The Relationship Between Selected CNR1, MC4R, LEP, FTO and VDR Gene Polymorphisms and Several Basic Toxicological Parameters Among Persons Occupationally Exposed to Arsenic, Cadmium and Lead.

The purpose of this work was to assess the influence of selected CNR1, MC4R, LEP, FTO and VDR FOKI gene polymorphisms on blood and urine concentration markers of lead, cadmium and arsenic in a population directly exposed to these metals. Eighty-five people exposed to lead, arsenic and cadmium were qualified to take part in the study. Standard urine samples and 25mL of venous blood from each worker were collected to assay basic laboratory and toxicological markers as well as selected single nucleotide polymorphisms (SNPs) within CNR1-cannabinoid receptor 1 gene (rs806368, rs806381, rs1049353, rs12720071), MC4R-melanocortin 4 receptor gene (rs17782313), LEP-leptin promoter gene (rs7799039), FTO-alpha-ketoglutarate-dependent dioxygenase gene (rs9939609) and VDR-vitamin D receptor (rs10735810) genes. It appeared that, except for the MC4R SNP, all the other polymorphisms were found to be associated with various laboratory parameters. Arsenic concentration in urine was associated with all four CNR1 and LEP SNPs, while cadmium concentration in blood was affected by the VDR polymorphism. Moreover, some significant relationships were also observed between CNR1 rs1049353 and FTO rs9939609 gene variants and markers of lead exposure. These results imply SNPs within genes coding for proteins involved in development of metabolic syndrome may be of prognostic value for persons directly exposed to lead, cadmium and arsenic.

Novel engineered TRAIL-based chimeric protein strongly inhibits tumor growth and bypasses TRAIL resistance.

Targeting of the TRAIL-DR4/5 pathway was proposed as a promising approach for specific induction of apoptosis in cancer cells. Clinical trials, however, showed inadequate efficiency of TRAIL as a monotherapy. It is a widely held view that the application of multifunctional molecules or combination therapy may lead to substantial improvement. Here, we demonstrate the effectiveness and safety of a novel chimeric protein, AD-O51.4, which is a TRAIL equipped with positively charged VEGFA-derived effector peptides. The study was performed in multiple cancer cell line- and patient-derived xenografts. A pharmacokinetic profile was established in monkeys. AD-O51.4 strongly inhibits tumor growth, even leading to complete long-term tumor remission. Neither mice nor monkeys treated with AD-O51.4 demonstrate symptoms of drug toxicity. AD-O51.4 exhibits a satisfactory half-life in plasma and accumulates preferentially in tumors. The cellular mechanism of AD-O51.4 activity involves both cytotoxic effects in tumor cells and antiangiogenic effects on the endothelium. The presence of DRs in cancer cells is crucial for AD-O51.4-driven apoptosis execution. The TRAIL component of the fusion molecule serves as an apoptosis inducer and a cellular anchor for the effector peptides in TRAIL-sensitive and TRAIL-resistant cancer cells, respectively. The FADD-dependent pathway, however, seems to be not indispensable in death signal transduction; thus, AD-O51.4 is capable of bypassing the refractoriness of TRAIL. AD-O51.4-driven cell death, which exceeds TRAIL activity, is achieved due to the N-terminally fused polypeptide, containing VEGFA-derived effector peptides. The high anticancer efficiency of AD-O51.4 combined with its safety has led to the entry of AD-O51.4 into toxicological studies.

Quality of life and health behaviours of patients with tuberculosis - sex differences.

