The Association between Vitamin D Receptor Expression and Prolonged Overall Survival in Breast Cancer.

Summary In this study, we analyzed vitamin D receptor (VDR) expression and survival in a breast cancer patient cohort of 82 breast cancer patients. Immunohistochemical analysis was possible in 91.5% of the patients (75/82). Staining was evaluated using the semi-quantitative assay according to Remmele and Stegner (immunoreactivity score [IRS]). IRS 0–1 was negative/very low, IRS 2–4 was moderate to high, and IRS 6–12 was high. Statistical analysis was performed by Spearman’s correlation test (p<0.05 significant). Overall survival was analyzed using Kaplan-Meier estimations. Only 6 patients had a negative IRS. Moderate IRS values were present in 20 patients. Most of the patients had a high IRS (49). For survival analysis, data were dichotomized (IRS 0–4: negative to moderate and IRS 6–12: high VDR expression). In univariate analysis, VDR expression showed significant differences in progression-free survival (PFS) and overall survival (OS). Patients with high IRS scores showed significantly better PFS and OS than patients with moderate/negative IRS scores for VDR expression. Tumor size was significantly correlated to PFS. When analyzed separately, the three different IRS groups showed significant differences in VDR expression. The present data suggest that VDR expression in breast cancer tissue may be of clinical significance, and the results provide evidence that VDR may be a factor with prognostic relevance. (J Histochem Cytochem 60:121–129, 2012). Keywords: breast cancer, vitamin D receptor, immunohistochemistry, prognosi

Deficiency of CCAAT/enhancer binding protein-epsilon reduces atherosclerotic lesions in LDLR-/- Mice

10.1371/journal.pone.0085341PLoS ONE91-POLN

Serum 25-hydroxyvitamin D levels in hospitalized adults with community-acquired pneumonia

Introduction: Community‐acquired pneumonia (CAP) is the infectious disease with the highest number of deaths worldwide. Several studies have shown an association between vitamin D deficiency and increases susceptibility to respiratory tract infections. Objective: The aim of this study was to evaluate the serum 25‐hydroxyvitamin D (25OHD) levels in hospitalized adults in general room with CAP. Materials and methods: An observational study was carried out in 207 hospitalized adults of both sex with CAP (>18 years) from Rosario city, Argentina (32° 52′ 18″S) between July 2015 and June 2016. Results: In total, 167 patients were included in the data analysis [59% women (57.4 ± 19.6 years), body mass index 27.2 ± 7.8 kg/m2]. In brief, 63% showed unilobar infiltrate and 37% were multilobar. The CURB‐65 index was 66.5% low risk, 16.0% intermediate risk and 17.5% high risk. According to Charlson comorbidity index (CCI) 53.5% had not comorbidity (CCI = 0) and 46.5% showed CCI ≥ 1. The 25OHD level was: 11.92 ± 7.6 ng/mL (51.5%: 30 ng/mL). Higher 25OHD were found in male (female: 10.8 ± 6.7 ng/mL, male: 13.5 ± 8.5 ng/mL, P = .02) and 25OHD correlated with age (r = –.17; P = .02). 25‐Hydroxyvitamin D was also correlated with CURB65 index (r = –.13; P = .049), CCI (r = –.20, P = .007) and with the 10 years of life expectative (%) (r = .19; P = .008). In addition, higher 25OHD were found with lower CCI (CCI 0 = 13.0 ± 8.2 ng/mL, CCI ≥ 1= 10.5 ± 6.7 ng/mL; P = .0093). Conclusions: Hospitalized adults with CAP have lower 25OHD levels and would be associated with the severity of CAP.Fil: Brance, María Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Laboratorio de Biología Ósea; ArgentinaFil: Miljevic, Julio Norberto. Provincia de Santa Fe. Municipalidad de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Tizziani, Raquel. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Provincia de Santa Fe. Municipalidad de Rosario; ArgentinaFil: Taberna, María E.. Provincia de Santa Fe. Municipalidad de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Grossi, Georgina P.. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Provincia de Santa Fe. Municipalidad de Rosario; ArgentinaFil: Toni, Pablo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Provincia de Santa Fe. Municipalidad de Rosario; ArgentinaFil: Valentini, Elina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Sanatorio de la Mujer; ArgentinaFil: Trepat, Andrea. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Sanatorio de la Mujer; ArgentinaFil: Zaccardi, Julia. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Hospital Español de Rosario; ArgentinaFil: Moro, Juan. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Hospital Español de Rosario; ArgentinaFil: Finuci Curi, Baltasar. Provincia de Santa Fe. Ministerio de Salud. Hospital Provincial de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Tamagnone, Norberto. Provincia de Santa Fe. Ministerio de Salud. Hospital Provincial de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Ramirez, Mariano. Sanatorio Plaza de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Severini, Javier. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Provincia de Santa Fe. Municipalidad de Rosario; ArgentinaFil: Chiarotti, Pablo Ignacio. Provincia de Santa Fe. Municipalidad de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Consiglio, Francisco. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Sanatorio Laprida de Rosario; ArgentinaFil: Piñeski, Raúl. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Sanatorio Laprida de Rosario; ArgentinaFil: Ghelfi, Albertina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Provincia de Santa Fe. Ministerio de Salud. Hospital Escuela "Eva Perón"; ArgentinaFil: Kilstein, Jorge Guillermo. Provincia de Santa Fe. Ministerio de Salud. Hospital Escuela "Eva Perón"; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Street, Eduardo. Hospital Rosendo García de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Moretti, Dino. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Sanatorio Delta de Rosario; ArgentinaFil: Oliveto, Viviana. Sanatorio Nuestra Señora del Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Mariño, Marcelo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Sanatorio Británico de Rosario; ArgentinaFil: Manera, Jorge. Sanatorio Británico de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; ArgentinaFil: Brun, Lucas Ricardo Martín. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentin

Vitamin D deficiency in human and murine sepsis

Objectives: Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and ICU mortality but causality of these associations has not been demonstrated. To determine whether sepsis and severe sepsis are associated with vitamin D deficiency and to determine whether vitamin D deficiency influences the severity of sepsis.  Design, Setting, and Patients: Sixty-one patients with sepsis and severe sepsis from two large U.K. hospitals and 20 healthy controls were recruited. Murine models of cecal ligation and puncture and intratracheal lipopolysaccharide were undertaken in normal and vitamin D deficient mice to address the issue of causality.  Measurements and Main Results: Patients with severe sepsis had significantly lower concentrations of 25-hydroxyvitamin D3 than patients with either mild sepsis or age-matched healthy controls (15.7 vs 49.5 vs 66.5 nmol/L; p = 0.0001). 25-hydroxyvitamin D3 concentrations were significantly lower in patients who had positive microbiologic culture than those who were culture negative (p = 0.0023) as well as those who died within 30 days of hospital admission (p = 0.025). Vitamin D deficiency in murine sepsis was associated with increased peritoneal (p = 0.037), systemic (p = 0.019), and bronchoalveolar lavage (p = 0.011) quantitative bacterial culture. This was associated with reduced local expression of the cathelicidin-related antimicrobial peptide as well as evidence of defective macrophage phagocytosis (p = 0.029). In the intratracheal lipopolysaccharide model, 1,500 IU of intraperitoneal cholecalciferol treatment 6 hours postinjury reduced alveolar inflammation, cellular damage, and hypoxia.  Conclusions: Vitamin D deficiency is common in severe sepsis. This appears to contribute to the development of the condition in clinically relevant murine models and approaches to correct vitamin D deficiency in patients with sepsis should be developed

Calcifediol-loaded liposomes for local treatment of pulmonary bacterial infections.

The influence of vitamin D3 and its metabolites calcifediol (25(OH)D) and calcitriol on immune regulation and inflammation is well described, and raises the question of potential benefit against bacterial infections. In the current study, 25(OH)D was encapsulated in liposomes to enable aerosolisation, and tested for the ability to prevent pulmonary infection by Pseudomonas aeruginosa. Prepared 25(OH)D-loaded liposomes were nanosized and monodisperse, with a negative surface charge and a 25(OH)D entrapment efficiency of approximately 23%. Jet nebulisation of liposomes was seen to yield an aerosol suitable for tracheo-bronchial deposition. Interestingly, 25(OH)D in either liposomes or ethanolic solution had no effect on the release of the proinflammatory cytokine KC from Pseudomonas-infected murine epithelial cells (LA-4); treatment of infected, human bronchial 16-HBE cells with 25(OH)D liposomes however resulted in a significant reduction in bacterial survival. Together with the importance of selecting an application-appropriate in vitro model, the current study illustrates the feasibility and practicality of employing liposomes as a means to achieve 25(OH)D lung deposition. 25(OH)D-loaded liposomes further demonstrated promising effects regarding prevention of Pseudomonas infection in human bronchial epithelial cells

Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates

BackgroundAbout 45% of the human genome is comprised of mobile transposable elements or "junk DNA". The exaptation or co-option of these elements to provide important cellular functions is hypothesized to have played a powerful force in evolution; however, proven examples are rare. An ancient primate-specific Alu short interspersed element (SINE) put the human CAMP gene under the regulation of the vitamin D pathway by providing a perfect vitamin D receptor binding element (VDRE) in its promoter. Subsequent studies demonstrated that the vitamin D-cathelicidin pathway may be a key component of a novel innate immune response of human to infection. The lack of evolutionary conservation in non-primate mammals suggested that this is a primate-specific adaptation. Evidence for evolutionary conservation of this regulation in additional primate lineages would provide strong evidence that the TLR2/1-vitamin D-cathelicidin pathway evolved as a biologically important immune response mechanism protecting human and non-human primates against infection.ResultsPCR-based amplification of the Alu SINE from human and non-human primate genomic DNA and subsequent sequence analysis, revealed perfect structural conservation of the VDRE in all primates examined. Reporter gene studies and induction of the endogenous CAMP gene in Rhesus macaque peripheral blood mononuclear cells demonstrated that the VDREs were conserved functionally. In addition, New World monkeys (NWMs) have maintained additional, functional steroid-hormone receptor binding sites in the AluSx SINE that confer retinoic acid responsiveness and provide potential thyroid hormone receptor binding sites. These sites were less well-conserved during human, ape and Old World monkey (OWM) evolution and the human CAMP gene does not respond to either retinoic acid or thyroid hormone.ConclusionWe demonstrated that the VDRE in the CAMP gene originated from the exaptation of an AluSx SINE in the lineage leading to humans, apes, OWMs and NWMs and remained under purifying selection for the last 55-60 million years. We present convincing evidence of an evolutionarily fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals. Evolutionary selection to place the primate CAMP gene under regulation of the vitamin D pathway potentiates the innate immune response and may counter the anti-inflammatory properties of vitamin D

Cation Exchange Of 1,2,3-Trizole Metal-Organic Frameworks

27 pagesCation exchange of various metal salts into cadmium triazolate was explored using methods outlined by Dr. Mircea Dincǎ, modified for a shorter reaction time. Products were structurally analyzed using PXRD analysis. Cation exchange products maintained the cadmium triazolate structure apart from copper. Several other metal salts would destroy the crystal structure at higher concentrations while copper would do the same at low concentrations. Solvent and temperature studies were done on the copper exchange reaction, determining that bulkier solvents can reduce the reaction energy while increasing reaction temperature had similar effects of increasing metal solvent concentration. Both UV-Vis-NIR analysis as well as SEM-EDX data suggests that our exchange reactions were successful with presence of cobalt and copper in their respective exchange reactions as well as changing metal characteristics in our exchange products

Chloroquine treatment of ARPE-19 cells leads to lysosome dilation and intracellular lipid accumulation: possible implications of lysosomal dysfunction in macular degeneration

Age-related macular degeneration (AMD) is the leading cause of vision loss in elderly people over 60. The pathogenesis is still unclear. It has been suggested that lysosomal stress may lead to drusen formation, a biomarker of AMD. In this study, ARPE-19 cells were treated with chloroquine to inhibit lysosomal function. Chloroquine-treated ARPE-19 cells demonstrate a marked increase in vacuolation and dense intracellular debris. These are identified as chloroquine-dilated lysosomes and lipid bodies with LAMP-2 and LipidTOX co-localization, respectively. Dilation is an indicator of lysosomal dysfunction. Chloroquine disrupts uptake of exogenously applied rhodamine-labeled dextran by these cells. This suggests a disruption in the phagocytic pathway. The increase in LAMP protein levels, as assessed by Western blots, suggests the possible involvement in autophagy. Oxidative stress with H2O2 does not induce vacuolation or lipid accumulation. These findings suggest a possible role for lysosomes in AMD. Chloroquine treatment of RPE cells may provide insights into the cellular mechanisms underlying AMD

Reply to "Overstated Claims of Efficacy and Safety. Comment On:Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections. Nutrients 2020, 12, 1181"

We thank Vorland et al [...