Body composition indices as predictors of humoral response to mRNA vaccination against COVID-19 in patients on maintenance hemodialysis.

INTRODUCTION: Patients on maintenance hemodialysis show lower serological response to mRNA vaccines. Main causes that contribute to this phenomenon are uremic milieu and older age. However, there are no data on the impact of body composition parameters to humoral response. MATERIALS AND METHODS: In this retrospective study, we used data from adult patients on maintenance hemodialysis who received vaccination with 2 doses of BNT162b2. Quantitative determination of antibodies to SARS-CoV-2 spike (S) protein receptor binding domain was performed using the Elecsys immunoassay. Antibody levels higher than 0.8 and 264 U/mL were considered positive and protective, respectively. Body composition parameters were assessed using multifrequency bioelectrical impedance spectroscopy. RESULTS: Overall, 49 patients were included in the study. Three weeks after the 1st vaccination, 34% of patients, and 3 weeks and 3 months after the 2nd vaccination, 100% of patients had detectable titers. Protective titer was developed in 43% of patients 3 weeks after the 2nd vaccination and then decreased to 24% 3 months after the 2nd vaccination. More years on dialysis were correlated to the absence of protective titers. Higher prediction marker values correlated to poor antibody response, and phase angle was negatively associated with the development of protective titers. Patients with protective titers at 3 months after the 2nd vaccination had significantly lower prediction marker and higher phase angle values. CONCLUSION: Parameters of body composition correlate and affect antibody response in patients on hemodialysis. The main observation is that immunogenicity of mRNA vaccines is influenced by phase angle and prediction marker.

Factors associated with anti-SARS-CoV-2 antibody titres 3 months post-vaccination with the second dose of BNT162b2 vaccine: a longitudinal observational cohort study in western Greece.

OBJECTIVES: Vaccination against SARS-CoV-2 has been extensively deployed during COVID-19 pandemic. One efficient method to evaluate response to vaccination is the assessment of humoral immunity by measuring SARS-CoV-2 antibody titres. We investigated the association between anthropometric parameters (age, body mass index), smoking, diabetes, statin use, hypertension, levels of 25(OH)D and dehydroepiandrosterone sulfate (DHEAS), and SARS-CoV-2 antibody titres after vaccination. DESIGN: In this longitudinal observational cohort study, 712 subjects were tested for SARS-CoV-2 antibodies 3 months after the second dose of BNT162b2 vaccine. Multiple linear regression analysis was performed to identify which factors are associated with the antibody titres. SETTING: Healthcare units of western Greece (University Hospital of Patras and "St Andrews" State General Hospital of Patras). PARTICIPANTS: All adults receiving their second dose of BNT162b2 vaccine at the participating healthcare units were eligible to participate in the study. Exclusion criteria were SARS-CoV-2 infection or positive SARS-CoV-2 antibody titre at baseline. Patients who did not provide all necessary information were excluded from our analyses. RESULTS: We found age to be negatively associated with antibody titre (-0.005; 95% CI -0.009 to -0.001, p=0.0073), as was male gender (-0.11; 95% CI -0.1738 to -0.04617, p=0.0008). The interaction of age and gender was significant (-0.01090; 95% CI -0.01631 to -0.005490, p<0.0001), highlighting that the rate of decline in antibody titre with increasing age tends to be higher in men rather than in women. No linear trend was found between DHEAS levels and antibody titres when the lower quartile of DHEAS levels was used as reference. Tobacco use was associated with low antibody titre (-0.1097; 95% CI -0.174 to -0.046, p=0.0008) but overweight, obese or underweight subjects had similar antibody responses to normal-weight individuals. Although subjects with diabetes and hypertension had numerically lower antibody titres, this association was not statistically significant. Vitamin D levels showed no clear relationships with antibody titres. CONCLUSIONS: Age, male gender and tobacco use are negatively associated with antibody titres after COVID-19 vaccination, but our data showed no clear correlation with vitamin D levels. TRIAL REGISTRATION NUMBER: NCT04954651; Results.

Nitric oxide stimulates migration of human endothelial and prostate cancer cells through up-regulation of pleiotrophin expression and its receptor protein tyrosine phosphatase beta/zeta.

