Phosphatidylinositol 4-kinase IIIß mediates contraction-induced GLUT4 translocation and shows its anti-diabetic action in cardiomyocytes.

In the diabetic heart, long-chain fatty acid (LCFA) uptake is increased at the expense of glucose uptake. This metabolic shift ultimately leads to insulin resistance and a reduced cardiac function. Therefore, signaling kinases that mediate glucose uptake without simultaneously stimulating LCFA uptake could be considered attractive anti-diabetic targets. Phosphatidylinositol-4-kinase-IIIß (PI4KIIIß) is a lipid kinase downstream of protein kinase D1 (PKD1) that mediates Golgi-to-plasma membrane vesicular trafficking in HeLa-cells. In this study, we evaluated whether PI4KIIIß is involved in myocellular GLUT4 translocation induced by contraction or oligomycin (an F1F0-ATP synthase inhibitor that activates contraction-like signaling). Pharmacological targeting, with compound MI14, or genetic silencing of PI4KIIIß inhibited contraction/oligomycin-stimulated GLUT4 translocation and glucose uptake in cardiomyocytes but did not affect CD36 translocation nor LCFA uptake. Addition of the PI4KIIIß enzymatic reaction product phosphatidylinositol-4-phosphate restored oligomycin-stimulated glucose uptake in the presence of MI14. PI4KIIIß activation by PKD1 involves Ser294 phosphorylation and altered its localization with unchanged enzymatic activity. Adenoviral PI4KIIIß overexpression stimulated glucose uptake, but did not activate hypertrophic signaling, indicating that unlike PKD1, PI4KIIIß is selectively involved in GLUT4 translocation. Finally, PI4KIIIß overexpression prevented insulin resistance and contractile dysfunction in lipid-overexposed cardiomyocytes. Together, our studies identify PI4KIIIß as positive and selective regulator of GLUT4 translocation in response to contraction-like signaling, suggesting PI4KIIIß as a promising target to rescue defective glucose uptake in diabetics.

Tyrosine phosphorylation and Fcgamma receptor-mediated phagocytosis.

Phagocytosis of IgG-opsonized particulate material in hematopoietic cells is mediated by Fcgamma receptors (FcgammaRs). Interaction of the receptors with Fc domains of IgG triggers transduction of phagocytic signal in which a key role is played by phosphorylation of tyrosine residues of the receptors. These residues are arranged into a specific motif (immunoreceptor tyrosine-based activation motif; ITAM) which is located either in the cytoplasmic part of FcgammaRIIA or in gamma chains associated with FcgammaRI and FcgammaRIIIA. The conserved tyrosine residues are phosphorylated by, and associate with, tyrosine kinases of Src and Syk families. Coordinated action of these components initiates numerous intracellular events leading finally to local rearrangement of the actin-based cytoskeleton and internalization of the particles.

Mortality in the cotton industry workers: results of a cohort study.

The cohort consisted of persons found on the payroll of one of the Lódz cotton plants in 1964-1993 who were employed in the plant for at least 10 years. Death risk by causes was analysed using standardised mortality ratios (SMRs) calculated by the person-years method. The general population of Poland was used as the reference. In all, 7892 people were observed. As of December 31, 1995, the follow-up was completed for 7545 people (2852 men and 4693 women), i.e. the availability of the cohort was 95.6%. A total of 2069 deaths were recorded; the information on the cause of death was available for 97% of the subjects. In the male cohort, the level of the general mortality was the same as in the general population (SMR = 99). However, there was a significant increase in the number of deaths from diseases of the digestive system (SMR = 142) and larynx cancer (SMR = 188). The analysis of the results by production departments revealed in the weaving department significantly higher mortality from atherosclerosis (SMR = 141), peritoneal carcinoma (SMR = 1057) and melanoma (SMR = 677); and in the spinning department the increased risk of the hypertensive disease (SMR = 239), atherosclerosis (SMR = 175), and Hodgkin's disease (SMR = 768). Mortality in the female cohort was lower than that in the general population (SMR = 88). None of the disease groups or tumour sites caused statistically significant excess deaths either in the total cohort or in subcohorts selected according to departments. Special attention was paid to the chemical processing departments where chemicals used could contribute to the increased risk of death from cancer. Our analysis did not reveal any significant increase either in the total cohort of the workers employed in those departments or in the cohorts analyzed by duration of employment. Our results confirm the lower risk of lung cancer in the analysed group as compared with that in the general population. The numerous, but statistically insignificant increases in the incidence of malignant tumours at some specific sites detected in the subcohorts, distinguished according to the duration of employment or department, confirm the reported findings on the incidence of oral cavity, nose, throat, and larynx tumours among people exposed to harmful agents in the cotton industry.

