Upfront docetaxel with androgen deprivation therapy in the elderly patient with metastatic hormone-naïve prostate cancer: Single institution experience

Upfront docetaxel with androgen deprivation therapy in the elderly patient with metastatic hormone-naïve prostate cancer: Single institution experienc

Prediction of ovarian cancer prognosis and response to chemotherapy by a serum-based multiparametric biomarker panel

Currently, there are no effective biomarkers for ovarian cancer prognosis or prediction of therapeutic response. The objective of this study was to examine a panel of 10 serum biochemical parameters for their ability to predict response to chemotherapy, progression and survival of ovarian cancer patients. Sera from ovarian cancer patients were collected prior and during chemotherapy and were analysed by enzyme-linked immunosorbent assay for CA125, kallikreins 5, 6, 7, 8, 10 and 11, B7-H4, regenerating protein IV and Spondin-2. The odds ratio and hazard ratio and their 95% confidence interval (95% CI) were calculated. Time-dependent receiver-operating characteristic (ROC) curves were utilised to evaluate the prognostic performance of the biomarkers. The levels of several markers at baseline (c0), or after the first chemotherapy cycle (rc1), predicted chemotherapy response and overall or progression-free survival in univariate analysis. A multiparametric model (c0 of CA125, KLK5, KLK7 and rc1 of CA125) provided predictive accuracy with area under the ROC curve (AUC) of 0.82 (0.62 after correction for overfitting). Another marker combination (c0 of KLK7, KLK10, B7-H4, Spondin-2) was useful in predicting short-term (1-year) survival with an AUC of 0.89 (0.74 after correction for overfitting). All markers examined, except KLK7 and regenerating protein IV, were powerful predictors of time to progression (TTP) among chemotherapy responders. Individual and panels of biomarkers from the kallikrein family (and other families) can predict response to chemotherapy, overall survival, short-term (1-year) survival, progression-free survival and TTP of ovarian cancer patients treated with chemotherapy

Functional Role of Kallikrein 6 in Regulating Immune Cell Survival

Kallikrein 6 (KLK6) is a newly identified member of the kallikrein family of secreted serine proteases that prior studies indicate is elevated at sites of central nervous system (CNS) inflammation and which shows regulated expression with T cell activation. Notably, KLK6 is also elevated in the serum of multiple sclerosis (MS) patients however its potential roles in immune function are unknown. Herein we specifically examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur.Using murine whole splenocyte preparations and the human Jurkat T cell line we demonstrate that KLK6 robustly supports cell survival across a range of cell death paradigms. Recombinant KLK6 was shown to significantly reduce cell death under resting conditions and in response to camptothecin, dexamethasone, staurosporine and Fas-ligand. Moreover, KLK6-over expression in Jurkat T cells was shown to generate parallel pro-survival effects. In mixed splenocyte populations the vigorous immune cell survival promoting effects of KLK6 were shown to include both T and B lymphocytes, to occur with as little as 5 minutes of treatment, and to involve up regulation of the pro-survival protein B-cell lymphoma-extra large (Bcl-XL), and inhibition of the pro-apoptotic protein Bcl-2-interacting mediator of cell death (Bim). The ability of KLK6 to promote survival of splenic T cells was also shown to be absent in cell preparations derived from PAR1 deficient mice.KLK6 promotes lymphocyte survival by a mechanism that depends in part on activation of PAR1. These findings point to a novel molecular mechanism regulating lymphocyte survival that is likely to have relevance to a range of immunological responses that depend on apoptosis for immune clearance and maintenance of homeostasis

Kallikrein-related peptidase 6 regulates epithelial-to-mesenchymal transition and serves as prognostic biomarker for head and neck squamous cell carcinoma patients

Background: Dysregulated expression of Kallikrein-related peptidase 6 (KLK6) is a common feature for many human malignancies and numerous studies evaluated KLK6 as a promising biomarker for early diagnosis or unfavorable prognosis. However, the expression of KLK6 in carcinomas derived from mucosal epithelia, including head and neck squamous cell carcinoma (HNSCC), and its mode of action has not been addressed so far. Methods: Stable clones of human mucosal tumor cell lines were generated with shRNA-mediated silencing or ectopic overexpression to characterize the impact of KLK6 on tumor relevant processes in vitro. Tissue microarrays with primary HNSCC samples from a retrospective patient cohort (n = 162) were stained by immunohistochemistry and the correlation between KLK6 staining and survival was addressed by univariate Kaplan-Meier and multivariate Cox proportional hazard model analysis. Results: KLK6 expression was detected in head and neck tumor cell lines (FaDu, Cal27 and SCC25), but not in HeLa cervix carcinoma cells. Silencing in FaDu cells and ectopic expression in HeLa cells unraveled an inhibitory function of KLK6 on tumor cell proliferation and mobility. FaDu clones with silenced KLK6 expression displayed molecular features resembling epithelial-to-mesenchymal transition, nuclear β-catenin accumulation and higher resistance against irradiation. Low KLK6 protein expression in primary tumors from oropharyngeal and laryngeal SCC patients was significantly correlated with poor progression-free (p = 0.001) and overall survival (p < 0.0005), and served as an independent risk factor for unfavorable clinical outcome. Conclusions: In summary, detection of low KLK6 expression in primary tumors represents a promising tool to stratify HNSCC patients with high risk for treatment failure. These patients might benefit from restoration of KLK6 expression or pharmacological targeting of signaling pathways implicated in EMT

