Clusters of Conserved Beta Cell Marker Genes for Assessment of Beta Cell Phenotype

The aim of this study was to establish a gene expression blueprint of pancreatic beta cells conserved from rodents to humans and to evaluate its applicability to assess shifts in the beta cell differentiated state. Genome-wide mRNA expression profiles of isolated beta cells were compared to those of a large panel of other tissue and cell types, and transcripts with beta cell-abundant and -selective expression were identified. Iteration of this analysis in mouse, rat and human tissues generated a panel of conserved beta cell biomarkers. This panel was then used to compare isolated versus laser capture microdissected beta cells, monitor adaptations of the beta cell phenotype to fasting, and retrieve possible conserved transcriptional regulators.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

GLI1 Confers Profound Phenotypic Changes upon LNCaP Prostate Cancer Cells That Include the Acquisition of a Hormone Independent State

The GLI (GLI1/GLI2) transcription factors have been implicated in the development and progression of prostate cancer although our understanding of how they actually contribute to the biology of these common tumours is limited. We observed that GLI reporter activity was higher in normal (PNT-2) and tumourigenic (DU145 and PC-3) androgen-independent cells compared to androgen-dependent LNCaP prostate cancer cells and, accordingly, GLI mRNA levels were also elevated. Ectopic expression of GLI1 or the constitutively active ΔNGLI2 mutant induced a distinct cobblestone-like morphology in LNCaP cells that, regarding the former, correlated with increased GLI2 as well as expression of the basal/stem-like markers CD44, β1-integrin, ΔNp63 and BMI1, and decreased expression of the luminal marker AR (androgen receptor). LNCaP-GLI1 cells were viable in the presence of the AR inhibitor bicalutamide and gene expression profiling revealed that the transcriptome of LNCaP-GLI1 cells was significantly closer to DU145 and PC-3 cells than to control LNCaP-pBP (empty vector) cells, as well as identifying LCN2/NGAL as a highly induced transcript which is associated with hormone independence in breast and prostate cancer. Functionally, LNCaP-GLI1 cells displayed greater clonal growth and were more invasive than control cells but they did not form colonies in soft agar or prostaspheres in suspension suggesting that they do not possess inherent stem cell properties. Moreover, targeted suppression of GLI1 or GLI2 with siRNA did not reverse the transformed phenotype of LNCaP-GLI1 cells nor did double GLI1/GLI2 knockdowns activate AR expression in DU145 or PC-3 cells. As such, early targeting of the GLI oncoproteins may hinder progression to a hormone independent state but a more detailed understanding of the mechanisms that maintain this phenotype is required to determine if their inhibition will enhance the efficacy of anti-hormonal therapy through the induction of a luminal phenotype and increased dependency upon AR function

Causes and effects of cellular oxidative stress as a result of MDMA abuse.

3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) is a substituted amphetamine with potent central nervous stimulant effects. Increasing evidence suggests that one way of MDMA-induced toxicity involves the production of reactive oxygen and reactive nitrogen species and a subsequent production of oxidative/nitrosative stress. The free radicals can originate from several molecular pathways (oxidative deamination of monoamine, metabolic pathways, cathecolamines autoxidation, and hyperthermia) and their harmful effect causing potential biological damage such as lipoperoxidation and cellular death. The role of oxidative stress in mediating MDMA toxicity is illustrated by decreases in the activity of the endogenous enzymatic and non enzymatic antioxidants observed in cells in vitro and in animals model. This review examines the available evidence for the involvement of oxidative stress in the mechanisms of MDMA-induced cellular damage with the aim to contribute to the understanding of the cellular and molecular mechanisms involved in MDMA toxicity

Passage of mannitol into the brain around gliomas : a potential cause of rebound phenomenon. A study on 21 patients.

Widespread use of mannitol to reduce brain edema and lower elevated ICP in brain tumor patients continues to be afflicted by the so-called rebound phenomenon. Leakage of mannitol into the brain parenchyma through an altered BBB and secondary reversal of osmotic gradient is considered the major cause of rebound . This has only been demonstrated experimentally in animals. As a contribution to this issue we decided to research the possible passage of mannitol into the brain after administration to 21 brain tumor patients. METHODS: Mannitol (18% solution; 1 g/kg) was administered as a bolus to patients (ten had malignant glioma, seven brain metastases and four meningioma) about 30 minutes before craniotomy. During resection, a sample of the surrounding edematous white matter was taken at the same time as a 10 ml venous blood sample. Mannitol concentrations were measured in plasma and white matter by a modified version of the enzyme assay of Blonquist et al. RESULTS: In most glioma patients, mannitol concentrations in white matter were 2 to 6 times higher than in plasma (mean 3.5 times). In meningioma and metastases patients plasma concentrations of mannitol were higher than white matter concentrations except in three cases with infiltration by neoplastic cells. CONCLUSIONS: The results of our study show that even after a single bolus, mannitol may leak through the altered BBB near gliomas, reversing the initial plasma-to-blood osmotic gradient, aggravating peritumoral edema and promoting rebound of ICP

Delta-9-THC and cannabidiol impaired antioxidant cellular status and induced oxidative stress and lipoperoxidation in DBTRG-05MG glioblastoma cell line.

