Palo Alto Health Care System

Palo Alto, CA, United States

Palo Alto Health Care System

Palo Alto, CA, United States
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Garin M.C.,University of Pennsylvania | Arnold A.M.,University of Washington | Lee J.S.,Stanford University | Lee J.S.,Palo Alto Health Care System | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Background: Subclinical thyroid dysfunction is common in the elderly, yet its relationship with hip fracture and bone mineral density (BMD) is unclear. Objective: We examined the association between endogenous subclinical hyper- and hypothyroidism and hip fracture and BMD in older adults. Methods: A total of 4936 US individuals 65 years old or older enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of incident hip fracture were performed by thyroid status, over a median follow-up of 12 years. A cross-sectional analysis of thyroid status and BMD was performed in a subset of 1317 participants who had dual-energy x-ray absorptiometry scans. Models were adjusted for risk factors and stratified by sex. Results: No association was found between subclinical hypothyroidism and incident hip fracture compared with euthyroidism, when assessed at a single time point or persisting at two time points, in either women [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.69-1.20 for a single and HR 0.79, 95% CI 0.52-1.21 for two time points] or men (HR 1.27, 95% CI 0.82-1.95 for a single and HR 1.09,95%CI 0.57-2.10 for two time points). Likewise, no association was found between subclinical hyperthyroidism and incident hip fracture in either sex (HR 1.11, 95% CI 0.55-2.25 in women and HR 1.78, 95% CI 0.56-5.66 in men). No association was found between subclinical thyroid dysfunction and BMD at the lumbar spine, total hip, or femoral neck sites. Conclusions: Our data suggest no association between subclinical hypothyroidism or subclinical hyperthyroidismandhip fracture risk orBMDin oldermenandwomen.Additional data areneeded to improve the precision of estimates for subclinical hyperthyroidism and in men. Copyright © 2014 by the Endocrine Society.

Hicks B.M.,University of Michigan | Johnson W.,University of Edinburgh | Durbin C.E.,Michigan State University | Blonigen D.M.,Palo Alto Health Care System | And 2 more authors.
Development and Psychopathology | Year: 2013

We used a longitudinal twin design to examine selection effects of personality traits at age 11 on high-risk environmental contexts at age 14 and the extent to which these contexts mediated risk for substance abuse at age 17. Socialization at age 11 (willingness to follow rules and endorse conventional values) predicted exposure to contextual risk at age 14. Contextual risk partially mediated the effect of socialization on substance abuse, though socialization also had a direct effect. In contrast, boldness at age 11 (social engagement and assurance, thrill seeking, and stress resilience) also predicted substance abuse directly but was unrelated to contextual risk. There was substantial overlap in the genetic and shared environmental influences on socialization and contextual risk, and genetic risk in socialization contributed to substance abuse indirectly via increased exposure to contextual risk. This suggests that active gene-environment correlations related to individual differences in socialization contributed to an early, high-risk developmental trajectory for adolescent substance abuse. In contrast, boldness appeared to index an independent and direct genetic risk factor for adolescent substance abuse. © 2013 Cambridge University Press.

Dong B.,Palo Alto Health Care System | Wu M.,Palo Alto Health Care System | Li H.,Palo Alto Health Care System | Kraemer F.B.,Palo Alto Health Care System | And 4 more authors.
Journal of Lipid Research | Year: 2010

We investigated the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the resistance of dyslipidemic hamsters to statin-induced LDL-cholesterol (LDL-C) reduction and the molecular mechanism by which statins modulated PCSK9 gene expression in vivo. We utilized the fructose diet-induced dyslipidemic hamsters as an in vivo model and rosuvastatin to examine its effects on liver PCSK9 and LDL receptor (LDLR) expression and serum lipid levels. We showed that rosuvastatin induced PCSK9 mRNA to a greater extent than LDLR mRNA in the hamster liver. The net result was that hepatic LDLR protein level was reduced. This correlated closely with an increase in serum LDL-C with statin treatment. More importantly, we demonstrated that in addition to an increase in sterol response element binding protein 2 (SREBP2) expression, rosuvastatin treatment increased the liver expression of hepatocyte nuclear factor 1 α (HNF1α), the newly identified key transactivator for PCSK9 gene expression. Our study suggests that the inducing effect of rosuvastatin on HNF1α is likely a underlying mechanism accounting for the higher induction of PCSK9 than LDLR because of the utilization of two transactivators (HNF1α and SREBP2) in PCSK9 transcription versus one (SREBP2) in LDLR transcription. Thus, the net balance is in favor of PCSK9-induced degradation of LDLR in the hamster liver, abrogating the effect of rosuvastatin on LDL-C lowering.

