A Real-World Observational Study to Evaluate the Safety and Effectiveness of Fluticasone Furoate-Oxymetazoline Fixed Dose Combination Nasal Spray in Patients with Allergic Rhinitis.

BACKGROUND: Allergic rhinitis (AR) has shown an increasing prevalence leading to a considerable medical and social burden. Nasal congestion is the cardinal symptom of AR, and the upper respiratory tract is most affected by this long-lasting ailment. Intranasal corticosteroids alleviate nasal congestion, along with other symptoms of AR, but their effect is not evident immediately. Oxymetazoline has a rapid onset of action, but its use should be limited to 3-5 days. OBJECTIVE: The study aimed to evaluate the safety and effectiveness of the fixed-dose combination nasal spray containing fluticasone furoate and oxymetazoline hydrochloride (FF + OXY) 27.5/50 mcg once daily in patients with AR in a real-world clinical setting. METHODS: The study was a prospective, open-label, single-arm, multicenter, real-world observational study conducted in patients with AR for a period of 28 days. Patients (n = 388) with a diagnosis of AR were treated with a combination of FF + OXY nasal spray. Total nasal symptom score (TNSS), total ocular symptom score (TOSS) and total symptom score (TSS) were documented at baseline and at the end of study period. The overall effectiveness of treatment with FF + OXY was rated by the investigators as very good/good/satisfactory/poor (4-point Likert scale) for each patient. RESULTS: Treatment with FF + OXY resulted in significant reduction in the TNSS, TOSS and TSS, from 7.18 ± 3.38 at baseline to 0.20 ± 0.84 (p < 0.001), from 2.34 ± 2.29 at baseline to 0.09 ± 0.53 (p < 0.001), from 9.51 ± 4.94 at baseline to 0.29 ± 1.32 (p < 0.001) at 28 days respectively. With respect to effectiveness, the investigators reported very good effectiveness in 52.12% of patients. No serious adverse events were reported. CONCLUSION: The fixed-dose combination of once-daily fluticasone furoate and oxymetazoline hydrochloride nasal spray 27.5/50 mcg was effective in relieving the nasal congestion and reduction of TNSS, TOSS and TSS in patients suffering from AR. The combination was safe and well tolerated with no rebound congestion throughout the treatment period.

Prostate Cancer Associated Lipid Signatures in Serum Studied by ESI-Tandem Mass Spectrometryas Potential New Biomarkers.

Prostate cancer (PCa) is one amongst the most common cancersin western men. Incidence rate ofPCa is on the rise worldwide. The present study deals with theserum lipidome profiling of patients diagnosed with PCa to identify potential new biomarkers. We employed ESI-MS/MS and GC-MS for identification of significantly altered lipids in cancer patient's serum compared to controls. Lipidomic data revealed 24 lipids are significantly altered in cancer patinet's serum (n = 18) compared to normal (n = 18) with no history of PCa. By using hierarchical clustering and principal component analysis (PCA) we could clearly separate cancer patients from control group. Correlation and partition analysis along with Formal Concept Analysis (FCA) have identified that PC (39:6) and FA (22:3) could classify samples with higher certainty. Both the lipids, PC (39:6) and FA (22:3) could influence the cataloging of patients with 100% sensitivity (all 18 control samples are classified correctly) and 77.7% specificity (of 18 tumor samples 4 samples are misclassified) with p-value of 1.612×10-6 in Fischer's exact test. Further, we performed GC-MS to denote fatty acids altered in PCa patients and found that alpha-linolenic acid (ALA) levels are altered in PCa. We also performed an in vitro proliferation assay to determine the effect of ALA in survival of classical human PCa cell lines LNCaP and PC3. We hereby report that the altered lipids PC (39:6) and FA (22:3) offer a new set of biomarkers in addition to the existing diagnostic tests that could significantly improve sensitivity and specificity in PCa diagnosis.

Prostate cancer-associated autoantibodies in serum against tumor-associated antigens as potential new biomarkers.

