BSV163/DOPE-mediated TRAIL gene transfection acts synergistically with chemotherapy against cisplatin-resistant ovarian cancer.

Ovarian cancer is the seventh most frequently diagnosed cancer among women worldwide. Most patients experience recurrence and succumb eventually to resistant disease, underscoring the need for an alternative treatment option. In the presented manuscript, we investigated the effect of the TRAIL-gene, transfected by an innovative bioinspired lipid vector BSV163/DOPE in the presence or absence of cisplatin, to fight against sensitive and resistant ovarian cancer. We showed that BSV163/DOPE can transfect ovarian cancer cell lines (Caov3, OVCAR3, and our new cisplatin-resistant, CR-Caov3) safely and efficiently. In addition, TRAIL-gene transfection in association with cisplatin inhibited cellular growth more efficiently (nearly 50% in Caov3 cells after the combined treatment, and 15% or 25% by each treatment alone, respectively) owing to an increase in apoptosis rate, caspases activity and TRAIL's death receptors expression. Most importantly, such synergistic effect was also observed in CR-Caov3 cells demonstrated by an apoptosis rate of 35% following the combined treatment in comparison with 17% after TRAIL-gene transfection or 6% after cisplatin exposition. These results suggest this combination may have potential application for sensitive as well as refractory ovarian cancer patients.

Suicide gene strategies applied in ovarian cancer studies.

Ovarian cancer represents the most lethal gynecological malignancy among women in developed countries. Despite the recent innovations, the improvements in the 5-year survival rate have been insufficient and the management of this disease still remains a challenge. The fact that the majority of patients experience recurrent or resistant disease have substantiated the necessity of an innovative treatment. Among various strategies investigated, the recent strides made in gene delivery techniques have made gene therapy, including suicide gene strategies, a potential alternative for treating ovarian cancer. Various suicide gene candidates, which are capable of promoting cancer cell apoptosis directly after its entry or indirectly by prodrug administration, can be separated into three systems using enzyme-coding, toxin or pro-apoptotic genes. With this review, we aim to provide an overview of different suicide genes depending on therapeutic strategies, the vectors used to deliver these transgenes specifically to malignant cells, and the combined treatments of these genes with various therapeutic regimens.

Optimal Design for Compliant Mechanism Flexure Hinges: Bridge-Type.

Compliant mechanisms' design aims to create a larger workspace and simple structural shapes because these mechanical systems usually have small dimensions, reduced friction, and less bending. From that request, we designed optimal bridge-type compliant mechanism flexure hinges with a high magnification ratio, low stress by using a flexure joint, and especially no friction and no bending. This joint was designed with optimal dimensions for the studied mechanism by using the method of grey relational analysis (GRA), which is based on the Taguchi method (TM), and finite element analysis (FEA). Grey relational grade (GRG) has been estimated by an artificial neural network (ANN). The optimal values were in good agreement with the predicted value of the Taguchi method and regression analysis. The finite element analysis, signal-to-noise analysis, surface plot, and analysis of variance demonstrated that the design dimensions significantly affected the equivalent stress and displacement. The optimal values of displacement were also verified by the experiment. The outcomes were in good agreement with a deviation lower than 6%. Specifically, the displacement amplification ratio was obtained as 65.36 times compared with initial design.

Microstructure and Mechanical Properties of Butt Joints between Stainless Steel SUS304L and Aluminum Alloy A6061-T6 by TIG Welding.

