Common fragile site instability in normal cells: Lessons and perspectives

Mechanisms and events related to common fragile site (CFS) instability are well known in cancer cells. Here, we argue that normal cells remain an important experimental model to address questions related to CFS instability in the absence of alterations in cell cycle and DNA damage repair pathways, which are common features acquired in cancer. Furthermore, a major gap of knowledge concerns the stability of CFSs during gametogenesis. CFS instability in meiotic or postmeiotic stages of the germ cell line could generate chromosome deletions or large rearrangements. This in turn can lead to the functional loss of the several CFS‐associated genes with tumor suppressor function. Our hypothesis is that such mutations can potentially result in genetic predisposition to develop cancer. Indirect evidence for CFS instability in human germ cells has been provided by genomic investigations in family pedigrees associated with genetic disease. The issue of CFS instability in the germ cell line should represent one of the future efforts, and may take advantage of the existence of sequence and functional conservation of CFSs between rodents and humans.     

Incidence and Risk Factors for Hepatitis C Virus Infection among Illicit Drug Users in Italy

So far, only three small outdated studies have investigated hepatitis C virus (HCV) incidence and risk factors among illicit drug users (DUs) in Italy. Thus, during 2007–2010, we conducted a prospective cohort study among DUs attending 17 Italian rehabilitation centers serving urban areas. Two hundred eighty-four HCV-uninfected DUs were prospectively followed by interview and anti-HCV antibody and RNA testing every 6 months. Incidence was calculated using the person-years method. Infection predictors were assessed by time-dependent Cox analysis. Participants were mostly male (83.4%), under opioid substitution therapy (OST) (78.9%), non-injecting DUs (67.9%), and with a mean age of 30.8. Ninety-one of 224 DUs initially under OST interrupted treatment during the follow-up. Overall HCV incidence was 5.83/100 person-years at risk (PYAR) [95% confidence intervals (CI), 3.63–9.38]. The incidence did not significantly differ according the participants’ sociodemographic characteristics or the degree of urbanization of the towns involved in the study. The incidence was higher for DUs under than for those not under OST (6.23 vs 4.50/100 PYAR; p = 0.681). Incidence was also higher for those with than for those without OST interruption (7.17 vs 5.04/100 PYAR; p = 0.55). However, all these differences were non-significant. At last follow-up visit, a significant decrease in frequency of sharing equipment for preparation/using drugs (by injection or not) was observed by analyzing either the whole cohort or DUs under OST only. Anti-HCV seroconversion resulted independently associated with sharing drug preparation/use equipment, backloading, having a HCV-positive sexual partner, or household and (marginally) intravenous injection. In this study, HCV incidence was non-negligible and OST seemed to lack effectiveness in reducing it. In Italy, implementation of combined harm reduction interventions and antiviral treatment of chronically infected DUs would be needed.     

Effect of air-drying temperature on the effectiveness of silane primers and coupling blends in the repair of a microhybrid resin composite

PURPOSE: To evaluate the effect of different silane agents and air-drying temperatures on the repair strength of a microfilled hybrid composite. MATERIALS AND METHODS: Composite cylinders (8 x 4 mm) of Gradia Direct Anterior (GC, N=36), stored in a saline solution at 37 degrees C for 1 month, were sandblasted (50-microm aluminium oxide), cleaned (35% phosphoric acid) and randomly divided into six groups (n=6). Two prehydrolyzed silane primers (Monobond-S, Ivoclar-Vivadent, Porcelain Primer, Bisco), a non prehydrolyzed silane primer (Porcelain Liner M, Sun Medical) and three silane/adhesive coupling agents (Porcelain Bond Activator-PBA/Clearfil New Bond, PBA/Clearfil SE Bond, PBA/Clearfil Tri-S Bond, Kuraray) were investigated. Silane-coated surfaces were air dried at two different temperatures (23 degrees C and 38 degrees C) and repairs (8 x 8 mm) were fabricated (Gradia Direct Anterior). Unrepaired composite cylinders (8 x 8 mm, n=6) were used as control to evaluate the cohesive strength of the material. Microtensile bond strength measurements (microTBS) were performed. Results: The silane agent applied (p < 0.001), the airdrying temperature (p < 0.001) and their interaction (p < 0.001) were significant factors (two-way ANOVA, Tukey test; p < 0.05). Silane primers achieved inferior microTBS when air dried at 23 degrees C as compared to silane/adhesive blends. Warm air-drying was significantly beneficial to composite repairs mediated by silane primers. Comparable results were achieved by silane/adhesive couplings at 23 degrees C and 38 degrees C. At 38 degrees C all the intermediate agents resulted in repair microTBS that were comparable to the 24-h cohesive strength of the composite (one-way ANOVA, Dunnett t-tests; p < 0.05). CONCLUSION: The chemical interactions between silane primers and compozite substrate may be optimized through warm airdrying. Silane/adhesive couplings were not influenced by the air drying temperature.     

