ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma. Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin

In recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are at the basis of drug resistance. Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi. In this paper we focus on the involvement of activation of ErbB3 receptor following early exposure of melanoma cells to BRAF or MEK inhibitors, and the following induction of PI3K/AKT pathway. Although different mechanisms have been invoked in the past at the basis of this activation we show here with a combination of approaches that autocrine production of neuregulin by melanoma cells is a major factor responsible for ErbB3 phosphorylation and downstream AKT activation. Interestingly the kinetic of neuregulin production and of the ensuing ErbB3 phosphorylation is different in different melanoma cell lines which underscores the high degree of tumor heterogeneity. Moreover, heterogeneity is further highlighted by the evidence that in different cell lines neuregulin upregulation can occur at the transcriptional or at the post-transcritpional level. Finally we complement our study by showing with a liquid biopsy assay that circulating tumor cells (CTCs) from melanoma patients undergo upregulation of ErbB3 phosphorylation in vivo shortly after initiation of therapy

The Nature of the Chemical Bond in Linear Three-Body Systems: From I3− to Mixed Chalcogen/Halogen and Trichalcogen Moieties

The 3 centre-4 electrons (3c-4e) and the donor/acceptor or charge-transfer models for the description of the chemical bond in linear three-body systems, such as I3− and related electron-rich (22 shell electrons) systems, are comparatively discussed on the grounds of structural data from a search of the Cambridge Structural Database (CSD). Both models account for a total bond order of 1 in these systems, and while the former fits better symmetric systems, the latter describes better strongly asymmetric situations. The 3c-4e MO scheme shows that any linear system formed by three aligned closed-shell species (24 shell electrons overall) has reason to exist provided that two electrons are removed from it to afford a 22 shell electrons three-body system: all combinations of three closed-shell halides and/or chalcogenides are considered here. A survey of the literature shows that most of these three-body systems exist. With some exceptions, their structural features vary continuously from the symmetric situation showing two equal bonds to very asymmetric situations in which one bond approaches to the value corresponding to a single bond and the second one to the sum of the van der Waals radii of the involved atoms. This indicates that the potential energy surface of these three-body systems is fairly flat, and that the chemical surrounding of the chalcogen/halogen atoms can play an important role in freezing different structural situations; this is well documented for the I3− anion. The existence of correlations between the two bond distances and more importantly the linearity observed for all these systems, independently on the degree of their asymmetry, support the state of hypervalency of the central atom

Ultrasound assisted extraction and liposome encapsulation of olive leaves and orange peels:how to transform biomass waste into valuable resources with antimicrobial activity

Every year million tons of by-products and waste from olive and orange processing are produced by agri-food industries, thus triggering environmental and economic problems worldwide. From the perspective of a circular economy model, olive leaves and orange peels can be valorized in valuable products due to the presence of bioactive compounds such as polyphenols exhibiting beneficial effects on human health.The aqueous extracts of olive leaves and orange peels rich in phenolic compounds were prepared by ultrasound-assisted extraction. Both extracts were characterized in terms of yield of extraction, total phenolic content and antioxidant capacity; the polyphenolic profiles were deeper investigated by HPLC-MS analysis.Each extract was included in liposomes composed by a natural phospholipid, 1,2-dioleoyl-sn-glycero-3-phosphocholine, and cholesterol prepared according to the thin-layer evaporation method coupled with a sonication process.The antimicrobial activity of the extracts, free and loaded in liposomes, was investigated according to the broth macrodilution method against different strains of potential bacterial pathogenic species: Staphylococcus aureus (NCIMB 9518), Bacillus subtilis (ATCC 6051) and Enterococcus faecalis (NCIMB 775) as Gram-positive, while Escherichia coli (NCIMB 13302), Pseudomonas aeruginosa (NCIMB 9904) and Klebsiella oxytoca (NCIMB 12259) as Gram-negative.The encapsulation of olive leaves extract in liposomes enhanced its antibacterial activity against S. aureus by an order of magnitude

Benefits of parent training in the rehabilitation of deaf or hard of hearing children of hearing parents: a systematic review