The tungsten inert gas (TIG) welding method most commonly used to weld ferrous metals, nonferrous metals, and other metals since it is simple, easily implemented, and achieves consistent high-quality welds. In this study, butt joints produced between aluminum alloy A6061-T6 and stainless steel SUS304L have been achieved by using TIG welding with ER4047 filler metal. The macrostructure and microstructure of the resulting specimens were analyzed by means of an optical microscope (OM), a scanning electron microscope (SEM), and an energy dispersive X-ray spectrometer (EDS). A uniform intermetallic layer was found at the interface between the stainless steel and the weld seam having a thickness of 2 µm, and the intermetallic compound (IMC) includes Fe4Al13, Fe2Al5, and FeAl3 phases. The micro-hardness and tensile strength of the weld joints were also investigated. Due to Si content in the compensating metal, there was a prevention of iron diffusion into the aluminum, thus hindering the development of the IMC layer and reducing its thickness in such a way that the weld joint strength increases. The analyzed results show that the average micro-hardness of the stainless steel, weld seam, aluminum alloys, and IMC layer were 218 HV, 88.3 HV, 63.3 HV, and 411 HV, respectively. The fracture occurred at the brazed interface, and the ultimate tensile strength value reached 225 MPa.

An Investigation of the Microstructure of an Intermetallic Layer in Welding Aluminum Alloys to Steel by MIG Process.

Butt joints of A5052 aluminum alloy and SS400 steel, with a new type of chamfered edge, are welded by means of metal inert gas welding and ER4043 Al-Si filler metal. The microhardness and microstructure of the joint are investigated. An intermetallic layer is found on the surface of the welding seam and SS400 steel sheet. The hardness of the intermetallic layer is examined using the Vickers hardness test. The average hardness values at the Intermetallic (IMC) layer zone and without the IMC layer zone were higher than that of the welding wire ER4043. The tensile strength test showed a fracture at the intermetallic layer when the tensile strength is 225.9 MPa. The tensile value test indicated the average of welds was equivalent to the 85% tensile strength of the A5052 aluminum alloy. The thickness of the intermetallic layers is non-uniform at different positions with the ranges from 1.95 to 5 µm. The quality of the butt joint is better if the intermetallic layer is minimized. The Si crystals which appeared at the welding seam, indicating that this element participated actively during the welding process, also contributed to the IMC layer's formation.

A diagnosis of the metabolic syndrome in youth that resolves by adult life is associated with a normalization of high carotid intima-media thickness and type 2 diabetes mellitus risk: the Bogalusa heart and cardiovascular risk in young Finns studies.

OBJECTIVES: The aim of this study was to examine the effect of resolution from metabolic syndrome (MetS) between youth and adulthood on carotid artery intima-media thickness (IMT) and type 2 diabetes mellitus (T2DM). BACKGROUND: Published findings demonstrate that youth with MetS are at increased risk of cardio-metabolic outcomes in adulthood. It is not known whether this risk is attenuated in those who resolve their MetS status. METHODS: Participants (n = 1,757) from 2 prospective cohort studies were examined as youth (when 9 to 18 years of age) and re-examined 14 to 27 years later. The presence of any 3 components (low high-density lipoprotein cholesterol, high triglycerides, high glucose, high blood pressure, or high body mass index) previously shown to predict adult outcomes defined youth MetS; the harmonized MetS criteria defined adulthood MetS. Participants were classified according to their MetS status at baseline and follow-up and examined for risk of high IMT and T2DM. RESULTS: Those with MetS in youth and adulthood were at 3.4 times the risk (95% confidence interval: 2.4 to 4.9) of high IMT and 12.2 times the risk (95% confidence interval: 6.3 to 23.9) of T2DM in adulthood compared with those that did not have MetS at either time-point, whereas those that had resolved their youth MetS status by adulthood showed similar risk to those that did not have MetS at either time-point (p > 0.20 for all comparisons). CONCLUSIONS: Although youth with MetS are at increased risk of adult high IMT and T2DM, these data indicate that the resolution of youth MetS by adulthood can go some way to normalize this risk to levels seen in those who have never had MetS.

Correlates of age onset of type 2 diabetes among relatively young black and white adults in a community: the Bogalusa Heart Study.

OBJECTIVE: The risk factors for middle-age onset of type 2 diabetes are well known. However, information is scant regarding the age onset of type 2 diabetes and its correlates in community-based black and white relatively young adults. RESEARCH DESIGN AND METHODS: This prospective cohort study consisted of normoglycemic (n = 2,459) and type 2 diabetic (n = 144) adults aged 18-50 years who were followed for an average of 16 years. RESULTS: The incidence rate of the onset of type 2 diabetes was 1.6, 4.3, 3.9, and 3.4 per 1,000 person-years for age-groups 18-29, 30-39, and 40-50 and total sample, respectively. Incidences of diabetes increased with age by race and sex groups (P for trend ≤ 0.01); higher in black females versus white females and blacks versus whites in total sample (P < 0.05). In a multivariable Cox model, baseline parental diabetes (hazard ratio [HR] 5.24) and plasma insulin were significantly associated with diabetes incidence at the youngest age (18-29 years); black race, BMI, and glucose at age 30-39 years; female sex, parental diabetes (HR 2.44), BMI, ratio of triglycerides and HDL cholesterol (TG/HDL-C ratio), and glucose at age 40-50 years; and black race, parental diabetes (HR 2.44), BMI, TG/HDL-C ratio, and glucose in whole cohort. Further, patients with diabetes, regardless of age onset, displayed a significantly higher prevalence of maternal history of diabetes at baseline (P < 0.01). CONCLUSIONS: In relatively young adults, predictability of baseline cardiometabolic risk factors along with race, sex, and parental history of diabetes for the onset of type 2 diabetes varied by age-group. These findings have implications for early prevention and intervention in relatively young adults.

Elevated liver function enzymes are related to the development of prediabetes and type 2 diabetes in younger adults: the Bogalusa Heart Study.

OBJECTIVE: Elevations in alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT), surrogate markers of liver dysfunction and nonalcoholic fatty liver, are considered as part of metabolic syndrome and related type 2 diabetes. However, information is limited regarding the long-term predictability of ALT and GGT in the development of prediabetes and type 2 diabetes. RESEARCH DESIGN AND METHODS: In this retrospective cohort study, normoglycemic (n = 874), prediabetic (n = 101), and diabetic (n = 80) adults aged 26-50 years (average age 41.3 years) were followed over an average period of 16 years since their young adulthood (aged 18-38 years, average age 25.1 years), with measurements of cardiometabolic risk factor variables including ALT and GGT. RESULTS: The follow-up prevalence rate of adult diabetes status by quartiles of baseline ALT and GGT levels showed an adverse trend for both prediabetes (P < 0.05) and diabetes (P < 0.01). In a longitudinal multivariate logistic regression analysis that included anthropometric, hemodynamic, and metabolic variables, as well as alcohol consumption and smoking, individuals with elevated baseline ALT and GGT levels (per 1-SD increment) were 1.16 and 1.20 times, respectively, more likely to develop diabetes (P = 0.05 for ALT and P < 0.01 for GGT); no such associations were noted for prediabetes. Regarding the predictive value of ALT and GGT, the area under the receiver operating curve analysis yielded C values ranging from 0.70 to 0.82, with values significantly higher for diabetes compared with prediabetes. CONCLUSIONS: These findings in younger adults suggest potential clinical utility of including ALT and GGT as biomarkers in diabetes risk assessment formulations.

Glycemic status, metabolic syndrome, and cardiovascular risk in children.

The metabolic syndrome and adult manifestation of prediabetes and diabetes are major public health problems that begin in childhood. Prevention must be considered as a serious public health issue. Health education and health promotion of school children needs incorporation as a community effort.

Progression of segment-specific carotid artery intima-media thickness in young adults (from the Bogalusa Heart Study).

