The effect of caspase-9 in the differentiation of SH-SY5Y cells.

Neuroblastoma is the most common solid malignant tumor in infants and young children. Its origin is the incompletely committed precursor cells from the autonomic nervous system. Neuroblastoma cells are multipotent cells with a high potency of differentiation into the neural cell types. Neural differentiation leads to the treatment of neuroblastoma by halting the cell and tumor growth and consequently its expansion. Caspases are a family of proteins involved in apoptosis and differentiation. The present study aimed to investigate the potential role of caspase-9 activation on the differentiation of the human neuroblastoma SH-SY5Y cells. Here we investigated the caspase-9 and 3/7 activity during 1,25-dihydroxycholecalciferol (D3)-mediated differentiation of SH-SY5Y cells and took advantage of the inducible caspase-9 system in putting out the differentiation of the neuroblastoma cells. D3-induced differentiation of the cells could lead to activation of caspase-9 and caspase-3/7, astrocyte-like morphology, and increased expression of Glial fibrillary acidic protein (GFAP). By using the inducible caspase-9 system, we showed differentiation of SH-SY5Y cells to astrocyte-like morphology and increased level of GFAP expression. Furthered studies using a specific caspase-9 inhibitor showed inhibition of differentiation mediated by D3 or caspase-9 to astrocyte-like cells. These results show the potency of caspase-9 to direct differentiation of the human neuroblastoma SH-SY5Y cells into cells showing an astrocyte-like morphology.

Human resources for health density and its associations with child and maternal mortality in the Islamic Republic of Iran.

BACKGROUND: The Family Physician and Social Protection Scheme for Iranian rural inhabitants was launched in June 2005 to improve physician density. To our knowledge, a comprehensive study of the impact of the Scheme on mortality-related health indicators has not been conducted. AIMS: To investigate the effects of health workforce density on maternal, neonatal, infant and under-5 mortality rates in rural areas of the Islamic Republic of Iran between 2005 and 2011. METHODS: We built mixed-effects Poisson regression models including mortality measures as response variables and physician and behvarz (community-based health worker) densities as independent variables, using data from the Iranian Vital Horoscope tool, annual Households Income and Expenditure Survey, and DTARH software. We also included population sizes, age of inhabitants, rate of urbanization, years of schooling, and wealth index in each district, as well as effect of time, as covariates. RESULTS: Physician density was significantly associated with child mortality rates (1.5%, 1.1% and 63.5% decrease in neonatal, under-5 and maternal mortality with a 1-unit increase in physician density per 1000 individuals). In the model built for infant mortality rate, physician density and behvarz densities were not significantly associated with this measure. CONCLUSIONS: Improving the distribution of family physicians was associated with lower child and maternal mortality. Improvements in behvarz densities were not associated with decrements in these rates, which probably calls for improvement in access to more professional health services and facilities.

Hepatocellular carcinoma incidence at national and provincial levels in Iran from 2000 to 2016: A meta-regression analysis.

BACKGROUND: The incidence of Hepatocellular carcinoma (HCC), the most common primary liver cancer with high mortality, is undergoing global change due to evolving risk factor profiles. We aimed to describe the epidemiologic incidence of HCC in Iran by sex, age, and geographical distribution from 2000 to 2016. METHODS: We used the Iran Cancer Registry to extract cancer incidence data and applied several statistical procedures to overcome the dataset's incompleteness and misclassifications. Using Spatio-temporal and random intercept mixed effect models, we imputed missing values for cancer incidence by sex, age, province, and year. Besides, we addressed case duplicates and geographical misalignments in the data. RESULTS: Age-standardized incidence rate (ASIR) increased 1.17 times from 0.57 (95% UI: 0.37-0.78) per 100,000 population in 2000 to 0.67 (0.50-0.85) in 2016. It had a 21.8% total percentage change increase during this time, with a 1.28 annual percentage change in both sexes. Male to female ASIR ratio was 1.51 in 2000 and 1.57 in 2016. Overall, after the age of 50 years, HCC incidence increased dramatically with age and increased from 1.19 (0.98-1.40) in the 50-55 age group to 6.65 (5.45-7.78) in the >85 age group. The geographical distribution of this cancer was higher in the central, southern, and southwestern regions of Iran. CONCLUSION: The HCC incidence rate increased from 2000 to 2016, with a more significant increase in subgroups such as men, individuals over 50 years of age, and the central, southern, and southwestern regions of the country. We recommend health planners and policymakers to adopt more preventive and screening strategies for high-risk populations and provinces in Iran.

