This study examines the role of MTHFR gene polymorphism (rs1801133) in women with lipedema (LIPPY) body composition parameters compared to a control group (CTRL).
We carried out a study on a sample ...of 45 LIPPY and 50 women as a CTRL. Body composition parameters were examined by Dual-energy X-ray Absorptiometry (DXA). A genetic test was performed for the MTHFR polymorphism (rs1801133, 677C>T) using a saliva sample for LIPPY and CTRL groups. Mann-Whitney tests evaluated statistically significant differences between four groups (carriers and non-carriers of the MTHFR polymorphism for LIPPY and CTRL groups) on anthropometric/body composition parameters to identify patterns.
LIPPY showed significantly higher (p<0.05) anthropometric parameters (weight, BMI, waist, abdominal, hip circumferences) and lower waist/hip ratio (p<0.05) compared to the CTRL group. The association between the polymorphism alleles related to the rs1801133 MTHFR gene and the body composition values LIPPY carriers (+) showed an increase in fat tissue of legs and fat region of legs percentage, arm's fat mass (g), leg's fat mass (g), and leg's lean mass (g) (p<0.05) compared to CTRL (+). Lean/fat arms and lean/fat legs were lower (p<0.05) in LIPPY (+) than in CTRL (+). In the LIPPY (+), the risk of developing the lipedema disease was 2.85 times higher (OR=2.85; p<0.05; 95% confidence interval = 0.842-8.625) with respect to LIPPY (-) and CTRL.
The presence or absence of MTHFR polymorphism offers predictive parameters that could better characterize women with lipedema based on the association between body composition and MTHFR presence.
Among the genes involved in obesity, the Fat mass and obesity-associated gene (FTO) is certainly one of the most known and the relation between FTO rs9939609 and BMI is highly discussed; ...nevertheless, data about its influence on body composition are limited.
We carried out a study on a sample of 1066 Italian subjects, whose body composition and FTO rs9939609 were analyzed.
We found significant relations between FTO with arm (p=0.01), abdomen (p=0.00), and trunk circumferences (p=0.00), BMI (p=0.01), FM% (p=0.00), and android FM% (p=0.01), whereas no relations were found between FTO and both gynoid fat and lean mass.
To conclude, the relation between FTO and BMI is confirmed and is related specifically with android FM%. These results indicated that FTO rs9939609 may be a genetic etiological factor for obesity. Indeed, the specificity for the android FM% would indicate FTO as an etiological factor in the development of cardiovascular diseases.
The aim of this study was to verify the effects of Italian Mediterranean Diet (IMD), consisting of organic versus conventional foods, on body composition, and biochemical parameters in a healthy ...individuals and in Chronic Kidney Disease (CKD) patients, in order to decrease cardiovascular diseases (CVD) risk factor and the progression of renal diseases.
After providing a written fully informed consent to the study, 150 Caucasian Italian men were recruited: 100 healthy male individuals (mean age 44,66+/-13,98 years; range 30-65 years) and 50 male CKD patients (mean age 46,25+/-5,97 years; range 42-54 years). These patients were affected by stage 2 and 3 of Chronic Renal Failure according to the K-DOQI 2003. Usual dietary intake and physical activity, during the previous 12 months were estimated by a semiquantitative food-frequency questionnaire. The following were measured at baseline and after consumption of conventional/organic 14 days IMD: Body mass index (BMI), Body composition, by Dual-X absorptiometry (DXA) scanner, total plasma homocysteine (tHcy), serum phosphorus, glycemia concentrations, lipid profile, and microalbuminuria.
A significant reduction of total homocysteine (tHcy) and phosphorus blood values were observed in the studied subjects. Body composition analysis by DXA highlighted high significant differences between conventional (T(0)) and organic diet (T(1)) for fat mass parameter, expressed as kilograms and as percentage (p<0.001). Improvement of lean body mass was observed in CDK patients (p=0.004).
Our study clearly demonstrates that the Italian Mediterranean Organic Diet (IMOD), according to the "Nicotera diet", was able to reduce tHcy, phosphorus, microalbuminuria levels and CVD risk in healthy individuals and in CDK patients.
Impairment of the immune response and aberrant expression of microRNAs are emerging hallmarks of tumour initiation/progression, in addition to driver gene mutations and epigenetic modifications. We ...performed a preliminary survey of independent adenoma and colorectal cancer (CRC) miRnoma data sets and, among the most dysregulated miRNAs, we selected miR-27a and disclosed that it is already upregulated in adenoma and further increases during the evolution to adenocarcinoma. To identify novel genes and pathways regulated by this miRNA, we employed a differential 2DE-DIGE proteome analysis. We showed that miR-27a modulates a group of proteins involved in MHC class I cell surface exposure and, mechanistically, demonstrated that calreticulin is a miR-27a direct target responsible for most downstream effects in epistasis experiments. In vitro miR-27a affected cell proliferation and angiogenesis; mouse xenografts of human CRC cell lines expressing different miR-27a levels confirmed the protein variations and recapitulated the cell growth and apoptosis effects. In vivo miR-27a inversely correlated with MHC class I molecules and calreticulin expression, CD8(+) T cells infiltration and cytotoxic activity (LAMP-1 exposure and perforin release). Tumours with high miR-27a, low calreticulin and CD8(+) T cells' infiltration were associated with distant metastasis and poor prognosis. Our data demonstrate that miR-27a acts as an oncomiRNA, represses MHC class I expression through calreticulin downregulation and affects tumour progression. These results may pave the way for better diagnosis, patient stratification and novel therapeutic approaches.
