Calciprotein Particles Link Disturbed Mineral Homeostasis with Cardiovascular Disease by Causing Endothelial Dysfunction and Vascular Inflammation.

An association between high serum calcium/phosphate and cardiovascular events or death is well-established. However, a mechanistic explanation of this correlation is lacking. Here, we examined the role of calciprotein particles (CPPs), nanoscale bodies forming in the human blood upon its supersaturation with calcium and phosphate, in cardiovascular disease. The serum of patients with coronary artery disease or cerebrovascular disease displayed an increased propensity to form CPPs in combination with elevated ionised calcium as well as reduced albumin levels, altogether indicative of reduced Ca2+-binding capacity. Intravenous administration of CPPs to normolipidemic and normotensive Wistar rats provoked intimal hyperplasia and adventitial/perivascular inflammation in both balloon-injured and intact aortas in the absence of other cardiovascular risk factors. Upon the addition to primary human arterial endothelial cells, CPPs induced lysosome-dependent cell death, promoted the release of pro-inflammatory cytokines, stimulated leukocyte adhesion, and triggered endothelial-to-mesenchymal transition. We concluded that CPPs, which are formed in the blood as a result of altered mineral homeostasis, cause endothelial dysfunction and vascular inflammation, thereby contributing to the development of cardiovascular disease.

Apoptosis-mediated endothelial toxicity but not direct calcification or functional changes in anti-calcification proteins defines pathogenic effects of calcium phosphate bions.

Calcium phosphate bions (CPB) are biomimetic mineralo-organic nanoparticles which represent a physiological mechanism regulating the function, transport and disposal of calcium and phosphorus in the human body. We hypothesised that CPB may be pathogenic entities and even a cause of cardiovascular calcification. Here we revealed that CPB isolated from calcified atherosclerotic plaques and artificially synthesised CPB are morphologically and chemically indistinguishable entities. Their formation is accelerated along with the increase in calcium salts-phosphates/serum concentration ratio. Experiments in vitro and in vivo showed that pathogenic effects of CPB are defined by apoptosis-mediated endothelial toxicity but not by direct tissue calcification or functional changes in anti-calcification proteins. Since the factors underlying the formation of CPB and their pathogenic mechanism closely resemble those responsible for atherosclerosis development, further research in this direction may help us to uncover triggers of this disease.

Mimiviridae, Marseilleviridae, and virophages as emerging human pathogens causing healthcare-associated infections.

AIM: During the last decade it became obvious that viruses belonging to Mimiviridae and Marseilleviridae families (order Megavirales), may be potential causative agents of pneumonia. Thus, we have performed a review of the association of Mimiviridae, Marseilleviridae, and virophages with pneumonia, particularly healthcare-associated pneumonia, and other infections of the respiratory tract. RESULTS AND DISCUSSION: According to the analysis of the published articles, viruses belonging to Mimiviridae family can be potential agents of both community-acquired and healthcare-associated pneumonia. In particular, these viruses may be associated with poor outcome in patients of intensive care units. The exact mechanism of their pathogenicity, however, still remains unclear. The discrepancies between the results obtained by serological and genomic methods could be explained by the high polymorphism of nucleotide sequences of Mimiviridae family representatives. Further investigations on the Mimiviridae pathogenicity and on the determination of Mimiviridae-caused pneumonia risk groups are required. However, the pathogenicity of the viruses belonging to Marseilleviridae family and virophages is unclear up to now.

Genetic predisposition to calcific aortic stenosis and mitral annular calcification.