Carotid intima-media thickness (CIMT) progression is predictive of future cardiovascular events in middle-age and older adults. However, information is scant on segment-specific CIMT progression by race (black vs white) and gender and its predictors during short-term follow-up in asymptomatic young adults. B-mode ultrasound images of the far walls of both carotid arteries were obtained in 842 subjects aged 24 to 43 years and enrolled in the Bogalusa Heart Study (70% whites and 42% men). The CIMT and cardiometabolic risk variables were measured at baseline and after an average of 2.4 years. The mean CIMT progression rates/year adjusted for age, race, and gender were greatest at the bulb, followed by the internal and common carotid segments (p <0.0001). In a multivariate logistic model, age, mean arterial pressure, and high-density lipoprotein cholesterol were significantly associated with common CIMT progression. Smoking, age, insulin resistance index, and mean arterial pressure were significantly associated with bulb CIMT progression; and the waist/height ratio, smoking, age, and mean arterial pressure were significantly associated with internal CIMT progression, independent of the baseline CIMT and traditional cardiometabolic risk variables, including adiponectin, C-reactive protein, and intercellular adhesion molecules. In addition, the status of progression was associated with a greater prevalence of metabolic syndrome (common and internal CIMT, p <0.05; bulb CIMT, p <0.0001) and diabetes (bulb CIMT only, p <0.001). In conclusion, in younger adults, the magnitude of progression of CIMT within a short period varied in a segment-specific manner, regardless of race or gender, and was predictable using modifiable traditional risk factors. This could have implications for preventive and interventional cardiology.

Fasting plasma glucose levels within the normoglycemic range in childhood as a predictor of prediabetes and type 2 diabetes in adulthood: the Bogalusa Heart Study.

OBJECTIVES: To determine whether childhood elevated fasting plasma glucose (FPG) levels within the normoglycemic range predict diabetes in adulthood. DESIGN: Retrospective cohort study. SETTING: Community of Bogalusa, Louisiana. PARTICIPANTS: Normoglycemic (n = 1723), prediabetic (n = 79), and type 2 diabetic (n = 47) adults aged 19 to 44 years followed up serially for an average of 21 years since childhood. Main Exposures Association of elevated baseline childhood FPG levels with the prediabetic or diabetic status at the last survey in adulthood. MAIN OUTCOME MEASURES: Receiver operating characteristic analysis and longitudinal logistic regression odds ratios. RESULTS: The prevalent rate of adult diabetes status by quartiles of baseline childhood FPG levels showed an adverse trend for prediabetes (P < .001) and diabetes (P = .03), with an apparent threshold occurring at or above the 50th percentile (86 mg/dL). Regarding the predictive value of the above threshold, the area under the receiver operating curve analysis yielded a C value of 0.855 for prediabetes and 0.789 for diabetes models, with sensitivity and specificity, respectively, of 76.9% and 85.2% for prediabetes and 75.0% and 76.0% for diabetes. In a multivariate analysis that included anthropometric, hemodynamic, and metabolic variables from childhood to adulthood and baseline childhood FPG status (> or = vs < 50th percentile), individuals with elevated childhood FPG levels were 3.40 times more likely to develop prediabetes (P < .001) and 2.06 times more likely to develop diabetes (P = .05) as adults. CONCLUSION: The fact that elevated FPG level in childhood, even within the normoglycemic range, is a predictor of type 2 diabetes in younger adulthood has implications for health care policy.

Utility of childhood glucose homeostasis variables in predicting adult diabetes and related cardiometabolic risk factors: the Bogalusa Heart Study.

