Fatty acid profile in peri-prostatic adipose tissue and prostate cancer aggressiveness in African-Caribbean and Caucasian patients

BACKGROUND: Genetic and nutritional factors have been linked to the risk of aggressive prostate cancer (PCa). The fatty acid (FA) composition of peri-prostatic adipose tissue (PPAT), which reflects the past FA intake, is potentially involved in PCa progression. We analysed the FA composition of PPAT, in correlation with the ethno-geographical origin of the patients and markers of tumour aggressiveness. METHODS: From a cohort of 1000 men treated for PCa by radical prostatectomy, FA composition of PPAT was analysed in 156 patients (106 Caucasians and 50 African-Caribbeans), 78 with an indolent tumour (ISUP group 1 + pT2 + PSA <10 ng/mL) and 78 with an aggressive tumour (ISUP group 4-5 + pT3). The effect of FA extracted from PPAT on in-vitro migration of PCa cells DU145 was studied in 72 patients, 36 Caucasians, and 36 African-Caribbeans. RESULTS: FA composition differed according to the ethno-geographical origin. Linoleic acid, an essential n-6 FA, was 2-fold higher in African-Caribbeans compared with Caucasian patients, regardless of disease aggressiveness. In African-Caribbeans, the FA profile associated with PCa aggressiveness was characterised by low level of linoleic acid along with high levels of saturates. In Caucasians, a weak and negative association was observed between eicosapentaenoic acid level (an n-3 FA) and disease aggressiveness. In-vitro migration of PCa cells using PPAT from African-Caribbean patients was associated with lower content of linoleic acid. CONCLUSION: These results highlight an important ethno-geographical variation of PPAT, in both their FA content and association with tumour aggressiveness

Towards the Establishment of a Porcine Model to Study Human Amebiasis

BACKGROUND: Entamoeba histolytica is an important parasite of the human intestine. Its life cycle is monoxenous with two stages: (i) the trophozoite, growing in the intestine and (ii) the cyst corresponding to the dissemination stage. The trophozoite in the intestine can live as a commensal leading to asymptomatic infection or as a tissue invasive form producing mucosal ulcers and liver abscesses. There is no animal model mimicking the whole disease cycle. Most of the biological information on E. histolytica has been obtained from trophozoite adapted to axenic culture. The reproduction of intestinal amebiasis in an animal model is difficult while for liver amebiasis there are well-described rodent models. During this study, we worked on the assessment of pigs as a new potential model to study amebiasis. METHODOLOGY/PRINCIPAL FINDINGS: We first co-cultured trophozoites of E. histolytica with porcine colonic fragments and observed a disruption of the mucosal architecture. Then, we showed that outbred pigs can be used to reproduce some lesions associated with human amebiasis. A detailed analysis was performed using a washed closed-jejunal loops model. In loops inoculated with virulent amebas a severe acute ulcerative jejunitis was observed with large hemorrhagic lesions 14 days post-inoculation associated with the presence of the trophozoites in the depth of the mucosa in two out four animals. Furthermore, typical large sized hepatic abscesses were observed in the liver of one animal 7 days post-injection in the portal vein and the liver parenchyma. CONCLUSIONS: The pig model could help with simultaneously studying intestinal and extraintestinal lesion development

P2X4 receptor promotes mammary cancer progression by sustaining 3 autophagy and associated mesenchymal transition

Metastatic progression is a major burden for breast cancer patients and is associated with the ability of cancer cells to overcome stressful conditions, such as nutrients deprivation and hypoxia, and to gain invasive properties. Autophagy and epithelial-to-mesenchymal transition are critical contributors to these processes. Here, we show that the P2X4 purinergic receptor is upregulated in breast cancer biopsies from patients and it is primarily localised in endolysosomes. We demonstrate that P2X4 enhanced invasion in vitro, as well as mammary tumour growth and metastasis in vivo. The pro-malignant role of P2X4 was mediated by the regulation of lysosome acidity, the promotion of autophagy and cell survival. Furthermore, the autophagic activity was associated with epithelial–to-mesenchymal transition (EMT), and this role of P2X4 was even more pronounced under metabolic challenges. Pharmacological and gene silencing of P2X4 inhibited both autophagy and EMT, whereas its rescue in knocked-down cells led to the restoration of the aggressive phenotype. Together, our results demonstrate a previously unappreciated role for P2X4 in regulating lysosomal functions and fate, promoting breast cancer progression and aggressiveness.</p

Phosphorylation of NHERF1 S279 and S301 differentially regulates breast cancer cell phenotype and metastatic organotropism

Metastatic cancer cells are highly plastic for the expression of different tumor phenotype hallmarks and organotropism. This plasticity is highly regulated but the dynamics of the signaling processes orchestrating the shift from one cell phenotype and metastatic organ pattern to another are still largely unknown. The scaffolding protein NHERF1 has been shown to regulate the expression of different neoplastic phenotypes through its PDZ domains, which forms the mechanistic basis for metastatic organotropism. This reprogramming activity was postulated to be dependent on its differential phosphorylation patterns. Here, we show that NHERF1 phosphorylation on S279/S301 dictates several tumor phenotypes such as in vivo invasion, NHE1-mediated matrix digestion, growth and vasculogenic mimicry. Remarkably, injecting mice with cells having differential NHERF1 expression and phosphorylation drove a shift from the predominantly lung colonization (WT NHERF1) to predominately bone colonization (double S279A/S301A mutant), indicating that NHERF1 phosphorylation also acts as a signaling switch in metastatic organotropism

Efficacy and safety of oral fludarabine phosphate in previously untreated patients with chronic lymphocytic leukemia.