Valvular calcification precedes the development of valvular stenosis and may represent an important early phenotype for valvular heart disease. It is known that development of valvular calcification is likely to occur among members of a family. However, the knowledge about the role of genomic predictive markers in valvular calcification is still elusive. Aims of this review are to assess the impact of gene polymorphisms on risk and severity of aortic stenosis and mitral annular calcification. According to the results of the investigations carried out, all polymorphisms may be divided into the three groups conferring the level of evidence of their association with valvular stenosis. It is possible to conclude that apoB (XbaI, rs1042031, and rs6725189), ACE (rs4340), IL10 (rs1800896 and rs1800872), and LPA (rs10455872) gene polymorphisms may be associated with valvular calcific stenosis with a relatively high level of evidence. A number of other polymorphisms, such as PvuII polymorphism within the ORα gene, rs1042636 polymorphism within the CaSR gene, rs3024491, rs3021094, rs1554286, and rs3024498 polymorphisms within the IL10 gene, rs662 polymorphism within the PON1 gene, rs2276288 polymorphism within the MYO7A gene, rs5194 polymorphism within the AGTR1 gene, rs2071307 polymorphism within the ELN gene, rs17659543 and rs13415097 polymorphisms within the IL1F9 gene may correlate with a risk of calcific valve stenosis with moderate level of evidence. Finally, rs1544410 polymorphism within the VDR gene, E2 and E4 alleles within the apoE gene, rs6254 polymorphism within the PTH gene, and rs1800871 polymorphism within the IL10 gene may be associated with aortic stenosis with low level of evidence.

Correlation between genetic polymorphisms within IL-1B and TLR4 genes and cancer risk in a Russian population: a case-control study.

In the last decade, a growing interest has been devoted to the evaluation of the impact of single nucleotide polymorphisms (SNP) on cancer risk. According to the results of multiple studies, among the genes that have a considerable influence on cancer risk are those encoding pattern recognition receptors, cytokines, and antioxidant defense enzymes. Nonetheless, the effect of numerous SNPs within these genes on cancer risk has been scarcely investigated. A case-control study of 401 cases and 300 sex- and age-matched controls was performed in order to explore the role of IL1B_1473G/C (rs1143623), SOD1_7958A/G (rs4998557), TLR4_1196C/T (rs4986791), IL10_1082A/G (rs1800896), IL17A_197G/A (rs2275913), and TLR4_896A/G (rs4986790) polymorphisms in the susceptibility to colorectal cancer (n = 244), gastric carcinoma (n = 72), and ovarian cancer (n = 85). The analysis revealed a significant relationship between the presence of heterozygous genotypes for IL1B_1473G/C and TLR4_896A/G polymorphisms and higher risk of rectal cancer (codominant model, OR = 1.67; 95% CI, 1.06-2.63; p = 0.048 and OR = 2.25; 95% CI, 1.26-4.02; p = 0.014, respectively). In addition, the variant G/G genotype of the IL10_1082A/G SNP was associated with a 2.5-fold increase in ovarian cancer risk with a borderline significance (codominant model, OR = 2.45; 95% CI, 1.14-5.25; p = 0.069). Similarly, the carriers of the C/T genotype for the TLR4_1196C/T polymorphism were more susceptible to rectal cancer with a borderline significance (codominant model, OR = 1.42; 95% CI, 0.80-2.51 p = 0.06). No statistically significant associations were found when stratifying the sample by subgroups of age, sex, and clinicopathological characteristics. Finally, we observed six combinations of haplotypes for the examined SNPs, each of which either profoundly increased or decreased cancer risk. The results from our study provided evidence that IL1B_1473G/C and TLR4_896A/G SNPs are implicated in rectal cancer development in a Russian population. Further research should be addressed to clarify the role of the abovementioned polymorphisms in cancer etiology.

Colorectal cancer risk factors among the population of South-East Siberia: a case-control study.

