ERBB3 as a therapeutic target in glioblastoma: overexpression can make the difference

By exploiting an integrated experimental platform based on patient-derived cancer stem cells, we identified a glioblastoma subset characterized by inheritable Erb-B2 Receptor Tyrosine Kinase 3 (ERBB3) overexpression, metabolic dependency on ERBB3 signaling, and liability to ERBB3 targeting. We provide insights on why some glioblastomas may rely on ERBB3 and how to recognize them

The long-lasting protective effect of HGF in cardiomyoblasts exposed to doxorubicin requires a positive feed-forward loop mediated by ERK1,2-TIMP1-STAT3

Previous studies showed that the hepatocyte growth factor (HGF)–Met receptor axis plays long-lasting cardioprotection against doxorubicin anti-cancer therapy. Here, we explored the mechanism(s) underlying the HGF protective effect. DNA damage was monitored by histone H2AX phosphorylation and apoptosis by proteolytic cleavage of caspase 3. In doxorubicin-treated H9c2 cardiomyoblasts, the long-lasting cardioprotection is mediated by activation of the Ras/Raf/Mek/Erk (extracellular signal-regulated kinase 1,2) signaling pathway and requires Stat3 (signal transducer and activator of transcription 3) activation. The HGF protection was abrogated by the Erk1,2 inhibitor, PD98059. This translated into reduced Y705 phosphorylation and impaired nuclear translocation of Stat3, showing crosstalk between Erk1,2 and Stat3 signaling. An array of 29 cytokines, known to activate Stat3, was interrogated to identify the molecule(s) linking the two pathways. The analysis showed a selective increase in expression of the tissue inhibitor of metalloproteinases-1 (Timp1). Consistently, inhibition in cardiomyoblasts of Timp1 translation by siRNAs blunted both Stat3 activation and the cardioprotective effect of HGF. Thus, Timp1 is responsible for the generation of a feed-forward loop of Stat3 activation and helps cardiomyocytes to survive during the genotoxic stress induced by anthracyclines

Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10.

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Effect of Different Irrigating Solutions and Endodontic Sealers on Bond Strength of the Dentin - Post Interface with and without Defects.

Abstract Aims. To investigate how the interfacial shear strength of the dentin – post interface with and without defects changes for different combinations irrigant/sealer. Methods. In forty human decoronated and instrumented teeth, fibreglass posts were in-serted. The obtained root segments were randomly assigned to four different groups ac-cording to the irrigant adopted and the cement used to seal the root canal. The root segments were processed for metyl-methacrylate embedding. Serial sections were obtained and sub-mitted to histomorphometric analyses in order to observe any defect of adhesion at the dentin – post interface and to measure the defects’ dimension. The serial sections were also submitted to micro-push-out test. The measured shear strength values were subjected to statistical analysis by one-way ANOVA. The values of bond strength determined for the defective samples were correlated with the dimension of the defects. Finite element models were built to interpret and corroborate the experimental findings. Results. ANOVA showed that the generic combination irrigant/sealer does not affect the interfacial shear strength values. The bond strength of the samples without defects was av-eragely twice as large as that of the defective samples. The defects occupying more than 12 % of the total transverse section area of the endodontic cement layer led to a reduction of the bond strength of about 70 %. The predictions of the finite element models were in agreement with the experimental results. Conclusion. Defects occupying less than 2 % of the total transverse section area of the cement layer were shown to be acceptable as they have rather negligible effects on the shear strength values. Technologies/protocols should be developed to minimize the number and the size of the defects

A network study to differentiate suicide attempt risk profiles in male and female patients with major depressive disorder

Suicide attempts are a possible consequence of Major Depressive Disorder (MDD), although their prevalence varies across different epidemiological studies. Suicide attempt is a significant predictor of death by suicide, highlighting its importance in understanding and preventing tragic outcomes. Researchers are increasingly recognizing the need to study the differences between males and females, as several distinctions emerge in terms of the characteristics, types and motivations of suicide attempts. These differences emphasize the importance of considering gender-specific factors in the study of suicide attempts and developing tailored prevention strategies. We conducted a network analysis to represent and investigate which among multiple neurocognitive, psychosocial, demographic and affective variables may prove to be a reliable predictor for identifying the 'suicide attempt risk' (SAR) in a sample of 81 adults who met DSM-5 criteria for MDD. Network analysis resulted in differences between males and females regarding the variables that were going to interact and predict the SAR; in particular, for males, there is a stronger link toward psychosocial aspects, while for females, the neurocognitive domain is more relevant in its mnestic subcomponents. Network analysis allowed us to describe otherwise less obvious differences in the risk profiles of males and females that attempted to take their own lives. Different neurocognitive and psychosocial variables and different interactions between them predict the probability of suicide attempt unique to male and female patients