A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast

The mammalian tumor suppressor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), inhibits cell growth and survival by dephosphorylating phosphatidylinositol-(3,4,5)-trisphosphate (PI[3,4,5]P3). We have found a homologue of PTEN in the fission yeast, Schizosaccharomyces pombe (ptn1). This was an unexpected finding because yeast (S. pombe and Saccharomyces cerevisiae) lack the class I phosphoinositide 3-kinases that generate PI(3,4,5)P3 in higher eukaryotes. Indeed, PI(3,4,5)P3 has not been detected in yeast. Surprisingly, upon deletion of ptn1 in S. pombe, PI(3,4,5)P3 became detectable at levels comparable to those in mammalian cells, indicating that a pathway exists for synthesis of this lipid and that the S. pombe ptn1, like mammalian PTEN, suppresses PI(3,4,5)P3 levels. By examining various mutants, we show that synthesis of PI(3,4,5)P3 in S. pombe requires the class III phosphoinositide 3-kinase, vps34p, and the phosphatidylinositol-4-phosphate 5-kinase, its3p, but does not require the phosphatidylinositol-3-phosphate 5-kinase, fab1p. These studies suggest that a pathway for PI(3,4,5)P3 synthesis downstream of a class III phosphoinositide 3-kinase evolved before the appearance of class I phosphoinositide 3-kinases

Mortality inequalities measured by socioeconomic indicators in Brazil: a scoping review

OBJECTIVE Summarize the literature on the relationship between composite socioeconomic indicators and mortality in different geographical areas of Brazil. METHODS This scoping review included articles published between January 1, 2000, and August 31, 2020, retrieved by means of a bibliographic search carried out in the Medline, Scopus, Web of Science, and Lilacs databases. Studies reporting on the association between composite socioeconomic indicators and all-cause, or specific cause of death in any age group in different geographical areas were selected. The review summarized the measures constructed, their associations with the outcomes, and potential study limitations. RESULTS Of the 77 full texts that met the inclusion criteria, the study reviewed 24. The area level of composite socioeconomic indicators analyzed comprised municipalities (n = 6), districts (n = 5), census tracts (n = 4), state (n = 2), country (n = 2), and other areas (n = 5). Six studies used composite socioeconomic indicators such as the Human Development Index, Gross Domestic Product, and the Gini Index; the remaining 18 papers created their own socioeconomic measures based on sociodemographic and health indicators. Socioeconomic status was inversely associated with higher rates of all-cause mortality, external cause mortality, suicide, homicide, fetal and infant mortality, respiratory and circulatory diseases, stroke, infectious and parasitic diseases, malnutrition, gastroenteritis, and oropharyngeal cancer. Higher mortality rates due to colorectal cancer, leukemia, a general group of neoplasms, traffic accident, and suicide, in turn, were observed in less deprived areas and/or those with more significant socioeconomic development. Underreporting of death and differences in mortality coverage in Brazilian areas were cited as the main limitation. CONCLUSIONS Studies analyzed mortality inequalities in different geographical areas by means of composite socioeconomic indicators, showing that the association directions vary according to the mortality outcome. But studies on all-cause mortality and at the census tract level remain scarce. The results may guide the development of new composite socioeconomic indicators for use in mortality inequality analysis

Differentials in death count records by databases in Brazil in 2010

OBJECTIVE To compare the death counts from three sources of information on mortality available in Brazil in 2010, the Mortality Information System (SIM - Sistema de Informações sobre Mortalidade ), Civil Registration Statistic System (RC - Sistema de Estatísticas de Resgistro Civil ), and the 2010 Demographic Census at various geographical levels, and to confirm the association between municipal socioeconomic characteristics and the source which showed the highest death count. METHODS This is a descriptive and comparative study of raw data on deaths in the SIM, RC and 2010 Census databases, the latter held in Brazilian states and municipalities between August 2009 and July 2010. The percentage of municipalities was confirmed by the database showing the highest death count. The association between the source of the highest death count and socioeconomic indicators - the Índice de Privação Brasileiro (IBP – Brazilian Deprivation Index) and Índice de Desenvolvimento Humano Municipal (IHDM – Municipal Human Development Index) - was performed by bivariate choropleth and Moran Local Index of Spatial Association (LISA) cluster maps. RESULTS Confirmed that the SIM is the database with the highest number of deaths counted for all Brazilian macroregions, except the North, in which the highest coverage was from the 2010 Census. Based on the indicators proposed, in general, the Census showed a higher coverage of deaths than the SIM and the RC in the most deprived (highest IBP values) and less developed municipalities (lowest IDHM values) in the country. CONCLUSION The results highlight regional inequalities in how the databases chosen for this study cover death records, and the importance of maintaining the issue of mortality on the basic census questionnaire

Prodrug Strategy for PSMA-targeted Delivery of TGX-221 to Prostate Cancer Cells

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit. Recent studies showed that TGX-221 has anti-proliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles were significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than the naked drug, and the drug clearance rate was 17.5-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment

Retroviral expression of a kinase-defective IGF-I receptor suppresses growth and causes apoptosis of CHO and U87 cells in-vivo