Implantation Serine Proteinase 1 Exhibits Mixed Substrate Specificity that Silences Signaling via Proteinase-Activated Receptors

Implantation S1 family serine proteinases (ISPs) are tryptases involved in embryo hatching and uterine implantation in the mouse. The two different ISP proteins (ISP1 and ISP2) have been detected in both pre- and post-implantation embryo tissue. To date, native ISP obtained from uterus and blastocyst tissues has been isolated only as an active hetero-dimer that exhibits trypsin-like substrate specificity. We hypothesised that in isolation, ISP1 might have a unique substrate specificity that could relate to its role when expressed alone in individual tissues. Thus, we isolated recombinant ISP1 expressed in Pichia pastoris and evaluated its substrate specificity. Using several chromogenic substrates and serine proteinase inhibitors, we demonstrate that ISP1 exhibits trypsin-like substrate specificity, having a preference for lysine over arginine at the P1 position. Phage display peptide mimetics revealed an expanded but mixed substrate specificity of ISP1, including chymotryptic and elastase activity. Based upon targets observed using phage display, we hypothesised that ISP1 might signal to cells by cleaving and activating proteinase-activated receptors (PARs) and therefore assessed PARs 1, 2 and 4 as potential ISP1 targets. We observed that ISP1 silenced enzyme-triggered PAR signaling by receptor-disarming. This PAR-disarming action of ISP1 may be important for embryo development and implantation

Pirt, a TRPV1 Modulator, Is Required for Histamine-Dependent and -Independent Itch

Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood. Recent work has begun to identify genes that contribute to detecting itch at the molecular level. Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation. Pirt−/− mice exhibit deficits in cellular and behavioral responses to various itch-inducing compounds, or pruritogens. Pirt contributes to both histaminergic and nonhistaminergic itch and, crucially, is involved in forms of itch that are both TRPV1-dependent and -independent. Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways

Automated office blood pressure measurements in primary care are misleading in more than one third of treated hypertensives: The VALENTINE-Greece Home Blood Pressure Monitoring study

Abstract Background This study assessed the diagnostic reliability of automated office blood pressure (OBP) measurements in treated hypertensive patients in primary care by evaluating the prevalence of white coat hypertension (WCH) and masked uncontrolled hypertension (MUCH) phenomena. Methods Primary care physicians, nationwide in Greece, assessed consecutive hypertensive patients on stable treatment using OBP (1 visit, triplicate measurements) and home blood pressure (HBP) measurements (7 days, duplicate morning and evening measurements). All measurements were performed using validated automated devices with bluetooth capacity (Omron M7 Intelli-IT). Uncontrolled OBP was defined as ≥140/90 mmHg, and uncontrolled HBP was defined as ≥135/85 mmHg. Results A total of 790 patients recruited by 135 doctors were analyzed (age: 64.5 ± 14.4 years, diabetics: 21.4%, smokers: 20.6%, and average number of antihypertensive drugs: 1.6 ± 0.8). OBP (137.5 ± 9.4/84.3 ± 7.7 mmHg, systolic/diastolic) was higher than HBP (130.6 ± 11.2/79.9 ± 8 mmHg; difference 6.9 ± 11.6/4.4 ± 7.6 mmHg, p Conclusions In primary care, automated OBP measurements are misleading in approximately 40% of treated hypertensive patients. HBP monitoring is mandatory to avoid overtreatment of subjects with WCH phenomenon and prevent undertreatment and subsequent excess cardiovascular disease in MUCH

Predictions for the future of kallikrein-related peptidases in molecular diagnostics

Kallikrein-related peptidases (KLKs) form a cancer-related ensemble of serine proteases. This multigene family hosts the most widely used cancer biomarker that is PSA-KLK3, with millions of tests performed annually worldwide. The present report provides an overview of the biomarker potential of the extended KLK family (KLK1-KLK15) in various disease settings and envisages approaches that could lead to additional KLK-driven applications in future molecular diagnostics. Particular focus is given on the inclusion of KLKs into multifaceted cancer biomarker panels that provide enhanced diagnostic, prognostic and/or predictive accuracy in several human malignancies. Such panels have been described so far for prostate, ovarian, lung and colorectal cancers. The role of KLKs as biomarkers in non-malignant disease settings, such as Alzheimer’s disease and multiple sclerosis, is also commented upon. Predictions are given on the challenges and future directions regarding clinically oriented KLK research

Parasites and immunotherapy: with or against?

Immunotherapy is a sort of therapy in which antibody or antigen administrates to the patient in order to treat or reduce the severity of complications of disease. This kind of treatment practiced in a wide variety of diseases including infectious diseases, autoimmune disorders, cancers and allergy. Successful and unsuccessful immunotherapeutic strategies have been practiced in variety of parasitic infections. On the other hand parasites or parasite antigens have also been considered for immunotherapy against other diseases such as cancer, asthma and multiple sclerosis. In this paper immunotherapy against common parasitic infections, and also immunotherapy of cancer, asthma and multiple sclerosis with parasites or parasite antigens have been reviewe