The significance of beta-catenin, E-cadherin, and P-cadherin expressions in neoplastic progression of colorectal mucosa: an immunohistochemical study

BACKGROUND AND STUDY AIMS: The purpose of the current study was to investigate the role of beta-catenin, E-cadherin and P-cadherin in colorectal carcinogenesis using tissue array method. PATIENTS AND METHODS: Core tissue biopsies were taken from paraffin-embedded tissue blocks of 167 cases including 26 normal mucosae (NM), 99 colorectal polyps (10 hyperplastic polyps (HP), 8 traditional serrated (TSA), 17 tubular (TA), 37 tubulovillous (TVA), and 27 villous adenomas (VA)), 14 adenomas with intramucosal carcinoma (ACA), and 28 colorectal cancers (CCA). Immunohistochemistry was performed using antibodies to beta-catenin, E-cadherin, and P-cadherin. Distribution of positivity was assessed using percentage expression while an arbitrary grading scale was used for staining intensity. RESULTS: beta-catenin expression was cytoplasmic, membranous, and nuclear. Both E-cadherin and P-cadherin expressions were confined to cytoplasmic-membranous compartments. Membranous expression of beta-catenin significantly decreased in CCA (p < 0.01). Nuclear beta-catenin expression significantly increased in close correlation with neoplastic sequence reaching its highest expression in ACA and CCA (p < 0.001). Polyps with intraepithelial neoplasia (IEN) showed significantly higher nuclear beta-catenin expression in parallel with increasing grades of IEN (p < 0.001). E-cadherin and P-cadherin expression increased in polyps, whereas a significant decrease in their expression was observed in CCA (p < 0.001) while E-cadherin expression significantly increased in CCA compared to NM (p < 0.001), no such difference was observed in P-cadherin expression. CONCLUSIONS: Nuclear beta-catenin expression correlating with the grade of IEN in polyps and carcinomas supports its role in colorectal carcinogenesis. E-cadherin and P-cadherin expressions in adenomas suggest that these molecules might have role in adenoma formation though not necessarily be involved in neoplastic progression.     

Urotensin Inhibition with Palosuran Could Be a Promising Alternative in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive and a life-threatening disease with its high morbidity and mortality ratios. On searching for new shining targets in pathogenesis, we noticed, in our previous studies, urotensin-II (UII) in systemic sclerosis with potent angiogenic and pro-fibrotic features. Owing to the mimicking properties of UII with endothelin-1 (ET1), we attempted to investigate the effect of palosuran in a PAH rat model. Thirty rats were randomly divided into three groups, with each group comprising 10 rats: group 1 (control group) received the vehicle subcutaneously, instead of monocrotaline (MCT) and vehicle; group 2 (MCT group) received subcutaneous MCT and vehicle; and group 3 (MCT + palosuran group) received subcutaneous MCT and palosuran. Serum UII, ET1, transforming growth factor-β1 (TGF-β1) levels, pulmonary arteriolar pathology of different diameter vessels, and cardiac indices were evaluated. The ET1, TGF-β1, and UII levels were significantly diminished in the treatment group, similar to the controls (p?<?0.001). Right ventricular hypertrophy index and mean pulmonary arterial pressure scores were also significantly reduced in the treatment group (p?=?0.001). Finally, in the 50–125-μm diameter arterioles, in contrast to Groups 3 and 1, there was a statistically significant thickness (p?<?0.01) in the arteriolar walls of rats in Group 2. The treatment effect on arteries of more than 125-μm diameters was found to be valuable but not significant. Owing to its healing effect on hemodynamic, histological, and biochemical parameters of MCT-induced PAH, palosuran as an antagonist of UII might be an optional treatment alternative for PAH.     

Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice

Adriamycin (ADR) is a commonly used chemotherapeutic agent that also produces significant tissue damage. Mutations to mitochondrial DNA (mtDNA) and reductions in mtDNA copy number have been identified as contributors to ADR-induced injury. ADR nephropathy only occurs among specific mouse inbred strains, and this selective susceptibility to kidney injury maps as a recessive trait to chromosome 16A1-B1. Here, we found that sensitivity to ADR nephropathy in mice was produced by a mutation in the Prkdc gene, which encodes a critical nuclear DNA double-stranded break repair protein. This finding was confirmed in mice with independent Prkdc mutations. Overexpression of Prkdc in cultured mouse podocytes significantly improved cell survival after ADR treatment. While Prkdc protein was not detected in mitochondria, mice with Prkdc mutations showed marked mtDNA depletion in renal tissue upon ADR treatment. To determine whether Prkdc participates in mtDNA regulation, we tested its genetic interaction with Mpv17, which encodes a mitochondrial protein mutated in human mtDNA depletion syndromes (MDDSs). While single mutant mice were asymptomatic, Prkdc/Mpv17 double-mutant mice developed mtDNA depletion and recapitulated many MDDS and ADR injury phenotypes. These findings implicate mtDNA damage in the development of ADR toxicity and identify Prkdc as a MDDS modifier gene and a component of the mitochondrial genome maintenance pathway.     

Providing insights into atherosclerosis: A case of multivessel coronary artery disease with an anomalous straightforward vessel spared from atherosclerosis

Atherosclerotic plaques tend to involve arterial localizations in which blood flow is not laminar due to arterial bends and bifurcations. A 49-year-old man was admitted to hospital with breathlessness and was subsequently diagnosed with left ventricular failure. Coronary angiography revealed three-vessel coronary artery disease and an anomalous extra left anterior descending artery taking off from the right sinus of Valsalva and spared from atherosclerosis. The absence of side branches and the relative lack of bends in arterial geometry were considered to be the cause of resistance to atherosclerosis. The present case identifies local flow conditions as an important factor determining the genesis of atherosclerosis in arterial segments.     

Anti-pancreatic antibody in Turkish patients with inflammatory bowel disease and first-degree relatives

AIM: To identify the role of anti-pancreatic antibody (PAB) in the diagnosis of inflammatory bowel diseases (IBD) among Turkish patients, and its frequency in firstdegree relatives.METHODS: PAB and anti-Saccharomyces cerevisiae (ASCA) were examined in serum samples of 214 subjects including patients with Crohn’s disease (CD, n = 64), ulcerative colitis (UC, n = 63), first-degree relatives of patients with CD (n = 25), first-degree relatives of patients with UC (n = 28),and a control group with gastrointestinal symptoms other than (IBD) (n = 34) by indirect immunofluorescence Positivity of PAB and ASCA was compared in terms of Vienna classification, disease activity and medications used.RESULTS: In terms of PAB positivity, no difference was found between patients with CD (14.1%) and UC (7.9%) however, significant difference was observed between patients with CD and subjects in the control group (P < 0.05). No difference was found between patients with CD and their relatives in terms of ASCA positivity, whereas a significant difference was found between other groups (P < 0.001). Compared to ASCA, the sensitivity of the PAB was 19% (7/37), its specificity was 93% (25/27), positive predictive value was 77% (7/9) and negative predictive value was 45% (25/55). ASCA was found with significantly higher prevalence in patients with CD activity index > 150 (P < 0.05).CONCLUSION: PAB is valuable in the diagnosis of IBD rather than CD, but cannot be used alone for diagnostic purposes. PAB is not superior to ASCA in CD diagnosis and in detecting CD among relatives of patients with CD.     