Cyclooxygenase-2 dependent and independent antitumor effects induced by celecoxib in urinary bladder cancer cells

Transitional cell carcinoma of the urinary bladder is the second most common genitourinary malignancy in people in the United States. Cyclooxygenase-2 (COX-2) is overexpressed in bladder cancer. COX-2 inhibitors have had antitumor activity against bladder cancer, but the mechanisms of action are unclear. Clinically relevant concentrations of COX-2 inhibitors fail to inhibit proliferation in standard in vitro assays. In pilot experiments, different culture conditions [standard monolayer, modified monolayer, soft agar, collagen, and poly(2-hydroxyethyl methacrylate)-coated plates] were assessed to determine conditions suitable for the study of COX inhibitor growth-inhibitory effects. This was followed by studies of the effects of clinically relevant concentrations of a selective COX-2 inhibitor (celecoxib) on urinary bladder cancer cell lines (HT1376, TCCSUP, and UMUC3). Celecoxib (相似文献   

Electrochemotherapy Treatment of Locally Advanced and Metastatic Soft Tissue Sarcomas: Results of a Non-Comparative Phase II Study

Aims

Our aim was to evaluate the activity, toxicity, and feasibility of electrochemotherapy (ECT) in patients with soft-tissue sarcomas (STS).

Methods

A two-stage phase II trial was conducted between October 2006 and March 2012. Patients (N = 34) with locally advanced or metastatic STS, unsuitable for standard oncological treatments and with maximum 3-cm deep tumors, received an intravenous bolus of bleomycin (15,000 IU/m²), followed by tumor electroporation according to the European Standard Operating Procedures of ECT. Outcome measures included local response according to response evaluation criteria in solid tumors (RECIST), toxicity and tumor control. Feasibility measures included the accuracy of electrode placement and the intensity of electric current flowing in tumor tissue.

Results

Median tumor size was 4.0 cm (range 2–12). Objective response, assessed on 71 target lesions, was 92.2 % (complete 32.3, 95 % CI 28–64). A total of 15 patients received up to four cycles due to incomplete response, but re-treatment did not significantly improve outcome (p = 0.205). After a median follow-up of 19.3 months, 2-year local control rate was 72.5 %. Median time to local failure (N = 11 patients) was 5.1 months. Tumor response (p = 0.041) and control (p = 0.047) correlated with histological grading. Relevant toxicity consisted of G3 skin ulceration and soft tissue necrosis (35 and 23 % of patients, respectively), although this was manageable on an outpatient basis. The accuracy of electrode placement was 47.1 %, and the adequacy of electroporative current 85.3 %.

Conclusions

ECT may represent an active and safe treatment to achieve local control in advanced STS patients with symptomatic disease. Future research challenges include the improvement of electrode placement and voltage delivery together with the containment of soft tissue toxicity.     

Clinical outcome and quality of life of patients surviving 20 years or longer after heart transplantation

To evaluate outcome and quality of life (QoL) in ≥20 years survivors after heart transplantation. Patients surviving ≥20 years with a single graft were retrospectively reviewed. Heterotopic, multiorgan and retransplantations were excluded. QoL was evaluated using the SF‐36 survey. Eight hundred and twenty‐seven heart transplants were performed from 1981 to 1993, and among these, 131 (16%) patients survived ≥20 years; 98 (75%) were male and mean age at transplant was 43 ± 13 years. Conditional survival in these 20 years survivors was 74.1 ± 4.3% at 23 years and 60.9 ± 5.3% at 25 years (45 deaths, 34%). Forty‐four (34%) patients suffered rejection ≥2R. Conditional survival free from rejection ≥2R was 68 ± 4.1% at 5 years and 66.4 ± 4.2% at 10 years. Thirty‐five (27%) patients had cardiac allograft vasculopathy (CAV) grade 2–3. Conditional CAV‐free survival was 76 ± 3.8% at 20 years and 72.1 ± 4% at 25. Sixty‐nine (53%) patients developed malignancy, mostly skin cancers. Conditional malignancy‐free survival was 53.5 ± 4.4% at 20 years and 45.2 ± 4.6% at 25 years. At latest follow‐up, 24.0 ± 3.0 years after transplantation, mean left ventricular ejection fraction was 62 ± 11% and mean physical and mental scores were 57 ± 23 and 58 ± 21, respectively. Sixteen per cent of heart recipients survived ≥20 years with good ventricular performance and QoL. CAV and malignancies account for late morbidity and mortality.