Non-small cell lung cancer (NSCLC) accounts for ∼80% of all lung cancers. Although some advances in lung cancer therapy have been made, patient survival is still quite poor. Two microRNAs, miR-221 ...and miR-222, upregulated by the MET proto-oncogene, have been already described to enhance cell survival and to induce TNF-related apoptosis-inducing ligand (TRAIL) resistance in NSCLC cell lines, through the downregulation of p27(kip1), PTEN and TIMP3. Here, we further investigated this pathway and showed that miR-130a, expressed at low level in lung cancer cell lines, by targeting MET was able to reduce TRAIL resistance in NSCLC cells through the c-Jun-mediated downregulation of miR-221 and miR-222. Moreover, we found that miR-130a reduced migratory capacity of NSCLC. A better understanding of MET-miR-221 and 222 axis regulation in drug resistance is the key in developing new strategies in NSCLC therapy.
The deep waters of the western Mediterranean are known to have an almost constant trend towards higher salinity and temperature values since the 1950s. Recent observations have shown an acceleration ...of this tendency, which has been attributed by some authors to the effect of the propagation of the signal of the Eastern Mediterranean Transient, from east to west. From 2004 to 2006 five basin‐scale oceanographic cruises evidenced a relevant change in the deep structure of the western Mediterranean. In less than two years almost the whole deep basin has been filled with highly saline and warm new deep water, which substantially renewed the resident deep water. The paper shows evidence of the rapid basin‐wide extension of the event, giving insights into the origin and the propagation of the new deep water towards the basin interior and showing the evolution of the deep characteristics.
The therapeutic effects of the dopamine D2 receptor (D2R) agonist, bromocriptine, in type 2 diabetes (T2D) have been attributed to central nervous system actions. However, peripheral dopamine ...directly modulates glucose uptake in insulin-sensitive tissues and lipid metabolism in adipose tissue (AT). We hypothesized that the dopaminergic system may be impaired in the adipose tissue of patients with T2D and that the therapeutic actions of bromocriptine could involve the modulation of metabolism in this tissue.
The expression of dopamine receptors was evaluated in visceral AT samples from patients with obesity and stratified in several groups: insulin sensitive (IS); insulin resistance (IR) normoglycaemic; insulin resistant prediabetic; insulin resistant diabetic, according to Ox-HOMA2IR, fasting glycaemia and HbA1c levels. T2D Goto-Kakizaki rats (GK) were fed a high-caloric diet (HCD) for five months and treated with bromocriptine (10 mg/kg/day, i.p.) in the last month. The levels of dopaminergic system mediators and markers of insulin sensitivity and glucose and lipid metabolism were assessed in the peri-epididymal adipose tissue (pEWAT) and brown (BAT) adipose tissues, liver, and skeletal muscle.
Patients with IR presented a decreasing trend of DRD1 expression in the visceral adipose tissue, being correlated with the expression of UCP1, PPARA, and insulin receptor (INSR) independently of insulin resistance and body mass index. Although no differences were observed in DRD2, DRD4 expression was significantly decreased in patients with prediabetes and T2D. In HCD-fed diabetic rats, bromocriptine increased D1R and tyrosine hydroxylase (TH) levels in pEWAT and the liver. Besides reducing adiposity, bromocriptine restored GLUT4 and PPARγ levels in pEWAT, as well as postprandial InsR activation and postabsorptive activation of lipid oxidation pathways. A reduction of liver fat, GLUT2 levels and postprandial InsR and AMPK activation in the liver was observed. Increased insulin sensitivity and GLUT4 levels in BAT and an improvement of the overall metabolic status were observed.
Bromocriptine treatment remodels adipose tissue and the liver dopaminergic system, with increased D1R and TH levels, resulting in higher insulin sensitivity and catabolic function. Such effects may be involved in bromocriptine therapeutic effects, given the impaired expression of dopamine receptors in the visceral adipose tissue of IR patients, as well as the correlation of D1R expression with InsR and metabolic mediators.
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•Patients with insulin resistance have imbalanced VAT dopamine receptors expression.•Bromocriptine restored D1R and TH in pEWAT and the liver of an obese T2DM animal model.•Bromocriptine improves pEWAT insulin sensitivity and lipid oxidation pathways.•Peripheral modulation of the dopaminergic system may constitute a therapeutic target.
Age-related hearing loss (ARHL) is the most frequent sensory disorder in the elderly, affecting approximately one-third of people aged more than 65 years. Despite a large number of people affected, ...ARHL is still an area of unmet clinical needs, and only a few ARHL susceptibility genes have been detected so far.
In order to further investigate the genetics of ARHL, we analyzed a series of 46 ARHL candidate genes, selected according to previous Genome Wide Association Studies (GWAS) data, literature updates and animal models, in a large cohort of 464 Italian ARHL patients. We have filtered the variants according to a) pathogenicity prediction, b) allele frequency in public databases, c) allele frequency in an internal cohort of 113 healthy matched controls, and 81 healthy semi-supercentenarians. After data analysis, all the variants of interest have been tested by functional “in silico” or “in vitro” experiments (i.e., molecular dynamics simulations and protein translation analysis) to assess their pathogenic role, and the expression of the mutated genes have been checked in mouse or zebrafish inner ear.