OBJECTIVE This study examines the usefulness of childhood glucose homeostasis variables (glucose, insulin, and insulin resistance index [homeostasis model assessment of insulin resistance {HOMA-IR}]) in predicting pre-diabetes and type 2 diabetes and related cardiometabolic risk factors in adulthood. RESEARCH DESIGN AND METHODS This retrospective cohort study consisted of normoglycemic (n = 1,058), pre-diabetic (n = 37), and type 2 diabetic (n = 25) adults aged 19-39 years who were followed on average for 17 years since childhood. RESULTS At least 50% of the individuals who ranked highest (top quintile) in childhood for glucose homeostasis variables maintained their high rank by being above the 60th percentile in adulthood. In a multivariate model, the best predictors of adulthood glucose homeostasis variables were the change in BMI Z score from childhood to adulthood and childhood BMI Z score, followed by the corresponding childhood levels of glucose, insulin, and HOMA-IR. Further, children in the top decile versus the rest for insulin and HOMA-IR were 2.85 and 2.55 times, respectively, more likely to develop pre-diabetes; children in the top decile versus the rest for glucose, insulin, and HOMA-IR were 3.28, 5.54, and 5.84 times, respectively, more likely to develop diabetes, independent of change in BMI Z score, baseline BMI Z score, and total-to-HDL cholesterol ratio. In addition, children with adverse levels (top quintile versus the rest) of glucose homeostasis variables displayed significantly higher prevalences of, among others, hyperglycemia, hypertriglyceridemia, and metabolic syndrome. CONCLUSIONS Adverse levels of glucose homeostasis variables in childhood not only persist into adulthood but also predict adult pre-diabetes and type 2 diabetes and relate to cardiometabolic risk factors.

Distribution and cardiovascular risk correlates of plasma soluble intercellular adhesion molecule-1 levels in asymptomatic young adults from a biracial community: the Bogalusa Heart Study.

PURPOSE: That circulating soluble form of intercellular adhesion molecule-1 (sICAM-1) is associated with an increased risk for coronary artery disease is well recognized. However, information is scant regarding the distribution and cardiovascular (CV) risk correlates of sICAM-1 in asymptomatic young adults. METHODS: Plasma sICAM-1 was measured in 1,184 black and white persons in the Bogalusa Heart Study cohort (70% white, 43% male), aged 24 to 44 years. CV risk was assessed in terms of CV risk factors, status of parental CV disease, and composite carotid intima-media thickness (IMT). RESULTS: sICAM-1 levels displayed race difference (whites > blacks, p<0.0001), but no sex difference. In multivariate analysis including age, race, sex, smoking status, waist circumference, mean arterial pressure, low- and high-density lipoprotein (LDL and HDL) cholesterols, triglycerides, insulin resistance index, C-reactive protein (CRP), and adiponectin, the significant predictors of sICAM-1, in order of entry, were race (white > black), smoking, CRP, and waist circumference. Furthermore, there was a smoking by waist circumference interaction in that smoking attenuated the magnitude of correlation between waist circumference and sICAM-1. Levels of sICAM-1 adjusted for age, race, sex, and smoking increased with number of metabolic syndrome components (p for trend<0.01); positive family history of CV disease (p<0.05); and increased in composite carotid IMT specific for age, race, and sex (p for trend<0.05). CONCLUSION: These findings underscore the potential value of plasma sICAM-1 as an additional biomarker for CV risk among asymptomatic young adults.

Influence of childhood parental history of type 2 diabetes on the pre-diabetic and diabetic status in adulthood: the Bogalusa Heart Study.

To assess the association of childhood parental history of type 2 diabetes and the risk of diabetes in adulthood. Observations were made on a community-based cohort of normoglycemic (n = 1619), pre-diabetic (n = 78), and type 2 diabetic (n = 50) adult subjects followed serially for cardiovascular risk factors over 22 years from childhood and noting their relation to a parental history of diabetes. In a longitudinal multivariate model including parental diabetes observed in the offspring's childhood, BMI, MAP, HDL cholesterol, LDL cholesterol, triglycerides, insulin, and glucose, adjusted for age, age(2), race, sex, and race by sex interaction, parental diabetes and adverse changes in LDL cholesterol and glucose were independently associated with pre-diabetic status in adulthood (regression coefficient [beta] = 0.74 (95% CI: 0.04-1.45), 0.44 (95% CI: 0.24-0.64), and 1.99 (95% CI: 1.73-2.25), respectively), while parental diabetes and adverse changes in BMI, HDL cholesterol, and glucose were associated with the diabetic status (beta = 1.14 (95% CI: 0.35-1.92), 0.08 (95% CI: 0.05-0.11), -0.51 (95% CI: -1.03 to -0.003), and 1.79 (95% CI: 1.48-2.09), respectively). Childhood parental history of diabetes along with adverse changes in adiposity, glucose, and lipoprotein variables of metabolic syndrome since childhood are associated with the increased risk of pre-diabetic and diabetic status in adulthood.