Colorectal cancer remains one of the most widespread malignancies in the world. However, there is a lack of comprehensive studies considering colorectal cancer risk factors among Russian populations, particularly in Siberia. The aim of this investigation was to determine the impact of various lifestyle, dietary, family, and socioeconomical factors on colorectal cancer risk in South-East Siberia. We recruited 185 Russian colorectal cancer cases and 210 gender-, age-, and ethnicity-matched asymptomatic controls with no history of any malignant tumor, using a specially designed questionnaire to obtain relevant information. After the statistical analysis, we defined several significant factors affecting colorectal cancer risk. Among these were smoking (OR=2.13, 95%CI=1.4- 3.24, P=0.0004), being overweight (BMI between 25-30, OR=2.45, 95%CI=1.49-4.03, P=0.0004), alcohol drinking (OR=8.73, 95%CI=5.49-13.87, P<0.0001), beer drinking (OR=9.24, 95%CI=5.14-16.61, P<0.0001), consumption of hard liquor (OR=9.37, 95%CI=5.92-14.82, P<0.0001), excessive red meat consumption (P<0.0001), excessive intake of red meat products (P<0.0001), excessive intake of dairy products (P<0.0001), excessive sour cream and cheese consumption (P<0.0001 and 0.0002, respectively), spicy food consumption (OR=2.87, 95%CI=1.9-4.33, P<0.0001), family history of gastrointestinal malignant tumors (OR=3.99, 95%CI=2.09-7.59, P<0.0001), and income exceeding twice the subsistence minimum (OR=5.34, 95%CI=3.35-8.53, P<0.0001). Certain factors, such as high concentration of salt in the food and precancerous colonic lesions, demonstrated borderline significance (OR=3.45, 95%CI=1.68-7.1, P=0.0008, and OR=5.25, 95%CI=1.94-14.22, P=0.001, respectively). Some factors were established as protective, like consumption of rye bread and both rye and wheat bread (OR=0.32, 95%CI=0.21-0.5, P<0,0001, and OR=0.07, 95%CI=0.02-0.21, P<0.0001, respectively), and also low concentration of salt in the food, although this was of borderline significance (OR=0.43, 95%CI=0.26-0.69, P=0.0006). ABO and Rhesus blood antigens were not associated with increased colorectal cancer risk. These results should be definitely applied for elaboration of programs of colorectal cancer prevention in Russia, particularly in Siberia.

Analysis of cancer incidence and mortality in the industrial region of South-East Siberia from 1991 through 2010.

Kemerovo is an industrial region of the Russian Federation characterized by highly developed mining, chemical, metallurgical and power industries. Many of the factories were closed down due to the socioeconomical crisis in the early 90's, and economic potential of the survivors has also decreased significantly. Paradoxically, this has led to the improvement of the ecological situation in the region and elimination of exposure to many chemical carcinogens. This factor, in combination with the improvement of oncological care, might be expected to have lead to a decline of cancer incidence and mortality in the region. To assess trends of cancer incidence and mortality in Kemerovo Region, we therefore carried out an analysis of relevant epidemiological data during 1991-2010. In fact, a significant increase of cancer incidence overall was revealed during 2001-2010. Male cancer incidence was significantly higher than female cancer incidence. Regarding gastric cancer incidence, statistically significant differences during 2001-2010 were found only for men, and male incidence exceeded female incidence. Concerning colorectal cancer incidence, it was lower during 2001-2005 and 2006-2010 as compared to the period of 1991-1996. Lung cancer incidence was significantly higher during 1991-2000 compared to 2001-2010. Among urban populations, cancer incidence was higher in comparison with rural population, but a gradual steady convergence of trends of cancer incidence among urban and rural populations was noted. Lung cancer, breast cancer, colorectal cancer, non-melanoma skin cancer, and gastric cancer are the most prevalent cancer forms in Kemerovo Region. There were no differences in cancer mortality between 2001-2005 and 2006-2010; however, male cancer mortality exceeded female cancer mortality. A similar situation was observed for gastric cancer, colorectal cancer, and lung cancer. Cancer mortality among urban populations exceeded mortality among rural population, for both genders. We suggest that these data can be used for development of modern programs of cancer prevention and early diagnostics in industrial regions of Siberia.

The role of calcifying nanoparticles in biology and medicine.

Calcifying nanoparticles (CNPs) (nanobacteria, nanobacteria-like particles, nanobes) were discovered over 25 years ago; nevertheless, their nature is still obscure. To date, nobody has been successful in credibly determining whether they are the smallest self-replicating life form on Earth, or whether they represent mineralo-protein complexes without any relation to living organisms. Proponents of both theories have a number of arguments in favor of the validity of their hypotheses. However, after epistemological analysis carried out in this review, all arguments used by proponents of the theory about the physicochemical model of CNP formation may be refuted on the basis of the performed investigations, and therefore published data suggest a biological nature of CNPs. The only obstacle to establish CNPs as living organisms is the absence of a fairly accurately sequenced genome at the present time. Moreover, it is clear that CNPs play an important role in etiopathogenesis of many diseases, and this association is independent from their nature. Consequently, emergence of CNPs in an organism is a pathological, not a physiological, process. The classification and new directions of further investigations devoted to the role of CNPs in biology and medicine are proposed.