National and provincial population-based incidence and mortality of skin cancer in Iran; 1990-2016.

PURPOSE: To estimate the national and provincial estimates of incidence, mortality and burden of skin cancer in Iran from 1990 to 2016. METHODS: The data for incidence and mortality rates were collected from the National and Subnational Burden of Diseases (NASBOD) project. We employed a two-stage spatiotemporal model to estimate cancer incidence based on sex, age, province and year. The national and subnational age and gender specific trends were calculated from 1990 to 2016. Mortality-to-incidence ratio (MIR) was considered as an indicator of cancer care quality. RESULTS: At the national level, the age standardized incidence rate (ASIR) of skin cancer decreased 1.29 times, from 23.6 (95% uncertainty interval [UI], 17.1-31.1) per 100 000 persons in 1990 to 18.2 (95% UI, 15.8-20.6) in 2016; a similar trend was seen in both males and females. The highest ASIR was seen in 2000. National estimates of the age standardized mortality rate (ASMR) steadily decreased from 2.8 per 100 000 persons (95% UI, 1.9-4.1) in 1990 to 0.2 (95% UI, 0.1-0.3) per 100 000 persons in 2015. The MIR decreased continuously from 1990 to 2015 in all provinces and among both genders. The age standardized rate of years of life lost also decreased 8.7 times, from 30.1 (95% UI, 20.2-45.1) in 1990 to 3.5 (95% UI, 2.3-5.3) in 2015. CONCLUSIONS: During the study period, skin cancer ASIR, ASMR and burden steadily decreased among the Iranian population. The declining MIR for all provinces from 1990 to 2015 was a proxy of early detection and high-quality medical care for skin cancer in Iran. These results can be beneficial to policymakers and health planners to make correct decisions and determine proper resource allocation.

Insight into blood pressure targets for universal coverage of hypertension services in Iran: the 2017 ACC/AHA versus JNC 8 hypertension guidelines.

BACKGROUND: We compared the prevalence, awareness, treatment, and control of hypertension in Iran based on two hypertension guidelines; the 2017 ACC/AHA -with an aggressive blood pressure target of 130/80 mmHg- and the commonly used JNC8 guideline cut-off of 140/90 mmHg. We shed light on the implications of the 2017 ACC/AHA for population subgroups and high-risk individuals who were eligible for non-pharmacologic and pharmacologic therapies. METHODS: Data was obtained from the Iran national STEPS 2016 study. Participants included 27,738 adults aged ≥25 years as a representative sample of Iranians. Regression models of survey design were used to examine the determinants of prevalence, awareness, treatment, and control of hypertension. RESULTS: The prevalence of hypertension based on JNC8 was 29.9% (95% CI: 29.2-30.6), which soared to 53.7% (52.9-54.4) based on the 2017 ACC/AHA. The percentage of awareness, treatment, and control were 59.2% (58.0-60.3), 80.2% (78.9-81.4), and 39.1% (37.4-40.7) based on JNC8, which dropped to 37.1% (36.2-38.0), 71.3% (69.9-72.7), and 19.6% (18.3-21.0), respectively, by applying the 2017 ACC/AHA. Based on the new guideline, adults aged 25-34 years had the largest increase in prevalence (from 7.3 to 30.7%). They also had the lowest awareness and treatment rate, contrary to the highest control rate (36.5%) between age groups. Compared with JNC8, based on the 2017 ACC/AHA, 24, 15, 17, and 11% more individuals with dyslipidaemia, high triglycerides, diabetes, and cardiovascular disease events, respectively, fell into the hypertensive category. Yet, based on the 2017 ACC/AHA, 68.2% of individuals falling into the hypertensive category were eligible for receiving pharmacologic therapy (versus 95.7% in JNC8). LDL cholesterol< 130 mg/dL, sufficient physical activity (Metabolic Equivalents≥600/week), and Body Mass Index were found to change blood pressure by - 3.56(- 4.38, - 2.74), - 2.04(- 2.58, - 1.50), and 0.48(0.42, 0.53) mmHg, respectively. CONCLUSIONS: Switching from JNC8 to 2017 ACC/AHA sharply increased the prevalence and drastically decreased the awareness, treatment, and control in Iran. Based on the 2017 ACC/AHA, more young adults and those with chronic comorbidities fell into the hypertensive category; these individuals might benefit from earlier interventions such as lifestyle modifications. The low control rate among individuals receiving treatment warrants a critical review of hypertension services.

