Somatostatin receptor type 2-based reporter expression after plasmid-based in vivo gene delivery to non-small cell lung cancer.

Plasmids tend to have much lower expression than viruses. Gene expression after systemic administration of plasmid vectors has not been assessed using somatostatin receptor type 2 (SSTR2)-based reporters. The purpose of this work was to identify gene expression in non-small cell lung cancer (NSCLC) after systemic liposomal nanoparticle delivery of plasmid containing SSTR2-based reporter gene. In vitro, Western blotting was performed after transient transfection with the plasmid cytomegalovirus (CMV)-SSTR2, CMV-TUSC2-IRES-SSTR2, or CMV-TUSC2. SSTR2 is the reporter gene, and TUSC2 is a therapeutic gene. Mice with A549 NSCLC lung tumors were injected intravenously with CMV-SSTR2, CMV-TUSC2-IRES-SSTR2, or CMV-TUSC2 plasmids in DOTAP:cholesterol-liposomal nanoparticles. Two days later, mice were injected intravenously with 111In-octreotide. The next day, biodistribution was performed. The experiment was repeated including single-photon emission computed tomography/computed tomography (SPECT/CT). Immunohistochemistry was performed. In vitro, SSTR2 expression was similar in cells transfected with CMV-SSTR2 or CMV-TUSC2-IRES-SSTR2. TUSC2 expression was similar in cells transfected with CMV-TUSC2 or CMV-TUSC2-SSTR2. Biodistribution demonstrated significantly greater 111In-octreotide uptake in tumors from mice injected with CMV-TUSC2-IRES-SSTR2 or CMV-SSTR2 than the control plasmid, CMV-TUSC2 (p < .05). Gamma-camera and SPECT/CT imaging illustrated SSTR2 expression in tumors in mice injected with CMV-TUSC2-IRES-SSTR2 or CMV-SSTR2 versus background with control plasmid. Immunohistochemistry corresponded with imaging. SSTR2-based reporter imaging can visualize gene expression in lung tumors after systemic liposomal nanoparticle delivery of plasmid containing SSTR2-based reporter gene or SSTR2 linked to a second therapeutic gene, such as TUSC2.

Hedgehog signaling inhibition by the small molecule smoothened inhibitor GDC-0449 in the bone forming prostate cancer xenograft MDA PCa 118b.

BACKGROUND: Hedgehog signaling is a stromal-mesenchymal pathway central to the development and homeostasis of both the prostate and the bone. Aberrant Hedgehog signaling activation has been associated with prostate cancer aggressiveness. We hypothesize that Hedgehog pathway is a candidate therapeutic target in advanced prostate cancer. We confirm increased Hedgehog signaling in advanced and bone metastatic castrate resistant prostate cancer and examine the pharmacodynamic effect of Smoothened inhibition by the novel reagent GDC-0449 in an experimental prostate cancer model. METHODS: Hedgehog signaling component expression was assessed in tissue microarrays of high grade locally advanced and bone metastatic disease. Male SCID mice subcutaneously injected with the bone forming xenograft MDA PCa 118b were treated with GDC-0449. Hedgehog signaling in the tumor microenvironment was assessed by proteomic and species specific RNA expression and compared between GDC-0449 treated and untreated animals. RESULTS: We observe Hedgehog signaling in high grade locally advanced and bone marrow infiltrating disease. Evidence of paracrine activation of Hedgehog signaling in the tumor xenograft, was provided by increased Sonic Hedgehog expression in human tumor epithelial cells, coupled with increased Gli1 and Patched1 expression in the murine stromal compartment, while normal murine stroma did not exhibit Hh signaling expression. GDC-0449 treatment attenuated Hh signaling as evidenced by reduced expression of Gli1 and Ptch1. Reduction in proliferation (Ki67) was observed with no change in tumor volume. CONCLUSIONS: GDC-0449 treatment is pharmacodynamically effective as evidenced by paracrine Hedgehog signaling inhibition and results in tumor cell proliferation reduction. Understanding these observations will inform the clinical development of therapy based on Hedgehog signaling inhibition.