The present study is a systematic review on the effectiveness of Parent Training (PT) and coaching in deaf and hard of hearing (DHH) rehabilitation programs which reviews and synthesizes the existing body of evidence to assess the benefits of these programs in enhancing parents’ sensitivity, responsivity and promoting language development in DHH children during the first years after HA fitting or CI activation. Five published studies met the Population, Intervention, Comparison and Outcomes (PICO) inclusion criteria and were eligible to be included, but heterogeneity in terms of the study design, interventions and outcomes did not allow for performing a meta-analysis. All included studies shared the view that a parent’s learning is a circular (rather than frontal) process, and the results appear promising in terms of enhancing parents’ responsiveness and promoting DHH child language development. Nevertheless, the available evidence was judged to not be robust enough due to limitations in the studies’ designs. Further high-quality evidence is needed to evaluate the true degree of clinical value and the cost effectiveness of PT programs aimed at increasing parents’ responsiveness to their DHH childre

Crystal structure of 4,4′-(disulfanediyl)dipyridinium chloride triiodide

4,4 '-(Disulfanediyl)dipyridinium chloride triiodide, C10H10N2S22+center dot Cl-center dot I-3(-), (1) was synthesized by reaction of 4,4 '-dipyridyldisulfide with ICl in a 1:1 molar ratio in dichloromethane solution. The structural characterization of 1 by SC-XRD analysis was supported by elemental analysis, FT-IR, and FT-Raman spectroscopic measurements

JAK3/STAT5/6 Pathway Alterations Are Associated with Immune Deviation in CD8+ T Cells in Renal Cell Carcinoma Patients

To investigate the molecular mechanisms underlying altered T cell response in renal cell carcinoma (RCC) patients, we compared autologous and allogeneic CD8+ T cell responses against RCC line from RCC patients and their HLA-matched donors, using mixed lymphocyte/tumor cell cultures (MLTCs). In addition, we analyzed the expression of molecules associated with cell cycle regulation. Autologous MLTC responder CD8+ T cells showed cytotoxic activity against RCC cell lines; however the analysis of the distribution of CD8+ T-cell subsets revealed that allogenic counterparts mediate superior antitumor efficacy. In RCC patients, a decreased proliferative response to tumor, associated with defects in JAK3/STAT5/6 expression that led to increased p27KIP1 expression and alterations in the cell cycle, was observed. These data define a molecular pathway involved in cell cycle regulation that is associated with the dysfunction of tumor-specific CD8+ effector cells. If validated, this may define a therapeutic target in the setting of patients with RCC

Long-Term Results of Combined Tunica Albuginea Plication and Penile Prosthesis Implantation for Severe Penile Curvature and Erectile Dysfunction

Penile prosthesis implantation is the recommended treatment in patients with penile curvature and severe erectile dysfunction (ED) not responding to pharmacotherapy. Most patients with mild-to-moderate curvature can expect cylinder insertion to correct both ED and penile curvature. In patients with severe curvature and in those with persistent curvature after corporeal dilation and prosthesis placement, intraoperative penile “modelling” over the inflated prosthesis has been introduced as an effective treatment. We report for the first time the long-term results of a patient treated with combined penile plication and placement of an inflatable penile prosthesis

Impact of active lifestyle on the primary school children saliva microbiota composition