The non-apoptotic role of caspase-9 promotes differentiation in leukemic cells.

Caspase family contains cysteine proteases involving in the key cellular processes, such as apoptosis, inflammation, and autophagy. There is a growing body of evidence that caspase family also plays a role in cellular differentiation. Evidence suggests that caspase-9 is among the most important members with non-apoptotic roles in the execution of differentiation. Since drug-induced differentiation in some types of cancer cells is a promising treatment, we have investigated caspase-9 activity during differentiation of a cancer cell; leukemia. We demonstrate that caspase-9 has increased activity during differentiation and also the inhibition of caspase-9 will prevent the granulocytic differentiation of leukemic cells. In addition, we studied the differentiation induction mediated by caspase-9 using an inducible variant of caspase-9. Results indicate the caspase-9 mediated differentiation accompanied by a reduction in the expression of CD33 and an increase in CD15. Notably, all of the events occur when cell viability remains constant. Owing to the evidence, caspase-9 activity is considered as a central factor in the execution of differentiation in leukemic cells.

Effects of the Human Amniotic Membrane on the Cartilage Graft: Prognosis and Absorption in White Rabbits.

BACKGROUND: Cartilage grafts are generally accepted for the restoration and reconstruction of nasal contours. The main concern that plastic surgeons may need to address after surgery pertains to the resorption and disfigurement of the grafted cartilage, especially in allogenic and heterogenic grafts. METHODS: A total of 12 white rabbits were divided into three groups according to the types of graft including autograft, allograft, and heterograft. We used three shapes of grafts, including block, crushed, and diced cartilage in the upper, middle, and lower rows. However, in each rabbit, these grafts were divided into two columns of wrapped and unwrapped grafts, with human amniotic membrane (HAM) grafted on each side of the rabbit's back. RESULTS: In total, 60 specimens underwent histopathological examination. No inflammation was observed in about 50% of the block-shaped conchal cartilages with HAM, and in 50%, less than 25 inflammatory cells per unit were seen. The prognosis and absorption of autograft specimens in block-shaped cartilages with HAM were significantly better compared with other shapes of cartilages with HAM and without HAM. The proliferation rate of fibroblasts in autograft and allograft specimens was more than that in heterograft specimens with HAM. CONCLUSION: Our findings have demonstrated the new role of HAM in clinical applications, indicating that HAM may be used as a low-cost, easily accessible alternative for wrapping in cartilage grafts instead of fascia or surgicel in early future. It is useful for improving the long-term outcomes and decreasing the resorption rate.

Economic Inequality in Life Satisfaction and Self-perceived Health in Iranian Children and Adolescents: The CASPIAN IV Study.

