Increased expression levels of Syntaxin 1A and Synaptobrevin 2/Vesicle-Associated Membrane Protein-2 are associated with the progression of bladder cancer.

Gene expression is tightly regulated in time and space through a multitude of factors consisting of signaling molecules. Soluble N-ethylmaleimide-sensitive-factor attachment protein receptors (SNARE) are membrane proteins responsible for the intercellular trafficking of signals through endocytosis and exocytosis of vesicles. Altered expression of SNARE proteins in cellular communication is the major hallmark of cancer phenotypes as indicated in recent studies. SNAREs play an important role in maintaining cell growth and epithelial membrane permeability of the bladder and are not only involved in cancer progression but also metastatic cell invasion through SNARE-mediated trafficking. Synaptobrevin2/Vesicle associated membrane protein-2 (v-SNARE) and Syntaxin (t-SNARE) form a vesicular docking complex during endocytosis. Some earlier studies have shown a critical role of SNARE in colon, lungs, and breast cancer progression and metastasis. In this study, we analyzed the relative expression of the STX1A and VAMP2 (SYB2) for their possible association in the progression and metastasis of bladder cancer. The profiling of the genes showed a significant increase in STX1A and VAMP2 expression (p < 0.001) in high-grade tumor cells compared to normal and low-grade tumors. These findings suggest that elevated expression of STX1A and VAMP2 might have caused the abnormal progression and invasion of cancer cells leading to the transformation of cells into high-grade tumor in bladder cancer.

Novel and recurrent LDLR gene mutations in Pakistani hypercholesterolemia patients.

The majority of patients with the autosomal dominant disorder familial hypercholesterolemia (FH) carry novel mutations in the low density lipoprotein receptor (LDLR) that is involved in cholesterol regulation. In different populations the spectrum of mutations identified is quite different and to date there have been only a few reports of the spectrum of mutations in FH patients from Pakistan. In order to identify the causative LDLR variants the gene was sequenced in a Pakistani FH family, while high resolution melting analysis followed by sequencing was performed in a panel of 27 unrelated sporadic hypercholesterolemia patients. In the family a novel missense variant (c.1916T > G, p.(V639G)) in exon 13 of LDLR was identified in the proband. The segregation of the identified nucleotide change in the family and carrier status screening in a group of 100 healthy subjects was done using restriction fragment length polymorphism analysis. All affected members of the FH family carried the variant and none of the non-affected members nor any of the healthy subjects. In one of the sporadic cases, two sequence changes were detected in exon 9, one of these was a recurrent missense variant (c.1211C > T; p.T404I), while the other was a novel substitution mutation (c.1214 A > C; N405T). In order to define the allelic status of this double heterozygous individual, PCR amplified fragments were cloned and sequenced, which identified that both changes occurred on the same allele. In silico tools (PolyPhen and SIFT) were used to predict the effect of the variants on the protein structure, which predicted both of these variants to have deleterious effect. These findings support the view that there will be a novel spectrum of mutations causing FH in patients with hypercholesterolaemia from Pakistan.

Caveolin-1 and dynamin-2 overexpression is associated with the progression of bladder cancer.