Pleiotrophin (PTN) is a secreted growth factor involved in angiogenesis and tumor growth. We have recently shown that low concentrations of hydrogen peroxide (HP) stimulate PTN expression, through activation of the transcription factor AP-1. In the present work, we studied the possible involvement of endothelial nitric oxide synthase (eNOS) and the role of nitric oxide (NO) in the regulation of PTN expression, as well as involvement of the latter in the NO-induced human endothelial and prostate cancer cell migration. Inhibition of eNOS or the downstream effector soluble guanylate cyclase (sGC) completely suppressed HP-induced AP-1 activities that lead to PTN expression and cell migration. The NO donor sodium nitroprusside (SNP) through activation of sGC significantly and concentration-dependently increased expression of PTN, through transcriptional activation of the corresponding gene. Moreover, SNP had no effect on the migration of stably transfected prostate cancer cells that do not express PTN and knockdown of PTN receptor protein tyrosine phosphatase beta/zeta (RPTPbeta/zeta) completely abolished SNP-induced cell migration. NO added exogenously or produced endogenously by low concentrations of HP through stimulation of sGC activates extracellular signal-regulated kinase[1/2] (ERK[1/2]) and leads to PTN expression and cell migration. On the other hand, p38, which also intervenes in the up-regulation of PTN expression by low concentrations of HP, seems to act upstream of eNOS and does not intervene in the SNP-induced PTN expression and cell migration. The above data suggest that PTN through its receptor RPTPbeta/zeta is a mediator of the stimulatory effects of eNOS/NO on human endothelial and prostate cancer cell migration.

Heparin affin regulatory peptide/pleiotrophin negatively affects diverse biological activities in C6 glioma cells.

Heparin affin regulatory peptide (HARP) or pleiotrophin seems to be involved in the progression of several tumors of diverse origin. In this study, we tried to determine the role of HARP in rat C6 glioma cells by using an antisense strategy for inhibition of HARP expression. Decrease of the expression of endogenous HARP in C6 cells (AS-C6 cells) significantly increased proliferation, migration, and anchorage-independent growth of cells. Implantation of AS-C6 cells onto chicken embryo chorioallantoic membranes resulted in a significant increase of tumor-induced angiogenesis compared with that induced by non-transfected or C6 cells transfected with the plasmid alone (PC-C6 cells). In the same line, conditioned medium from AS-C6 cells significantly increased endothelial cell proliferation, migration, and tube formation in vitro compared with the effect of conditioned medium from C6 or PC-C6 cells. Interestingly, vascular endothelial growth factor (VEGF) induced C6 cell proliferation and migration, and SU1496, a selective inhibitor of VEGF receptor 2 (VEGFR2), blocked increased glioma cell growth, migration, and angiogenicity observed in AS-C6 cell cultures. The above results seem to be due to a direct interaction between HARP and VEGF in the culture medium of C6 and PC-C6 cells, while AS-C6 cells secreted comparable amounts of VEGF that do not interact with HARP. Collectively, these data suggest that HARP negatively affects diverse biological activities in C6 glioma cells, mainly due to binding of HARP to VEGF, which may sequester secreted VEGF from signalling through VEGFR2.

Amifostine protects blood vessels from the effects of ionizing radiation.

Amifostine (WR-2721) is a well-known radioprotective drug, selective for normal cells. The purpose of the present study was to define whether amifostine protects the vascular network from the effects of X-rays. We used the in vivo system of chicken embryo chorioallantoic membrane (CAM) as a model of angiogenesis. Amifostine reversed the early X-rays- induced decrease in the number of CAM blood vessels and reversed the early radiation-induced apoptosis of CAM cells. It also inhibited the increase in tyrosine nitration of actin and a-tubulin, which was observed 6 hours after CAM irradiation, when there was a significant decrease in non-protein SH groups. Furthermore, C6 rat glioma cells were inoculated on CAM and tumor growth, as well as tumor-induced angiogenesis, was estimated on haematoxylin-eosin-stained paraffin sections. Amifostine inhibited the post irradiation increase of C6 tumor-induced angiogenesis. These data suggest that amifostine protects CAM cells and blood vessels from the effects of X-rays, through mechanisms that do not depend solely on its free radical scavenging properties.

Irradiated C6 glioma cells induce angiogenesis in vivo and activate endothelial cells in vitro.

Malignant gliomas are angiogenesis dependent and present a remarkable degree of resistance to radiotherapy. In the present work, we studied the effect of irradiation of C6 glioma cells on their proliferation and activation in vitro and on glioma cell-induced angiogenesis in vivo and in vitro. Irradiation of C6 glioma cells decreased cell proliferation in a dose-dependent manner. Interestingly, metalloproteinase-2 and -9 expression and secretion, as well as integrin alpha(v) expression, increased with elevated doses of X rays 48 hr after irradiation and was mostly evident at the higher doses used. When pre-irradiated C6 cells were implanted on nonirradiated chicken embryo chorioallantoic membranes (CAMs), there was a significant dose-dependent increase in tumor induced angiogenesis, compared to angiogenesis induced by nonirradiated cells. Similar results were obtained when C6 cells were irradiated 48 hr after their inoculation onto nonirradiated CAMs. In the same line, conditioned medium from irradiated C6 cells significantly increased endothelial cell proliferation and migration in vitro, in a manner dependent on the dose of X rays. These results explain at least in part the low effectiveness of radiation therapy of malignant gliomas and support the notion that inhibition of angiogenesis in parallel with radiotherapy may represent a new therapeutic approach.