Cyclin E correlates with manganese superoxide dismutase expression and predicts survival in early breast cancer patients receiving adjuvant epirubicin-based chemotherapy.

Anthracycline-based chemotherapy represents a milestone in the treatment of breast cancer. We previously demonstrated in an in vitro model that cyclin E overexpression is associated with increased expression of manganese superoxide dismutase (MnSOD) and resistance to doxorubicin. In the present study, immunohistochemical expression of cyclin E and MnSOD was evaluated in 134 early breast cancer patients receiving adjuvant epirubicin-based chemotherapy regimens containing epirubicin. Both parameters were correlated with the available clinicopathological parameters and with the outcome of patients. Overexpression of cyclin E and MnSOD was detected in 46 (34.3%) and 56 (41.8%) patients, respectively, and expression levels of the two proteins were related. Disease-free and alive patients displayed a lower mean percentage of cyclin E-expressing cells than relapsed and dead patients, respectively. Kaplan-Meier survival analysis demonstrated a significant separation between high versus low cyclin E-expressing tumors in terms of overall survival (P = 0.038 by log-rank). Similar results were obtained considering the subset of node-negative patients separately. No significant relationship with patient outcome was observed for MnSOD expression levels. At multivariate analysis cyclin E failed to demonstrate an independent prognostic value. In conclusion, the results of the present study support previous evidence that increased cyclin E expression is associated with higher MnSOD expression levels and poorer outcome, at least as evaluated in terms of overall survival. Further studies are warranted to evaluate the usefulness of cyclin E as a prognostic marker to identify breast cancer patients at higher risk of death from the disease when treated with adjuvant anthracycline-based therapy

The role of ubiquitin ligase E3A in polarized contact guidance and rescue strategies in UBE3A-deficient hippocampal neurons

Background: Although neuronal extracellular sensing is emerging as crucial for brain wiring and therefore plasticity, little is known about these processes in neurodevelopmental disorders. Ubiquitin protein ligase E3A (UBE3A) plays a key role in neurodevelopment. Lack of UBE3A leads to Angelman syndrome (AS), while its increase is among the most prevalent genetic causes of autism (e.g., Dup15q syndrome). By using microstructured substrates that can induce specific directional stimuli in cells, we previously found deficient topographical contact guidance in AS neurons, which was linked to a dysregulated activation of the focal adhesion pathway. Methods: Here, we study axon and dendrite contact guidance and neuronal morphological features of wild-type, AS, and UBE3A-overexpressing neurons (Dup15q autism model) on micrograting substrates, with the aim to clarify the role of UBE3A in neuronal guidance. Results: We found that loss of axonal contact guidance is specific for AS neurons while UBE3A overexpression does not affect neuronal directional polarization along microgratings. Deficits at the level of axonal branching, growth cone orientation and actin fiber content, focal adhesion (FA) effectors, and actin fiber-binding proteins were observed in AS neurons. We tested different rescue strategies for restoring correct topographical guidance in AS neurons on microgratings, by either UBE3A protein re-expression or by pharmacological treatments acting on cytoskeleton contractility. Nocodazole, a drug that depolymerizes microtubules and increases cell contractility, rescued AS axonal alignment to the gratings by partially restoring focal adhesion pathway activation. Surprisingly, UBE3A re-expression only resulted in partial rescue of the phenotype. Conclusions: We identified a specific in vitro deficit in axonal topographical guidance due selectively to the loss of UBE3A, and we further demonstrate that this defective guidance can be rescued to a certain extent by pharmacological or genetic treatment strategies. Overall, cytoskeleton dynamics emerge as important partners in UBE3A-mediated contact guidance responses. These results support the view that UBE3A-related deficits in early neuronal morphogenesis may lead to defective neuronal connectivity and plasticity

Metronomic oral cyclophosphamide (MOC) in the salvage therapy of heavily treated recurrent ovarian cancer patients: a retrospective, multicenter study

The aim of this multicenter, retrospective study was to evaluate the efficacy and safety of metronomic oral cyclophosphamide (MOC) in heavily treated, relapsed ovarian cancer (ROC) patients

Heritability and Demographic Analyses in the Large Isolated Population of Val Borbera Suggest Advantages in Mapping Complex Traits Genes

Isolated populations are a useful resource for mapping complex traits due to shared stable environment, reduced genetic complexity and extended Linkage Disequilibrium (LD) compared to the general population. Here we describe a large genetic isolate from the North West Apennines, the mountain range that runs through Italy from the North West Alps to the South.The study involved 1,803 people living in 7 villages of the upper Borbera Valley. For this large population cohort, data from genealogy reconstruction, medical questionnaires, blood, anthropometric and bone status QUS parameters were evaluated. Demographic and epidemiological analyses indicated a substantial genetic component contributing to each trait variation as well as overlapping genetic determinants and family clustering for some traits.The data provide evidence for significant heritability of medical relevant traits that will be important in mapping quantitative traits. We suggest that this population isolate is suitable to identify rare variants associated with complex phenotypes that may be difficult to study in larger but more heterogeneous populations