BACKGROUND: Phosphatidylinositol-3,4,5-triphosphate (PtdInsP3) signaling is elevated in many tumors due to loss of the tumor suppressor PTEN, and leads to constitutive activation of Akt, a kinase involved in cell survival. Reintroduction of PTEN in cells suppresses transformation and tumorigenicity. While this approach works in-vitro, it may prove difficult to achieve in-vivo. In this study, we investigated whether inhibition of growth factor signaling would have the same effect as re-expression of PTEN. METHODS: Dominant negative IGF-I receptors were expressed in CHO and U87 cells by retroviral infection. Cell proliferation, transformation and tumor formation in athymic nude mice were assessed. RESULTS: Inhibition of IGF-IR signaling in a CHO cell model system by expression of a kinase-defective IGF-IR impairs proliferation, transformation and tumor growth. Reduction in tumor growth is associated with an increase in apoptosis in-vivo. The dominant-negative IGF-IRs also prevented growth of U87 PTEN-negative glioblastoma cells when injected into nude mice. Injection of an IGF-IR blocking antibody αIR3 into mice harboring parental U87 tumors inhibits tumor growth and increases apoptosis. CONCLUSION: Inhibition of an upstream growth factor signal prevents tumor growth of the U87 PTEN-deficient glioma to the same extent as re-introduction of PTEN. This result suggests that growth factor receptor inhibition may be an effective alternative therapy for PTEN-deficient tumors

A Comparison of Mathematical Models for Polarization of Single Eukaryotic Cells in Response to Guided Cues

Polarization, a primary step in the response of an individual eukaryotic cell to a spatial stimulus, has attracted numerous theoretical treatments complementing experimental studies in a variety of cell types. While the phenomenon itself is universal, details differ across cell types, and across classes of models that have been proposed. Most models address how symmetry breaking leads to polarization, some in abstract settings, others based on specific biochemistry. Here, we compare polarization in response to a stimulus (e.g., a chemoattractant) in cells typically used in experiments (yeast, amoebae, leukocytes, keratocytes, fibroblasts, and neurons), and, in parallel, responses of several prototypical models to typical stimulation protocols. We find that the diversity of cell behaviors is reflected by a diversity of models, and that some, but not all models, can account for amplification of stimulus, maintenance of polarity, adaptation, sensitivity to new signals, and robustness

Mortality inequalities measured by socioeconomic indicators in Brazil: a scoping review

Objective: Summarize the literature on the relationship between composite socioeconomic indicators and mortality in different geographical areas of Brazil. Methods: This scoping review included articles published between January 1, 2000, and August 31, 2020, retrieved by means of a bibliographic search carried out in the Medline, Scopus, Web of Science, and Lilacs databases. Studies reporting on the association between composite socioeconomic indicators and all-cause, or specific cause of death in any age group in different geographical areas were selected. The review summarized the measures constructed, their associations with the outcomes, and potential study limitations. Results: Of the 77 full texts that met the inclusion criteria, the study reviewed 24. The area level of composite socioeconomic indicators analyzed comprised municipalities (n = 6), districts (n = 5), census tracts (n = 4), state (n = 2), country (n = 2), and other areas (n = 5). Six studies used composite socioeconomic indicators such as the Human Development Index, Gross Domestic Product, and the Gini Index; the remaining 18 papers created their own socioeconomic measures based on sociodemographic and health indicators. Socioeconomic status was inversely associated with higher rates of all-cause mortality, external cause mortality, suicide, homicide, fetal and infant mortality, respiratory and circulatory diseases, stroke, infectious and parasitic diseases, malnutrition, gastroenteritis, and oropharyngeal cancer. Higher mortality rates due to colorectal cancer, leukemia, a general group of neoplasms, traffic accident, and suicide, in turn, were observed in less deprived areas and/or those with more significant socioeconomic development. Underreporting of death and differences in mortality coverage in Brazilian areas were cited as the main limitation. Conclusions: Studies analyzed mortality inequalities in different geographical areas by means of composite socioeconomic indicators, showing that the association directions vary according to the mortality outcome. But studies on all-cause mortality and at the census tract level remain scarce. The results may guide the development of new composite socioeconomic indicators for use in mortality inequality analysis

Differentials in death count records by databases in Brazil in 2010

Objective: To compare the death counts from three sources of information on mortality available in Brazil in 2010, the Mortality Information System (SIM – Sistema de Informações sobre Mortalidade ), Civil Registration Statistic System (RC – Sistema de Estatísticas de Resgistro Civil ), and the 2010 Demographic Census at various geographical levels, and to confirm the association between municipal socioeconomic characteristics and the source which showed the highest death count. Methods: This is a descriptive and comparative study of raw data on deaths in the SIM, RC and 2010 Census databases, the latter held in Brazilian states and municipalities between August 2009 and July 2010. The percentage of municipalities was confirmed by the database showing the highest death count. The association between the source of the highest death count and socioeconomic indicators – the Índice de Privação Brasileiro (IBP – Brazilian Deprivation Index) and Índice de Desenvolvimento Humano Municipal (IHDM – Municipal Human Development Index) – was performed by bivariate choropleth and Moran Local Index of Spatial Association (LISA) cluster maps. Results: Confirmed that the SIM is the database with the highest number of deaths counted for all Brazilian macroregions, except the North, in which the highest coverage was from the 2010 Census. Based on the indicators proposed, in general, the Census showed a higher coverage of deaths than the SIM and the RC in the most deprived (highest IBP values) and less developed municipalities (lowest IDHM values) in the country. Conclusion: The results highlight regional inequalities in how the databases chosen for this study cover death records, and the importance of maintaining the issue of mortality on the basic census questionnaire

Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoceptors

The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by β-adrenoceptors, in most species involving a strong β3-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of β-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to β-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in β-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and β-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder