Sensitivity of Global Translation to mTOR Inhibition in REN Cells Depends on the Equilibrium between eIF4E and 4E-BP1

Initiation is the rate-limiting phase of protein synthesis, controlled by signaling pathways regulating the phosphorylation of translation factors. Initiation has three steps, 43S, 48S and 80S formation. 43S formation is repressed by eIF2α phosphorylation. The subsequent steps, 48S and 80S formation are enabled by growth factors. 48S relies on eIF4E-mediated assembly of eIF4F complex; 4E-BPs competitively displace eIF4E from eIF4F. Two pathways control eIF4F: 1) mTORc1 phosphorylates and inactivates 4E-BPs, leading to eIF4F formation; 2) the Ras-Mnk cascade phosphorylates eIF4E. We show that REN and NCI-H28 mesothelioma cells have constitutive activation of both pathways and maximal translation rate, in the absence of exogenous growth factors. Translation is rapidly abrogated by phosphorylation of eIF2α. Surprisingly, pharmacological inhibition of mTORc1 leads to the complete dephosphorylation of downstream targets, without changes in methionine incorporation. In addition, the combined administration of mTORc1 and MAPK/Mnk inhibitors has no additive effect. The inhibition of both mTORc1 and mTORc2 does not affect the metabolic rate. In spite of this, mTORc1 inhibition reduces eIF4F complex formation, and depresses translocation of TOP mRNAs on polysomes. Downregulation of eIF4E and overexpression of 4E-BP1 induce rapamycin sensitivity, suggesting that disruption of eIF4F complex, due to eIF4E modulation, competes with its recycling to ribosomes. These data suggest the existence of a dynamic equilibrium in which eIF4F is not essential for all mRNAs and is not displaced from translated mRNAs, before recycling to the next

Stable population structure in Europe since the Iron Age, despite high mobility

Ancient DNA research in the past decade has revealed that European population structure changed dramatically in the prehistoric period (14,000–3000 years before present, YBP), reflecting the widespread introduction of Neolithic farmer and Bronze Age Steppe ancestries. However, little is known about how population structure changed from the historical period onward (3000 YBP - present). To address this, we collected whole genomes from 204 individuals from Europe and the Mediterranean, many of which are the first historical period genomes from their region (e.g. Armenia and France). We found that most regions show remarkable inter-individual heterogeneity. At least 7% of historical individuals carry ancestry uncommon in the region where they were sampled, some indicating cross-Mediterranean contacts. Despite this high level of mobility, overall population structure across western Eurasia is relatively stable through the historical period up to the present, mirroring geography. We show that, under standard population genetics models with local panmixia, the observed level of dispersal would lead to a collapse of population structure. Persistent population structure thus suggests a lower effective migration rate than indicated by the observed dispersal. We hypothesize that this phenomenon can be explained by extensive transient dispersal arising from drastically improved transportation networks and the Roman Empire’s mobilization of people for trade, labor, and military. This work highlights the utility of ancient DNA in elucidating finer scale human population dynamics in recent history

Identification of novel therapeutic targets to selectively eliminate senescent cells in prostate cancer.

Despite recent progresses, prostate cancer (PC) is still the second most diagnosed cancer and the sixth leading cause of cancer death among men worldwide. Commonly used anticancer treatments to eradicate PC are based on chemotherapy and radiotherapy, with or without a castration-based strategy in which androgen deprivation is achieved by pharmacological or surgical castration. Efficacy of all these types of therapies also rely on their abilities to induces \u201cpremature\u201d senescence, a cellular state characterized by the irreversible arrest of cell growth that affects both normal and cancer proliferating cells. However, despite the proliferation block, senescent cells remain metabolically and synthetically active: indeed, they release many cytokines and chemokines known as senescence-associated secretory phenotype (SASP) able to affect nearby cells. In particular conditions, SASP may promote cellular proliferation and angiogenesis thus inducing tumour progression and invasiveness. For this reason, elimination of senescent cells from tumours can avoid cancer metastasis and relapse. In our study, starting from a proteomic and bioinformatic analysis of FDG-based FACS-sorted PTEN null murine prostate tumour cells, we identify membrane proteins upregulated on senescent population that can be exploited as potential targets for the development of new therapeutic strategy for senescent cells clearance

Spatial heterogeneity of occlusive thrombus in acute ischemic stroke: A systematic review

Following the advent of mechanical thrombectomy, occlusive clots in ischemic stroke have been amply characterized using conventional histopathology. Many studies have investigated the compositional variability of thrombi and the consequences of thrombus composition on treatment response. More recent evidence has emerged about the spatial heterogeneity of the clot or the preferential distribution of its components and compact nature. Here we review this emerging body of evidence, discuss its potential clinical implications, and propose the development of adequate characterization techniques

Neoadjuvant treatment of soft tissue sarcoma

PURPOSE: The aim of this study was to evaluate disease-free survival (DFS), overall survival and toxicity of patients who underwent preoperative therapy for soft tissue sarcoma. MATERIALS AND METHODS: The data of 38 consecutive patients affected by soft tissue sarcoma were retrospectively analysed. Six (15.8 %) patients were treated only with neoadjuvant radiotherapy, and 32 (84.2 %) with neoadjuvant chemo-radiation therapy. Surgery was performed within 4-6 weeks after the completion of neoadjuvant treatment. RESULTS: Median follow-up was 4.9 years (range 1-13.7 years). All patients received preoperative external beam radiotherapy (RT). Most patients (84.2 %) underwent neoadjuvant chemotherapy treatment associated with radiotherapy. After neoadjuvant treatment, the majority of patients underwent wide excision (32 out of 38) and five patients had marginal surgery; only one patient underwent amputation. Local recurrence was observed in only two patients (5.2 %). Fourteen (36.8 %) patients experienced metastatic relapse. At the time of our analysis 13 patients (34.2 %) had died due to metastatic spread of the disease. In our series, DFS in relation to distant metastases (DM) showed a significant result for lower limb involvement (p = 0.038) and marginal excision (p = 0.024), both predictors of a worse DFS, histology was statistically significant although it was not possible to evaluate the risk for specific histology due to the small number of events in the different subtypes. CONCLUSIONS: The results obtained from our study are encouraging with regard to the feasibility and efficacy of preoperative RT in the treatment of soft tissue sarcoma in view of the results obtained in terms of local control, limb sparing and safety