Lipid peroxidation, erythrocyte superoxide-dismutase activity and trace metals in young male footballers

Physical training is known to induce oxidative stress in individuals subjected to intense exercise. In this study, we investigated plasma malondialdehyde (MDA) levels and erythrocyte superoxide dismutase (SOD) activity of 25 young male footballers and a control group of similar age. Red blood cell (RBC) count, haemoglobin (Hb) and haematocrit (Hct) values, and copper (Cu) and zinc (Zn) levels were also examined. The maximal oxygen uptake (VO2max) of all subjects was determined in order to establish their functional capacity. The main finding of the present study was that plasma MDA levels, one of the most commonly used markers of lipid peroxidation, of this group of footballers aged under 21 decreased slightly when compared with those of the control group (p < 0.001). In contrast, erythrocyte SOD activity was higher in the footballer group than in the controls (p < 0.001). Footballers who are under regular training showed an improved antioxidant activity in comparison to sedentary controls. Plasma copper concentration, RBC count and Hb concentration of the footballer group were all significantly lower than those of the control group, (p < 0.001, p < 0.01, p < 0.01, respectively). Investigating the footballers' data with Spearman's correlation analyses, the correlation coefficients (r) between Zn/Cu ratio and SOD was positive (r=0.44; p < 0.05); and between VO2max and SOD (r=0.42; p < 0.05) were both positive. On the basis of statistical analysis, we suggest that regular exercise may be beneficial in cases of oxidative damage by reducing the amount of lipid peroxidation and increasing the activity of the antioxidant enzyme SOD.     

TLR-2 Arg753Gln, TLR-4 Asp299Gly, and TLR-4 Thr399Ile polymorphisms in Henoch Schonlein purpura with and without renal involvement

Infections may trigger or aggravate glomerulonephritidis and renal vasculitis like Henoch Schonlein purpura (HSP). HSP is seen more frequently in patients with familial Mediterranean fever in which TLR-2 Arg753Gln polymorphism frequency is increased. Although renal involvement is the most important factor affecting the prognosis in HSP, it is not known which patients will have renal disease or why some patients have severe renal involvement while some others have mild renal disease. We investigated the role of TLR-2 and TLR-4 polymorphisms on the incidence and severity of renal involvement in HSP patients. We studied HSP patients with and without nephritis (n = 15 for each group) and healthy controls (n = 100). TLR-2 Arg753Gln and TLR-4 Asp299Gly/Thr399Ile polymorphisms were analyzed with polymerase chain reaction–restriction fragment length polymorphism method. The frequency of TLR-2 Arg753Gln, TLR-4 Asp299Gly, and Thr399Ile polymorphisms in healthy controls were 1, 3, and 2%, respectively. The frequencies of these polymorphisms were not different in HSP patients with or without nephritis compared to healthy controls. TLR-3 Arg753Gln, TLR-4 Asp299Gly, and Thr399Ile polymorphisms are not increased in HSP or HSP nephritis patients.     

Genome-wide analyses on loss of heterozygosity in head and neck squamous cell carcinomas

Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor survival rate. Identifying the tumor suppressor gene (TSG) loci by genomic studies is an important step to uncover the molecular mechanisms involved in HNSCC pathogenesis. We therefore performed comprehensive analyses on loss of heterozygosity (LOH) using a genome-wide panel of 191 microsatellite markers in 22 HNSCC samples. We found 53 markers with significantly high LOH (>30%) on 21 chromosomal arms; the highest values of those were observed on 3p, 9p, 13q, 15q, and 17p, corresponding to D3S2432 (67%), D9S921-D9S925 (67%) and GATA62F03 (86%), D13S1493 (60%), D15S211 (62%), and D17S1353 (88%), respectively. Fifteen hot spots of LOH were defined in 13 chromosomal arms: 2q22-23, 4p15.2, 4q24-25, 5q31, 8p23, 9p23-24, 9q31.3, 9q34.2, 10q21, 11q21-22.3, 14q11-13, 14q22.3, 17p13, 18q11, and 19q12 as loci reported previously in HNSCCs. Furthermore, we identified five novel hot spots of LOH on three chromosomal arms in HNSCC at 2q33 (D2S1384), 2q37 (D2S125), 8q12-13 (D8S1136), 8q24 (D8S1128), and 15q21 (D15S211). In conclusion, our comprehensive allelotype analyses have unveiled and confirmed a total of 20 possible TSG loci that could be involved in the development of HNSCC. These results provide useful clues for identification of putative TSGs involved in HNSCC by fine mapping of the suspected regions and subsequent analysis for functional genes.