Engineering Properties of PVA Fibre-Reinforced Geopolymer Mortar Containing Waste Oyster Shells.

Recycling crushed waste oyster shells (WOS) as a fine aggregate is an attractive method of disposal. However, its use in geopolymer mortar has not been reported. The influence of PVA fibres on the engineering properties of the new geopolymer mortar is still unclear. To bridge the gap, this study investigated the influence of various PVA fibre contents (0-1.05 vol%) on the flowability, compressive, flexural strengths, drying shrinkage, sorptivity, chloride resistance, porosity, fibre dispersion, embodied CO2 emissions (ECO2e), and embodied energy (EE) of the geopolymer mortar. The results indicated that the inclusion of 0.15-1.05 vol% of PVA fibres improved the flexural strength by 10.10-42.31% and reduced the drying shrinkage by 13.37-65.79%. The flowability and compressive strength decreased by 10.78-34.28% and 7.50-27.65%, respectively, but they were sufficient for construction. The sorptivity increased by 1.45-15.16%, and the chloride resistance decreased by 15.09-56.35%, but the geopolymer mortar was still classified as low chloride penetrability. In summary, the optimal content of PVA fibres is 0.45 vol%, and the geopolymer mortar has good engineering properties and eco-efficiency. The cost analysis and high-temperature resistance of the geopolymer mortar are neglected in this study, which should be evaluated in future work.

Synergistic tumor suppression by coexpression of FUS1 and p53 is associated with down-regulation of murine double minute-2 and activation of the apoptotic protease-activating factor 1-dependent apoptotic pathway in human non-small cell lung cancer cells.

FUS1 is a novel tumor suppressor gene identified in human chromosome 3p21.3 region. Loss of expression and deficiency of posttranslational modification of FUS1 protein have been found in a majority of human lung cancers. Restoration of wild-type FUS1 in 3p21.3-deficient human lung cancer cells exhibited a potent tumor suppression function in vitro and in vivo. In this study, we evaluated the combined effects of FUS1 and tumor suppressor p53 on antitumor activity and explored the molecular mechanisms of their mutual actions in human non-small cell lung cancer (NSCLC) cells. We found that coexpression of FUS1 and p53 by N-[1-(2,3-dioleoyloxyl)propyl]-NNN-trimethylammoniummethyl sulfate:cholesterol nanoparticle-mediated gene transfer significantly and synergistically inhibited NSCLC cell growth and induced apoptosis in vitro. We also found that a systemic treatment with a combination of FUS1 and p53 nanoparticles synergistically suppressed the development and growth of tumors in a human H322 lung cancer orthotopic mouse model. Furthermore, we showed that the observed synergistic tumor suppression by FUS1 and p53 concurred with the FUS1-mediated down-regulation of murine double minute-2 (MDM2) expression, the accumulation and stabilization of p53 protein, as well as the activation of the apoptotic protease-activating factor 1 (Apaf-1)-dependent apoptotic pathway in human NSCLC cells. Our results therefore provide new insights into the molecular mechanism of FUS1-mediated tumor suppression activity and imply that a molecular therapy combining two or more functionally synergistic tumor suppressors may constitute a novel and effective strategy for cancer treatment.

Tumor suppressor 101F6 and ascorbate synergistically and selectively inhibit non-small cell lung cancer growth by caspase-independent apoptosis and autophagy.

101F6 is a candidate tumor suppressor gene harbored on chromosome 3p21.3, a region with frequent and early allele loss and genetic alterations in many human cancers. We previously showed that enforced expression of wild-type 101F6 by adenoviral vector-mediated gene transfer significantly inhibited tumor cell growth in 3p21.3-deficient non-small cell lung cancer (NSCLC) cells in vitro and in vivo. The molecular mechanism of 101F6-mediated tumor suppression is largely unknown. A computer-aided structural and functional model predicts the 101F6 protein to be a member of the cytochrome b561 protein family that is involved in the regeneration of the antioxidant ascorbate. 101F6 protein is expressed in normal lung bronchial epithelial cells and fibroblasts but is lost in most lung cancers. Treatment with 101F6 nanoparticle-mediated gene transfer in combination with a subpharmacologic dose (200-500 micromol/L) of ascorbate synergistically and selectively inhibited lung cancer cell growth in vitro. Systemic injection of 101F6 nanoparticles plus the i.p. injection of ascorbate synergistically inhibited both tumor formation and growth in human NSCLC H322 orthotopic lung cancer mouse models (P<0.001). Furthermore, exogenous expression of 101F6 enhanced intracellular uptake of ascorbate, leading to an accumulation of cytotoxic H(2)O(2) and a synergistic killing of tumor cells through caspase-independent apoptotic and autophagic pathways. The antitumor synergism showed by the combination treatment with systemic administration of 101F6 nanoparticles and ascorbate on lung cancer offers an attractive therapeutic strategy for future clinical trials in cancer prevention and treatment.

