Molecular cytogenetics of prostate cancer

Prostate cancer is the most common malignancy among men in many developed countries. One-fourth of prostate cancers are diagnosed at metastatic stage but there is no curative treatment for such disease and palliative androgen withdrawal therapy remains the most used one. Thus, understanding the molecular events that underlie the development and progression of prostate cancer could help to answer many clinical questions on its treatment. In this review article, I want to illustrate some of the most interesting findings (by fluorescence in situ hybridization and comparative genomic hybridization) in the molecular cytogenetics of prostate cancer.     

Expansion of bronchial epithelial cell populations by in vitro culture of explants from dysplastic and histologically normal sites

Most Colombian populations stem from the admixture of Caucasians, Amerindians and Negroids. In the world, these two latter ethnical groups show a significantly higher prevalence of epilepsy than the former one. We tested the hypothesis that the high prevalence of idiopathic epilepsy with generalized tonic clonic seizures found in the Antioquian population (Paisas), from Colombia, is due to their possible joint Negroid and Amerindian ethnic components. We have previously demonstrated that inheritance is the principal factor for developing epilepsy in this community. Analyses of racial admixture, heterogeneity between populations, genetic distance, and phyletic relationships were performed among epileptic and non epileptic samples from the Antioquian community. Also Caucasians, Spaniards, Basques, Jews, Chileans, Negroids, Amerindians and Mongoloids were included in the analysis. Four highly polymorphic blood systems were used as genetic markers: RH, MNS, ABO and FY. They were chosen because of their high discriminant power in these ethnic groups. In the population affected with idiopathic epilepsy, the estimated Negroid and Amerindian rates of admixture were low (3% and 14%, respectively). Although, these degrees of admixture can be explained due to common ancestral origins, the estimated proportion of Amerindian admixture in the epileptic affected population, was significantly higher than the estimated for the Non affected Antioquian population. The latter finding is consistent with the analysis of heterogeneity between populations that discriminated epileptic population from non epileptic Antioquian population (p < 0.05). Epileptic and non epileptic Paisas clustered in topology with Caucasians, very close to Spaniards and Basques and highly distant from Negroids and Amerindians. Thus, far, the origin of the high prevalence of idiopathic epilepsy in the Antioquian (Paisa) population cannot be explained by the hypothetical joint Negroid and Amerindian ethnical admixture, but using additional genetic markers and other methods of racial estimation of admixture it is necessary to corroborate if the Amerindian admixture component is significantly higher in the epileptic population than in the non epileptic Paisa population.     

Compartments, wingless and engrailed: patterning the ventral epidermis of Drosophila embryos

Recent experiments on the wing disc of Drosophila have shown that cells at the interface between the anterior and posterior compartments drive pattern formation by becoming the source of a morphogen. Here we ask whether this model applies to the ventral embryonic epidermis. First, we show that interfaces between posterior (engrailed ON) and anterior (engrailed OFF) cells are required for pattern formation. Second, we provide evidence that Wingless could play the role of the morphogen, at least within part of the segmental pattern. We looked at the cuticular structures that develop after different levels of uniform Wingless activity are added back to unsegmented embryos (wingless- engrailed-). Because it is rich in landmarks, the T1 segment is a good region to analyse. There, we find that the cuticle formed depends on the amount of added Wingless activity. For example, a high concentration of Wingless gives the cuticle elements normally found near the top of the presumed gradient. Unsegmented embryos are much shorter than wild type. If Wingless activity is added in stripes, the embryos are longer than if it is added uniformly. We suggest that the Wingless gradient landscape affects the size of the embryo, so that steep slopes would allow cells to survive and divide, while an even distribution of morphogen would promote cell death. Supporting the hypothesis that Wingless acts as a morphogen, we find that these stripes affect, at a distance, the type of cuticle formed and the planar polarity of the cells.     