INTRODUCTION: Despite the introduction of effective antituberculosis drugs, tuberculosis (TB) is still a serious health problem and one of the most significant causes of death among infectious diseases. Current publications indicate an increase of tuberculosis cases among smokers, diabetics, malnurished subjects and those abusing alcohol and drugs. In the literature, there are only few studies raising the topic of the quality of life (QoL), stress management and health behaviour among patients with tuberculosis. The aim of this study was to evaluate QoL of patients with tuberculosis taking into account gender differences. In the study, the analysis of knowledge, health behaviour and stress management among TB patients depending on sex was carried out. MATERIAL AND METHODS: The study included 80 subjects diagnosed with TB (including 38 females) who were hospitalised at the Regional Hospital Centre of Kotlina Jeleniogórska, Medical Unit Wysoka Laka, Pulmonology and Phthisiology Department in Kowary between August 2012 and January 2013. The following questionnaires were used in the study: Mini-COPE - evaluating stress management, WHOQoL - assessing the quality of life of patients, IZZ - assessing health behaviour. RESULTS: A difference with regards to sociodemographic profile between females and males was observed. Half of the women surveyed were working (50% vs 19% of men), whereas half of men were entitled to unemployment benefit (50% vs 18.4% of women). More than half of women lived with their family (55.3%), whereas 47.6% of men lived alone. The majority of the subjects consumed alcohol occasionally (60.2% of women vs 45.2% of men), but as many as 31% of male patients vs 7.9% of females admitted that they consumed alcohol frequently. Among the respondents, people who consumed alcohol occasionally dominated (60.2% women vs. 45.2% of men), but as many as 31% of male patients vs. 7.9% of women admitted to consume alcohol frequently. Quality of life (QoL) assessment has shown no statistically significant differences between the sexes in this field. The respondents rated lowest their QoL in the physical domain, 12.4 ± 3.1 (12.9 ± 3.0 women vs. 11.8 ± 3.1 men) and 12.6 ± 2.4 in the environmental domain (13.1 ± 2.3 women vs 12.1± 2.4 men). Women received a higher rating of health behaviour on all subscales of the IZZ questionnaire, with the highest score in the prevention behaviour subscale (3.6 ± 0.7) and the lowest in the subscale of proper eating habits (3.1 ± 0.8). In men the highest score of health behaviour was observed in the subscale of positive mental attitude (3.1 ± 1.0) and the lowest in the subscale of proper eating habits (2.5 ± 0.8). CONCLUSIONS: 1. There are differences between sociodemographic profile of TB patients: women are younger, better educated, economically active and more likely to remain in relationships; 2. There is no difference in QoL of TB patients between the sexes, whereas there are differences in the strategies of stress management and in applied health behavior; 3. Differences between genders indicate the need for matching treatment and preventive action for different patients profiles based on the cooperation of doctors, social workers, therapists, and psychologists.

AD-O53.2--a novel recombinant fusion protein combining the activities of TRAIL/Apo2L and Smac/Diablo, overcomes resistance of human cancer cells to TRAIL/Apo2L.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors became promising molecules for selective targeting of tumor cells without affecting normal tissue. Unfortunately, cancer cells have developed a number of mechanisms that confer resistance to TRAIL\Apo2L-induced apoptosis, which substantiates the need for development of alternative therapeutic strategies. Here we present a recombinant variant of TRAIL\Apo2L peptide, named AD-O53.2, fused to the peptide-derived from Smac/Diablo protein-the natural inhibitor of the apoptotic X-linked IAP (XIAP) protein considered as a pro-apoptotic agent. The proposed mechanism of action for this construct involves specific targeting of the tumor by TRAIL\Apo2L followed by activation and internalization of pro-apoptotic peptide into the cancer cells. While in the cytoplasm , the Smac\Diablo peptide inhibits activity of X-linked IAP (XIAP) proteins and promotes caspase-mediated apoptosis. AD-O53.2 construct was expressed in E.coli and purified by Ion Exchange Chromatography (IEC). Derived protein was initially characterized by circular dichroism spectroscopy (CD), HPLC-SEC chromatography, surface plasmon resonance, protease activation and cell proliferation assays. Our Smac/Diablo-TRAIL fusion variant was tested against a panel of cancer cells (including lung, colorectal, pancreatic, liver, kidney and uterine) and showed a potent cytotoxic effect with the IC50 values in femtomolar range for the most sensitive cell lines, while it remained ineffective against non-transformed HUVEC cells as well as isolated normal human and rat hepatocytes. Importantly, the construct was well tolerated by animals and significantly reduced the rate of the tumor growth in colon and lung adenocarcinoma animal models.