Osservatorio Neologico della Lingua Italiana. Lessico e parole nuove dell’italiano

L’ONLI (Osservatorio Neologico della Lingua Italiana), costituito nel 1998, si è proposto di studiare il lessico italiano e la sua evoluzione nei decenni tra il XX e il XXI secolo, analizzando la neologia attraverso metodi d’indagine e regole dei meccanismi formativi delle parole nuove applicati ai contesti giornalistici raccolti nella sua banca dati tra il 1998 e il 2019. La proposta di classificazione dei neologismi adottata dall’ONLI ha permesso di evidenziare le linee di tendenza del lessico italiano, anche mediante il confronto di opinioni tra studiosi dei settori affini

Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids.

Oncogenic transformation is associated with profound changes in cellular metabolism, but whether tracking these can improve disease stratification or influence therapy decision-making is largely unknown. Using the iKnife to sample the aerosol of cauterized specimens, we demonstrate a new mode of real-time diagnosis, coupling metabolic phenotype to mutant PIK3CA genotype. Oncogenic PIK3CA results in an increase in arachidonic acid and a concomitant overproduction of eicosanoids, acting to promote cell proliferation beyond a cell-autonomous manner. Mechanistically, mutant PIK3CA drives a multimodal signaling network involving mTORC2-PKCζ-mediated activation of the calcium-dependent phospholipase A2 (cPLA2). Notably, inhibiting cPLA2 synergizes with fatty acid-free diet to restore immunogenicity and selectively reduce mutant PIK3CA-induced tumorigenicity. Besides highlighting the potential for metabolic phenotyping in stratified medicine, this study reveals an important role for activated PI3K signaling in regulating arachidonic acid metabolism, uncovering a targetable metabolic vulnerability that largely depends on dietary fat restriction. VIDEO ABSTRACT

NOTCH1-mutated chronic lymphocytic leukemia displays high endoplasmic reticulum stress response with druggable potential

IntroductionConstitutive activation of NOTCH1-wild-type (NT1-WT) signaling is associated with poor outcomes in chronic lymphocytic leukemia (CLL), and NOTCH1 mutation (c.7541_7542delCT), which potentiates NOTCH1 signaling, worsens the prognosis. However, the specific mechanisms of NOTCH1 deregulation are still poorly understood. Accumulative evidence mentioned endoplasmic reticulum (ER) stress/unfolded protein response (UPR) as a key targetable pathway in CLL. In this study, we investigated the impact of NOTCH1 deregulation on CLL cell response to ER stress induction, with the aim of identifying new therapeutic opportunities for CLL.MethodsWe performed a bioinformatics analysis of NOTCH1-mutated (NT1-M) and NT1-WT CLL to identify differentially expressed genes (DEGs) using the rank product test. Quantitative real-time polymerase chain reaction (qPCR), Western blotting, cytosolic Ca2+, and annexin V/propidium iodide (PI) assay were used to detect curcumin ER stress induction effects. A median-effect equation was used for drug combination tests. The experimental mouse model Eμ-TCL1 was used to evaluate the impact of ER stress exacerbation by curcumin treatment on the progression of leukemic cells and NOTCH1 signaling.Results and discussionBioinformatics analysis revealed gene enrichment of the components of the ER stress/UPR pathway in NT1-M compared to those in NT1-WT CLL. Ectopic expression of NOTCH1 mutation upregulated the levels of ER stress response markers in the PGA1 CLL cell line. Primary NT1-M CLL was more sensitive to curcumin as documented by a significant perturbation in Ca2+ homeostasis and higher expression of ER stress/UPR markers compared to NT1-WT cells. It was also accompanied by a significantly higher apoptotic response mediated by C/EBP homologous protein (CHOP) expression, caspase 4 cleavage, and downregulation of NOTCH1 signaling in NT1-M CLL cells. Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells. In Eμ-TCL1 leukemic mice, the administration of curcumin activated ER stress in splenic B cells ex vivo and significantly reduced the percentage of CD19+/CD5+ cells infiltrating the spleen, liver, and bone marrow (BM). These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL

