiation and chemotherapy by dampening the activation of DDR, thereby preventing apoptosis in gastric cells. Upon Helicobacter pylori infection, RNF43 loss of function reduced activation of DDR and apoptosis. Furthermore, RNF43 expression correlated with DDR activation in human gastric biopsy specimens, and RNF43 mutations found in gastric tumors conferred resistance to DNA damage. When exploring the molecular mechanisms behind, a direct interaction between RNF43 and γH2AX was observed. CONCLUSIONS: We identified a novel function for RNF43 in the stomach as a regulator of DDR. Loss of RNF43 function in gastric cells confers resistance to DNA damage-inducing radiotherapy and chemotherapy, suggesting RNF43 as a possible biomarker for therapy selection

Lymphotoxin &beta; receptor signalling executes <em>Helicobacter pylori</em>-driven gastric inflammation in a T4SS-dependent manner.

Objective Lymphotoxin &szlig; receptor (LT&szlig;R) signalling has been implicated in inflammation-associated tumour development in different tissues. We have analysed the role of LT&szlig;R and alternative NF-&kappa;B signalling in Helicobacter pylori-mediated gastric inflammation and pathology. Design We analysed several ligands and receptors of the alternative NF-&kappa;B pathway, RelB, p52 nuclear translocation and target genes in tissue samples of H. pylori-infected patients with different degrees of gastritis or early gastric tumours by in situ hybridisation, immunohistochemistry, Western blot and real-time PCR analyses. Molecular mechanisms involved in LT&szlig;R activation by H. pylori were assessed in vitro using human gastric cancer cell lines and distinct H. pylori isolates. The effects of blocking or agonistically activating LT&szlig;R on gastric pathology during challenge with a human pathogenic H. pylori strain were studied in a mouse model. Results Among the tested candidates, LT was significantly increased and activated alternative NF-&kappa;B signalling was observed in the gastric mucosa of H. pylori-infected patients. H. pylori induced LT&szlig;R-ligand expression in a type IV secretion system-dependent but CagA-independent manner, resulting in activation of the alternative NF-&kappa;B pathway, which was further enhanced by blocking canonical NF-&kappa;B during infection. Blocking LT&szlig;R signalling in vivo suppressed H. pylori-driven gastritis, whereas LT&szlig;R activation in gastric epithelial cells of infected mice induced a broadened pro-inflammatory chemokine milieu, resulting in exacerbated pathology. Conclusions LT&szlig;R-triggered activation of alternative NF- &kappa;B signalling in gastric epithelial cells executes H. pyloriinduced chronic gastritis, representing a novel target to restrict gastric inflammation and pathology elicited by H. pylori, while exclusively targeting canonical NF-&kappa;B may aggravate pathology by enhancing the alternative pathway