Research on multi-agent genetic algorithm based on tabu search for the job shop scheduling problem.

The solution to the job shop scheduling problem (JSSP) is of great significance for improving resource utilization and production efficiency of enterprises. In this paper, in view of its non-deterministic polynomial properties, a multi-agent genetic algorithm based on tabu search (MAGATS) is proposed to solve JSSPs under makespan constraints. Firstly, a multi-agent genetic algorithm (MAGA) is proposed. During the process, a multi-agent grid environment is constructed based on characteristics of multi-agent systems and genetic algorithm (GA), and a corresponding neighbor interaction operator, a mutation operator based on neighborhood structure and a self-learning operator are designed. Then, combining tabu search algorithm with a MAGA, the algorithm MAGATS are presented. Finally, 43 benchmark instances are tested with the new algorithm. Compared with four other algorithms, the optimization performance of it is analyzed based on obtained test results. Effectiveness of the new algorithm is verified by analysis results.

Dual-energy X-ray absorptiometry is a valid tool for assessing skeletal muscle mass in older women.

Assessing skeletal muscle mass (SMM) is critical in studying and detecting sarcopenia. Direct measurements by MRI or computerized tomography are expensive or high in radiation exposure. Dual-energy X-ray absorptiometry (DXA) is promising for body composition assessments, but the validity of DXA for predicting SMM in the elderly is still under investigation. The objective of this study was to assess the relationship between DXA-derived measurements of lean soft tissue mass (LSTM) and SMM in older women. Study participants were postmenopausal women (n = 101) recruited in southern Arizona. Total and regional body composition was measured using MRI and DXA (QDR4500w). The participants' mean age was 70.7 +/- 6.4 y and their mean BMI was 27.4 +/- 5.1 kg/m2. DXA-derived LSTM was highly correlated with MRI-derived SMM for the whole body (r = 0.94; P < 0.001) and leg region (r = 0.91; P < 0.001). In multivariate models, adjusting for age and DXA-derived percent fat slightly increased the amount of variance in SMM that can be explained by the DXA-derived LSTM assessments for the leg region but not for the total body. In conclusion, although the relationships between DXA measures and MRI-derived SMM vary by region of interest, the overall prediction of SMM by DXA is excellent. We conclude that DXA is a reliable method for cross-sectional assessments of SMM in older women.

Genetic Variant in ACVR2B Is Associated with Lean Mass.

INTRODUCTION: Low lean mass (LM) is a risk factor for chronic disease, a major cause of disability and diminished quality of life, and is a heritable trait. However, relatively few specific genetic factors have been identified as potentially influencing this trait. METHODS: In this study, we selected 1493 single-nucleotide polymorphisms (SNP) in 155 candidate genes involved in anabolic, catabolic, growth hormone, and other related pathways and examined their association with LM, assessed by dual-energy x-ray absorptiometry, in a sample of 2760 non-Hispanic and Hispanic white postmenopausal women from the Women's Health Initiative (WHI) Observational Study. We assessed the replication of our top findings in a meta-analysis of 20 genome-wide association studies (n = 38,292) conducted by the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Musculoskeletal Working Group. RESULTS: We identified 32 SNPs that had nominally significant associations with LM in the WHI cohort. In the replication stage, we find that SNP rs2276541 in the activin A receptor, type IIB (ACVR2B), was significantly associated with LM (ß = 0.15, P = 2.17 × 10). ACVR2B codes for a receptor for a negative regulator of skeletal muscle, myostatin, and has previously been identified in a candidate gene study as a determinant of skeletal muscle mass. CONCLUSIONS: Our findings support a previously proposed role of ACVR2B allelic variation as a determinant of muscle mass and extend prior findings in men and women. Additional large-scale studies will be needed to confirm our findings in different populations.

Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer.

Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation. Administration of VT-464 in a metastatic CRPC patient presenting with high tumoral expression of both androgen receptor (AR) and CYP17A1, showed significant reduction in the level of both dehydroepiandrosterone (DHEA) and serum PSA. Treatment of a CRPC patient-derived xenograft, MDA-PCa-133 expressing H874Y AR mutant with VT-464, reduced the increase in tumor volume in castrate male mice more than twice as much as the vehicle (P < 0.05). Mass spectrometry analysis of post-treatment xenograft tumor tissues showed that VT-464 significantly decreased intratumoral androgens but not cortisol. VT-464 also reduced AR signaling more effectively than abiraterone in cultured PCa cells expressing T877A AR mutant. Collectively, this study suggests that VT-464 therapy can effectively treat CRPC and be used in precision medicine based on androgen receptor mutation status.

Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers.

PURPOSE: Morphologically heterogeneous prostate cancers that behave clinically like small-cell prostate cancers (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, morphologically diverse, "aggressive variant prostate cancer (AVPC)" also share molecular features with SCPC. EXPERIMENTAL DESIGN: Fifty-nine prostate cancer samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them, were stained for markers aberrantly expressed in SCPC. DNA from 36 and 8 PDX was analyzed by Oncoscan for copy number gains (CNG) and losses (CNL). We used the AVPC PDX to expand observations and referenced publicly available datasets to arrive at a candidate molecular signature for the AVPC. RESULTS: Irrespective of morphology, Ki67 and Tp53 stained ≥10% cells in 80% and 41% of samples, respectively. RB1 stained <10% cells in 61% of samples and AR in 36%. MYC (surrogate for 8q) CNG and RB1 CNL showed in 54% of 44 samples each and PTEN CNL in 48%. All but 1 of 8 PDX bore Tp53 missense mutations. RB1 CNL was the strongest discriminator between unselected castration-resistant prostate cancer (CRPC) and the AVPC. Combined alterations in RB1, Tp53, and/or PTEN were more frequent in the AVPC than in unselected CRPC and in The Cancer Genome Atlas samples. CONCLUSIONS: Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53, and/or PTEN.

An analysis: colon cancer mortality in Tianjin, China, from 1981 to 2000.

AIM: To analyze the data from Tianjin Cancer Registry of mortality due to colon cancer from 1981 to 2000 in Tianjin, China. METHODS: Tumors diagnosed in this study were coded according to ICD-9. Mortality rates were calculated by sex and calendar year of diagnosis. RESULTS: Seventy point four percent of colon cancer deaths occurred in the age group of 55-79 years and the mortality rate reached its peak in the age group of 75-80 years. The average age at death was 64.10 years. An ascending trend was observed in the mean age of death due to colon cancer from 1981 through 2000. However, as for the sex ratio, there was no clear trend exhibited. During 1981-2000, the total number of deaths was 2147, 1041 males and 1106 females. The mean mortality rate of colon cancer was 3.04/100,000. The mortality caused by colon cancer ascended from 1981 to 2000. CONCLUSION: The epidemic trend of colon cancer in Tianjin and its risk factors and prevention should be studied further.

Human immunodeficiency virus knowledge and attitudes among hospital-based healthcare professionals in Guangxi Zhuang Autonomous Region, People's Republic of China.

