Pigment epithelium-derived factor expression prolongs survival and enhances the cytotoxicity of low-dose chemotherapy in castration-refractory prostate cancer.

There is currently no cure for advanced castration-refractory prostate cancer (CRPC) despite the recent approval of several new therapeutic agents. We report here the anti-tumor effect of the angio-inhibitory pigment epithelium-derived factor (PEDF) in the metastatic LNCaP-derivative CRPC CL1 model and explore PEDF anti-neoplasic efficacy in combination with low-dose chemotherapy. Androgen-sensitive LNCaP and CRPC PC3 cell lines were examined as comparison. Using a retroviral expression system, we showed that PEDF limited the proliferation of all prostatic cell lines tested; an effect attributed to interleukin 8 (IL8)-CXCR1/IL8RA inhibition. PEDF also reduced the number and size of 3D tumor spheroids in vitro, but only induced cell differentiation in CRPC spheroids. Similarly, PEDF inhibited the migration of CRPC cells suggesting both anti-proliferative and anti-migratory functions. In vivo, PEDF decreased by 85% and 65% the growth of subcutaneous (s.c.) PC3 and CL1 tumors, respectively. In the CL1 orthotopic model, tumor intake with lethal metastases was found in all animals; nevertheless, PEDF prolonged the median survival of tumor-bearing mice (95% confidence interval: 53 ± 0.001 to 57 ± 1 days). Accordingly, PEDF delayed the emergence of skeletal-related event in intra-tibial xenografts. Next, we evaluated low-dose docetaxel (DTX; 5, 1, 0.5 mg/kg) or cyclophosphamide (CTX; 10-20 mg/kg) on established s.c. PC3 tumors that conditionally express PEDF anti-tumoral epitope/NT3. Although NT3-DTX-5 mg/kg combination was inefficient, NT3-DTX-1 mg/kg and -0.5 mg/kg inhibited by 95% and 87.8%, respectively, tumor growth compared with control and induced tumor stasis. Both NT3-CTX combinations were advantageous. Inversely, PEDF-DTX-5 mg/kg and PEDF-CTX-10 mg/kg delayed the most CL1 tumor growth (15, 11 and 5 days for PEDF-DTX-5 mg/kg, PEDF-CTX-10 mg/kg and single treatments, respectively) with elevated apoptosis and serum thrombospondin-1 as possible mechanism and marker, respectively. As well, both PEDF-CTX-10 mg/kg and PEDF-DTX-5 mg/kg prolonged significantly the survival of tumor-bearing mice compared with single treatments. Metastases were reduced in PEDF-DTX-5 mg/kg compared with other treatments, suggesting that PEDF-DTX delayed metastases formation. Our results advocate that PEDF/low-dose chemotherapy may represent a new therapeutic alternative for CRPC.

Extraluminal colonic carcinoma invading into kidney: a case report and review of the literature.

Renal metastasis from primary colon cancer is very rare, comprising less than 3% of secondary renal neoplasms. There are just 11 cases reported in the medical literature of colonic adenocarcinoma metastatic to the kidney. Of these cases, none occurred via direct invasion. We report a unique case of a 51-year-old female with extraluminal colonic adenocarcinoma which directly invaded into the kidney. Additionally, we investigate the causal relationship between the site of invasion and a previous stab injury by reviewing the role of the peritoneum and Gerota's fascia in preventing the spread of metastatic cancer into the perirenal space. Due to the rarity of this event, we present this case including a review of the existing literature relative to the diagnosis and treatment.

Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer: review of the literature.