Pubblicazione on-line http://cong35.sifweb.org/congresso_abs_view.php?id=35

The role of doxorubicin and epirubicin in the treatment of patients with metastatic hormone-refractory prostate cancer.

Advanced hormone-refractory prostate cancer (HRPC) is characterized by prevalently osteoblastic bone metastases which are what mostly affect these patients' quality of life and make the assessment of response to treatment particularly difficult by commonly used criteria. HRPC cannot be cured by any available therapeutic option, and chemotherapy has to be still considered as a palliative treatment. The anthracyclines doxorubicin (Dox) and epirubicin (Epi), alone or in combination with other agents, have been extensively used in the treatment of HRPC, but controversial results have been reported. The majority of reviewed studies reported a pain reduction in >50% of patients receiving Dox or Epi, suggesting a substantial palliative effect by their use in metastatic HRPC. The weekly schedule of anthracyclines seemed to achieve similar results to the 3-weekly schedule but with a better toxicity profile. Although the toxic adverse effects were usually manageable when anthracyclines were combined with other agents, toxicity was severe by a number of aggressive regimens. Docetaxel is today approved for the treatment of HRPC, and must be considered the standard platform on which new agents may be combined. Given that HRPC includes a heterogeneous group of patients with variable rates of tumour growth, the combination of docetaxel with active agents such as anthracyclines may deserve further clinical investigation

Tolerability of cabazitaxel in patients with metastatic castration-resistant prostate cancer progressing after docetaxel and abiraterone acetate: a single-institution experience.

Both abiraterone acetate (AA) and cabazitaxel (Cbz) have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel (D). Although no standard sequencing has been established as yet, Cbz has recently been proven to be active after AA. However, to date, few data are available on its safety in this setting. Therefore, the primary endpoint of this study was to investigate Cbz tolerability in mCRPC patients treated previously with D and AA. From April 2011 to the present, 43 mCRPC patients received AA after D at our institution. Of these, 22 patients were subsequently treated with Cbz and were evaluable for toxicity in the present retrospective study. Cbz was administered at a dose of 25 mg/m plus 10 mg oral prednisone every 3 weeks. Adverse events (AEs) were reported using the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0. Despite the advanced stage of disease and frailty of our study population, there were no unexpected side effects. The most common AEs were hematologic. Neutropenia was observed in nine (40.9%) patients and of grade≥3 in six (27.2%). No febrile neutropenia occurred. The most common nonhematologic AEs were diarrhea and asthenia, reported in eight (36.3%) and in five (22.7%) patients, respectively. In this setting, Cbz toxicity seems to be manageable and comparable with second-line Cbz. Therefore, our results seem to support the safety of Cbz as a third-line treatment for mCRPC patients

Folinic acid, 5-fluorouracil and mitomycin C in metastatic breast cancer patients previously treated with at least two chemotherapy regimens.

PURPOSE: To assess the activity and safety of combined folinic acid (FA), 5-fluorouracil (5-FU) and mitomycin C (MMC) in metastatic breast cancer patients previously treated with at least two chemotherapy regimens. PATIENTS AND METHODS: A total of 104 consecutive patients were enrolled for treatment with FA 100 mg/m(2) plus 5-FU 400 mg/m(2) i.v. on days 1-5, and MMC 3 mg/m(2) on days 3-5 (FFM). The cycles were repeated every 21 days until progression, severe toxicity or patient refusal. RESULTS: Of the 104 patients, 96 were evaluable for response and toxicity. The overall response rate was 43% (95% confidence interval 32.8-53.2%); 40 patients achieved stable disease (42%) and 15 progressed (15%). In a retrospectively defined subgroup of patients with clinical resistance to taxanes (12 patients) or anthracyclines (14 patients), the response rate was 42%. The median time to progression was 8 months (3-18 months), and the median overall survival was 10.5+ months (2-36 months). The most common treatment-related adverse events were stomatitis, neutropenia, nausea/vomiting and diarrhea. Stomatitis, neutropenia and thrombocytopenia were the only grade 4 treatment-related adverse events, and occurred in no more than 3% of patients. CONCLUSION: The tested FFM regimen seems to offer a valid option for patients with metastatic breast cancer who have been pretreated with two or more chemotherapeutic lines or who have failed on regimens containing anthracyclines or taxanes