Caveolae-mediated endocytosis regulates cell adhesion and growth in an anchorage-dependent manner. Studies of the endocytic function of caveolae have suggested a wide-ranging list of cargoes, including a number of receptors and extracellular proteins, ligands and nutrients from the extracellular matrix. Disruption of the processes of caveolae-mediated endocytosis mediated by signaling proteins is critical to cellular integrity. Caveolin-1 and dynamin-2 are the 2 major proteins associated with endocytotic function. Mechanistically, dynamin-2 has a co-equal role with caveolin-1 in terms of caveolae-derived endosome formation. Recent studies have revealed the pathological outcomes associated with the dysregulation of caveolin-1 and dynamin-2 expression. Increased expression levels of the gene for caveolin, Cav-1, resulting in augmented cellular metastasis and invasion, have been demonstrated in various types of cancer, and overexpression of the gene for dynamin-2, DNM2, has been associated with tumorigenesis in cervical, pancreatic and lung cancer. An increased expression of Cav-1 and DNM2 is known to be associated with the invasive behavior of cancer cells, and with cancer progression. Furthermore, it has been previously demonstrated that, in caveolar assembly and caveolae mediated endocytosis, Cav-1 interacts directly with DNM2 during the processes. Altered expression of the 2 genes is critical for the normal function of the cell. The expression patterns of Cav-1 and DNM2 have been previously examined in bladder cancer cell lines, and were each demonstrated to be overexpressed. In the present study, the expression levels of these 2 genes in bladder cancer samples were quantified. The gene expression levels of Cav-1 and DNM2 were identified to be increased 8.88- and 8.62-fold, respectively, in tumors compared with the normal controls. Furthermore, high-grade tumors exhibited significantly increased expression levels of Cav-1 and DNM2 (both P<0.0001) compared with the low-grade tumors. In addition, compared with normal control samples, the expression of the 2 genes in tumor samples was observed to be highly significant (P<0.0001), with a marked positive correlation identified for the tumors (Pearson's correlation coefficient, r=0.80 for the tumor samples vs. r=0.32 in the normal control samples). Taken together, the results of the present study demonstrated that the overexpression of Cav-1 and DNM2 genes, and a determination of their correlation coefficients, may be a potential risk factor for bladder cancer, in addition to other clinical factors.

Frequency of occurrence of urinary tract infection in double j stented versus non-stented renal transplant recipients.

Prophylactic ureteric stenting in renal transplant recipients prevents major surgical complications such as ureteric leak and obstruction on the one hand while, on the other hand, it is associated with complications like urinary tract infections (UTI), hematuria, stent migration, stent encrustation and forgotten stents. UTI is documented to be most common complication associated with double J (DJ) stent. In this retrospective observational study involving 157 patients, we compared the frequency of occurrence of UTI in DJ-stented versus non-stented renal transplant recipients. The study patients had undergone renal transplantation, with or without DJ-stenting, between January 2007 and June 2012. The mean age of the study subjects was 34.01 ± 14.63 years. The patients were followed-up for one year post-transplantation with regular evaluation, including detailed assessment, complete blood picture, renal function tests, routine urine examination and cultures. Data were collected through chart and electronic record review. Of a total of 157 patients, 61 (38.85%) developed UTI, including 30 of 74 stented patients (40.54%) and 31 of 83 non-stented renal transplant recipients (37.34%). Relative risk was calculated to be 1.08. The mean serum creatinine at the end of one year was 1.47 mg/dL in DJ-stented patients and 1.36 mg/dL in nonstented patients. Our study suggests that there is no significant difference in the frequency of UTI between DJ-stented and non-stented renal transplant recipients.

Primary renal aspergillosis and xanthogranulomatous pyelonephritis in an immuno-competent toddler.

Aspergillosis is primarily a pulmonary disease so that renal aspergillosis is usually secondary to hematogenous spread from lungs. Primary renal aspergillosis, though a rare entity, is still seen in immuno-compromised individuals. Renal aspergillosis may lead to formation of focal abscesses, fungal bezoars and may cause ureteric obstruction. Treatment involves stabilization of patient and removal of fungal bezoars along with administration of anti-fungal agents. This report describes the case of localized primary renal aspergillosis with fungal bezoar formation in 2 years old immuno-competent child who presented in sepsis and acute renal failure and was successfully managed by nephroscopic removal of fungal bezoar and intravenous voriconazole. The other kidney required nephrectomy for xanthogranulomatous pyelonephritis.

Giant dedifferentiated retroperitoneal liposarcoma.

A 72 years old lady presented with a gradually increasing abdominal mass for the last 25 years, with more rapid increase in the last 05 years. Examination revealed a large mass spanning the whole abdomen. CAT scan revealed a huge retroperitoneal tumour, with tortuous ureters passing through the tumour and three tiny nodules in the right lung field. A subtotal piecemeal excision of the tumour was done after stenting the ureters with single J stents. The excised tumour mass weighed 46 Kg. The patient had a prolonged ileus that recovered in 5 days. Histopathology revealed the mass to be dedifferentiated liposarcoma. The patient and the family were satisfied with the short-term outcome of the surgery. She was ambulating with little support and was able to manage her daily affairs.