Cancer mortality in rubber tire workers in Poland.

The study aimed at assessing cancer risk in a cohort of workers employed in the rubber tire production. The cohort consisted of 17,747 workers (11,660 men and 6087 women) employed in a rubber tire plant for at least three months during the years 1950-1995. The cohort follow-up was completed on December 31, 1995. Deaths by causes were analyzed using standardized mortality ratio (SMR) calculated by the person-years method. The mortality pattern of the general population of Poland was used as the reference. The study indicated significantly lower total mortality in the cohort (men: SMR = 72; women: SMR = 62) as compared to the general population, which is an example of a well known "healthy worker effect". The number of deaths from malignant neoplasms was also lower than expected (men: SMR = 67; women: SMR = 64). Only in a very small sub-cohort of men involved in dosing and mixing of raw material for the production of rubber, an excess of total mortality (SMR = 104) and from all cancers (SMR = 115) was found. Mortality from all neoplasms was enhanced (SMR = 108) in the sub-cohort of women employed in the technical service work area. When analyzing individual cancer sites in men of the whole cohort or sub-cohorts, the observed number of deaths from cancers of the lip, tongue, pharynx, stomach, gallbladder, pancreas, peritoneum, articular cartilage, connective tissue, skin, testis, prostate, bladder, kidney, brain, as well as from Hodgkin's disease, multiple myeloma and leukemia was larger than the expected number. Among women the excess mortality was due to cancers of the large myeloma and leukemia. The SMR calculated for these sites were statistically insignificant. The cohort under study was "young" and thus relatively small numbers of deaths were recorded. The excess mortality, based quite frequently on single cases of selected cancer sites, cannot be regarded as a basis for final conclusions. Nevertheless, the fact that these observations are in agreement with the findings of other authors who carried out studies in the rubber industry of other countries justifies the need to follow-up this cohort in the future.

[Exposure to carcinogens in industry. Evaluation of the situation and proposition of an information system]. / Zagrozenie substancjami rakotwórczymi w przemysle. Ocena sytuacji wraz a propozycja systemu informacyjnego.

This article presents an estimate of occupational exposure from carcinogens in the industrial plants belonging to the former departments of chemistry and light industry. The occurrence of 13 compounds listed as carcinogens in the list prepared in 1985 by the Chief Sanitary Inspector and 40 substances suspected of carcinogenic effects on the basis of the list prepared by the Institute of Occupational Medicine was taken into account. In the industries mentioned, 11 thousand persons were found to be exposed to the factors considered to be carcinogenic. The most numerous group constituted the employees working in contact with benzene (50%), vinyl chloride (19%), polycyclic aromatic hydrocarbons (17%) and asbestos (11%). A system of collection, analysis and qualitative evaluation of the information on exposure to those factors is necessary to enable efficient control of exposure to those factors. Basing on the experiences gained in the course of data collection and verification, the guidelines and documentation for "A System of Information on Carcinogenic Substances" presented in this article, have been prepared.

[Occupational neoplasms in Poland in the years 1971-1994]. / Nowotwory pochodzenia zawodowego w Polsce w latach 1971-1994.

The analysis of the incidence of malignant neoplasms, recognised as occupational disease, in Poland during the years 1971-94 was based on occupational disease certificates sent obligatory to the Nofer institute of Occupational Medicine (Lódz) by all sanitary and epidemiological stations under the Ministry of Health and Social Welfare and the Polish State Railways. During the period study 1118 occupational neoplasms were diagnosed, including 1042 cases (93.2%) of neoplasms in males. Among males malignant Ineoplasms of lung (36.1%), larynx (25.5%), bladder (14.7), skin (6%), lymphatic and haematopoietic tissue (3.4%) and pleura (2.9%) were most common. The rate occupational neoplasms in the total number of neoplasms registered accounted for 0.11% in males and 0.01% in females. PAH (29.1%), asbestos dust (18.8%), ionizing radiation (13.8%), chromium and its compounds (13.5%) and benzidine (9.8%) belong to the most frequent causes of malignant neoplasms in males, and ionizing radiation (31.5%) and asbestos dust (30.3%) in females. The number of neoplasms recognised as occupational disease is very low. Underestimation of occupational neoplasms is very common throughout the world, but it is particularly high in Poland if we take the incidence of pleura mesothelioma as an example. This is mainly due to: (1) the lack of clinical and morphological specificity of occupationally induced neoplasms; (2) a long latency; (3) the influence of other factors confounding the effect of occupational exposure; (4) a relatively small number of occupational carcinogens identified thus far; (5) limited knowledge of occupational carcinogens and criteria for occupational disease certification, and unsatisfactory interviewing skills among doctors who diagnose cancer disease. The identification of a harmful factor and the size of exposure to it, belongs to the weakest point in certifying the occupational background of the disease. The essential conclusions presented stress the urgent need for establishing the system facilitating the diagnosis and certification of occupational neoplasms.

