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Aim: To further evaluate the antiemetic efficacy of single-dose versus multiple-dose dexamethasone (DEX) against nausea and vomiting caused by cisplatin. Materials & methods: Two similar non-inferiority studies were pooled. Patients were randomized to single-day DEX or multiple-day DEX plus palonosetron and neurokinin-1 receptor-antagonists (NK-1RAs). The primary endpoint was complete response (CR; no vomiting and no rescue medication) during the overall phase. Results: The combined analysis included 242 patients. The absolute risk difference between single day versus multi-day DEX for CR was -2% (95% CI, -14 to 9%). Conclusion: Administration of single-dose DEX offers comparable antiemetic control to multiple-day DEX when combined with palonosetron and an NK-1RA in the setting of single-day cisplatin.

Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC), leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tumour markers are standard tools for the differential diagnosis of cancer. However, the occurrence of nonspecific symptoms and different malignancies involving the same cancer site may lead to a high proportion of misclassifications. Classification accuracy can be improved by combining information from different markers using standard data mining techniques, like Decision Tree (DT), Artificial Neural Network (ANN), and k-Nearest Neighbour (KNN) classifier. Unfortunately, each method suffers from some unavoidable limitations. DT, in general, tends to show a low classification performance, whereas ANN and KNN produce a "black-box" classification that does not provide biological information useful for clinical purposes., Methods: Logic Learning Machine (LLM) is an innovative method of supervised data analysis capable of building classifiers described by a set of intelligible rules including simple conditions in their antecedent part. It is essentially an efficient implementation of the Switching Neural Network model and reaches excellent classification accuracy while keeping low the computational demand. LLM was applied to data from a consecutive cohort of 169 patients admitted for diagnosis to two pulmonary departments in Northern Italy from 2009 to 2011. Patients included 52 malignant pleural mesotheliomas (MPM), 62 pleural metastases (MTX) from other tumours and 55 benign diseases (BD) associated with pleurisies. Concentration of three tumour markers (CEA, CYFRA 21-1 and SMRP) was measured in the pleural fluid of each patient and a cytological examination was also carried out. The performance of LLM and that of three competing methods (DT, KNN and ANN) was assessed by leave-one-out cross-validation., Results: LLM outperformed all other considered methods. Global accuracy was 77.5% for LLM, 72.8% for DT, 54.4% for KNN, and 63.9% for ANN, respectively. In more details, LLM correctly classified 79% of MPM, 66% of MTX and 89% of BD. The corresponding figures for DT were: MPM = 83%, MTX = 55% and BD = 84%; for KNN: MPM = 58%, MTX = 45%, BD = 62%; for ANN: MPM = 71%, MTX = 47%, BD = 76%. Finally, LLM provided classification rules in a very good agreement with a priori knowledge about the biological role of the considered tumour markers., Conclusions: LLM is a new flexible tool potentially useful for the differential diagnosis of pleural mesothelioma.

Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.

Prosenescence therapy has recently emerged as a novel therapeutic approach for treating cancer. However, this concept is challenged by conflicting evidence showing that the senescence-associated secretory phenotype (SASP) of senescent tumor cells can have pro- as well as antitumorigenic effects. Herein, we report that, in Pten-null senescent tumors, activation of the Jak2/Stat3 pathway establishes an immunosuppressive tumor microenvironment that contributes to tumor growth and chemoresistance. Activation of the Jak2/Stat3 pathway in Pten-null tumors is sustained by the downregulation of the protein tyrosine phosphatase PTPN11/SHP2, providing evidence for the existence of a novel PTEN/SHP2 axis. Importantly, treatment with docetaxel in combination with a JAK2 inhibitor reprograms the SASP and improves the efficacy of docetaxel-induced senescence by triggering a strong antitumor immune response in Pten-null tumors. Altogether, these data demonstrate that immune surveillance of senescent tumor cells can be suppressed in specific genetic backgrounds but also evoked by pharmacological treatments., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