Unlabelled: The aim of the study was to evaluate the effects of Active or Sedentary lifestyle on saliva microbiota composition in Italian schoolchildren. Methods: Male (114) and female children (8-10 years) belonging to five primary schools in the neighborhoods of Turin were classified as active (A) or sedentary (S) based on PAQ-C-It questionnaire. PCR amplification of salivary DNA targeted the hypervariable V3-V4 regions of the 16S rRNA bacterial genes. DADA2 workflow was used to infer the Amplicon Sequence Variants and the taxonomic assignments; the beta-diversity was obtained by PCoA with the UniFrac method; LEfSe algorithm, threshold at 5%, and Log LDA cutoff at ±0.5 were used to identify differently abundant species in A compared to S saliva sample. Daily food intake was assessed by 3-Days food record. The metabolic potential of microbial communities was assessed by PICRUSt. Results: No significant differences were found in individual's gender distribution (p = 0.411), anthropometry, BMI (p > 0.05), and all diet composition between A and S groups (p > 0.05). Eight species were differently abundant: Prevotella nigrescens (LDA score = -3.76; FDR = 1.5×10-03), Collinsella aerofaciens (LDA score = -3.17; FDR = 7.45×10-03), Simonsiella muelleri (LDA score = -2.96; FDR = 2.76×10-05), Parabacteroides merdae (LDA score = -2.43; FDR = 1.3×10-02) are enriched in the A group; Gemella parahaemolysans, Prevotella aurantiaca (LDA score = -3.9; FDR = 5.27×10-04), Prevotella pallens (LDA score = 4.23; FDR = 1.93×10-02), Neisseria mucosa (LDA score = 4.43; FDR = 1.31×10-02; LDA score = 2.94; FDR = 7.45×10-03) are enriched in the S group. A prevalence of superpathway of fatty acid biosynthesis initiation (E. coli) and catechol degradation II (meta-cleavage pathway) was found in saliva from A compared to S children. Conclusion: Our results showed that active children had an enrichment of species and genera mainly associated with a healthier profile. By contrast, the genera and the species enriched in the sedentary group could be linked to human diseases

Impacted Central Incisors in the Upper Jaw in an Adolescent Patient: Orthodontic-Surgical Treatment—A Case Report

The inclusion of both maxillary permanent central incisors is uncommon. This condition compromises face aesthetics, phonation andmasticatory function. Therefore, early diagnosis is essential to avoid complications and failures. There are various reasons for inclusion, but supernumerary teeth are the leading cause. Early causes of removal and rapid expansion of the palate determine a high probability of success with the spontaneous eruption of the impacted elements. However, it is often necessary to proceed with a surgical–orthodontic treatment. The inclination of teeth in relation to the midline and the root maturation degree determine prognosis and therapeutic timing. In this case report, the orthopantomogram (OPG) X-ray of a 9-year-old boy revealed two impacted supernumerary teeth in the anterior maxillary region, preventing the eruption of the permanent upper central incisors. The impacted supernumerary teeth were surgically removed at different times. A straight wire multibrackets technique associated with a fixed palatal appliance was used. The palatal appliance featured an osteomucous resin support at the level of the retroincisal papilla. Subsequently, surgical exposure was carried out using the closed eruption technique and elastictraction, bringing 11 and 21 back into the arch

A predictive decision support system for coronavirus disease 2019 response management and medical logistic planning

Objective: Coronavirus disease 2019 demonstrated the inconsistencies in adequately responding to biological threats on a global scale due to a lack of powerful tools for assessing various factors in the formation of the epidemic situation and its forecasting. Decision support systems have a role in overcoming the challenges in health monitoring systems in light of current or future epidemic outbreaks. This paper focuses on some applied examples of logistic planning, a key service of the Earth Cognitive System for Coronavirus Disease 2019 project, here presented, evidencing the added value of artificial intelligence algorithms towards predictive hypotheses in tackling health emergencies. Methods: Earth Cognitive System for Coronavirus Disease 2019 is a decision support system designed to support healthcare institutions in monitoring, management and forecasting activities through artificial intelligence, social media analytics, geo- spatial analysis and satellite imaging. The monitoring, management and prediction of medical equipment logistic needs rely on machine learning to predict the regional risk classification colour codes, the emergency rooms attendances, and the fore- cast of regional medical supplies, synergically enhancing geospatial and temporal dimensions. Results: The overall performance of the regional risk colour code classifier yielded a high value of the macro-average F1-score (0.82) and an accuracy of 85%. The prediction of the emergency rooms attendances for the Lazio region yielded a very low root mean square error (<11 patients) and a high positive correlation with the actual values for the major hos- pitals of the Lazio region which admit about 90% of the region’s patients. The prediction of the medicinal purchases for the regions of Lazio and Piemonte has yielded a low root mean squared percentage error of 16%. Conclusions: Accurate forecasting of the evolution of new cases and drug utilisation enables the resulting excess demand throughout the supply chain to be managed more effectively. Forecasting during a pandemic becomes essential for effective government decision-making, managing supply chain resources, and for informing tough policy decisions