Citations

ObjectivesIndividuals with bipolar disorder have high rates of other medical comorbidity, which is associated with higher mortality rates and worse course of illness. The present study examined common predictors of medical comorbidity.MethodsThe Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE) enrolled 482 participants with bipolar I or bipolar II disorder in a six‐month, randomized comparative effectiveness trial. Baseline assessments included current and lifetime DSM‐IV‐TR diagnoses, demographic information, psychiatric and medical history, severity of psychiatric symptoms, level of functioning, and a fasting blood draw. Medical comorbidities were categorized into two groups: cardiometabolic (e.g., diabetes, hyperlipidemia, and metabolic syndrome) and non‐cardiovascular (e.g., seizures, asthma, and cancer). Additionally, we looked at comorbid substance use (e.g., smoking and drug dependence).ResultsWe found that 96.3% of participants had at least one other medical comorbidity. Older age predicted a greater likelihood of having a cardiometabolic condition. Early age of onset of bipolar symptoms was associated with a lower chance of having a cardiometabolic condition, but a greater chance of having other types of medical comorbidity. Additional predictors of other medical comorbidities in bipolar disorder included more time spent depressed, less time spent manic/hypomanic, and longer duration of illness. Medications associated with weight gain were associated with low high‐density lipoprotein and abnormal triglycerides.ConclusionsThere appears to be a substantial medical burden associated with bipolar disorder, highlighting the need for collaborative care among psychiatric and general medical providers to address both psychiatric and other medical needs concomitantly in this group of patients.

Abstract Background Proteins pathogenic in Alzheimer's disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD. Methods Blood exosomes obtained at one time‐point from patients with AD (n = 57) or frontotemporal dementia (FTD) (n = 16), and at two time‐points from others (n = 24) when cognitively normal and 1 to 10 years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD‐pathogenic exosomal proteins were extracted and quantified by enzyme‐linked immunosorbent assays. Results Mean exosomal levels of total tau, P‐T181‐tau, P‐S396‐tau, and amyloid β 1–42 (Aβ1–42) for AD and levels of P‐T181‐tau and Aβ1–42 for FTD were significantly higher than for case‐controls. Step‐wise discriminant modeling incorporated P‐T181‐tau, P‐S396‐tau, and Aβ1–42 in AD, but only P‐T181‐tau in FTD. Classification of 96.4% of AD patients and 87.5% of FTD patients was correct. In 24 AD patients, exosomal levels of P‐S396‐tau, P‐T181‐tau, and Aβ1–42 were significantly higher than for controls both 1 to 10 years before and when diagnosed with AD. Conclusions Levels of P‐S396‐tau, P‐T181‐tau, and Aβ1–42 in extracts of neurally derived blood exosomes predict the development of AD up to 10 years before clinical onset.

Abstract Introduction The epithelial-mesenchymal transition (EMT) pathway contributes to epithelial ovarian cancer (EOC) progression. Previously we identified associations of single nucleotide polymorphisms (SNPs) in EMT-related genes and EOC risk (data not shown). To further investigate the role of EMT-related gene variants in EOC and to derive more reliable risk estimates, we evaluated associations for 795 SNPs from 278 EMT-related genes in a replication study of 43 studies within the Ovarian Cancer Association Consortium (OCAC). Methods The study population included 14,736 cases and 23,448 controls of European ancestry, 89 cases and 200 controls of African ancestry, and 249 cases and 1574 controls of Asian ancestry. The 795 SNPs were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). For women of European ancestry, both invasive cancers combined and the four main histological subtypes (serous [n=8,372], endometroid [n=2,068], clear cell [n=1,025] and mucinous [n=943] were analyzed, while for women of African and Asian ancestries only the serous subtype was analyzed. SNP analyses were conducted using unconditional logistic regression under a log-additive model separately for women of each ancestry. All analyses were adjusted for study site and population substructure within each ancestry. Results For women of European ancestry, the strongest evidence of an association for invasive cancers combined was observed for IGF1R rs10794486 (OR=1.05, 95%CI=1.02-1.09, P=0.002), which was also associated with serous (P=0.019), but not the other histological subtypes. In the histological subtype-specific analysis, the most significant association for serous was observed at NRP2 rs3771044 (OR=1.09, 95%CI=1.03-1.15, P=0.00014), for endometroid at rs1770247 (13q31.3, OR=1.16, 95%CI=1.07-1.25, P=0.00028), for clear cell at rs4848300 (2q13, OR=0.84, 95%CI=0.76-0.93, P=0.00099) and for mucinous at SEMA4B rs8030039 (OR=1.09, 95%CI=1.01-1.17, P=0.00019). For women of African ancestry, the strongest association for serous histological subtype was observed at F9 rs6048 (OR=1.71, 95%CI=1.17-2.50, P=0.006). This SNP was not significant in women of European or Asian ancestry. The strongest association for women of Asian ancestry was IGF1R rs10794486 (OR=1.68, 95%CI=1.16-2.45, P=0.007), which was also significant in women of European, but not African, ancestry. Conclusion Findings from this large study provide additional evidence that variants in EMT-related genes may be associated with ovarian cancer risk and that EMT susceptibility loci may differ by ovarian cancer histological subtypes. Furthermore, the findings suggest that susceptibility locus for the serous subtype may be different for women of African ancestry. Future studies are warranted to confirm these findings. Citation Format: Ernest K. Amankwah, Jonathan Tyrer, Hui-Yi Lin, Ya-Yu Tsai, Zhihua Chen, Gang Han, Xiaotao Qu, Ellen Goode, Julie Cunninghan, Edward Iverson, Susan Ramus, Andrew Berchuck, Joellen Schildkraut, Alvaro Monteiro, Simon Gayther, Steven Narod, Paul Pharoah, Thomas A. Sellers, Catherine Phelan. Epithelial-mesenchymal transition (EMT) gene variants influence epithelial ovarian cancer risk in women of European, African and Asian ancestry. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1352. doi:10.1158/1538-7445.AM2013-1352