This multi-step approach led to the characterization of a series of ultra-rare likely pathogenic variants in DCLK1, SLC28A3, CEP104, and PCDH20 genes, contributing to describe the first association of these genes with ARHL in humans.
These results provide essential insights on the understanding of the molecular bases of such a complex, heterogeneous and frequent disorder, unveiling new possible targets for the future development of innovative therapeutic and preventive approaches that could improve the quality of life of the millions of people affected worldwide.
Colorectal cancer (CRC) is a global health concern, and the incidence of early onset (EO) CRC, has an upward trend. This study delves into the genomic landscape of EO-CRC, specifically focusing on ...pediatric (PED) and young adult (YA) patients, comparing them with adult (AD) CRC. In this retrospective monocentric investigation, we performed targeted next-generation sequencing to compare the mutational profile of 38 EO-CRCs patients (eight PED and 30 YA) to those of a ‘control group’ consisting of 56 AD-CRCs. Our findings reveal distinct molecular profiles in EO-CRC, notably in the WNT and PI3K-AKT pathways. In pediatrics, we observed a significantly higher frequency of RNF43 mutations, whereas APC mutations were more prevalent in adult cases. These observations suggest age-related differences in the activation of the WNT pathway. Pathway and copy number variation analysis reveal that AD-CRC and YA-CRC have more similarities than the pediatric patients. PED shows a peculiar profile with CDK6 amplification and the enrichment of lysine degradation pathway. These findings may open doors for personalized therapies, such as PI3K-AKT pathway inhibitors or CDK6 inhibitors for pediatric patients. Additionally, the distinct molecular signatures of EO-CRC underscore the need for age-specific treatment strategies and precision medicine. This study emphasizes the importance of comprehensive molecular investigations in EO-CRCs, which can potentially improve diagnostic accuracy, prognosis, and therapeutic decisions for these patients. Collaboration between the pediatric and adult oncology community is fundamental to improve oncological outcomes for this rare and challenging pediatric tumor.
•Italian Taste is a large-scale study aimed at exploring influences on food choice.•IT explores the complex interplay of factors contributing to food preferences.•Genetic, physiological, personality, ...sociocultural factors are considered.•Associations among personality, attitudes, PROP, familiarity and liking are shown.
Food choice is influenced by many interacting factors in humans. Its multidimensional and complex nature is well recognized, particularly within the sensory and consumer food science field. However, the vast majority of the studies aimed at understanding determinants of food choices, preferences, and eating behaviours are affected by important limitations: the limited number of factors that are considered at once and the sample size. Furthermore, sensory and hedonic responses to actual food stimuli are often not included in such studies.
The Italian Taste project is a large-scale study (three thousand respondents in three years) launched by the Italian Sensory Science Society aimed at addressing these limitations by exploring the associations among a variety of measures – biological, genetic, physiological, psychological and personality-related, socio-cultural – describing the dimensions of food liking, preference, behaviour and choice, and their relevance in determining individual differences within a given food culture framework. In addition, the study includes also the collection of sensory and hedonic responses to actual food stimuli commonly consumed in Italy and prepared to elicit a variation in the strength (from weak to strong) of bitterness, sweetness, saltiness, sourness, pungency, umami and astringency.
The aims of the present paper are twofold. Firstly, the paper is aimed to illustrate the variables selected to explore the different dimensions of food choice and to report the experimental procedure adopted for data collection. Secondly, the paper is aimed at showing the potential of the Italian Taste dataset on the basis of the data collected in the first year of the project. For the purpose, we selected a small number of variables known to influence food choices from data collected in the first year of the project on 1225 individuals.
As new methods for multivariate analysis of genome wide association studies become available, it is important to be able to combine results from different cohorts in a meta-analysis. The R package ...MultiMeta provides an implementation of the inverse-variance-based method for meta-analysis, generalized to an n-dimensional setting.
The R package MultiMeta can be downloaded from CRAN.
dragana.vuckovic@burlo.trieste.it; vi1@sanger.ac.uk
Supplementary data are available at Bioinformatics online.
Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, ...pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC).
In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta’s phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases.
RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1–2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64–32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25–7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not.
Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.
Hydrological and current measurements, collected in the Tyrrhenian Sea during May–June 2004, are analyzed with an inverse box model (IBM) to establish the mean circulation patterns of the basin ...during spring 2004. These patterns are compared with those provided by a high‐resolution, primitive equation model (the Princeton ocean model, or POM) implemented over the area to simulate the mean basin circulation during the survey. The good agreement between the two circulation fields, despite the differences and the respective limitations of the employed methods, represents solid evidence for the reliability of the estimated dynamical structures. Moreover, the POM reveals the short spatial variability of the basin not always resolved by IBM because of the low spatial resolution of the in situ measurements. The comparative study indicates the Tyrrhenian basin as an extremely active region of the Mediterranean Sea, characterized by a rich mesoscale dynamics. This work provides, for the first time after more than 25 years, a novel qualitative assessment of the Tyrrhenian Sea spring circulation, together with a robust quantitative estimation of the water mass stream fluxes inside the basin and of the exchanges with the adjacent regions.
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