Effect of alpha‐lipoic acid and myoinositol on endometrial inflammasome from recurrent pregnancy loss women

Problem: A significant increased expression/activation of one of the most well‐characterized inflammasomes, the NAcht leucine‐rich‐repeat protein‐3 (NALP‐3), in the endometrium from idiopathic recurrent pregnancy loss women (RPL) has been previously found by our research group. We therefore, suggested this event as being one of the molecular mechanisms altering endometrial inflammatory status during early pregnancy. In the present research, we attempt to investigate whether molecules with anti‐inflammatory activity, alpha‐lipoic acid (ALA), and/or myoinositol affect the endometrial NALP‐3 expression and activation. Method of study: Women with a history of idiopathic RPL (n = 30) were included in the study and compared to a control group (n = 15). Endometrial tissues were collected by hysteroscopy during the mid‐luteal phase. RPL women underwent a three‐month prescription of tablets containing ALA plus myoinositol (Sinopol®). After treatment, hysteroscopic biopsies were repeated in RPL patients. Inflammasome expression was evaluated by immunohistochemical and Western blot analysis. NALP‐3 activation was studied by quantifying the secretion of both caspase‐1 and interleukin IL)‐1ß and IL‐18 through ELISA. In ex vivo experiments, the effects of each molecule on endometrial inflammasome were studied. Results: Sinopol® significantly reduced the RPL endometrial inflammasome expression and activation. ALA, but not myoinositol, significantly reduced the endometrial inflammasome expression and activity. Conclusion: Our data suggest a role for ALA on RPL inflammasome. Understanding the mechanisms involved in RPL and the observation that specific molecules are able to interfere with such complex at the endometrium might provide new rational design approaches to a personalized evaluation of endometrial status and, ultimately, a targeted medicine

Clinical utility of trabectedin for the treatment of ovarian cancer: current evidence

Among the pharmaceutical options available for treatment of ovarian cancer, attention has been increasingly focused on trabectedin (ET-743), a drug which displays a unique mechanism of action and has been shown to be active in several human malignancies. Currently, single agent trabectedin is approved for treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, and in association with pegylated liposomal doxorubicin for treatment of patients with relapsed partially platinum-sensitive ovarian cancer. This review aims at summarizing the available evidence about the clinical role of trabectedin in the management of patients with epithelial ovarian cancer. Novel perspectives coming from a better understanding of trabectedin mechanisms of action and definition of patients subgroups likely susceptible to benefit of trabectedin treatment are also presented

The cl2/dro1/ccdc80 null mice develop thyroid and ovarian neoplasias

We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80(-/-) mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80(-/-) mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis

Psychological treatments and psychotherapies in the neurorehabilitation of pain. Evidences and recommendations from the italian consensus conference on pain in neurorehabilitation

BACKGROUND: It is increasingly recognized that treating pain is crucial for effective care within neurological rehabilitation in the setting of the neurological rehabilitation. The Italian Consensus Conference on Pain in Neurorehabilitation was constituted with the purpose identifying best practices for us in this context. Along with drug therapies and physical interventions, psychological treatments have been proven to be some of the most valuable tools that can be used within a multidisciplinary approach for fostering a reduction in pain intensity. However, there is a need to elucidate what forms of psychotherapy could be effectively matched with the specific pathologies that are typically addressed by neurorehabilitation teams. OBJECTIVES: To extensively assess the available evidence which supports the use of psychological therapies for pain reduction in neurological diseases. METHODS: A systematic review of the studies evaluating the effect of psychotherapies on pain intensity in neurological disorders was performed through an electronic search using PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews. Based on the level of evidence of the included studies, recommendations were outlined separately for the different conditions. RESULTS: The literature search yielded 2352 results and the final database included 400 articles. The overall strength of the recommendations was medium/low. The different forms of psychological interventions, including Cognitive-Behavioral Therapy, cognitive or behavioral techniques, Mindfulness, hypnosis, Acceptance and Commitment Therapy (ACT), Brief Interpersonal Therapy, virtual reality interventions, various forms of biofeedback and mirror therapy were found to be effective for pain reduction in pathologies such as musculoskeletal pain, fibromyalgia, Complex Regional Pain Syndrome, Central Post-Stroke pain, Phantom Limb Pain, pain secondary to Spinal Cord Injury, multiple sclerosis and other debilitating syndromes, diabetic neuropathy, Medically Unexplained Symptoms, migraine and headache. CONCLUSIONS: Psychological interventions and psychotherapies are safe and effective treatments that can be used within an integrated approach for patients undergoing neurological rehabilitation for pain. The different interventions can be specifically selected depending on the disease being treated. A table of evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation is also provided in the final part of the pape