Dual targeting of ptp1b and aldose reductase with marine drug phosphoeleganin: A promising strategy for treatment of type 2 diabetes

An in-depth study on the inhibitory mechanism on protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes, including analysis of the insulin signalling pathway, of phosphoeleganin, a marine-derived phosphorylated polyketide, was achieved. Phosphoeleganin was demonstrated to inhibit both enzymes, acting respectively as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, in silico docking analyses to evaluate the interaction mode of phosphoeleganin with both enzymes were performed. Interestingly, this study showed that phosphoeleganin is the first example of a dual inhibitor polyketide extracted from a marine invertebrate, and it could be used as a versatile scaffold structure for the synthesis of new designed multiple ligands

The FHP01 DDX3X helicase inhibitor exerts potent anti-tumor activity in vivo in breast cancer pre-clinical models

Inhibition of DDX3X expression or activity reduces proliferation in cells from various tumor tissues, in particular in breast cancer, and its expression often correlates to tumor aggressiveness. This makes DDX3X a prominent candidate for the design of drugs for novel personalized therapeutic strategies. Starting from an in silico drug discovery approach, a group of molecules has been selected by molecular docking at the RNA binding site of DDX3X. Here, the most promising among them, FHP01, was evaluated in breast cancer preclinical models. Specifically, FHP01 exhibited very effective antiproliferative and killing activity against different breast cancer cell types, among which those from triple-negative breast cancer (TNBC). Interestingly, FHP01 also inhibited WNT signaling, a key tumorigenic pathway already correlated to DDX3X functions in breast cancer model cell lines. Ultimately, FHP01 also caused a significant reduction, in vivo, in the growth of MDA MB 231- derived TNBC xenograft models. Importantly, FHP01 showed good bioavailability and no toxicity on normal peripheral blood mononuclear cells in vitro and on several mouse tissues in vivo. Overall, our data suggest that the use of FHP01 and its related compounds may represent a novel therapeutic approach with high potential against breast cancer, including the triple-negative subtype usually correlated to the most unfavorable outcomes because of the lack of available targeted therapies

Abdominal Adiposity Is Associated With Elevated C-Reactive Protein Independent of BMI in Healthy Nonobese People

Objective: There is debate over the most appropriate adiposity markers of obesityassociated health risks. We evaluated the relationship between fat distribution and highsensitivity C-reactive protein (hs-CRP), independent of total adiposity. Research design and methods : We studied 350 people with abdominal adiposity (waist-to-hip ratio (WHR) ≥0.9 in male and ≥0.85 in female subjects) and 199 control subjects (WHR< 0.9 in male and <0.85 in female subjects) matched for BMI and age. We measured hs-CRP and major cardiovascular risk factors. Results Participants with abdominal adiposity had BMI similar to that in control subjects (24.8 ±2.5 vs. 24.7 ±2.2 kg/m2, respectively), but significantly higher waist circumference (96.4 6.±0 vs. 83.3 ±6.7 cm; p < 0.01) and WHR (1.07 ± 0.08 vs. 0.85 ±0.05; p<0.001). Compared with the control subjects, participants with abdominal adiposity had an adverse cardiovascular risk factor profile, significantly higher hs-CRP (1.96 ±2.60 vs. 1.53 ± 1.74 mg/dl; p< 0.01), and a twofold prevalence of elevated CRP values (≥3 mg/dl). Conclusions In non obese people, moderate abdominal adiposity is associated with markers of subclinical inflammation independent of BMI

Medical expenditures associated with diabetes among youth with medicaid coverage

Background: Information on diabetes-related excess medical expenditures for youth is important to understand the magnitude of financial burden and to plan the health care resources needed for managing diabetes. However, diabetes-related excess medical expenditures for youth covered by Medicaid program have not been investigated recently. Objective: To estimate excess diabetes-related medical expenditures among youth aged below 20 years enrolled in Medicaid programs in the United States. Methods: We analyzed data from 2008 to 2012 MarketScan multistate Medicaid database for 6502 youths with diagnosed diabetes and 6502 propensity score matched youths without diabetes, enrolled in fee-for-service payment plans. We stratified analysis by Medicaid eligibility criteria (poverty or disability). We used 2-part regression models to estimate diabetes-related excess medical expenditures, adjusted for age, sex, race/ethnicity, year of claims, depression status, asthma status, and interaction terms. Results: For poverty-based Medicaid enrollees, estimated annual diabetes-related total medical expenditure was $9046 per person [$3681 (no diabetes) vs. $12,727 (diabetes); P<0001], of which 41.7$9944 per person ($14,149 vs.$24,093; P<0001), of which 41.5% was accounted for by prescription drugs, 31.3% by inpatient, and 27.3% by outpatient care. Conclusions: The per capita annual diabetes-related medical expenditures in youth covered by publicly financed Medicaid programs are substantial, which is larger among those with disabilities than without disabilities. Identifying cost-effective ways of managing diabetes in this vulnerable segment of the youth population is needed

