What's known on the subject? and What does the study add? Despite the popularity of PSA blood testing for prostate cancer, there are a number of important limitations of this popular serum marker including the limited ability to accurately distinguish patients with and without prostate cancer and those who harbour an aggressive form of the disease. This is especially true when the total PSA is <10 ng/mL. Thus, significant efforts have been placed to find new serum markers that can help overcome these limitations. In this review article, we discuss the emerging role of the various precursor forms of PSA (proPSAs), with a special emphasis on [‐2]proPSA in the detecion and management of early prostate cancer. The clinical utility of Prostate Health Index (phi) is also discussed. Despite the overall success of prostate‐specific antigen (PSA) blood test, its use as a serum marker for prostate cancer has been limited due to the lack of specificity, especially in men presenting with a total PSA (tPSA) level of <10 ng/mL. PSA testing has also resulted in an increase in the number of patients being diagnosed with low‐grade, potentially clinically insignificant prostate cancer. There is therefore an urgent need for new markers that can accurately detect as well as differentiate patients with aggressive vs unaggressive prostate cancer. In this review, we discuss the emerging role of precursor forms of PSA (proPSAs) and the Prostate Health Index (phi) measurement in the detection and management of early stage prostate cancer. A literature search was conducted using PubMed® to identify key studies. Studies to date suggest that [‐2]proPSA, a truncated form of proPSA is the most cancer‐specific form of all, being preferentially expressed in cancerous prostatic epithelium and being significantly elevated in serum of men with prostate cancer. There is evidence to suggest that %[‐2]proPSA measurement ([‐2]proPSA/free PSA [fPSA] × 100) improves the specificity of both tPSA and fPSA in detecting prostate cancer. phi incorporating [‐2]proPSA, fPSA and tPSA measurements has also yielded promising results and appears superior to tPSA and fPSA in predicting those patients with prostate cancer. Increased phi levels also seem to preferentially detect patients harbouring more aggressive disease. Further studies in the form of large, multicentre, prospective trials with detailed health economic analyses are required to evaluate the true clinical applicability of these novel markers.
Intense efforts of research are made for developing antitumor vaccines that stimulate T cell-mediated immunity. Tumor cells specifically express at their surfaces antigenic peptides presented by MHC class I and recognized by CTL. Tumor antigenic peptides hold promise for the development of novel cancer immunotherapies. However, peptide-based vaccines face two major limitations: the weak immunogenicity of tumor Ags and their low metabolic stability in biological fluids. These two hurdles, for which separate solutions exist, must, however, be solved simultaneously for developing improved vaccines. Unfortunately, attempts made to combine increased immunogenicity and stability of tumor Ags have failed until now. Here we report the successful design of synthetic derivatives of the human tumor Ag Melan-A/MART-1 that combine for the first time both higher immunogenicity and high peptidase resistance. A series of 36 nonnatural peptide derivatives was rationally designed on the basis of knowledge of the mechanism of degradation of Melan-A peptides in human serum and synthesized. Eight of them were efficiently protected against proteolysis and retained the antigenic properties of the parental peptide. Three of the eight analogs were twice as potent as the parental peptide in stimulating in vitro Melan-specific CTL responses in PBMC from normal donors. We isolated these CTL by tetramer-guided cell sorting and expanded them in vitro. The resulting CTL efficiently lysed tumor cells expressing Melan-A Ag. These Melan-A/MART-1 Ag derivatives should be considered as a new generation of potential immunogens in the development of molecular anti-melanoma vaccines.
ObjectivesTo prospectively test the diagnostic accuracy of the percentage of prostate specific antigen (PSA) isoform [-2]proPSA (%p2PSA) and the Prostate Health Index (PHI), and to determine their role for discrimination between significant and insignificant prostate cancer at initial and repeat prostate biopsy in men aged ≤65 years. Patients and MethodsThe diagnostic performance of %p2PSA and PHI were evaluated in a multicentre study. In all, 769 men aged ≤65 years scheduled for initial or repeat prostate biopsy were recruited in four sites based on a total PSA (t-PSA) level of 1.6-8.0 ng/mL World Health Organization (WHO) calibrated (2-10 ng/mL Hybritechcalibrated). Serum samples were measured for the concentration of t-PSA, free PSA (f-PSA) and p2PSA with Beckman Coulter immunoassays on Access-2 or DxI800 instruments. PHI was calculated as (p2PSA/f-PSA 9 √t-PSA). Uni-and multivariable logistic regression models and an artificial neural network (ANN) were complemented by decision curve analysis (DCA). ResultsIn univariate analysis %p2PSA and PHI were the best predictors of prostate cancer detection in all patients In multivariate analysis PHI we added to a base model of age, prostate volume, digital rectal examination, t-PSA and %f-PSA. PHI was strongest in predicting prostate cancer in all patients, at initial and repeat biopsy and for significant prostate cancer (AUC 0.73, 0.68, 0.78 and 0.72, respectively). In DCA for all patients the ANN showed the broadest threshold probability and best net benefit. PHI as single parameter and the base model + PHI were equivalent with threshold probability and net benefit nearing those of the ANN. For significant cancers the ANN was the strongest parameter in DCA. ConclusionThe present multicentre study showed that %p2PSA and PHI have a superior diagnostic performance for detecting prostate cancer in the PSA range of 1.6-8.0 ng/mL compared with t-PSA and %f-PSA at initial and repeat biopsy and for predicting significant prostate cancer in men aged ≤65 years. They are equally superior for counselling patients before biopsy.
GastrinlCCK, G protein-coupled receptors have been shown to mediate proliferative effects of their endogenons ligands. In the present study, we examined the signal transduction mechanisms linked to the GICCK, receptor occupancy. We report here that gastrin stimulates MAP kinase activation in a dose-and time-dependent manner, a pathway known to play a key role in cell proliferation. We also characterized the molecular events, upstream of p21-Ras, that may link the MAP kinase pathway to GICCK, receptors. Gastrin induced a rapid and transient increase in tyrosine phosphorylation of several proteins including the 2 isoforms (46 and 52 kDa) of the adaptor protein She. Phosphorylated She subsequently associated with a complex that includes Grb2 and the p21-Ras activator, SOS. Our results also indicate that SOS becomes phosphorylated in response to gastrin as shown by a reduction in electrophoretic mobility of the protein. Tyrosine phosphorylation of She and subsequent complex formation with Grb2 and SOS appear to be a common mechanism by which tyrosine kinase receptors and the GICCK, G proteincoupled receptor stimulate the Ras-dependent MAP kinase pathway.
Anogenital warts are a common clinical manifestation of genital infection with human papillomavirus type 6b (HPV-6b). Accumulating data indicate that an effective cellular immune response is required for the control of HPV infections. However, in a minority of patients there is a high rate of recurrence of wart lesions. We report the characterization of both local and systemic HPV-specific cellular immune responses in three patients with a history of recurrent genital warts. Although the patients had chronic recurrent wart lesions, we have shown that each had both detectable intralesional and peripheral HPV-specific T lymphocytes. Interestingly, the lesion-infiltrating T cells were specific for only one HPV antigen, focusing on only a few epitopes. Conversely, the T cells derived from peripheral blood recognized a broader range of HPV antigens. The characteristics of the HPV-specific cellular immunity that we have shown in these patients may be indicative of a failure to mount an effective response against the virus. This would be consistent with the chronic nature of the disease in these specific individuals. These observations could be relevant to the design and immunomonitoring of immunotherapeutic vaccines for persistent HPV infections.
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