Li H.,Palo Alto Health Care System | Liu J.,Palo Alto Health Care System
Biochemical Journal | Year: 2012

PCSK9 (proprotein convertase subtilisin/kexin type 9) plays an important role in control of plasma LDL (low-density lipoprotein) cholesterol metabolism by modulating the degradation of hepatic LDL receptor. Previous studies demonstrated that PCSK9 is a target gene of the SREBP2 [SRE (sterol-regulatory element)- binding protein 2] that activates PCSK9 gene transcription through an SRE motif of the promoter. In addition to SREBP2, HNF1α(hepatic nuclear factor 1α) positively regulates PCSK9 gene transcription in hepatic cells through a binding site located 28 bp upstream from SRE. In the present study, we have identified a novel HINFP (histone nuclear factor P) recognitionmotif residing between the HNF1 motif and SRE that is essential for basal and sterol-regulated transcriptions of the PCSK9 promoter. Mutation of this motif lowers the basal promoter activity and abolishes the sterol-mediated repression as well as the SREBP2-induced activation of the PCSK9 promoter. We show further that the activity of SREBP2 in stimulating PCSK9 promoter activity is greatly enhanced by HINFP. Additional experiments suggest that HINFP and its cofactor NPAT (nuclear protein of the ataxia telangectasia mutated locus) form a functional complex, and NPAT may subsequently recruit the HAT (histone acetyltransferase) cofactor TRRAP (transformation/transactivation domain-associated protein) to facilitate the histone H4 acetylation of the PCSK9 promoter. Knockdown of HINFP, NPAT or TRRAP each markedly reduces the amount of acetylated histone H4 on the PCSK9 promoter region and lowers PCSK9 protein levels. Importantly, by utilizing co-immunoprecipitation assays, we have demonstrated a direct interaction between SREBP2 and HINFP and its cofactorsNPAT/TRRAP. Taken together, these new findings identify HINFP as a co-activator in SREBP-mediated transactivation of PCSK9 gene expression. ©The Authors Journal compilation © 2012 Biochemical Society.

Dong B.,Palo Alto Health Care System | Kan C.F.K.,Palo Alto Health Care System | Singh A.B.,Palo Alto Health Care System | Liu J.,Palo Alto Health Care System
Journal of Lipid Research | Year: 2013

Long-chain acyl-CoA synthetases (ACSL) play key roles in fatty acid metabolism in liver and other metabolic tissues in an isozyme-specific manner. In this study, we examined the effects of a fructose-enriched diet on expressions of ACSL isoforms in the liver of hamsters. We showed that the fructose diet markedly reduced the mRNA and protein expressions of ACSL3 in hamster liver without significant effects on other ACSLs. The decrease in ACSL3 abundance was accompanied by a reduction in ACSL-catalyzed synthesis of arachidonyl-CoA and oleoyl-CoA in liver homogenates of hamsters fed the fructose diet as opposed to normal diet. We further showed that fructose diet specifi- cally reduced expressions of three key components of the LXR signaling pathway, namely, liver X receptor (LXR) α , LXR β , and retinoid X receptor (RXR) β . Exogenous expression and activation of LXR α / β increased hamster ACSL3 promoter activities in a LXR-responsive element (LXRE)- dependent fashion. Finally, we showed that treating hamsters with LXR agonist GW3965 increased hepatic ACSL3 expression without affecting other ACSL isoforms. Furthermore, the ligand-induced increases of ACSL3 expression were accompanied with the reduction of hepatic triglyceride levels in GW3965-treated hamster liver. Altogether, our studies demonstrate that fructose diet has a negative impact on LXR signaling pathway in liver tissue and reduction of ACSL3 expression/activity could be a causal factor for fructose- induced hepatic steatosis. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.