BACKGROUND AND OBJECTIVE: Since the discovery of human immunodeficiency virus (HIV) on the Chinese mainland in 1985, the virus has spread to all provinces and autonomous regions. Although much research emphasis has been placed on studying behaviors and transmission knowledge among high-risk populations, especially drug abusers and commercial sex workers, little has been done to measure understanding within other risk groups. The objective of this study was to investigate HIV/acquired immunodeficiency syndrome (AIDS) knowledge and attitudes among hospital-based healthcare professionals in Guangxi Zhuang Autonomous Region in southern China. METHODS: Data were gathered through a questionnaire completed by a convenience sample of individuals from three diverse hospitals. RESULTS: Insufficient knowledge of the disease and its transmission resulted in more than 90% of the respondents expressing apprehension about contracting the virus and nearly 24% expressing reservations about caring for infected patients. CONCLUSION: Uncorrected, such attitudes and knowledge deficiencies have the potential to impact negatively on the quality of care, patient-practitioner safety, and proper postexposure prophylaxis.

Hip geometry in diabetic women: implications for fracture risk.

OBJECTIVE: Women with type 2 diabetes mellitus (T2DM) have a higher risk of fractures despite increased bone mineral density (BMD) as compared to women without diabetes. We hypothesized that bone strength is diminished in women with T2DM after accounting for lean body mass, which may contribute to their increased fracture risk. METHODS: Participants from Women's Health Initiative Observational Study were included in this cross-sectional study. These analyses include 3 groups of women: 1) T2DM women on diet or oral hypoglycemic agents (n=299); 2) T2DM women on insulin therapy (with or without oral agents) (n=128); and 3) Non-diabetic control women (n=5497). Hip structural analyses were done using the validated Beck's method on hip scans from dual energy x-ray absorptiometry (DXA). We compared BMD and section modulus (bending strength) at the narrow neck with and without correcting for total body DXA lean body mass. RESULTS: Women in all three groups were of similar ages (63.7, 64.6 and 64.2 years, respectively) and heights, but those with T2DM were heavier, with greater lean body weight vs controls (P<.001). In both diabetic groups, absolute BMD and section modulus were higher compared with controls. However, after adjusting for total lean body weight, diabetic women on insulin had significantly lower BMD and section modulus. CONCLUSION: Adjusted for lean body weight, the BMD and bending strength in the femoral neck are significantly lower in insulin-treated diabetic women vs controls. This may represent altered adaptation of bone modeling and explain the higher fracture risk in patients with T2DM.

Modeling a lethal prostate cancer variant with small-cell carcinoma features.

PURPOSE: Small-cell prostate carcinoma (SCPC) morphology predicts for a distinct clinical behavior, resistance to androgen ablation, and frequent but short responses to chemotherapy. We sought to develop model systems that reflect human SCPC and can improve our understanding of its biology. EXPERIMENTAL DESIGN: We developed a set of castration-resistant prostate carcinomas xenografts and examined their fidelity to their human tumors of origin. We compared the expression and genomic profiles of SCPC and large-cell neuroendocrine carcinoma (LCNEC) xenografts to those of typical prostate adenocarcinoma xenografts. Results were validated immunohistochemically in a panel of 60 human tumors. RESULTS: The reported SCPC and LCNEC xenografts retain high fidelity to their human tumors of origin and are characterized by a marked upregulation of UBE2C and other mitotic genes in the absence of androgen receptor (AR), retinoblastoma (RB1), and cyclin D1 (CCND1) expression. We confirmed these findings in a panel of samples of CRPC patients. In addition, array comparative genomic hybridization of the xenografts showed that the SCPC/LCNEC tumors display more copy number variations than the adenocarcinoma counterparts. Amplification of the UBE2C locus and microdeletions of RB1 were present in a subset, but none displayed AR nor CCND1 deletions. The AR, RB1, and CCND1 promoters showed no CpG methylation in the SCPC xenografts. CONCLUSION: Modeling human prostate carcinoma with xenografts allows in-depth and detailed studies of its underlying biology. The detailed clinical annotation of the donor tumors enables associations of anticipated relevance to be made. Future studies in the xenografts will address the functional significance of the findings.

Confounders in the association between exercise and femur bone in postmenopausal women.