BACKGROUND: The purpose of this study was to assess socioeconomic status (SES) inequality in life satisfaction (LS) and good self-perceived health (SPH) in Iranian children and adolescents. METHODS: This nationwide study was conducted as part of a fourth national school-based surveillance program performed on 14880 students aged 6-18 years who were living in urban and rural areas of 30 provinces of Iran between 2011 and 2012. Using principle component analysis, the SES of participants was constructed as single variable. SES inequality in LS and good SPH across the SES quintiles was assessed using the concentration index (C) and slope index of inequality (SII). The determinants of this inequality are investigated by the Oaxaca Blinder decomposition method. RESULTS: Frequency of LS along with the SES quintiles shifted significantly from 73.28% (95% CI: 71.49, 75.08) in the lowest quintile to 86.57% (95% CI:85.20, 87.93) in the highest SES quintile. Frequency of favorable SPH linearly increased from lowest SES quintile (76.18% (95% CI: 74.45, 77.92)) to highest SES quintile (83.39% (95% CI: 81.89, 84.89)). C index for LS and good SPH was negative, which suggests inequality was in favor of high SES group. SII for LS and SPH was 15.73 (95% CI: 12.10, 19.35) and 8.21 (95% CI: 5.46, 10.96)]. Living area and passive smoking were the most contributed factors in SES inequality of LS. Also passive smoking and physical activity were the most contributed factors in SES inequality of SPH. CONCLUSIONS: SES inequality in LS and good SPH was in favor of high SES group. These findings are useful for health policies, better programming and future complementary analyses.

Caspases interplay with kinases and phosphatases to determine cell fate.

Cellular differentiation is one of the critical processes in the life of multicellular organisms. In this phenomenon, a non-specialized cell is converted to a specialized one with its own specific function and morphology. One of the requirements for specialization is silencing of the pathways involved in cell proliferation in parallel with turning on the molecular mechanisms involved in differentiation. Similar to other biological phenomena, the change in cellular state from the proliferative to the differentiated needs molecular switches to persuade the change in response to the internal or external inducers. The quiddity of these molecular switches has not been identified, yet. However, there exists a growing body of evidence showing that the same agents involved in apoptosis have a broad contribution to differentiation progression. To our knowledge, this evidence is still ambiguous because it has raised fundamental questions that require more proof to be answered. The most important questions are: How can two totally different cellular fates act through a similar pathway? What is the separating edge? What forces a cell to choose one of them (death or differentiation)? To address these issues, we will concentrate on three groups of molecules; caspases as the key players of apoptosis, protein kinases, and phosphatases as the major regulators of many cellular and biochemical processes. The evidence reveals a triangle of caspases, kinases, and phosphatases in which their communication leads to the fine-tuning of caspases and consequently they determine cell fate.

Carbon nanotube-delivered iC9 suicide gene therapy for killing breast cancer cells in vitro.

AIM: To induce a safe death to MCF-7 human breast cancer cell line through gene therapy based on iC9 suicide gene. MATERIALS & METHODS: To induce apoptosis to MCF-7 cell line, iC9 gene was transfected using pyridine-functionalized multi-walled carbon nanotubes. Then, to enhance chemotherapy, iC9 suicide gene therapy was performed alongside. RESULTS: The results show that the MCF-7 cells were efficiently eliminated in a high percentage by this approach. Furthermore, the suicide gene by itself/in combination with the chemotherapeutic drugs managed to pass the cell cycle arrests. CONCLUSION: We introduced an in vitro treatment approach based on suicide gene therapy and the first step was taken toward the enhancement of chemotherapy, although more investigation is required.

Developing a circularly permuted variant of Renilla luciferase as a bioluminescent sensor for measuring Caspase-9 activity in the cell-free and cell-based systems.

Biosensors and whole cell biosensors consisting of biological molecules and living cells can sense a special stimulus on a living system and convert it to a measurable signal. A major group of them are the bioluminescent sensors derived from luciferases. This type of biosensors has a broad application in molecular biology and imaging systems. In this project, a luciferase-based biosensor for detecting and measuring caspase-9 activity is designed and constructed using the circular permutation strategy. The spectroscopic method results reveal changes in the biosensor structure. Additionally, its activity is examined in a cell-free coupled assay system. Afterward, the biosensor is utilized for measuring the cellular caspase-9 activity upon apoptosis induction in a cancer cell line. In following the gene of biosensor is sub-cloned into a eukaryotic vector and transfected to HEK293T cell line and then its activity is measured upon apoptosis induction in the presence and absence of a caspase-9 inhibitor. The obtained results show that the designed biosensor detects the caspase-9 activity in the cell-free and cell-based systems.