The limitations of the current prostate cancer (PCa) screening tests demands new biomarkers for early diagnosis of PCa. In this study, we aim to investigate serum autoantibody signatures as PCa specific biomarkers. PCa proteins were resolved by 2-DE and then transferred onto polyvinylidene difluoride membrane, which were subsequently incubated with either pooled serum from PCa patients or from normal controls. Mass spectrometry results have identified 18 antigens from 21 different 2-DE spots associated with PCa. Autoantibody response to antigens PRDX2, PRDX6 and ANXA11 in PCa patient's sera was confirmed using recombinant antigens. Further validation with an independent set of PCa patient's sera have shown relatively increased abundance of PRDX6 and ANXA11 antibodies in PCa patients. Formal concept analysis method was applied to assess whether the abundance of these autoantibodies could influence the classification of patients. However, sensitivity of the single antibody to discriminate prostate tumor and healthy controls varies from 70% to 80%, whereas combination of both PRDX6 and ANXA11 antibodies increased sensitivity to 90% for tumors and 100% for healthy controls. Therefore, we hereby report that the detection of these antibodies in PCa patient's serum in combination with the existing non-invasive diagnostic procedures may have significance in PCa diagnosis. BIOLOGICAL SIGNIFICANCE: The present study aimed to investigate serum autoantibody signatures as new biomarkers for early diagnosis of prostate cancer (PCa). To investigate serum autoantibodies in patients with PCa, we used proteomics approach based on two-dimensional gel electrophoresis (2-DE) and mass spectrometry. Total tissue proteins extracted from prostate were separated by 2-DE and then transferred onto polyvinylidene difluoride (PVDF) membrane, which were subsequently incubated with either pooled serum from PCa patients or from normal controls with no history for PCa. Proteomic analysis results have identified 18 antigens that showed antibody response specifically to cancer patient's serum. For validation experiments using recombinant antigens, confirmed autoantibody response to three antigens PRDX2, PRDX6 and ANXA11. Further validation using a second independent set of PCa patient's sera has shown relatively increased abundance of PRDX6 and ANXA11 antibodies specifically in PCa patients. Partition analysis of patients based on abundance of autoantibodies highlighted a combination of both PRDX6 and ANXA11 antibodies in serum with 90% sensitivity in case of tumors and 100% in case of healthy controls. Therefore, we hereby report that the detection of these antibodies in PCa patient's serum in combination with known markers may have significance in diagnosis of PCa with further validation in larger cohort of samples.

GCPII modulates oxidative stress and prostate cancer susceptibility through changes in methylation of RASSF1, BNIP3, GSTP1 and Ec-SOD.

Glutamate carboxypeptidase II (GCPII) haplotypes were found to influence susceptibility to prostate cancer. In the current study, we have elucidated the impact of these haplotypes on the expression of PSMA, BNIP3, Ec-SOD, GSTP1 and RASSF1 genes to understand the epigenetic basis of oxidative stress and prostate cancer risk. Expression analysis was carried out by RT-PCR. Bisulphite treated DNA was subjected to MS-PCR and COBRA for epigenetic studies. Plasma MDA and glutathione levels were measured. In prostate cancer, upregulation of BNIP3 (204.4 ± 23.77 vs. 143.9 ± 16.42 %, p = 0.03); and downregulation of Ec-SOD (105.8 ± 13.69 vs. 176.3 ± 21.1 %, p = 0.027) and RASSF1A (16.67 ± 16.0 vs. 90.8 ± 8.5 %, p = 0.0048) was observed. Hypomethylation of BNIP3 (31.25 ± 16.19 vs. 45.70 ± 2.42 %, p < 0.0001), hypermethylation of Ec-SOD (71.4 ± 6.75 vs. 10.0 ± 3.78 %, p < 0.0001) and RASSF1 (76.25 ± 12.53 vs. 30.0 ± 8.82 %, p = 0.0077) was observed in prostate cancer. The gene expression signature of PSMA, BNIP3, Ec-SOD, GSTP1, clearly demarcated cases and controls (AUC = 0.89 in the ROC curve). D191V variant of GCPII showed positive association with oxidative stress and inverse association with Ec-SOD expression. H475Y variant showed positive association with Ec-SOD expression and inverse association with oxidative stress. R190W variant was found to reduce oxidative stress by increasing glutathione levels. GCPII genetic variants contribute to increased oxidative stress and prostate cancer risk by modulating the CpG island methylation of Ec-SOD.

Association of glutamate carboxypeptidase II (GCPII) haplotypes with breast and prostate cancer risk.

In view of the pivotal role of glutamate carboxypeptidase II (GCPII) in carcinogenesis, its expression as prostate specific membrane antigen (PSMA) and folate hydrolase (FOLH1) may be influenced by its haplotypes, contributing to the etiology of prostate and breast cancer. To test this hypothesis, breast and prostate cancer cases and controls were subjected to whole gene screening of GCPII and correlated with plasma folate levels and PSMA expression. The impact of variants on a 3-dimensional structure of GCPII was explored by in silico studies. Six novel variations i.e. V108A, P160S, Y176H, D191V, G206R and G245S; and two known variations i.e. R190W and H475Y were identified in GCPII. All-wild haplotype and a haplotype harbouring D191V showed association with breast cancer risk while haplotypes harbouring V108A and P160S reduced the risk. Haplotypes with V108A and G245S variants showed increased risk for prostate cancer due to high PSMA expression while P160S conferred protection against prostate cancer. In silico studies suggests that P160S and R190W variants result in relaxed substrate binding facilitating either rapid catalysis or exchange of substrates and products in the active site which was substantiated by high plasma folate levels associated with these variants. On the contrary, D191V was associated with very low plasma folate levels despite having a high PSMA expression. This is the first comprehensive study examining variations in GCPII in relation to breast and prostate cancer risk. Changes in the plasma folate levels and changes in PSMA expression are associated with breast and prostate cancer risk respectively.

"True" mycotic aneurysm of the anastomotic site of the renal allograft artery.

The incidence of vascular complications after renal transplant as reported varies from 3.5% to 14%. Pseudoaneurysm formation at the site of the anastomosis is a rare complication, and only a few cases have been reported. There also were only a few reports of "true" mycotic aneurysms of the renal allograft artery. We present 2 patients with true mycotic aneurysmal formation of the renal allograft artery after a renal transplant. Both patients presented with fever and increasing serum creatinine levels. Cultures from aneurysm tissue samples have grown Aspergillus flavus. Both patients were subjected to an allograft nephrectomy, and amphotericin was given.

Paradoxical role of C1561T glutamate carboxypeptidase II (GCPII) genetic polymorphism in altering disease susceptibility.

Glutamate carboxypeptidase II (GCPII) is predominantly expressed in brain, intestinal mucosa and prostate cancer in the form of three splice variants i.e. N-acetylated-α-linked acidic dipeptidase (NAALADase), folyl poly-γ-glutamate carboxypeptidase (FGCP) and prostate specific membrane antigen (PSMA) respectively. Its inhibition was found to confer protection against certain neurological disorders and cancer. Despite the pivotal role of this enzyme, the most common polymorphism i.e. H475Y has not been explored comprehensively in all its splice variants. In this study, we have determined the role of this variant in different disease conditions such as breast and prostate cancers, autism, coronary artery disease (CAD) and miscarriages (N=1561). Genotyping was done by PCR-RFLP and dideoxy sequencing. Plasma folate levels were estimated by Axysm folate kit. GCPII expression was studied by semi-quantitative RT-PCR. In silico model was developed using PYMOL. We observed the protective role of H475Y variant in cancers [breast cancer; OR (95% CI): 0.81 (0.55-1.19), prostate cancer: OR (95% CI): 0.00 (0.00-0.66)], and in autism (OR (95% CI): 0.47 (0.21-1.03), whereas inflated risk was observed in CAD (OR (95% CI): 1.69 (1.20-2.37) and miscarriages [Maternal OR (95% CI): 3.26 (2.11-5.04); Paternal OR(95% CI): 1.99 (1.23-3.21)]. Further, this variant was found to impair the intestinal folate absorption in subjects with dietary folate intake in the lowest tertile (CC vs. CT in lowest tertile; 7.56±0.85ng/ml vs. 2.73±045ng/ml, p=0.005). In silico model of GCPII showed steric hindrance with H475Y resulting in stereochemical alteration of catalytic site, thus interfering with ligand binding. Statistically significant association was not observed between dietary folate levels and GCPII expression. However, a positive correlation was seen between plasma folate levels and GCPII expression (r=0.70, p<0.05). To conclude, our data suggests that GCPII H475Y variant shows inverse association with autism and cancer while showing positive association with CAD and miscarriages.

Prostate specific antigen in patients of benign prostate hypertrophy and carcinoma prostate.

Prostate Specific Antigen (PSA) has emerged as the most applicable and important tumor marker for carcinoma prostate. In the present study PSA was determined in serum of healthy subjects, patients of benign prostate hypertrophy (BPH) and Carcinoma Prostate (Ca-P) to evaluate its diagnostic efficiency in day to day management of prostate cancer patients and in differentiating patients of early prostate cancer from those with BPH. Receiver operating characteristic curve (ROC) revealed 2 ng/ml and 10 ng/ml cut off serum PSA level for BPH and untreated carcinoma prostate patients (Ca-P). An extremely significant increase (P<0.0001) was observed in mean PSA concentration in BPH patients and adenocarcinoma prostate patients when compared to healthy males. Clinical relevance of PSA was highlighted by a case study of cancer patient prior to any therapy till death.