Lipid peroxidation has supposed as the major biochemical alteration underling oxidant-induced cell injury in stress including numerous diseases. One of the natural molecules know to prevent or retard ...oxidation is alpha-lipoic acid (LA) and, therefore, the lipoic acid/dihydrolipoic acid (LA/DHLA) redox couple has received considerable attention. Recent studies have highlighted the potential of free LA and DHLA as powerful metabolic antioxidants that are able to scavenge the reactive oxygen species, to recycle other antioxidants. Our aim was to investigate the beneficial effects of LA in the treatment of Italian pre-obese and obese subjects. We screened 1612 subjects for enrollment; of these, 1127 subjects (445 men and 682 women, 18-60 age) met enrolment criteria and were enrolled in the study. According to body mass index (BMI) the 53% was obese and the 43% was pre-obese. The subjects were treated for 4 month with 800 mg/day of LA. In pre-obese subject significant reduction (p<0.001) of weight (8%, both gender), BMI (2 points), blood pressure, and abdominal circumference (female 6 cm, male 7 cm) were observed. In obese subjects significant reductions (p<0.001) of weight (9%, both gender), BMI (female 3 point, male 4 point), blood pressure and abdominal circumference (female 9 cm, male 11 cm) were observed. Our study indicated that LA is an ideal antioxidant candidate for the therapy of obesity related diseases. Further clinical studies should be considered to highlight the role and efficacy of LA treatment.
Insulin resistance and obesity are intimately related to a chronic low grade systemic inflammation. Interleukin-6 (IL-6) may influence the pathogenesis of obesity-related diseases. The aim of this ...study is to investigate the effect of body's fat mass on the relationships between -174G/C IL-6 promoter gene polymorphism, IL-6 circulating level and insulin resistance. A population of 150 Caucasian women was studied, subdivided according to their body composition in non-obese (NW), Normal Weight Obese (NWO) and preobese-obese (OB). The NWO subjects were found in an intermediate position between the NW and OB subjects in terms of body weight, fat mass percentage (FM%), abdominal FAT%, hs-CRP and plasma triglyceride level. Fasting plasma IL-6 concentration was positively correlated with the homeostasis model assessment for insulin resistance (HOMA-IR) in all subjects analyzed (P=0.0014). In NWO and OB women a significantly increased IL-6 mean value was observed compared with NW subjects. In G/G population, the IL-6 plasma level of NWO and OB was significantly higher with respect to NW. No significant differences of IL-6 concentrations were observed in the three groups carrying G/C genotype. NWO and OB women homozygous for the allele C have significantly lower value of IL-6 with respect to NW subjects. IL-6 concentration was positively correlated with FM% in G/G (R(2)=0.397, P<0.001) and was negatively correlated in C/C (R(2)=0.459, P=0.002). No significant correlation was observed in G/C genotype (R(2)=0.041, P=0.173). In conclusion our study confirms that, at least in Italian Caucasian females, the FM% is a major determinant of an increase in IL-6 production and insulin resistance. -174 G/C IL-6 promoter polymorphism represents a marker which could help to identify, time in advance, "vulnerable" individuals at risk of age and obesity related diseases.
The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. Mutations in PIK3CA, the gene coding the p110α catalytic subunit of PI3K, are ...frequent in cancer and result in PI3K pathway activation. About 25% of HER2-positive breast cancers also carry PIK3CA mutations, known to confer resistance to anti-HER2 therapy. Here we report the preclinical characterization of MEN1611, a potent and selective orally available PI3K inhibitor, showing high activity against p110α mutant isoforms and sparing the δ isoform.
In vivo efficacy studies were evaluated through Tumour Volume Inhibition % (TVI%) and mRECIST criteria using cancer cell lines and patient-derived xenograft (PDX) models. Pathway activation and protein degradation analyses were performed by western blot and capillary electrophoresis immunoassay. Immune modulation was evaluated using murine macrophages differentiated in vitro.
Consistent with its mechanism of action, MEN1611 down-modulates the PI3K/AKT signaling as well as selected downstream targets, both in vitro and in vivo. MEN1611 acts synergistically when combined with trastuzumab in several HER2-positive PIK3CA-mutated breast cancer cell lines and patient-derived xenograft models. The in vivo efficacy in trastuzumab-resistant models is supported by a long-lasting antitumor activity, paralleled by mechanistic down-regulation of pharmacodynamic biomarkers. Moreover, MEN1611 showed the ability to induce a dose-dependent alpha-isoform depletion, and to modulate the macrophage polarization towards a pro-inflammatory phenotype, consistent with its capability to co-inhibit P110γ.
Overall, these preclinical data support the progression in the development of MEN1611 in breast cancer and pave the way to the B-Precise-01 clinical study, a multicentre phase Ib study.
NCT03767335.
Menarini Ricerche S.p.A.
Menarini Ricerche S.p.A.
A. Fiascarelli: Full / Part-time employment: Menarini RIcerche S.p.A. G. Merlino: Full / Part-time employment: Menarini Ricerche S.p.A. S. Capano: Full / Part-time employment: Menarini Ricerche S.p.A. A. Paoli: Full / Part-time employment: Menarini Ricerche S.p.A.. A. Bressan: Full / Part-time employment: Menarini Ricerche. M. Bigioni: Full / Part-time employment: Menarini Ricerche S.p.A.. M. Scaltriti: Advisory / Consultancy: Memorial Sloan-Kettering Cancer Center. J. Arribas: Advisory / Consultancy: Vall d’Hebron Institute of Oncology. C. Bernadó Morales: Advisory / Consultancy: Vall d’Hebron Institute of Oncology. A. Pellacani: Leadership role, Full / Part-time employment: Menarini Ricerche S.p.A.. M. Salerno: Leadership role, Full / Part-time employment: Menarini Ricerche. M. Binaschi: Leadership role, Full / Part-time employment: Menarini Ricerche S.p.A.
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