Cellular and genetic requirements for delayed type hypersensitivity

All living organisms are continuously exposed to pathogenic agents from the surrounding milieu, e.g. viruses, bacteria, fungi and parasites. Skin and mucous membranes form efficient barriers to these agents, but sometimes this defense is overcome. If an infectious agent succeeds in penetrating into the "milieu int€rieur", at first granulocytes and mononuclear phagocytes become involved in the elimination of the intruding microorganisms. This part of the defense system is largely aspecific. Apart from this, vertebrates have a well developed immune system which can mount specific immune responses to invading organisms and foreign substances. The specificity of the immune reaction is based on the presence of receptors on the individual lymphocytes which recognize specifically any one of many foreign substances. Only after the recognition of the immunogenic material is a lymphocyte activated to perform its function. Immunogenic substances or antigens are operationally defined by their capacity to induce an immune response. The recognition of a particular antigen by the receptors of an individual lymphocyte is predetermined, i.e. the diversity of lymphocytes, each specific for one of the numerous imaginable foreign substances is generated before encounter with immunogenic material. In addition to the specificity of lymphocytes for a particular antigen, lymphocytes must also discriminate between self and non-self. If they should fail to do so, an immune response to tissues of the individual's own body would arise, leading to autoimmune disease (Burnet, 1972)

Interval carcinomas in the European Randomized Study of Screening for Prostate Cancer (ERSPC)-Rotterdam

BACKGROUND: The interval cancer rate is an important parameter for determining the sensitivity of a screening procedure and the screening interval. We evaluated the time and mechanism of detection and the stage distribution of interval prostate cancers diagnosed during a 4-year screening interval. METHODS: We determined the rate of interval cancers and the sensitivity of the screening protocol (involving prostate-specific antigen, digital rectal and transrectal ultrasound examinations) in a cohort of 17 226 men (8350 on the screened arm, 8876 on the control arm) enrolled consecutively on the European Randomized Study of Screening for Prostate Cancer-Rotterdam. Men on the screened arm received a first screen between October 1993 and December 1996 and a scheduled second screen 4 years later. Prostate cancers detected in men enrolled on the control arm over the same 4-year period and, between screens, in men on the screened arm, were identified by linkage to the Dutch national cancer registry. RESULTS: During the first screen, 412 prostate cancers were detected. During the subsequent 4-year period, 135 cancers were diagnosed in men in the control arm and 25 cancers were diagnosed in men in the screened arm. Seven of the 25 cancers were diagnosed in men who had refused a recommended biopsy at their initial screen. Of the remaining 18 cancers, all were classified as stage T1A-C or T2A and none were poorly differentiated or metastatic. The rate of interval cancers relative to the number of cancers in the control group was 18.5% (25/135), or 13.3% (18/135), if the seven who refused an initial biopsy were excluded. The sensitivity of the screening protocol was 79.8% when considering all 25 interval cancers and 85.5% when considering 18 interval cancers. CONCLUSION: The interval cancer rate with a 4-year screening interval was low, confirming that the screening procedure has a high sensitivity and that the 4-year screening interval is reasonable

Androgen receptor expression in human ovarian and uterine tissue of long term androgen-treated transsexual women

Androgen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated transsexual female patients. This was compared with AR expression in the ovaries and uteri of premenopausal and postmenopausal women not receiving treatment and in 10 ovaries of female patients with polycystic ovarian disease (PCOD). In the normal ovaries germinal epithelium, granulosa cells of antral follicles, corpus luteum, and thecal and stromal cells exhibited moderate AR expression. The more intense and uniform staining of ovarian stroma of female transsexual patients and those of patients with PCOD compared with ovarian stroma of normal controls was most remarkable. This similarity in histology and distribution of ARs supports the hypothesis that PCOD is an androgen-mediated disorder. Immunostaining for ARs was only occasionally detectable in the uteri of premenopausal and postmenopausal women. In contrast, myometrial and endometrial stroma of the uteri of female transsexual patients displayed an intense and diffuse nuclear immunostaining, but glandular epithelia remained unstained. Western blot analysis of the ovaries and uterine myometrial tissue samples from transsexual female patients confirmed the presence of the 110-kd AR molecule. Because the androgen treatment of some transsexual female patients was discontinued 6 weeks before they underwent hysterosalpingo-oophorectomy, our data indicate a stable and persistent androgen-induced up-regulation of AR expression in ovaries

Accumulating Progenitor Cells in the Luminal Epithelial Cell Layer Are Candidate Tumor Initiating Cells in a Pten Knockout Mouse Prostate Cancer Model

The PSA-Cre;Pten-loxP/loxP mouse prostate cancer model displays clearly defined stages of hyperplasia and cancer. Here, the initial stages of hyperplasia development are studied. Immunohistochemical staining showed that accumulated pAkt+ hyperplastic cells overexpress luminal epithelial cell marker CK8, and progenitor cell markers CK19 and Sca-1, but not basal epithelial cell markers. By expression profiling we identified novel hyperplastic cell markers, including Tacstd2 and Clu. Further we showed that at young age prostates of targeted Pten knockout mice contained in the luminal epithelial cell layer single pAkt+ cells, which overexpressed CK8, Sca-1, Tacstd2 and Clu; basal epithelial cells were always pAkt−. Importantly, in the luminal epithelial cell layer of normal prostates we detected rare Clu+Tacstd2+Sca-1+ progenitor cells. These novel cells are candidate tumor initiating cells in Pten knockout mice. Remarkably, all luminal epithelial cells in the proximal region of normal prostates were Clu+Tacstd2+Sca-1+. However, in PSA-Cre;Pten-loxP/loxP mice, the proximal prostate does not contain hyperplastic foci. Small hyperplastic foci in prostates of PSA-Cre;Pten-loxP/+ mice found at old age, showed complete Pten inactivation and a progenitor marker profile. Finally, we present a novel model of prostate development and renewal, including lineage-specific luminal epithelial progenitor cells. It is proposed that Pten deficiency induces a shift in the balance of differentiation to proliferation in these cells