Evolutionary concepts in predicting and evaluating the impact of mass chemotherapy schistosomiasis control programmes on parasites and their hosts

Schistosomiasis is a parasitic disease of significant medical and veterinary importance in many regions of the world. Recent shifts in global health policy have led towards the implementation of mass chemotherapeutic control programmes at the national scale in previously ‘neglected’ countries such as those within sub-Saharan Africa. Evolutionary theory has an important role to play in the design, application and interpretation of such programmes. Whilst celebrating the rapid success achieved to date by such programmes, in terms of reduced infection prevalence, intensity and associated human morbidity, evolutionary change in response to drug selection pressure may be predicted under certain circumstances, particularly in terms of the development of potential drug resistance, evolutionary changes in parasite virulence, transmission and host use, and/or competitive interactions with co-infecting pathogens. Theoretical and empirical data gained to date serve to highlight the importance of careful monitoring and evaluation of parasites and their hosts whenever and wherever chemotherapy is applied and where parasite transmission remains

PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation

© 2017 The Authors. PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely un-known. Here we show that PARK2is altered in over a third of all human cancers, and its depletion results in enhanced phosphatidylinositol 3-kinase/Akt (PI3K/Akt) activation and increased vulnerability to PI3K/Akt/mTOR inhibitors. PARK2 depletion contributes to AMPK-mediated activation of endothelial nitricoxide synthase (eNOS), enhanced levels of reactiveoxygen species, and a concomitant increase inoxidized nitric oxide levels, thereby promoting theinhibition of PTEN by S-nitrosylation and ubiquitination. Notably, AMPK activation alone is sufficient to induce PTEN S-nitrosylation in the absence of PARK2 depletion. Park2 loss and Pten loss also display striking cooperativity to promote tumorigenesis in vivo. Together, our findings reveal an important missing mechanism that might account for PTEN suppression in PARK2-deficient tumors, and they highlight the importance of PTEN S-nitrosylationin supporting cell survival and proliferation under conditions of energy deprivation.NIH P01-CA120964 (J.M.A. and L.C.C.) and R01-GM041890; Ministry of Education, Culture and Sport under the Program for Promoting and Hiring of Talent and its Employability (Subprogram for Mobility) of the Spanish Government; ICR; MRC grant MC_UP_1202/1

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Envejecimiento y restricción calórica: diferencias entre géneros en las adaptaciones del metabolismo energético

[spa] El principal objetivo de la presente tesis fue el estudio de las diferencias de género en la función mitocondrial en respuesta a la restricción calórica y al envejecimiento en dos tejidos clave en el control del balance energético, el tejido adiposo marrón (TAM), principal efector de la termogénesis facultativa, y el hígado, órgano clave en el metabolismo intermediario. Los resultados obtenidos en la presente tesis demuestran diferencias de género en ratas jóvenes en las adaptaciones del metabolismo energético, particularmente en el TAM y el hígado, en respuesta a la restricción calórica. El deterioro de la capacidad termogénica asociado al envejecimiento se ve afectado también por el género y la restricción calórica, teniendo esta última un efecto preventivo sobre la pérdida de la función mitocondrial en el TAM.[eng] The main objective of the current thesis was the study of gender differences in the response of mitochondrial function to caloric restriction and aging in two key tissues controlling energy balance: brown adipose tissue (BAT), the main effector of facultative thermogenesis; and liver, a key organ in the intermediary metabolism. The results obtained in the current thesis demonstrate gender differences in the adaptations of energy metabolism in young rats, particularly in BAT and liver in response to caloric restriction. The functional decline in thermogenic capacity with age is also affected by gender and caloric restriction, with the latter having a preventive effect on the loss of mitochondrial function in BAT