Deletion of inositol hexakisphosphate kinase 1 (IP6K1) reduces cell migration and invasion, conferring protection from aerodigestive tract carcinoma in mice.

Inositol hexakisphosphate kinases (IP6Ks), a family of enzymes found in all eukaryotes, are responsible for the synthesis of 5-diphosphoinositol pentakisphosphate (5-IP7) from inositol hexakisphosphate (IP6). Three isoforms of IP6Ks are found in mammals, and gene deletions of each isoform lead to diverse, non-overlapping phenotypes in mice. Previous studies show a facilitatory role for IP6K2 in cell migration and invasion, properties that are essential for the early stages of tumorigenesis. However, IP6K2 also has an essential role in cancer cell apoptosis, and mice lacking this protein are more susceptible to the development of aerodigestive tract carcinoma upon treatment with the oral carcinogen 4-nitroquinoline-1-oxide (4NQO). Not much is known about the functions of the equally abundant and ubiquitously expressed IP6K1 isoform in cell migration, invasion and cancer progression. We conducted a gene expression analysis on mouse embryonic fibroblasts (MEFs) lacking IP6K1, revealing a role for this protein in cell receptor-extracellular matrix interactions that regulate actin cytoskeleton dynamics. Consequently, cells lacking IP6K1 manifest defects in adhesion-dependent signaling, evident by lower FAK and Paxillin activation, leading to reduced cell spreading and migration. Expression of active, but not inactive IP6K1 reverses migration defects in IP6K1 knockout MEFs, suggesting that 5-IP7 synthesis by IP6K1 promotes cell locomotion. Actin cytoskeleton remodeling and cell migration support the ability of cancer cells to achieve their complete oncogenic potential. Cancer cells with lower IP6K1 levels display reduced migration, invasion, and anchorage-independent growth. When fed an oral carcinogen, mice lacking IP6K1 show reduced progression from epithelial dysplasia to invasive carcinoma. Thus, our data reveal that like IP6K2, IP6K1 is also involved in early cytoskeleton remodeling events during cancer progression. However, unlike IP6K2, IP6K1 is essential for 4NQO-induced invasive carcinoma. Our study therefore uncovers similarities and differences in the roles of IP6K1 and IP6K2 in cancer progression, and we propose that an isoform-specific IP6K1 inhibitor may provide a novel route to suppress carcinogenesis.

Civil construction work: The unseen contributor to the occupational and global disease burden.

BACKGROUND: Construction industry is the second largest employment giving industry in India with many semi-skilled or unskilled workers taking up the occupation for livelihood without any training and proper guidance. AIM: To evaluate the pathogenic association of cement exposure to occupational contact dermatoses as evidenced by immune markers and to correlate their pulmonary functions with years of exposure to cement. SETTING AND DESIGN: This was a cross-sectional study conducted among randomly selected cement workers. Methods and material: Evaluation of socioeconomic status (SES) and years of exposure of cement workers was done using a questionnaire. Clinical examination of skin lesions and strip patch test with application of potassium dichromate on unexposed skin was performed. Results were interpreted after 48 hours. Absolute eosinophil count (AEC) and IgE levels measured, and spirometric evaluation was performed. STATISTICAL ANALYSIS: Analysis of variance and Pearson's correlation test were used for data analysis. P < 0.05 was considered to be statistically significant. RESULTS: Clinically, skin lesions were noticed in 51%, elevated AEC in 47%, and raised Anti IgE in 73%. Two participants developed positive reactions to the skin strip patch test. Duration of exposure to cement and SES were compared with clinical skin lesions. Spirometry result was normal in 81%, obstruction in 8%, restriction in 10%, and mixed pattern in 1%. Forced expiratory volume at 1.0 second, forced expiratory flow (25-75%), and  (PEFR) Peak Expiratory Flow Rate were markedly reduced with years of exposure. Workers who had greater skin lesions and with increase in exposure had increased AEC and IgE levels, although statistically not significant. CONCLUSIONS: Exposure to cement and poor SES is strongly correlated to increased prevalence of skin lesions and reduced pulmonary functions.

Inositol pyrophosphates regulate RNA polymerase I-mediated rRNA transcription in Saccharomyces cerevisiae.

Ribosome biogenesis is an essential cellular process regulated by the metabolic state of a cell. We examined whether inositol pyrophosphates, energy-rich derivatives of inositol that act as metabolic messengers, play a role in ribosome synthesis in the budding yeast, Saccharomyces cerevisiae. Yeast strains lacking the inositol hexakisphosphate (IP6) kinase Kcs1, which is required for the synthesis of inositol pyrophosphates, display increased sensitivity to translation inhibitors and decreased protein synthesis. These phenotypes are reversed on expression of enzymatically active Kcs1, but not on expression of the inactive form. The kcs1Δ yeast cells exhibit reduced levels of ribosome subunits, suggesting that they are defective in ribosome biogenesis. The rate of rRNA synthesis, the first step of ribosome biogenesis, is decreased in kcs1Δ yeast strains, suggesting that RNA polymerase I (Pol I) activity may be reduced in these cells. We determined that the Pol I subunits, A190, A43 and A34.5, can accept a ß-phosphate moiety from inositol pyrophosphates to undergo serine pyrophosphorylation. Although there is impaired rRNA synthesis in kcs1Δ yeast cells, we did not find any defect in recruitment of Pol I on rDNA, but observed that the rate of transcription elongation was compromised. Taken together, our findings highlight inositol pyrophosphates as novel regulators of rRNA transcription.

Study of the effect of stress on skeletal muscle function in geriatrics.

BACKGROUND: Old age is associated with weakness of skeletal muscles and decrease in muscle functions. Usually in old-age, people undergo wasting of muscles, so they are more prone for fall and fracture. It has been stated that stress and cognition has an impact on muscle functions. This study was intended to demonstrate the effect of stress in muscle function in geriatrics. METHODS: This was a cross sectional study done at a charitable home in Chennai sub urban. The geriatric males and females in the old age home were included in this study. Sixty-four subjects were included and the persons with previous history of musculo skeletal and neurological disorders were excluded. Anthropometric parameters were recorded Maximum Voluntary Contraction (MVC) and Endurance Time (ET) were measured by hand grip dynamometer. Perceived stress score was measured by perceived stress scale questionnaire. Muscle function parameters and stress score was compared. RESULTS: Sixty-four subjects were included in this study and it was found out that there is a negative correlation between MVC & stress which was statistically significant. (r = -0.0675, P = 0.000). Age with MVC & ET showed a mild negative correlation but it was not significant. CONCLUSION: Hormones released during stress have a negative metabolic effect in skeletal muscle. Stress can induce earlier decline in muscle strength which will eventually lead to fall and fracture. Therefore, stress should be viewed as an independent risk factor for disability and other co morbid conditions.

Predicted equations for pulmonary function in normal adolescent south Indian population.

Pulmonary functions are affected by variables like age, sex, height, weight, and geographic location. Our study aims to establish predicted, equations for pulmonary functions in normal South Indian adolescent population. 400 subjects were grouped into pre & peripubertal (10-14 years) and pubertal (15 to 18 years) age categories. Anthropometric data collected, PFT assessed using portable data logging Spirometer MIR II. Mean FVC and FEV1 values were 2.80 L, 2.49 L in boys and 2.34 L, 2.12 L in girls respectively. Predicted equations for both adolescent age groups were generated by using linear regression analysis. PFT were significantly different in both age categories in boys and girls. PFT increased with increasing age and significantly correlated with the anthropometric parameters. Region specific and age specific predicted equations for PFT are generated from this study.