The protein dysferlin is abundantly expressed in skeletal and cardiac muscles, where its main function is membrane repair. Mutations in the dysferlin gene are involved in two autosomal recessive muscular dystrophies: Miyoshi myopathy and limb-girdle muscular dystrophy type 2B. Development of effective therapies remains a great challenge. Strategies to repair the dysferlin gene by skipping mutated exons, using antisense oligonucleotides (AONs), may be suitable only for a subset of mutations, while cell and gene therapy can be extended to all mutations. AON-treated blood-derived CD133+ stem cells isolated from patients with Miyoshi myopathy led to partial dysferlin reconstitution in vitro but failed to express dysferlin after intramuscular transplantation into scid/blAJ dysferlin null mice. We thus extended these experiments producing the full-length dysferlin mediated by a lentiviral vector in blood-derived CD133+ stem cells isolated from the same patients. Transplantation of engineered blood-derived CD133+ stem cells into scid/blAJ mice resulted in sufficient dysferlin expression to correct functional deficits in skeletal muscle membrane repair. Our data suggest for the first time that lentivirus-mediated delivery of full-length dysferlin in stem cells isolated from Miyoshi myopathy patients could represent an alternative therapeutic approach for treatment of dysferlinopathies., (© 2013 FEBS.)

Plasma cells (PCs) are terminally differentiated cells of the B-cell lineage that secrete antibodies at a high rate and are thought to lack the expression of the B-cell receptor (BCR). Here, we report that human IgA and IgM, unlike IgG, PCs express a membrane functional BCR associated with the Igα/Igβ heterodimer. BCR cross-linking on IgA and IgM PCs led to Ca(2+) mobilization and extracellular signal-regulated kinase 1/2 and AKT phosphorylation and impacted survival of IgA PCs. These findings demonstrate a significant difference between human IgG, IgM, and IgA PCs and suggest that the IgA PC repertoire may be modulated by specific antigens with implications for the regulation of the mucosal immune system.

Background: there is an intimate relation between transition metals and cell homeostasis due to the physiological necessity of metals in vivo. Particularly, iron (ferrous and ferric state) is utilized in many physiological processes of the cell but in excess has been linked with negative role contributing in many neurodegenerative processes., Objective: the aim of this study was to investigate which oxidation state of ionic iron (Ferrous (II) versus Ferric (III)) is more toxic to neuronal cells (SHSY(5)Y)., Materials and Methods: The neuroblastoma (SHSY(5)Y) cells were exposed to varying concentration of ferric and ferrous iron. Morphological studies using immunofluorescence staining and microscopic analysis as confirmed by intracellular glutathione (GSH) test demonstrated oxidative stress to cells in iron microenvironment. In addition, MTT assay was performed to evaluate the viability and metabolic state of the cells., Results: the results showed that ferrous form has significantly higher toxicity compared to the ferric ionic state of higher concentration. In addition, microscopic analysis shows cell fenestration at higher concentrations and swelling at intermediate ferric dosages as demonstrated by atomic force microscopy (AFM). Interestingly, the addition of a differentiation inducing factor, trans-retinoic rcid (RA) retains significant viability and morphological features of the cells irrespective of the ionic state of the iron. AFM images revealed clustered aggregates arising from iron chelation with RA., Conclusions: the results indicate that Fe (II) has more toxic effects on cells. In addition, it could be an interesting finding with respect to the antioxidant properties of RA as a chelating agent for the neurodegenerative therapeutics.

Two major mechanisms have been causally implicated in the establishment of cellular senescence: the activation of the DNA damage response (DDR) pathway and the formation of senescence-associated heterochromatic foci (SAHF). Here we show that in human fibroblasts resistant to premature p16(INK4a) induction, SAHF are preferentially formed following oncogene activation but are not detected during replicative cellular senescence or on exposure to a variety of senescence-inducing stimuli. Oncogene-induced SAHF formation depends on DNA replication and ATR (ataxia telangiectasia and Rad3-related). Inactivation of ATM (ataxia telangiectasia mutated) or p53 allows the proliferation of oncogene-expressing cells that retain increased heterochromatin induction. In human cancers, levels of heterochromatin markers are higher than in normal tissues, and are independent of the proliferative index or stage of the tumours. Pharmacological and genetic perturbation of heterochromatin in oncogene-expressing cells increase DDR signalling and lead to apoptosis. In vivo, a histone deacetylase inhibitor (HDACi) causes heterochromatin relaxation, increased DDR, apoptosis and tumour regression. These results indicate that heterochromatin induced by oncogenic stress restrains DDR and suggest that the use of chromatin-modifying drugs in cancer therapies may benefit from the study of chromatin and DDR status of tumours., (© 2011 Macmillan Publishers Limited. All rights reserved)