Neuroendocrine cells in the normal, hyperplastic and neoplastic prostate

Neuroendocrine cells can be demonstrated in normal, hyperplastic and neoplastic prostatic tissues. The products secreted by these cells can be used as tissue and/or serum markers but may also have biological effects. Neuroendocrine cells in prostate cancer most probably do not contain the androgen receptor and are therefore primarily androgen independent. Some of the neuropeptides secreted by the neuroendocrine cells may act as growth factor by activation of membrane receptors in an autocrine-paracrine fashion or by ligand-independent activation of the androgen receptor in neighboring non-neuroendocrine cells. Evidence is accumulating from experiments with tumor models that neuropeptides indeed can influence the growth of prostatic tumor cells. Future research on neuroendocrine differentiation may answer some questions concerning the biological behavior of clinical prostatic tumors

E-cadherin promotes intraepithelial expansion of bladder carcinoma cells in an in vitro model of carcinoma in situ

High-grade transitional cell carcinomas (TCCs) of the urinary bladder are frequently associated with carcinoma in situ, which may replace large areas of the mucosa of the urinary tract. The invasive component of TCCs often reveals a loss of expression of the cell-cell adhesion molecule E-cadherin, but the role of E-cadherin in the development and expansion of intraepithelial neoplasia is unknown. To study the underlying mechanism of intraepithelial expansion (IEE), we have developed an IEE assay. Human TCC cell lines were investigated in this IEE assay for their capacity to replace the surrounding normal murine urothelial cells. In vitro IEE appeared to be prominent in three (SD, RT112, and 1207) of the four E-cadherin-positive cell lines. Although the two E-cadherin-negative cell lines (T24 and J82) were able to penetrate surrounding normal urothelium as single cells, they largely lacked the capacity of IEE. These results prompted us to investigate whether the cell-cell adhesion molecule E-cadherin is an important determinant for IEE. T24 cells that were transfected with full-length mouse E-cadherin cDNA displayed an enhanced IEE rate. Transfection did not influence their proliferative capacity, their pattern and level of integrin expression, or their ability to expand in the absence of surrounding urothelium. The data suggest that E-cadherin-mediated cohesiveness is an important factor in the IEE of bladder carcinoma cells. These observations argue for a dual, paradoxical role of E-cadherin in bladder tumorigenesis. On the one hand, E-cadherin promotes the expansion of intraepithelial neoplasia; on the other hand, its loss correlates with invasive behavior

Value of tissue markers p27kip1, MIB-1, and CD44s for the pre-operative prediction of tumour features in screen-detected prostate cancer

The pre-operative prediction of prognostic tumour features in the radical prostatectomy specimen using routine clinicopathological variables remains limited. The present study evaluated the predictive value of the cell-cycle protein p27kip1, the proliferation marker MIB-1, and the cell-adhesion protein CD44s, determined on the diagnostic needle biopsy of asymptomatic men screened for prostate cancer. Of 81 screen-detected prostate cancers, representative biopsy cores and matched radical prostatectomy specimens were immunohistochemically stained for these tissue markers. Conventional pre-operative and post-operative clinicopathological variables were assessed and cancers were divided according to a validated tumour classification model (potentially harmless, clinically significant). Low (<50%) p27kip1 expression, high (≥10%) MIB-1 expression, and low (<25%) CD44s expression were considered adverse prognostic signs. Binary logistic regression analysis was performed to assess the most valuable predictors of clinically significant disease. An adverse prognostic immunostaining assessment on the biopsy was found in 10 (12.3%), 17 (21.0%), and 25 (30.9%) cases for p27kip1, MIB-1, and CD44s, respectively. The concordance in tissue marker assessment between the biopsy specimen and matched radical prostatectomy specimens was low for all three. The positive predictive value (PPV) of p27kip1 was 90.0%, remarkably higher than that of MIB-1 and CD44s (41.2% and 52.0%, respectively), indicating that a low radical prostatectomy p27kip1 score is expected if the biopsy p27kip1 score is low. Logistic regression analysis revealed that biopsy Gleason score (p<0.01) and p27kip1 assessment (p<0.01) remained the only significant predictors of clinically significant disease. All cases with low p27kip1 expression were found to have clinically significant disease after radical prostatectomy. The assessment of p27kip1 in the biopsy specimen might thus assist in distinguishing between potentially aggressive and potentially non-aggressive disease in prostate cancer screening. Copyrigh

The influence of the diagnostic technique on the histopathological diagnosis in malignant mesothelioma

In the histopathology of malignant mesotheliomas three different types (epithelial, connective tissue and mixed type) are distinguished. Some authors believe all tumours to be of mixed type, but consider that due to inadequate sampling or small biopsies this may be missed frequently. In this study the relationship between the histopathological diagnosis and the amount of tissue examined was investigated. In a series of 124 cases of malignant pleural mesothelioma a high percentage of mixed type tumours was found (55%). In cases where the decisive diagnostic procedure had been an Abrams biopsy (the "small-specimen" technique) mixed-type histology was found in 36%. If thoracoscopy, thoracotomy or autopsy (the "large-specimen" techniques) had delivered a definite diagnosis, mixed-type histology was found in 63%. Apparently diagnosing the mixed-type variety depends on the amount of tumour tissue obtained. However, the assumption that all mesotheliomas are of mixed type cannot be confirmed