Association and expression of the antigen-processing gene PSMB8, coding for low-molecular-mass protease 7, with vitiligo in North India: case-control study.

BACKGROUND: Vitiligo is a multifactorial, autoimmune, depigmenting disorder of the skin where aberrant presentation of autoantigens may have a role. OBJECTIVES: To study the association of two antigen-processing genes, PSMB8 and PSMB9, with vitiligo. METHODS: In total 1320 cases of vitiligo (1050 generalized and 270 localized) and 752 healthy controls were studied for the PSMB9 exon 3 G/A single-nucleotide polymorphism (SNP), PSMB8 exon 2 C/A SNP and PSMB8 intron 6 G/T SNP at site 37 360 using polymerase chain reaction (PCR)-restriction fragment length polymorphism. Real-time PCR was used for transcriptional expression of PSMB8 and cytokines. Expression of ubiquitinated proteins and phosphorylated-p38 (P-p38) was studied by Western blotting. RESULTS: Significant increases in PSMB8 exon 2 allele A (P < 2.07 × 10-6 , odds ratio 1·93) and genotypes AA (P < 1.03 × 10-6 , odds ratio 2·51) and AC (P < 1.29 × 10-6 , odds ratio 1·63) were observed in patients with vitiligo. Interferon-γ stimulation induced lower expression of PSMB8 in peripheral blood mononuclear cells of cases compared with controls, suggesting impaired antigen processing, which was confirmed by accumulation of ubiquitinated proteins in both lesional and nonlesional skin of patients with vitiligo. Expression of proinflammatory cytokines - interleukin (IL)-6, IL-1ß and IL-8 - was higher in the lesional skin. P-p38 expression was variable but correlated with the amount of ubiquitinated proteins in the lesional and nonlesional skin, suggesting that the inflammatory cytokine responses in lesional skin could be a result of both P-p38-dependent and -independent pathways. CONCLUSIONS: The PSMB8 exon 2 SNP is significantly associated with vitiligo. Accumulation of ubiquitinated proteins in skin of cases of vitiligo suggests their aberrant processing, which may promote the development of the disease.

Efficacy and toxicity of cetuximab with chemotherapy in recurrent and metastatic head and neck cancer: A prospective observational study.

BACKGROUND: In squamous cell carcinoma of the head and neck (SCCHN), epidermal growth factor receptor is expressed at very high levels. Hence, we have done this study to assess the response and tolerability of cetuximab and platinum-based chemotherapy in recurrent and metastatic (R/M) head and neck squamous cell cancer (HNSCC) in view of paucity of data from the Indian subcontinent. MATERIALS AND METHODS: In this prospective study, patients of R/M SCCHN were randomly enrolled from September 2012 to April 2015. Chemotherapy (cisplatin/carboplatin/5-fluorouracil) and cetuximab-based treatment were administered up to 6 cycles or unacceptable toxicity. The response rates (RRs), progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: In total, fifty patients were enrolled. The median age was 51.0 years. A total of 255 cycles of treatment were administered (median = 6 cycles/patient). Four patients (8.0%) experienced complete response and 21 (42.0%) experienced partial response. Twenty-one patients (42.0%) had stable disease and four patients (8.0%) experienced progressive disease. The disease control rate was 92.0%. Median PFS was 5.3 months (95% confidence interval [CI]: 4.52-6.14 months). Median OS was 9.933 months (95% CI: 8.58-11.28 months). There was statistically significant correlation between overall response and Eastern Cooperative Oncology Group performance status (P = 0.014), site of tumor (P = 0.027), and histological grade of tumor (P = 0.001). The main Grade 3/4 side effects seen were hematological in 44 (88%) and gastrointestinal in 28 (56%) patients. CONCLUSIONS: The RR of cetuximab plus chemotherapy of> 45% and the promising PFS rates are strong arguments for clinically testing this combination and this treatment schedule further in R/M HNSCC.

Study of efficacy and safety of modified adjuvant intraperitoneal chemotherapy regimen in carcinoma ovary.

OBJECTIVE: It has been demonstrated in few trials that intraperitoneal and intravenous (IP/IV) chemotherapy improves survival in advanced stage ovarian cancer (OC). However, in view of high treatment-related toxicities, various modifications in treatment schedules have been tried. In this study, response and tolerability of IP paclitaxel on day 8 with IV paclitaxel on day 1 and IV cisplatin day 2 in carcinoma ovary were evaluated. PATIENTS AND METHODS: In this prospective observational study, from March 2013 to December 2015, the efficacy and tolerability of adjuvant IP/IV chemotherapy in optimally cytoreduced Stage III epithelial OC (EOC) patients were assessed. RESULTS: Totally, sixty patients were enrolled. The median age of patients was 53 years (32-67 years). Out of a total of 360 IP cycles, 316 cycles (88%) were completed. Forty-five patients (76%) received all the 6 cycles by IP route. Eight out of those 45 patients had one or more adjustment including delay or dose reduction. After median follow-up of 22 months, eight patients (14%) had local or systemic recurrence. Median progression-free survival not reached yet. Catheter block was seen in five cases. Two cases had needle displacement and extravasations of drug around the port chamber. Six patients had Grade 3 abdominal pain and cramp. Grade 3/4 leukopenia was experienced by thirty patients (50%), but febrile neutropenia occurred in only 6 (10%) patients. Renal complication present in 4 (7%) patients. CONCLUSIONS: In Indian patients, adjuvant chemotherapy with day 8 I/P paclitaxel in optimally cytoreduced EOC is associated with comparable survival outcomes, less side effects and high treatment completion rate relative to literature published from Western countries.

