PARP inhibition: a promising therapeutic target in ovarian cancer

Ovarian cancer is burdened by the highest mortality rate among gynecological cancers. Gold standard is represented by the association of platinum-taxane -based chemotherapy and radical surgery. Despite several adjustments occurred in cytotoxic drug in last decades, most patients continue to relapse, and no significant enhancement has been reached in the overall survival. The development of drug resistance and the recurrence of disease have prompted the investigations of other targets that can be used in the treatment of ovarian cancers. Among such targets, polyadenosine diphosphate-ribose polymerase (PARP) represents a novel way to target specific patways involved in tumor growth. PARP accelerates the reaction of the polyADP-ribosylation of proteins implicated in DNA repair. PARP inhibitors have shown activity in cancers with BRCA mutations, with other deficient DNA repair genes or signaling pathways that modulate DNA repair, or in association with DNA damaging agents not involved in DNA repair dysfunction. A number of inhibitors for PARP has been developed, and such drugs are under investigation in clinical trials to identify their impact in the treatment of ovarian cancers. This review aims to summarize the recent researches and clinical progress on PARP inhibitors as novel target agents in ovarian cancer

Nutritional surveillance in Tuscany: maternal perception of nutritional status of 8-9 y-old school-children

Introduction. Overweight and obesity in the developmental age has become a public health problem. For this reason, prevention projects must be developed in advance with the aim to involve not only children, but their parents as well. Our objective is to evaluate the accuracy of the mothers? perceptions of adolescent nutritional status. Methods. Cross-sectional study. We selected a statistical sample of 3,076 subjects (1,583 males, 1,493 females), 8-9 y-old school-children of 164 3rd-grade elementary school classes from throughout Tuscany, as well as their mothers. The mothers? information was gathered via self-administered questionnaires, while the children were given an eating behaviour survey under the supervision of qualified personnel. Mothers? education level (self-reported) height and weight were collected; children?s height and weight were measured. The former were asked how they perceived their children?s body image. Results. A correlation exists between the mothers? perceptions of the nutritional state of their children via the silhouettes and the BMI classes of the children, which is equal to 80% with a k-Cohen for agreement equal to 0.58 (SE = 0.02; P : 0.0001). However, no correlation exists between the mothers? responses to the question ?In your opinion, is your child ??? and the child?s actual BMI class (the exact percentage correlation is equal to 75%, with a k-Cohen for agreement equal to 0.43 SE = 0.014; P : 0.0001). Discussion. Mothers have an accurate perception of the nutritional status of their children, correctly choosing the silhouette that corresponds to the child?s BMI profile without variation by gender. We can assume that mothers in our sample have a good concept about healthy nutritional status

Obturator prosthesis rehabilitation after maxillectomy: Functional and aesthetical analysis in 25 patients

The number of patients undergoing a surgical resection of the maxilla for oncological reasons is constantly increasing, the most common complication of which remains the communication between oral and nasal cavities. On the basis of data arising from the literature regarding the treatment options of maxillary oncological post-surgical defects, obturator prosthesis remains the most used worldwide. We studied 25 patients (with at least 1-year follow up) rehabilitated by obturator prosthesis after maxillary resection leading to oro-nasal communication, providing data on the objective/subjective evaluation of such rehabilitation and mastication performance measured by a two-color chewing gum test. The type of defect was classified according to the classification system proposed by Aramany. Among the patients in our study, 72% rated a higher score for either stability and retention than for aesthetic appearance, as confirmed by the Kapur score rated by clinicians. The two-color chewing gum test shows similar results as only one patient had insufficient chewing function. Interestingly, we found no correlation between the masticatory function and residual denture, confirming that the maxillary obturator remains a predictable solution in such patients regardless of the anatomical alterations following surgery

Nutritional Surveillance in Tuscany: eating habits at breakfast, mid-morning and afternoon snacks among 8-9 y-old children

Introduction.The prevalence of overweight and obesity in children is rapidly increasing in many countries. For that it has been interesting to investigate the eating habits of 8-9 y-old Tuscany children by paying attention to their meals frequency per day and their food choices in total and in relation to children?s Body Mass Index (BMI) classes. In addition we considered some environment factors that could affect the children eating behaviours, such as mother?s BMI and their education level. Methods. A statistical sample of 3,076 (1,583 males, 1,493 females), 8-9 year-old school-children was collected; weight and height were measured using standardized personnel and instruments. BMI classes were calculated using Cole et al.?s cutoff for children and adolescents. In order to evaluate the consumption frequency of individual meals and various foods, a Food Frequency Questionnaire (FFQ) was used, which was completed by the children themselves at school. A self-administered questionnaire revealed the weight and height of parents and their educational levels. Three educational levels were established: high, medium and low. Results. The results showed that 92.3% of children ate breakfast from 4-7 times a week, the vast majority at home, while only 3% declared consuming breakfast never or almost never. The most preferred breakfast consisted of milk and biscuits for all children?s BMI classes. 95.9% of children reported having mid-morning snack at school; fruit juice and tea are the most frequently consumed liquid foods, and pizza, salami sandwiches and pre-packaged snacks are the most frequently consumed solid foods in all BMI classes. 93.6% ate afternoon snack for the most part at home, even if 12% of children reported consuming it elsewhere; fruit juice and tea with pizza, sandwiches and pre-packaged snacks are still the most highly consumed foods by all children?s BMI classes. The consumption frequency of breakfast (P inf. 0.001), mid-morning (P inf. 0.05) and afternoon snack (P inf. 0.05) of 8-9 y-old Tuscany children decrease with increase the children?s BMI classes. The same tendency may be noted for the consumption frequency of breakfast in relation to mother?s BMI (P inf. 0.05) and their education level (P inf. 0.05). This data strengthens the thesis that some home environments can affect the children?s eating behaviours. Conclusion. No substantial differences in food choices at the meals analyzed were determined among normal weight, over weight and obese children. Children of normal weight had a greater tendency to consume meals more regularly. Mother?s BMI and their education level can have influence on children?eating behaviours