INTRODUCTION: Abundant animal and human evidence demonstrates that loading stimuli generate positive adaptive changes in bone, but effects of activity on bone mineral density (BMD) are often modest and frequently equivocal. HYPOTHESIS: Physical activity effects on the femur would be better reflected in measurements of geometry than BMD. STUDY DESIGN: Cross-sectional cohort study. METHODS: We used data from 6032 women of mixed ethnicity aged 50-79 yr who had dual-energy x-ray absorptiometry (DXA) scans of the total body and hip from the Women's Health Initiative observational study. Subjects were distributed in three ways: self-report categories included 1) tertiles of MET and 2) reported minutes per week walking for exercise. A third, more objective, category was based on tertile of lean body mass fraction (LMF) from DXA scans. Femur outcomes included conventional femoral neck and total hip BMD, bone mineral content and region area, and geometry measurements using the Hip Structure Analysis software. Outcomes were compared between activity groups using models adjusted for common confounders. RESULTS: Adjusted bone measurements showed similar activity effects with all three grouping variables, but these were greater and more significant when evaluated by LMF tertile. Women in the highest LMF tertile had the widest femurs. Differences in section modulus between highest and lowest tertile of LMF were 50%-80% greater than the association with bone mineral content and two to three times that on BMD. CONCLUSIONS: More active women in the Women's Health Initiative observational study had geometrically stronger femurs, although effects are underestimated, not apparent, or sometimes negative when using BMD as an outcome. CLINICAL RELEVANCE: Exercise improves the strength of the femur largely by adding bone to the outer cortical surface; this improves resistance to bending, but because of the way DXA measurements are made, this may paradoxically reduce BMD.

Stronger bone correlates with African admixture in African-American women.

Osteoporosis affects all populations, but the risk for low bone density and fracture varies greatly by self-reported race and ethnicity. In this article, the relationship between measured percent African admixture and hip structural geometry, estimated from the hip structural analysis (HSA) program, was examined in a subcohort of the Women's Health Initiative (WHI). The study sample included 793 African-American women and 8559 non-Hispanic white women. All the participants were postmenopausal, between the ages of 50 and 79 years, at the time of recruitment and were followed for up to 9 years. Bone density and hip geometry were assessed using dual-energy X-ray absorptiometry. African admixture was measured for African Americans using genetic ancestry informative markers. Multiple regression and mixed-effects models were used for cross-sectional and longitudinal analyses, respectively. Covariates assessed from questionnaires and physical measurements were included in the analysis to control for possible confounding effects. The study results show significant correlations between percent of African admixture and HSA assessments. In comparison with non-Hispanic white women, significantly greater bone strength, as indicated by higher hip bone mineral density and stronger hip geometry, in women with higher African admixture was observed. However, women with higher percent African admixture had larger reductions in bone strength than non-Hispanic white women during the follow-up.

Does obesity really make the femur stronger? BMD, geometry, and fracture incidence in the women's health initiative-observational study.

Heavier individuals have higher hip BMD and more robust femur geometry, but it is unclear whether values vary in proportion with body weight in obesity. We studied the variation of hip BMD and geometry across categories of body mass index (BMI) in a subset of postmenopausal non-Hispanic whites (NHWs) from the Women's Health Initiative Observational Cohort (WHI-OS). The implications on fracture incidence were studied among NHWs in the entire WHI-OS. Baseline DXA scans of hip and total body from 4642 NHW women were divided into BMI (kg/m(2)) categories: underweight (<18.5), healthy weight (18.5-24.9), overweight (25-29.9), and mild (30-34.9), moderate (35-39.9), and extreme obesity (>40). Femur BMD and indices of bone axial (cross-sectional area [CSA]) and bending strength (section modulus [SM]) were extracted from DXA scans using the hip structure analysis (HSA) method and compared among BMI categories after adjustment for height, age, hormone use, diabetes, activity level, femur neck-shaft angle, and neck length. The association between BMI and incident fracture was studied in 78,013 NHWs from the entire WHI-OS over 8.5 +/- 2.6 (SD) yr of follow-up. Fracture incidence (cases/1000 person-years) was compared among BMI categories for hip alone, central body (hip, pelvis, spine, ribs, and shoulder girdle), upper extremity (humerus and distal), and lower extremity (femur shaft and distal but not hip). Femur BMD, CSA, and SM were larger in women with higher BMI, but values scaled in proportion to lean and not to fat or total body mass. Women with highest BMI reported more falls in the 12 mo before enrollment, more prevalent fractures, and had lower measures of physical activity and function. Incidence of hip fractures and all central body fractures declined with BMI. Lower extremity fractures distal to the hip trended upward, and upper extremity incidence was independent of BMI. BMD, CSA, and SM vary in proportion to total body lean mass, supporting the view that bones adapt to prevalent muscle loads. Because lean mass is a progressively smaller fraction of total mass in obesity, femur BMD, CSA, and SM decline relative to body weight in higher BMI categories. Traumatic forces increase with body weight, but fracture rates at the hip and central body were less frequent with increasing BMI, possibly because of greater soft tissue padding. There was no evident protective effect in fracture rates at less padded distal extremity sites. Upper extremity fractures showed no variation with BMI, and lower extremity fracture rates were higher only in the overweight (BMI = 25-29.9 kg/m(2)).