Abstract Background: Circadian rhythms of biological processes are regulated by endogenous clock genes and clock-controlled genes. Aberrant expression of circadian clock genes may have important consequences on the transactivation of downstream targets that control the cell cycle and cellular proliferation potentially promoting carcinogenesis. Animal models indicate that several circadian rhythm genes are expressed in the ovaries, where they influence and are influenced by estrous cycles. The goal of the current study was to examine the association of circadian gene variants and epithelial ovarian cancer (EOC) risk. Methods: Thirty-one SNPs from five circadian genes (i.e., ARNTL, CRY2, KLF10, NPAS2, PER3, TIMELESS) were genotyped in 14,736 cases and 23,448 control women of European ancestry from 43 studies in the Ovarian Cancer Association Consortium (OCAC), on a custom Illumina iSelect designed for the Collaborative Oncological Gene-Environment Study (COGS). Both invasive cancers combined and the four main histological subtypes (serous [n=8,372], endometroid [n=2,068], clear cell [n=1,025] and mucinous [n=943] were analyzed, SNP analyses were conducted using unconditional logistic regression under a log-additive model. All analyses were adjusted for study site and population substructure. Results: Eleven SNPs were found to be associated with ovarian cancer risk. The SNPs most associated with serous cancer risk were KLF10 rs2513928 (OR=.95 p=6.1x10−3), rs2513927 (OR=1.05 p=6.1x10−3), rs2511703 (OR=1.05 p=9.8x10−3), rs3191333 (OR=1.05, p=1.5x10−2) and NPAS2 rs13012930 (OR=.95, p=3.5x10−2). Endometroid cancer risk was significantly associated with ARNTL SNPs rs10732458 (OR=1.3, p=1.0x10−2) and rs7117836 (OR=1.2, p=4.6x10−2), while clear cell cancer risk was associated with ARNTL rs1562438 (OR=.88, p=1.5x10−2), rs1026071 (OR=.89, p=1.8x10−2), and rs3816360 (OR=.91, p=4.8x10−2) and KLF10 rs2388232 (OR=1.1, p=3.3x10−2). No variants were significantly associated with mucinous cancer risk. Four SNPs in KLF10 were associated with cancer invasiveness; they were rs2513928 (OR=.95, p=1.8x10−3), rs3191333 (OR=1.04, p=1.4x10−2), rs2513927 (OR=1.04, p=1.9x10−2), and rs2511703 (OR=1.03, p=2.8x10−2). Conclusions: Data from the current study suggest that polymorphisms in circadian genes ARNTL, KLF10, and NPAS2 are significantly associated with ovarian cancer histopathologic subtypes and invasiveness. These findings merit further investigation and replication. Funding: R01 CA149429 Citation Format: Heather Jim, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Ellen L. Goode, Zhihua Chen, Ya-Yu Tsai, Julie M. Cunningham, Edward Iversen, Susan Ramus, Andrew Berchuck, Joellen Schildkraut, Alvaro Monteiro, Simon Gayther, Steven A. Narod, Thomas A. Sellers, Paul Pharoah, Catherine M. Phelan. Variation in circadian rhythm genes influence epithelial ovarian cancer risk and invasiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4850. doi:10.1158/1538-7445.AM2013-4850 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Abstract Background: Preplanned combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and North Central Cancer Treatment Group (NCCTG) (Alliance) N9831 Trial compared adjuvant chemotherapy with or without trastuzumab in women with HER2-positive breast cancer. The initial results were reported in 2005 and updated in early 2011 Methods: 4045 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The definitive analysis for OS will occur when 710 events have been reported. Results: Median time on study is 8 years. The required number of events have occurred for the definitive analysis for OS to be conducted by the end of September 2012. Updated analyses of disease free survival and related subgroups will also be presented. Supported by NCI grants U10-CA-12027, -69651, -37377, -69974, -44066, U24-CA-114732, CA25224; Breast Cancer Research Foundation; Genentech 35–03 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-5.