Early Diagnosis of Congenital Uterine Anomalies: Is the Three Dimensional Ultrasound Approach the Suitable Choice? 3D in Uterine Anomalies

Purposes: Congenital uterine anomalies (CUA) are benign conditions associated with relatively serious complications affecting the reproductive life. Due to their infrequency CUA are often misdiagnosed, exposing the patient to possible future complications. Case description: We report the cases of three women affected by an unknown CUA, which underwent three different diagnostic and surgical approaches. Conclusions: A correct and early diagnosis of CUA is mandatory to allow a correct clinical and therapeutic management. In our opinion we might avoid the use of MRI considered as the second line technique after 2D-US, keeping in mind that in CUA the diagnostic value of 3D-US has the same accuracy as MRI

Current challenges in glioblastoma : intratumour heterogeneity, residual disease and models to predict disease recurrence

Glioblastoma (GB) is the most common malignant primary brain tumour, and despite the availability of chemotherapy and radiotherapy to combat the disease, overall survival remains low with a high incidence of tumour recurrence. Technological advances are continually improving our understanding of the disease and in particular our knowledge of clonal evolution, intratumour heterogeneity and possible reservoirs of residual disease. These may inform how we approach clinical treatment and recurrence in GB. Mathematical modelling (including neural networks), and strategies such as multiple-sampling during tumour resection and genetic analysis of circulating cancer cells, may be of great future benefit to help predict the nature of residual disease and resistance to standard and molecular therapies in GB

A Small Molecule SMAC Mimic LBW242 Potentiates TRAIL- and Anticancer Drug-Mediated Cell Death of Ovarian Cancer Cells

BACKGROUND: Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (SMAC) has been described to sensitize for apoptosis. We have explored the pro-apoptotic activity of LBW242, a mimic of SMAC/DIABLO, on ovarian cancer cell lines (A2780 cells and its chemoresistant derivative A2780/ADR, SKOV3 and HEY cells) and in primary ovarian cancer cells. The effects of LBW242 on ovarian cancer cell lines and primary ovarian cancer cells was determined by cell proliferation, apoptosis and biochemical assays. PRINCIPAL FINDINGS: LBW242 added alone elicited only a moderate pro-apoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or anticancer drugs in inducing apoptosis of both ovarian cancer cell lines and primary ovarian cancer cells. Mechanistic studies show that LBW242-induced apoptosis in ovarian cancer cells is associated with activation of caspase-8. In line with this mechanism, c-FLIP overexpression inhibits LBW242-mediated apoptosis. CONCLUSION: LBW242 sensitizes ovarian cancer cells to the antitumor effects of TRAIL and anticancer drugs commonly used in clinic. These observations suggest that the SMAC/DIABLO mimic LBW242 could be of value for the development of experimental strategies for treatment of ovarian cancer

The Mutyh Base Excision Repair Gene Influences the Inflammatory Response in a Mouse Model of Ulcerative Colitis

BACKGROUND: The Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases. Mutations in the human MUTYH gene are responsible for colorectal cancer in familial adenomatous polyposis. Since defective DNA repair genes might contribute to the increased cancer risk associated with inflammatory bowel diseases, we compared the inflammatory response of wild-type and Mutyh(-/-) mice to oxidative stress. METHODOLOGY/PRINCIPAL FINDINGS: The severity of colitis, changes in expression of genes involved in DNA repair and inflammation, DNA 8-oxoguanine levels and microsatellite instability were analysed in colon of mice treated with dextran sulfate sodium (DSS). The Mutyh(-/-) phenotype was associated with a significant accumulation of 8-oxoguanine in colon DNA of treated mice. A single DSS cycle induced severe acute ulcerative colitis in wild-type mice, whereas lesions were modest in Mutyh(-/-) mice, and this was associated with moderate variations in the expression of several cytokines. Eight DSS cycles caused chronic colitis in both wild-type and Mutyh(-/-) mice. Lymphoid hyperplasia and a significant reduction in Foxp3(+) regulatory T cells were observed only in Mutyh(-/-) mice. CONCLUSIONS: The findings indicate that, in this model of ulcerative colitis, Mutyh plays a major role in maintaining intestinal integrity by affecting the inflammatory response

Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity

Practice patterns and 90-day treatment-related morbidity in early-stage cervical cancer

To evaluate the impact of the Laparoscopic Approach to Cervical Cancer (LACC) Trial on patterns of care and surgery-related morbidity in early-stage cervical cancer