Hormone therapy improves femur geometry among ethnically diverse postmenopausal participants in the Women's Health Initiative hormone intervention trials.

Loss of bone strength underlies osteoporotic fragility fractures. We hypothesized that hormone interventions significantly improve the structural geometry of proximal femur cross-sections. Study participants were from the Women's Health Initiative hormone intervention trials: either the conjugated equine estrogen (CEE) only (N(placebo) = 447, N(CEE) = 422) trial or the estrogen (E) plus progestin (P) (N(placebo) = 441, N(E+P) = 503) trial, who were 50-79 yr old at baseline and were followed up to 6 yr. BMD scans by DXA were conducted at baseline, year 1, year 3, and year 6. Femur geometry was derived from hip DXA scans using the hip structural analysis (HSA) method. Mixed effects models with the intent-to-treat analysis approach were used. There were no significant differences in treatment effects between the E-alone and the E + P trial, so the analyses were conducted with participants combined from both trials. Treatment benefits (p < 0.05) on femur geometry were observed as early as 1 yr after the intervention. From baseline to year 6, section modulus (a measure of maximum bending stress) was preserved, and buckling ratio (an index of cortical instability under compression) was reduced by hormone interventions (p < 0.05); the differences in the percent changes from baseline to year 6 between women on hormone intervention versus women on placebo were 2.3-3.6% for section modulus and -5.3% to - 4.3% for buckling ratio. Hormone interventions led to favorable changes in femur geometry, which may help explain the reduced fracture risk observed in hormone interventions.

Tumor-specific activation of human telomerase reverses transcriptase promoter activity by activating enhancer-binding protein-2beta in human lung cancer cells.

The up-regulated expression and telomerase activity of human telomerase reverse transcriptase (hTERT) are hallmarks of tumorigenesis. The hTERT promoter has been shown to promote hTERT gene expression selectively in tumor cells but not in normal cells. However, little is known about how tumor cells differentially activate hTERT transcription and induce telomerase activity. In this study, we identified activating enhancer-binding protein-2beta (AP-2beta) as a novel transcription factor that specifically binds to and activates the hTERT promoter in human lung cancer cells. AP-2beta was detected in hTERT promoter DNA-protein complexes formed in nuclear extracts prepared only from lung cancer cells but not from normal cells. We verified the tumor-specific binding activity of AP-2beta for the hTERT promoter in vitro and in vivo and detected high expression levels of AP-2beta in lung cancer cells. We found that ectopic expression of AP-2beta reactivated hTERT promoter-driven reporter green fluorescent protein (GFP) gene and endogenous hTERT gene expression in normal cells, enhanced GFP gene expression in lung cancer cells, and prolonged the life span of primary lung bronchial epithelial cells. Furthermore, we found that inhibition of endogenous AP-2beta expression by AP-2beta gene-specific small interfering RNAs effectively attenuated hTERT promoter-driven GFP expression, suppressed telomerase activity, accelerated telomere shortening, and inhibited tumor cell growth by induction of apoptosis in lung cancer cells. Our results demonstrate the tumor-specific activation of the hTERT promoter by AP-2beta and imply the potential of AP-2beta as a novel tumor marker or a cancer therapeutic target.