Distribution and cardiovascular risk correlates of hemoglobin A(1c) in nondiabetic younger adults: the Bogalusa Heart Study.

Excess glycated hemoglobin (HbA(1c)), an indicator of long-term glucose homeostasis, is recognized as a risk factor for cardiovascular (CV) disease and mortality even among persons without diabetes. However, information is scant regarding its distribution and correlates of CV risk in nondiabetic younger adults. This aspect was examined in a biracial (black-white) community-based sample of 1111 younger adults (mean age: 36.2 years; 71% white, 43% male) enrolled in the Bogalusa Heart Study. Blacks vs whites and women vs men had higher HbA(1c) values (P < .0001). In bivariate analysis adjusted for age, race, sex, and smoking status, significant adverse trends were noted for body mass index, waist circumference, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), total cholesterol to HDL-C ratio, insulin, glucose, and homeostasis model assessment of insulin resistance across HbA(1c) quartiles; trends were not significant for mean arterial blood pressure, triglycerides, C-reactive protein, adiponectin, and estimated glomerular filtration rate. In multivariate analysis, besides race and sex, total cholesterol to HDL-C ratio and waist circumference were independent correlates of HbA(1c). Furthermore, the prevalence of excess (top decile) HbA(1c) was 1.6-fold (P < .05) higher among those with metabolic syndrome defined by the National Cholesterol Education Program Adult Treatment Panel III and 2.1-fold (P < .01) and 1.5-fold (P < .05) higher, respectively, among those with positive parental history of CV disease and type 2 diabetes mellitus. These findings underscore the potential value of HbA(1c) in risk assessments of CV disease and type 2 diabetes mellitus in nondiabetic, apparently "healthy" younger adults.

Changes in risk variables of metabolic syndrome since childhood in pre-diabetic and type 2 diabetic subjects: the Bogalusa Heart Study.

OBJECTIVE: That type 2 diabetes is associated with the metabolic syndrome is known. However, information is lacking regarding the long-term and adverse changes of metabolic syndrome variables in the development of type 2 diabetes from childhood to adulthood. RESEARCH DESIGN AND METHODS: Observations were examined, retrospectively, in a community-based cohort of normoglycemic (n = 1,838), pre-diabetic (n = 90), and type 2 diabetic (n = 60) subjects followed serially for cardiovascular risk factors during childhood (4-11 years), adolescence (12-18 years), and adulthood (19-44 years). RESULTS: Diabetic subjects versus normoglycemic subjects had significantly higher levels of subscapular skinfold, BMI, triglycerides, glucose, insulin, and homeostasis model assessment of insulin resistance and lower levels of HDL cholesterol beginning in childhood and higher levels of mean arterial pressure (MAP) in adolescence and adulthood. In a multivariate model including BMI, MAP, HDL cholesterol, LDL cholesterol, triglycerides, glucose, and insulin, adjusted for age, age(2), race, sex, and race x sex interaction, adverse changes in glucose and LDL cholesterol were independently associated with pre-diabetic subjects, whereas adverse changes in BMI, glucose, and HDL cholesterol were associated with diabetic subjects. As young adults, pre-diabetic and diabetic groups displayed a significantly higher prevalence of obesity, hypertension, dyslipidemia, hyperinsulinemia, and metabolic syndrome. CONCLUSIONS: These findings indicate that adverse levels of risk variables of metabolic syndrome, adiposity, and measures of glucose homeostasis accelerating since childhood characterize the early natural history of type 2 diabetes and underscore the importance of early prevention and intervention on risk factors beginning in childhood.