Primary renal primitive neuroectodermal tumor.

Primitive Neuroectodermal Tumor of the kidney is a rare entity. Very few cases of primary renal PNET have been reported to date. Most literature about rPNET is isolated case reports. We report a case of rPNET in a 39-year-old male with a pre-operative diagnosis of renal cell carcinoma with renal vein thrombosis. The patient underwent radical nephrectomy with thrombolectomy, and histopathological examination revealed a highly aggressive tumor composed of monotonous sheets of round cells. Tumor cells were positive for CD 99 and FLI-1, hence confirming the diagnosis of Primitive Neuroectodermal Tumor. Post-surgery, patient was given VAC/IE-based adjuvant chemotherapy. In view of highly aggressive nature of this tumor, prompt diagnosis and imparting effective chemotherapy regimen to the patient is required, and it is important to differentiate PNET from other small round-cell tumors because of different therapeutic approach.

Second-line immunosuppressive treatment of childhood nephrotic syndrome: a single-center experience.

OBJECTIVE: Most cases of idiopathic nephrotic syndrome in childhood are responsive to corticosteroids. However, there is a small group of children that demonstrate steroid resistance (steroid-resistant nephrotic syndrome; SRNS), steroid dependence, or that frequently relapse (frequent-relapse steroid-sensitive nephrotic syndrome; FR-SSNS) which are more clinically difficult to treat. Therefore, second-line immunosuppressants, such as alkylating agents, calcineurin inhibitors, antimetabolites and, more recently, rituximab, have been used with varying success. The objective was to evaluate the response rates of various second-line therapies in the treatment of childhood nephrotic syndrome. STUDY DESIGN: A retrospective chart review of pediatric subjects with idiopathic nephrotic syndrome was conducted at a single tertiary care center (2007-2012). Drug responses were classified as complete response, partial response, and no response. RESULTS: Of the 188 charts reviewed, 121 children were classified as SSNS and 67 children as SRNS; 58% were classified as FR-SSNS. Sixty-five subjects were diagnosed with focal segmental glomerulosclerosis via biopsy. Follow-up ranged from 6 months to 21 years. The combined rate of complete and partial response for mycophenolate mofetil (MMF) was 65% (33/51) in SSNS and 67% (6/9) in SRNS. For tacrolimus, the response rate was 96% (22/23) for SSNS and 77% (17/22) for SRNS. Eighty-three percent (5/6) of SSNS subjects treated with rituximab went into complete remission; 60% relapsed after B-cell repletion. Eight refractory subjects were treated with combined MMF/tacrolimus/corticosteroid therapy with a 75% response rate. CONCLUSION: Our experience demonstrates that older medications can be replaced with newer ones such as MMF, tacrolimus, and rituximab with good outcomes and better side effect profiles. The treatment of refractory cases with combination therapy is promising.

Effects of SP500263, a novel selective estrogen receptor modulator, on bone, uterus, and serum cholesterol in the ovariectomized rat.

We describe here the activity of a novel selective estrogen receptor modulator, SP500263. When given to adult ovariectomized (OVX) rats for 28 days at doses of 0.3, 1, or 3 mg/kg/day, we found that SP500263 partially protected against OVX-induced loss of bone mineral content in the distal ends of femurs and in the whole bone. SP500263 also antagonized the OVX-induced increase in body weight. However, unlike 17beta-estradiol, SP500263 at efficacious doses did not prevent the OVX-induced loss in uterine wet weight. A small but significant effect on uterine wet weight was noted with raloxifene dosed at 1 mg/kg. As expected, SP500263 but not raloxifene acted as an estrogen antagonist on the uterus in adult rats when administered for 7 days at 30 mg/kg/day. Finally, SP500263 had no statistically significant effects on total serum cholesterol and serum triglycerides in OVX rats treated for 28 days. Raloxifene had no significant effects on body weight, bone mineral content, and serum cholesterol or triglycerides in the OVX-rat model. In summary, SP500263 is a new orally active SERM that acts in rats as an estrogen agonist on bone without causing uterine stimulatory effects.

Simultaneous overexpression of two stress proteins in rat cardiomyocytes and myogenic cells confers protection against ischemia-induced injury.

BACKGROUND: Mitochondria are known to be a major target during ischemic cardiac injury. Previous studies have shown that in rodent myogenic cells and in the hearts of transgenic mice in which the heat shock or stress protein 70 is increased, there is a marked tolerance to ischemia/reperfusion injury. Two other heat shock proteins (HSP60 and HSP10) are known to form, within the mitochondria, a chaperonin complex that is important for mitochondrial protein folding and function. We were then interested in investigating whether increased expression of these two stress proteins is able to protect myogenic cells against ischemia/reperfusion injury. METHODS AND RESULTS: We generated recombinant adenoviral vectors containing HSP60, HSP10, or a combination of the two genes. These adenoviral constructs overexpress significant amounts of these stress proteins in both rat neonatal cardiomyocytes and the myogenic H9 c2 cell line. Cells infected with an adenoviral construct overexpressing both HSP60 and HSP10 were found to be protected against simulated ischemia, whereas cells infected with adenoviral constructs overexpressing only HSP60 or HSP10 alone were not rendered tolerant to simulated ischemic injury. CONCLUSIONS: These results suggest that the simultaneous expression of these two proteins that form a chaperonin complex in the mitochondria plays an important role in the survival of myogenic cells after ischemia/reperfusion injury.