Podoplanin drives dedifferentiation and amoeboid invasion of melanoma

Melanoma is an aggressive skin cancer developing from melanocytes, frequently resulting in metastatic disease. Melanoma cells utilize amoeboid migration as mode of local invasion. Amoeboid invasion is characterized by rounded cell morphology and high actomyosin contractility driven by Rho GTPase signalling. Migrastatic drugs targeting actin polymerization and contractility are therefore a promising treatment option for metastatic melanoma. To predict amoeboid invasion and metastatic potential, biomarkers functionally linked to contractility pathways are needed. The glycoprotein podoplanin drives actomyosin contractility in lymphoid fibroblasts and is overexpressed in many cancers. We show that podoplanin enhances amoeboid invasion in melanoma. Podoplanin expression in murine melanoma drives rounded cell morphology, increasing motility, and invasion in vivo. Podoplanin expression is increased in a subset of dedifferentiated human melanoma, and in vitro is sufficient to upregulate melanoma-associated marker Pou3f2/Brn2. Together, our data define podoplanin as a functional biomarker for dedifferentiated invasive melanoma and a promising migrastatic therapeutic target

Burden of Cardiovascular Risk Factors Over Time and Arterial Stiffness in Youth With Type 1 Diabetes Mellitus: The SEARCH for Diabetes in Youth Study

Background: The incidence of type 1 diabetes mellitus (T1DM) in children is increasing, resulting in higher burden of cardiovascular diseases due to diabetes mellitus–related vascular dysfunction. Methods and Results: We examined cardiovascular risk factors (CVRFs) and arterial parameters in 1809 youth with T1DM. Demographics, anthropometrics, blood pressure, and laboratory data were collected at T1DM onset and 5 years later. Pulse wave velocity and augmentation index were collected with tonometry. ANOVA or chi�square tests were used to test for differences in measures of arterial parameters by CVRF. Area under the curve of CVRFs was entered in general linear models to explore determinants of accelerate vascular aging. Participants at the time of arterial measurement were 17.6±4.5 years old, 50% female, 76% non�Hispanic white, and duration of T1DM was 7.8±1.9 years. Glycemic control was poor (glycated hemoglobin, 9.1±1.8%). All arterial parameters were higher in participants with glycated hemoglobin ≥9% and pulse wave velocity was higher with lower insulin sensitivity or longer duration of diabetes mellitus. Differences in arterial parameters were found by sex, age, and presence of obesity, hypertension, or dyslipidemia. In multivariable models, higher glycated hemoglobin, lower insulin sensitivity, body mass index, blood pressure, and lipid areas under the curve were associated with accelerated vascular aging. Conclusions: In young people with T1DM, persistent poor glycemic control and higher levels of traditional CVRFs are independently associated with arterial aging. Improving glycemic control and interventions to lower CVRFs may prevent future cardiovascular events in young individuals with T1DM

Usefulness and limitations of comprehensive characterization of mRNA splicing profiles in the definition of the clinical relevance of BRCA1/2 variants of uncertain significance

Highly penetrant variants of BRCA1/2 genes are involved in hereditary predisposition to breast and ovarian cancer. The detection of pathogenic BRCA variants has a considerable clinical impact, allowing appropriate cancer-risk management. However, a major drawback is represented by the identification of variants of uncertain significance (VUS). Many VUS potentially affect mRNA splicing, making transcript analysis an essential step for the definition of their pathogenicity. Here, we characterize the impact on splicing of ten BRCA1/2 variants. Aberrant splicing patterns were demonstrated for eight variants whose alternative transcripts were fully characterized. Different events were observed, including exon skipping, intron retention, and usage of de novo and cryptic splice sites. Transcripts with premature stop codons or in-frame loss of functionally important residues were generated. Partial/complete splicing effect and quantitative contribution of different isoforms were assessed, leading to variant classification according to Evidence-based Network for the Interpretation of Mutant Alleles (ENIGMA) consortium guidelines. Two variants could be classified as pathogenic and two as likely benign, while due to a partial splicing effect, six variants remained of uncertain significance. The association with an undefined tumor risk justifies caution in recommending aggressive risk-reduction treatments, but prevents the possibility of receiving personalized therapies with potential beneficial effect. This indicates the need for applying additional approaches for the analysis of variants resistant to classification by gene transcript analyses

Castel di Sangro-Scontrone field camp – structural and applied geomorphology

The Geomorphological Field Camp 2014 in the Castel di Sangro-Scontrone area is the result of geological and geomorphological teaching field work activities carried out in Central Italy by a group of 23 students attending the Structural Geomorphology and Applied Geomorphology courses (Master's Degree in Geological Science and Technology of the Università degli Studi ‘G. d'Annunzio’ Chieti-Pescara, Italy, Department of Engineering and Geology). The Field Camp 2014 was organized in May 2014, following regular classes held during the fall term. General activities for the field camp were developed over four main stages: (1) preliminary analysis of the regional geological and geomorphological setting of the area; (2) preliminary activities for the analysis of the local area (orography, hydrography and photogeology investigations, and geographical information system processing); (3) field work, focused on the analysis of a specific issue concerning structural geomorphology or applied geomorphology (e.g. landscape evolution, river channel change, landslide distribution, and flood hazard); and (4) post-field work production of the map. Finally, the fundamental role of field work in the analysis of landscape and in land management was outlined: indeed, the overall field camp enhanced the crucial role of field-based learning for young geomorphologists in order to acquire a strong sensitivity to geomorphological processes and landscape evolution