Protein kinase C and mouse sciatic nerve regeneration

We have studied the role of protein kinase C (PKC) in peripheral nerve regeneration by using the cultured adult mouse sciatic nerve, which displays regrowth of sensory axons under serum-free conditions. By the use of immunohistochemistry we show that one of the isoforms of PKC, PKC beta, is present in the nerve cell bodies of normal nerves and is upregulated after injury. In spite of this, the specific PKC inhibitor chelerythrine at 5 microM, a concentration well above its IC50 value for PKC, failed to reduce the outgrowth distance of new axons. This was not due to impermeability of the drug, since the same concentration caused a clear reduction of the injury-induced proliferation of Schwann cells in the crush region. Likewise, HA-1004, an inhibitor of cyclic nucleotide-dependent protein kinases, also lacked effect on outgrowth when used on its own, even at very high concentrations (100 microM). In contrast, outgrowth was significantly reduced when 5 microM chelerythrine and 5 microM HA-1004 were used in combination. In conclusion, the present results suggest that PKC-activity is important but not indispensable for the regeneration process. Successful completion of the latter could be achieved by several, perhaps redundant, phosphorylation systems.     

Transforming growth factor beta 1 down-regulates vascular endothelial growth factor receptor 2/flk-1 expression in vascular endothelial cells

Although the importance of the vascular endothelial growth factor (VEGF)/VEGF tyrosine kinase receptor (VEGFR) system in angiogenesis is well established, very little is known about the regulation of VEGFR expression in vascular endothelial cells. We have cloned partial cDNAs encoding bovine VEGFR-1 (flt) and -2 (flk-1) and used them to study VEGFR expression by bovine microvascular- and large vessel-derived endothelial cells. Both cell lines express flk-1, but not flt. Transforming growth factor beta 1 (TGF-beta 1) reduced the high affinity 125I-VEGF binding capacity of both cell types in a dose-dependent manner, with a 2.0-2.7-fold decrease at 1-10 ng/ml. Cross-linking experiments revealed a decrease in 125I-VEGF binding to a cell surface monomeric protein corresponding to Flk-1 on the basis of its affinity for VEGF, molecular mass (185-190 kDa), and apparent internalization after VEGF binding. Immunoprecipitation and Western blot experiments demonstrated a decrease in Flk-1 protein expression, and TGF-beta 1 reduced flk-1 mRNA levels in a dose-dependent manner. These results imply that TGF-beta 1 is a major regulator of the VEGF/Flk-1 signal transduction pathway in endothelial cells.     

Pyogenic hepatic abscess. Changing trends over 42 years

OBJECTIVE: The authors document changes in the etiology, diagnosis, bacteriology, treatment, and outcome of patients with pyogenic hepatic abscesses over the past 4 decades. SUMMARY BACKGROUND DATA: Pyogenic hepatic abscess is a highly lethal problem. Over the past 2 decades, new roentgenographic methods, such as ultrasound, computed tomographic scanning, direct cholangiography, guided aspiration, and percutaneous drainage, have altered both the diagnosis and treatment of these patients. A more aggressive approach to the management of hepatobiliary and pancreatic neoplasms also has resulted in an increased incidence of this problem METHODS: The records of 233 patients with pyogenic liver abscesses managed over a 42-year period were reviewed. Patients treated from 1952 to 1972 (n = 80) were compared with those seen from 1973 to 1993 (n = 153). RESULTS: From 1973 to 1993, the incidence increased from 13 to 20 per 100,000 hospital admissions (p < 0.01. Patients managed from 1973 to 1993 were more likely (p < 0.01) to have an underlying malignancy (52% vs. 28%) with most of these (81%) being a hepatobiliary or pancreatic cancer. The 1973 to 1993 patients were more likely (p < 0.05) to be infected with streptococcal (53% vs. 30%) or Pseudomonas (30% vs. 9%) species or to have mixed bacterial and fungal 26% vs. 1%) infections. The recent patients also were more likely (p < 0.05) to be managed by percutaneous abscess drainage (45% vs. 0%). Despite having more underlying problems, overall mortality decreased significantly (p < 0.01) from 65% (in 1952 to 1972 period) to 31% (in 1973 to 1993 period). The reduction was greatest for patients with multiple abscesses (88% vs. 44%; p < 0.05) with either a malignant or a benign biliary etiology (90% vs. 38%; p < 0.05). Mortality was increased (p < 0.02) in patients with mixed bacterial and fungal abscesses (50%). From 1973 to 1993, mortality was lower (p = 0.19) with open surgical as opposed to percutaneous abscess drainage (14% vs. 26%). CONCLUSIONS: Significant changes have occurred in the etiology, diagnosis, bacteriology, treatment, and outcome patients with pyogenic hepatic abscesses over the past 4 decades. However, mortality remains high, and proper management continues to be a challenge. Appropriate systemic antibiotics and fungal agents as well as adequate surgical, percutaneous, or biliary drainage are required for the best results.