PURPOSE: Castration-refractory prostate cancer remains a therapeutic challenge even after introduction of docetaxel as first-line treatment. Castration-refractory prostate cancer cannot be cured by any available therapeutic option, and chemotherapy still needs to be considered palliative. The survival benefit is modest, and treating physicians are searching for alternative treatment options. Despite new drugs currently under investigation, some conventional and well known chemotherapeutic drugs are experiencing a renaissance. The development of anti-angiogenic approaches in cancer treatment has led to the development of metronomic dosing of conventional chemotherapeutic drugs including cyclophosphamide. The intention of this review is to evaluate the efficacy and toxicity of oral/metronomic cyclophosphamide in the treatment of patients with castration-refractory prostate cancer. MATERIALS AND METHODS: A comprehensive literature search was performed in different databases using various key words. Relevant articles and references between 1962 and 2010 were reviewed and analyzed for data regarding the association between oral cyclophosphamide treatment and prostate cancer. RESULTS: Oral cyclophosphamide is active in the treatment for castration-refractory prostate cancer even in patients treated with previous chemotherapy including docetaxel. It yields symptomatic and objective remissions. The side effects are usually grade 1-2 and easy to manage. Grade three to four side effects are less common. CONCLUSIONS: Oral cyclophosphamide treatment for patients with castration-refractory prostate cancer deserves more attention and validation, and warrants further testing of various treatment combinations. Given the fact that castration-refractory prostate cancer includes an extremely heterogeneous group of patients with variability of tumor growth rates, the combination of cyclophosphamide with other active agents such as angiogenesis inhibitors and immunomodulatory compounds need to be explored.

Genome-wide scan in a nationwide study sample of schizophrenia families in Finland reveals susceptibility loci on chromosomes 2q and 5q.

We have previously carried out two genome-wide scans in samples of Finns ascertained for schizophrenia from national epidemiological registers. Here, we report data from a third genome scan in a nationwide Finnish schizophrenia study sample of 238 pedigrees with 591 affected individuals. Of the 238 pedigrees, 53 originated from a small internal isolate (IS) on the eastern border of Finland with a well established genealogical history and a small number of founders, who settled in the community 300 years ago. The total study sample of over 1200 individuals were genotyped, using 315 markers. In addition to the previously identified chromosome 1 locus, two new loci were identified on chromosomes 2q and 5q. The highest LOD scores were found in the IS families with marker D2S427 (Z(max) = 4.43) and in the families originating from the late settlement region with marker D5S414 (Z(max) = 3.56). In addition to 1q, 2q and 5q, some evidence for linkage emerged at 4q, 9q and Xp, the regions also suggested by our previous genome scans, whereas, in the nationwide study sample, the region at 7q failed to show further evidence of linkage. The chromosome 5q finding is of particular interest, since several other studies have also shown evidence for linkage in the vicinity of this locus.

Endogenous SecA catalyzes preprotein translocation at SecYEG.

SecA is found in the cytosol and bound to the plasma membrane of Escherichia coli. Binding occurs either with high affinity at SecYEG or with low affinity to lipid. Domains of 65 and 30 kDa of SecYEG-bound SecA insert into the membrane upon interaction with preprotein and ATP. Azide blocks preprotein translocation, in vivo and in vitro, through interacting with SecA and preventing SecA deinsertion. This provides a measure of the translocation relevance of each form of SecA membrane association. We now report that azide acts exclusively on SecA that is cycling at SecYEG and has no effect on SecA lipid associations. SecA molecules recovered with sucrose gradient-purified inner membrane vesicles ("endogenous" SecA) support translocation at the same rate as "added" SecA molecules bound at SecYEG. Both endogenous and added SecA yield the same proteolytic fragments, which are distinct from those obtained from SecA once it has inserted into membranes at SecYEG or from SecA at lipidic sites. Endogenous and added SecA differ, however, in their resistance to urea extraction. The translocation supported by either endogenous or added SecA is blocked by azide or by antibody to SecY. We conclude that SecA functions in preprotein translocation only through cycling at SecYEG.

Standardized test performance of children with a history of prenatal exposure to multiple drugs/cocaine.

Twenty-four children, age 14 to 50 months, with a history of prenatal exposure to multiple drugs including cocaine, were matched by adjusted birth age and sex to 24 children with no history of drug exposure. All children had been living in stable, drug-free environments from at least the age of 11 months. Tests administered included the Sequenced Inventory of Communicative Development-Revised (SICD), the Bayley Scales of Infant Development, and the Peabody Picture Vocabulary Test-Revised (PPVT-R). Results indicated significant differences between groups and genders on the SICD when age was covaried and between groups on the Bayley. No groups or genders differed on the PPVT-R. Many (45.8%) of the children in the drug-exposed group qualified for intervention services according to Washington state criteria. Subject characteristics, other than age, did not play a significant role in the findings of group differences. It is concluded that, due to the cumulative effects of prenatal history, these children should be considered at risk for language delay.