Li H.,Palo Alto Health Care System | Liu J.,Palo Alto Health Care System
Journal of Biological Chemistry | Year: 2010

hnRNP K, a member of the family of heterogeneous ribonucleoproteins, is known to exert various functional roles in the nucleus, cytoplasm, and mitochondria to affect different cellular processes including chromatin remodeling, transcription, splicing, and translation. Here we report, for the first time, that hnRNPK is specifically involved in human LDL receptor (LDLR) gene transcription in HepG2 cells. We show that depletion of hnRNPK by siRNA transfection reduces the expression of LDLR mRNA and protein by more than 50% as measured by quantitative real-time PCR and Western blot analysis. Importantly, we show that the decay rate of LDLR mRNA is not affected by hnRNP K siRNA transfection, whereas the LDLR promoter activity is significantly decreased. Furthermore, overexpression of hnRNP K increased the LDLR promoter activity by the luciferase reporter assay. By utilizing a series of mutational and deletional constructs of LDLR promoter luciferase reporters, we mapped the K-responsive element to the repeat 3 (R3) sequence of the LDLR promoter. Electrophoretic mobility shift assays show that the K protein binds to a single-stranded DNA probe containing the CT-rich element of R3, which is in contrast to the requirement of double-stranded DNA for Sp1 to bind to R3. Finally, chromatin immunoprecipitation assays reveal a direct interaction of hnRNP K with the LDLR promoter in intact HepG2 cells. These new findings provide strong evidence demonstrating that hnRNP K is an important transactivator for human LDLR gene transcription. This work sheds new light on our current understanding of how LDLR gene expression is controlled at the transcriptional level.

Wu M.,Palo Alto Health Care System | Dong B.,Palo Alto Health Care System | Cao A.,Palo Alto Health Care System | Li H.,Palo Alto Health Care System | Liu J.,Palo Alto Health Care System
Atherosclerosis | Year: 2012

Background: PCSK9 has emerged as a key regulator of serum LDL-C metabolism by promoting the degradation of hepatic LDL receptor (LDLR). In this study, we investigated the effect of fasting on serum PCSK9, LDL-C, and hepatic LDLR expression in hamsters and further delineated the molecular pathways involved in fasting-induced repression of PCSK9 transcription. Results: Fasting had insignificant effects on serum total cholesterol and HDL-C levels, but reduced LDL-C, triglyceride and insulin levels. The decrease in serum LDL-C was accompanied by marked reductions of hepatic PCSK9 mRNA and serum PCSK9 protein levels with concomitant increases of hepatic LDLR protein amounts. Fasting produced a profound impact on SREBP1 expression and its transactivating activity, while having modest effects on mRNA expressions of SREBP2 target genes in hamster liver. Although PPARα mRNA levels in hamster liver were elevated by fasting, ligand-induced activation of PPARα with WY14643 compound in hamster primary hepatocytes did not affect PCSK9 mRNA or protein expressions. Further investigation on HNF1α, a critical transactivator of PCSK9, revealed that fasting did not alter its mRNA expression, however, the protein abundance of HNF1α in nuclear extracts of hamster liver was markedly reduced by prolonged fasting. Conclusion: Fasting lowered serum LDL-C in hamsters by increasing hepatic LDLR protein amounts via reductions of serum PCSK9 levels. Importantly, our results suggest that attenuation of SREBP1 transactivating activity owing to decreased insulin levels during fasting is primarily responsible for compromised PCSK9 gene transcription, which was further suppressed after prolonged fasting by a reduction of nuclear HNF1α protein abundance. © 2012.

Bachawal S.V.,Stanford University | Jensen K.C.,Stanford University | Jensen K.C.,Palo Alto Health Care System | Lutz A.M.,Stanford University | And 4 more authors.
Cancer Research | Year: 2013

While there is an increasing role of ultrasound for breast cancer screening in patients with dense breast, conventional anatomical ultrasound lacks sensitivity and specificity for early breast cancer detection. In this study, we assessed the potential of ultrasound molecular imaging using clinically translatable vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubbles (MBVEGFR2) to improve the diagnostic accuracy of ultrasound in earlier detection of breast cancer and ductal carcinoma in situ (DCIS) in a transgenic mouse model [FVB/N-Tg(MMTV-PyMT)634Mul] . In vivo binding specificity studies (n = 26 tumors) showed that ultrasound imaging signal was significantly higher (P < 0.001) using MBVEGFR2 than nontargeted microbubbles and imaging signal significantly decreased (P < 0.001) by blocking antibodies. Ultrasound molecular imaging signal significantly increased (P < 0.001)when breast tissue (n=315 glands) progressed fromnormal [1.65±0.17 arbitrary units (a.u.)] to hyperplasia (4.21±1.16), DCIS (15.95±1.31), and invasive cancer (78.1±6.31) and highly correlated with ex vivo VEGFR2 expression [R 2 = 0.84; 95% confidence interval (CI), 0.72-0.91; P < 0.001]. At an imaging signal threshold of 4.6 a.u., ultrasound molecular imaging differentiated benign from malignant entities with a sensitivity of 84% (95% CI, 78-88) and specificity of 89% (95% CI, 81-94). In a prospective screening trail (n = 63 glands), diagnostic performance of detecting DCIS and breast cancer was assessed and two independent readers correctly diagnosed malignant disease in more than 95% of cases and highly agreed between each other [intraclass correlation coefficient (ICC) = 0.98; 95% CI, 97-99]. These results suggest that VEGFR2-targeted ultrasound molecular imaging allows highly accurate detection of DCIS and breast cancer in transgenic mice and may be a promising approach for early breast cancer detection in women. © 2012 American Association for Cancer Research.