PURPOSE: A prospective, multicenter, open-label, phase II clinical trial to assess oral fludarabine phosphate treatment in terms of safety, efficacy, and quality of life. Reference to a historical group of patients treated with the intravenous (IV) formulation allowed the two formulations to be compared. PATIENTS AND METHODS: Patients with previously untreated B-cell chronic lymphocytic leukemia received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. Efficacy was assessed using International Workshop on Chronic Lymphocytic Leukemia and National Cancer Institute criteria for response. Safety monitoring included WHO toxicity grading for adverse events. Quality of life was also assessed. RESULTS: Eighty-one patients received treatment. According to International Workshop on Chronic Lymphocytic Leukemia criteria, the overall response rate was 71.6% (complete remission, 37.0%; partial remission, 34.6%). The response rate using National Cancer Institute criteria was 80.2% (complete remission, 12.3%; partial remission, 67.9%). Median time to progression was 841 days (range, 28 to 1,146 days). The most frequently reported grade 3/4 toxicity was myelosuppression. WHO grade 3/4 hematological toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). Gastrointestinal toxicity was more common with the oral formulation than with IV fludarabine phosphate, but was generally mild to moderate and did not require treatment. Statistically significant improvements in mean emotional and insomnia quality-of-life scores were seen after treatment. CONCLUSION: This study demonstrates that oral fludarabine phosphate is clinically effective and generally well tolerated by patients with previously untreated B-cell chronic lymphocytic leukemia. Oral fludarabine phosphate has a similar clinical efficacy and safety profile to the IV formulation. Oral fludarabine phosphate does not adversely affect quality of life and may improve emotional and insomnia scores.Clinical TrialClinical Trial, Phase IIComparative StudyJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Follow-Up Results of a Prospective, Multicenter, Open-Label Study of Oral Fludarabine Phosphate in Patients with Previously Untreated B-CLL.

Abstract The IV formulation of fludarabine phosphate is an effective treatment in patients with B-cell chronic lymphocytic leukemia (B-CLL), yielding overall response rates of 60% to 80%. An oral formulation of fludarabine phosphate has been developed. In a previously published multicenter, open-label, phase II clinical trial, 81 previously untreated B-CLL patients received 10-mg tablets of fludarabine phosphate (Fludara® oral) 40 mg/m2/day for 5 days, repeated every 4 weeks. The primary endpoint of the trial was response rate, and secondary endpoints included safety and quality of life assessments. Of 81 patients (mean age, 61.2 years; range, 30–75 years) with previously untreated B-CLL, 81.5% were classified as Binet stage B or C. The overall response rate (complete response [CR] + partial response [PR]) using National Cancer Institute (NCI) criteria was 80.2% (12.3% CR and 67.9% PR) and the median time to progression was 841 days (range, 28–1,146 days) (Rossi JF, et al. J Clin Oncol2004;22:1260–1267). The most frequently reported grade 3/4 adverse event was myelosuppression: WHO grade 3/4 hematologic toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). This analysis reports on the long-term follow-up of this cohort during the period from November 2001 to November 2004. Of the 74 patients eligible for the survival analysis, 61 were also assessed for duration of response using NCI criteria: 9 CR (14.8%) and 52 PR (82.2%). During the 3-year follow-up period, 22 (29.7%) patients did not progress. For those who progressed, median time to progression was 29.7 months, and median duration of response was 22.9 months. In 41 (80.4%) of these patients, an increase in circulating lymphocytes was reported as evidence of disease progression. In 23 patients (45.1%), an increase in the sum of the products of at least 2 lymph nodes and/or appearance of new palpable nodes was reported as evidence of disease progression. During the indicated follow-up period, 37 patients (50%) received subsequent treatment. Twelve patients (16.2%) died during the follow-up period: 7 patients (58.3%) due to disease progression, 3 patients (25.0%) due to adverse events, and 2 patients (16.7%) due to other causes. Results from this study suggest that oral fludarabine phosphate is clinically effective and well tolerated by patients with previously untreated B-CLL. Moreover, these data demonstrate that oral fludarabine phosphate achieves response rates and duration of response comparable to those achieved with first-line fludarabine phosphate IV therapy.</jats:p