[Mortality among workers of the rubber industry. III. Results of further observation of the male cohort]. / Umieralnosc wsród pracowników przemyslu gumowego. III. Wyniki dalszej obserwacji kohorty mezczyzn.

Mortality among workers of the rubber industry was assessed following the observation of the cohort comprised of 6,978 male workers who had started their employment in the plant producing rubber footwear during the years 1945-1973, and worked for, at least, three months. The condition of the cohort was assessed for December 31, 1990. Standardised mortality rate (SMR) was used as a measurement tool and it was calculated by means of the man-year method. The general population of Poland was taken as the reference population. General mortality in the cohort was significantly higher than in the reference population (2020 death, SMR = 110). Significant excess mortality due to atherosclerosis (205 deaths, SMR = 135) and cirrhosis of the liver (48 deaths, SMR = 170) was also noted. Total number of deaths due to malignant neoplasms-421-was slightly higher than expected. Significant excess of the bladder cancer (13 deaths, SMR = 357), the larynx cancer (23 deaths, SMR = 180) and the lung cancer (148 deaths, SMR = 122) was revealed. Significantly increased risk of the large intestine cancer (15 deaths, SMR = 242) was observed in the subcohort of workers employed in direct production departments.

[Mortality in the tire plant workers]. / Umieralnosc pracowników zakladu oponiarskiego.

This paper describes a cohort study of the mortality among workers employed in one of Polish tyre plants. The scope of the study was limited to the analysis of mortality from main disease categories. Mortality from particular cancer sites will be discussed in a separate publication. The cohort comprised 17,747 workers (11,660 men and 6,087 women) employed during the years 1950-95 for at least three months in the tyre plant. As of 31 December 1995, the follow-up of the cohort was completed. A detailed analysis of mortality by causes was carried out using standardised mortality ratio (SMR) calculated by the person-years method. The general population of Poland was used as the reference. The results indicated general mortality significantly lower in the cohort (men: SMR = 72; women: SMR = 62), than in the reference population. The number of observed deaths from main disease categories was also lower than those expected. The analysis by specific causes revealed significant excess of deaths, due to hypertensive disease among men (36 deaths, SMR = 142; 95% CI: 99-197). SMRs were also calculated in sub-cohorts identified by activities performed (preparatory works: production of tyres and inner tubes; maintenance; storage; others). General mortality in sub-cohorts was similar to that in the total cohort. After analysis by causes of death, some non-significant excess mortality could be observed. It was very small or it applied only to single cases of death. Excess mortality from hypertensive disease in male maintenance workers (21 deaths, SMR = 262; 95% CI: 162-400) was the only exception. The absence of adverse health effects pronounced by significant excess mortality should be attributed to a relatively short period of exposure among the majority of the followed-up workers (over 58% of workers in the cohort employed in the plant for a period shorter than five years) and to their young age. Almost 56% of workers in the cohort were born in the 1950s or later which means that at the end of the follow-up they were not older than 45 years. In order to complete the final mortality assessment the follow-up should continue.

Syk kinase, tyrosine-phosphorylated proteins and actin filaments accumulate at forming phagosomes during Fcgamma receptor-mediated phagocytosis.

Phagocytosis mediated by Fcgamma receptors (FcgammaRs) is thought to be regulated by a cascade of tyrosine phosphorylation events that finally leads to the rearrangement of submembranous actin-based cytoskeleton and internalization of particles. Suggestions concerning the functional relationship between protein tyrosine kinases, their substrates, and actin filament reorganization prompted us to determine cellular distribution of these elements during uptake of IgG-coated particles in murine thio-macrophages. We found that the onset of uptake of the particles was accompanied by tyrosine phosphorylation of several proteins, among which 90, 50, 40, 30, and 25 kDa polypeptides were distinguished. In most of the proteins the tyrosine hyperphosphorylation persisted up to 3 min of the uptake; however, kinetics of the phosphorylation of individual proteins varied. Immunofluorescence data showed that the phosphotyrosine-bearing proteins were localized in regions of the particle uptake, being concentrated at phagocytic cups and nascent phagosomes. The local enrichment in tyrosine phosphorylated proteins was correlated with accumulation of actin filaments at these early stages of phagosome formation. During phagosome maturation, both tyrosine phosphorylated proteins and microfilaments disappeared from the periphagosomal regions. Syk, one of the tyrosine kinases, was translocated to the regions where FcgammaR-mediated phagocytosis had started. On the contrary, no enrichment in phosphatidylinositol 3-kinase was detected in these places.