Genetic predictors of weight loss in overweight and obese subjects

The aim of our study was to investigate a large cohort of overweight subjects consuming a homogeneous diet to identify the genetic factors associated with weight loss that could be used as predictive markers in weight loss interventions. We retrospectively recruited subjects (N = 788) aged over 18 years with a Body Mass Index (BMI) between 25 and 40 kg/m(2) who were treated at our lipid unit for at least one year from 2008 to 2016, and we also recruited a control group (168 patients) with normal BMIs. All participants received counselling from a nutritionist that included healthy diet and physical activity recommendations. We genotyped 25 single nucleotide variants (SNVs) in 25 genes that were previously associated with obesity and calculated genetic scores that were derived from 25 SNVs. The risk allele in CADM2 showed a higher frequency in overweight and obese subjects than in controls (p = 0.007). The mean follow-up duration was 5.58 +/- 2.68 years. Subjects with lower genetic scores showed greater weight loss during the follow-up period. The genetic score was the variable that best explained the variations in weight from the baseline. The genetic score explained 2.4% of weight change variance at one year and 1.6% of weight change variance at the end of the follow-up period after adjusting for baseline weight, sex, age and years of follow-up

Differential effects of the second SARS-CoV-2 mRNA vaccine dose on T cell immunity in naive and COVID-19 recovered individuals

The rapid development of mRNA-based vaccines against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) led to the design of accelerated vaccination schedules that have been extremely effective in naive individuals. While a two-dose immunization regimen with the BNT162b2 vaccine has been demonstrated to provide a 95% efficacy in naive individuals, the effects of the second vaccine dose in individuals who have previously recovered from natural SARS-CoV-2 infection has not been investigated in detail. In this study, we characterize SARS-CoV-2 spike-specific humoral and cellular immunity in naive and previously infected individuals during and after two doses of BNT162b2 vaccination. Our results demonstrate that, while the second dose increases both the humoral and cellular immunity in naive individuals, COVID-19 recovered individuals reach their peak of immunity after the first dose. These results suggests that a second dose, according to the current standard regimen of vaccination, may be not necessary in individuals previously infected with SARS-CoV-2.Funding: Research reported in this publication was supported in part by the National Cancer Institute of the NIH (5R01HD102614-02; R01CA249204 and R01CA248984) and an ISMMS seed fund to E.G. The authors gratefully acknowledge use of the services and facilities of the Tisch Cancer Institute supported by a NCI Cancer Center Support Grant (P30 CA196521). M.S. was supported by a NCI training grant (T32CA078207). This work was supported by an ISMMS seed fund to J.O.; Instituto de Salud Carlos III (COV20-00668) to R.C.R.; the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 research call COV20/00181) co-financed by the European Development Regional Fund ‘‘A way to achieve Europe’’ to E.P.; the Instituto de Salud Carlos III, Spain (COV20/00170); the Government of Cantabria, Spain (2020UIC22-PUB-0019) to M.L.H.; the Instituto de Salud Carlos III (PI16CIII/00012) to P.P.; the Fondo Social Europeo e Iniciativa de Empleo Juvenil YEI (Grant PEJ2018-004557-A) to M.P.E.; and by REDInREN 016/009/009 ISCIII. This project has received funding from the European Union Horizon 2020 research and innovation programs VACCELERATE and INsTRuCT under grant agreements 101037867 and 860003

A Novel, Single Algorithm Approach to Predict Acenocoumarol Dose Based on CYP2C9 and VKORC1 Allele Variants

The identification of CYP2C9 and VKORC1 genes has strongly stimulated the research on pharmacogenetics of coumarins in the last decade. We assessed the combined influence of CYP2C9 *2 and *3, and VKORC1 c.-1639G>A, 497C>G, and 1173C>T variants, on acenocoumarol dosage using a novel algorithm approach, in 193 outpatients who had achieved stable anticoagulation. We constructed an “acenocoumarol-dose genotype score” (AGS, maximum score = 100) based on the number of alleles associated with higher acenocoumarol dosage carried by each subject for each polymorphism. The mean AGS was higher in the high-dose (>28mg/week) compared with the low-dose (<7mg/week) group (mean(SEM) of 84.1±3.4 vs. 62.2±4.8, P = 0.008). An AGS>70 was associated with an increased odds ratio (OR) of requiring high acenocoumarol dosage (OR: 3.347; 95%CI: 1.112–10.075; P = 0.032). In summary, although more research is necessary in other patient cohorts, and this algorithm should be replicated in an independent sample, our data suggest that the AGS algorithm could be used to help discriminating patients requiring high acenocoumarol doses to achieve stable anti-coagulation