Kim S.H.,Stanford University | Reaven G.,Stanford University | Lindley S.,Stanford University | Lindley S.,Palo Alto Health Care System
International Clinical Psychopharmacology | Year: 2011

C-reactive protein (CRP) is an inflammatory marker associated with obesity, insulin resistance, and cardiovascular disease. A recent study found CRP levels to be higher in individuals treated with certain antipsychotic medications such as olanzapine; however, it is not clear whether this is associated directly with drug intake or indirectly with drug-associated weight gain and insulin resistance. The objective of this study was to explore the potential predictors of CRP including insulin resistance, components of the metabolic syndrome, psychiatric diagnosis, and antipsychotic medication in patients treated with antipsychotics. Sixty-four outpatients without diabetes being treated with a single second generation antipsychotic medication had direct measurements of insulin resistance at the end of a 180-min infusion of glucose, insulin, and octreotide (insulin suppression test) as well as components of the metabolic syndrome. Insulin resistance was the strongest predictor of CRP (r=0.52, P<0.001). When adjusted for insulin resistance, there was no significant relationship between CRP and any of the components of the metabolic syndrome criteria, specific drug treatment or psychiatric diagnoses. In conclusion, insulin resistance is strongly associated with CRP levels and likely contributes to earlier associations between CRP and certain antipsychotic treatments. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Soltys S.G.,Stanford University | Choi C.Y.H.,Stanford University | Fee W.E.,Stanford University | Pinto H.A.,Stanford University | And 2 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: To assess the role of a planned neck dissection (PND) after sequential chemoradiotherapy for patients with head-and-neck cancer with N2-N3 nodal disease. Methods and Materials: We reviewed 90 patients with N2-N3 head-and-neck squamous cell carcinoma treated between 1991 and 2001 on two sequential chemoradiotherapy protocols. All patients received induction and concurrent chemotherapy with cisplatin and 5-fluorocuracil, with or without tirapazamine. Patients with less than a clinical complete response (cCR) in the neck proceeded to a PND after chemoradiation. The primary endpoint was nodal response. Clinical outcomes and patterns of failure were analyzed. Results: The median follow-up durations for living and all patients were 8.3 years (range, 1.5-16.3 year) and 5.4 years (range, 0.6-16.3 years), respectively. Of the 48 patients with nodal cCR whose necks were observed, 5 patients had neck failures as a component of their recurrence [neck and primary (n = 2); neck, primary, and distant (n = 1); neck only (n = 1); neck and distant (n = 1)]. Therefore, PND may have benefited only 2 patients (4%) [neck only failure (n = 1); neck and distant failure (n = 1)]. The pathologic complete response (pCR) rate for those with a clinical partial response (cPR) undergoing PND (n = 30) was 53%. The 5-year neck control rates after cCR, cPR→pCR, and cPR→pPR were 90%, 93%, and 78%, respectively (p = 0.36). The 5-year disease-free survival rates for the cCR, cPR→pCR, and cPR→pPR groups were 53%, 75%, and 42%, respectively (p = 0.04). Conclusion: In our series, patients with N2-N3 neck disease achieving a cCR in the neck, PND would have benefited only 4% and, therefore, is not recommended. Patients with a cPR should be treated with PND. Residual tumor in the PND specimens was associated with poor outcomes; therefore, aggressive therapy is recommended. Studies using novel imaging modalities are needed to better assess treatment response. © 2012 Elsevier Inc. All rights reserved.

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