Abstract The pivotal roles of the K-RAS and TGFβ signaling pathways have been well characterized in a number of normal and pathological conditions including human cancer. Hyperactivation of the ERBB/KRAS pathway is known to drive neoplastic transformation, tumorigenesis and metastasis in a large percentage of human cancers while the growth inhibitory actions of TGFβ are critical in preventing cancer. A better understanding of the antagonistic interaction and cross-talk between the K-RAS and TGFβ signaling pathways that control tumorigenesis and metastasis may give rise to novel therapeutic interventions. Our previous work has highlight the importance of SIAH2 in K-RAS-dependent tumorigenesis and metastasis in human cancer. In this study, we showed that SMAD2/3/4 – the essential downstream mediators of TGFβ signaling, are new SIAH2 substrates. SIAH2 physically interacts with, ubiquitinates and degrades SMAD2/3/4 (but not SMAD1 – the downstream mediator of the BMP signaling pathway). The identification of the SIAH2-mediated SMAD2/3/4 modulation/degradation may provide an additional mechanism to explain the well documented, but less understood ERBB/K-RAS and TGFβ antagonism described in normal development, tumorigenesis and metastasis. We propose that the tumor promoting activity of RAS/SIAH2 may be mediated through the degradation of SMAD2/3/4 proteins and thus the relief of TGFβ-dependent growth inhibition in response to ERBB/K-RAS activation. The discovery of the SIAH2-SMAD2/3/4 antagonism downstream of K-RAS and TGFβ signaling pathways may provide a novel mode of antagonistic cross-talk between these two important signaling pathways to explain the growth inhibitory action of the TGFβ pathway and the growth-promoting activity of the K-RAS pathway in the genesis, progression and metastasis of human cancer. Since the substrate specificity of ubiquitin-mediated proteolysis is primarily determined by the E3 ligase, our results provide new insights into the role of altered proteolysis in mediating the context-dependent ERBB/RAS-TGFβ antagonism and cross-talk in human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1980. doi:10.1158/1538-7445.AM2011-1980

Targeting a kinase common to both the EGFR and TNFα signaling pathways may prevent drug resistance in glioblastoma.

OBJECTIVES: ImproveCareNow (ICN) is the largest pediatric learning health system in the nation and started as a quality improvement collaborative. To test the feasibility and validity of using ICN data for clinical research, we evaluated the effectiveness of anti-tumor necrosis factor-α (anti-TNFα) agents in the management of pediatric Crohn disease (CD). METHODS: Data were collected in 35 pediatric gastroenterology practices (April 2007 to March 2012) and analyzed as a sequence of nonrandomized trials. Patients who had moderate to severe CD were classified as initiators or non-initiators of anti-TNFα therapy. Among 4130 patients who had pediatric CD, 603 were new users and 1211 were receiving anti-TNFα therapy on entry into ICN. RESULTS: During a 26-week follow-up period, rate ratios obtained from Cox proportional hazards models, adjusting for patient and disease characteristics and concurrent medications, were 1.53 (95% confidence interval [CI], 1.20–1.96) for clinical remission and 1.74 (95% CI, 1.33–2.29) for corticosteroid-free remission. The rate ratio for corticosteroid-free remission was comparable to the estimate produced by the adult SONIC study, which was a randomized controlled trial on the efficacy of anti-TNFα therapy. The number needed to treat was 5.2 (95% CI, 3.4–11.1) for clinical remission and 5.0 (95% CI, 3.4–10.0) for corticosteroid-free remission. CONCLUSIONS: In routine pediatric gastroenterology practice settings, anti-TNFα therapy was effective at achieving clinical and corticosteroid-free remission for patients who had Crohn disease. Using data from the ICN learning health system for the purpose of observational research is feasible and produces valuable new knowledge.