Differential effects of the second SARS-CoV-2 mRNA vaccine dose on T cell immunity in naive and COVID-19 recovered individuals

The rapid development of mRNA-based vaccines against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) led to the design of accelerated vaccination schedules that have been extremely effective in naive individuals. While a two-dose immunization regimen with the BNT162b2 vaccine has been demonstrated to provide a 95% efficacy in naive individuals, the effects of the second vaccine dose in individuals who have previously recovered from natural SARS-CoV-2 infection has not been investigated in detail. In this study, we characterize SARS-CoV-2 spike-specific humoral and cellular immunity in naive and previously infected individuals during and after two doses of BNT162b2 vaccination. Our results demonstrate that, while the second dose increases both the humoral and cellular immunity in naive individuals, COVID-19 recovered individuals reach their peak of immunity after the first dose. These results suggests that a second dose, according to the current standard regimen of vaccination, may be not necessary in individuals previously infected with SARS-CoV-2.Research reported in this publication was supported in part by the National Cancer Institute of the NIH (5R01HD102614-02; R01CA249204 and R01CA248984) and an ISMMS seed fund to E.G. The authors gratefully acknowledge use of the services and facilities of the Tisch Cancer Institute supported by a NCI Cancer Center Support Grant (P30 CA196521). M.S. was supported by a NCI training grant (T32CA078207). This work was supported by an ISMMS seed fund to J.O.; Instituto de Salud Carlos III (COV20-00668) to R.C.R.; the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 research call COV20/00181) co-financed by the European Development Regional Fund “A way to achieve Europe” to E.P.; the Instituto de Salud Carlos III, Spain (COV20/00170); the Government of Cantabria, Spain (2020UIC22-PUB-0019) to M.L.H.; the Instituto de Salud Carlos III (PI16CIII/00012) to P.P.; the Fondo Social Europeo e Iniciativa de Empleo Juvenil YEI (Grant PEJ2018-004557-A) to M.P.E.; and by REDInREN 016/009/009 ISCIII. This project has received funding from the European Union Horizon 2020 research and innovation programs VACCELERATE and INsTRuCT under grant agreements 101037867 and 860003.S

The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032)

Association between non-cholesterol sterol concentrations and Achilles tendon thickness in patients with genetic familial hypercholesterolemia

Abstract Background Familial hypercholesterolemia (FH) is a genetic disorder that result in abnormally high low-density lipoprotein cholesterol levels, markedly increased risk of coronary heart disease (CHD) and tendon xanthomas (TX). However, the clinical expression is highly variable. TX are present in other metabolic diseases that associate increased sterol concentration. If non-cholesterol sterols are involved in the development of TX in FH has not been analyzed. Methods Clinical and biochemical characteristics, non-cholesterol sterols concentrations and Aquilles tendon thickness were determined in subjects with genetic FH with (n = 63) and without (n = 40) TX. Student-t test o Mann–Whitney test were used accordingly. Categorical variables were compared using a Chi square test. ANOVA and Kruskal–Wallis tests were performed to multiple independent variables comparison. Post hoc adjusted comparisons were performed with Bonferroni correction when applicable. Correlations of parameters in selected groups were calculated applying the non-parametric Spearman correlation procedure. To identify variables associated with Achilles tendon thickness changes, multiple linear regression were applied. Results Patients with TX presented higher concentrations of non-cholesterol sterols in plasma than patients without xanthomas (P = 0.006 and 0.034, respectively). Furthermore, there was a significant association between 5α-cholestanol, β-sitosterol, desmosterol, 24S-hydroxycholesterol and 27-hydroxycholesterol concentrations and Achilles tendon thickness (p = 0.002, 0.012, 0.020, 0.045 and 0.040, respectively). Conclusions Our results indicate that non-cholesterol sterol concentrations are associated with the presence of TX. Since cholesterol and non-cholesterol sterols are present in the same lipoproteins, further studies would be needed to elucidate their potential role in the development of TX

MOESM1 of Association between non-cholesterol sterol concentrations and Achilles tendon thickness in patients with genetic familial hypercholesterolemia

Additional file 1: Table S1. Achilles tendon thickness association with serum non-cholesterol sterols concentrations adjusted by LDLc. Table S2. Achilles tendon thickness association with serum non-cholesterol sterols concentrations adjusted by total cholesterol