We examined fifty patients aged from 15 to 35 years, mean 23 +/- 5, with mitral valve prolapse (MVP) documented by two-dimensional echocardiography in the apical 4-chamber view as well as in the parasternal-long axis. The patients have been submitted to 4 tests: Valsalva maneuver, standing and exercise test and 24 hours ambulatory ECG monitoring. Fourty-five healthy subjects of similar age and sex served as controls. During the standing test the patients with MVP showed a significantly faster heart rate than the control subjects both in resting and in the standing position; during the exercise test they exhibited higher prevalence of ST segment and T wave abnormalities disappearing at the peak of the exercise. These observations support the hypothesis of a hyperadrenergic state. The greater bradycardia showed during the Valsalva maneuver, the lower heart rate and the higher incidence of bradyarrhythmias and A-V blocks during the sleeping period suggest an increased vagal tone. Our results suggest therefore that in subjects with MVP a dysfunction of both, sympathetic and parasympathetic nervous system is present.

Possible connections have been investigated between PVc (premature ventricular contractions) and echocardiographic patterns in 23 patients affected by MVPS. Pansystolic prolapse has been found in 12 cases and mid-systolic prolapse in 11. A correlation has been found between significant ventricular arrhythmias (50 PVc/24 h) and mid-systolic prolapse. These findings suggest the mechanical origin of cardiac rhythm disorders.

In the aim to clarify the magnitude and features of alterations in left ventricular function observed in patients with mitral valve prolapse syndrome (MVPS), we studied 41 patients with MVPS with M-mode echocardiography and computerized reading of recordings (with particular regard to the diastolic phase), and compared them with a control group of 15 healthy subjects matched for age and sex. Routine morphological and functional echocardiographic parameters were evaluated and, in addition, peak rates of movement of left ventricular endocardia, of wall thicknesses change and of cavity dimensions variations were obtained. Finally, a detailed analysis of various diastolic phases have been performed, according to the method proposed by Hanrath et al. There were no significant statistical differences in the morphological echocardiographic parameters (ventricular diameters, wall thicknesses) between the two groups. Patients with MVPS showed (compared to the control group) a significant increase in the peak rate of posterior wall endocardium movement during systole (1.64 +/- 0.42 vs 1.29 +/- 0.30, p less than 0.01) and a reduction of peak rate of interventricular septum thickening (1.21 +/- 0.36 vs 1.45 +/- 0.46, p less than 0.05). The comparison of all other systolic function parameters did not show statistical differences. As far as diastolic phase is concerned, no significant differences were found in the analysis of the peak velocities. However, evaluation of the diastolic phases demonstrated, in MVPS group, a significantly shorter slow filling period, both in absolute value (185.88 +/- 78.91 vs 303.15 +/- 117.58, p less than 0.001) and in percent of the whole diastole (37.42 +/- 11.88 vs 52.50 +/- 10.61, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

20 patients with previous myocardial infarction clinically suspected to have large impairment of ventricular wall kinesis were studied to evaluate the contribution of M-mode and two-dimensional echocardiography compared with the cineangiographic study in detecting left ventricular asynergy. Two-dimensional cross-sectional echocardiography yielded a satisfactory overlapping of results with ventriculography as far as left ventricular internal dimension and apical and posterior wall kinesis were concerned. The two-dimensional study proved to be an useful technique to observe the interventricular septum, in all its extension and the lateral wall as well. The M-mode technique, on the other hand, provided a reliable method, by means of the mitral valve echo, to determine the presence of elevated left-ventricular end-diastolic pressure; this was indicated by the occurrence of a B point, on the AC slope. A late opening of the mitral valve compared with the onset of left ventricular posterior wall relaxation phase, and other anomalies observed on the CD slope (SAM or pseudo-SAM), indicated pathological left ventricular kinesis. The failure of the left ventricular posterior wall to reach the septum moving the transducer from the aorta to the cardiac apex was considered indicative of apical dilatation, even if limited by a great number of false negatives. M-mode echocardiography provided also a quantitative evaluation of septal and postero-basal wall movement (particularly important from a prognostic point of view) and left ventricular end-diastolic dimension which, if corrected by body surface, resulted similar to those obtained by the two-dimensional technique. M-mode and Two-dimensional cross sectional echocardiography appeared to be complementary techniques which allow an adequate evaluation and diagnosis of left ventricular asynergy. They seem to be particularly useful to follow prospectively patients affected by myocardial infarction.