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1.  RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis 
Cell Death and Differentiation  2014;21(7):1061-1070.
Aerobic glycolysis or the Warburg effect contributes to cancer cell proliferation; however, how this glucose metabolism pathway is precisely regulated remains elusive. Here we show that receptor-interacting protein 1 (RIP1), a cell death and survival signaling factor, regulates mitochondrial oxidative phosphorylation and aerobic glycolysis. Loss of RIP1 in lung cancer cells suppressed peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression, impairing mitochondrial oxidative phosphorylation and accelerating glycolysis, resulting in spontaneous DNA damage and p53-mediated cell proliferation inhibition. Thus, although aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis causes cytostasis. Our data suggest that maintenance of glycolysis by RIP1 is pivotal to cancer cell energy homeostasis and DNA integrity and may be exploited for use in anticancer therapy.
doi:10.1038/cdd.2014.25
PMCID: PMC4207474  PMID: 24583643
receptor-interacting protein 1; metabolism; PGC-1α; glycolysis; oxidative phosphorylation; DNA damage
2.  Association between daily cigarette consumption and hypertension moderated by CYP2A6 genotypes in Chinese male current smokers 
Journal of human hypertension  2012;27(1):24-30.
The purpose of this study was to assess whether cytochrome P450 enzyme 2A6 (CYP2A6) genotypes moderate the association between smoking and hypertension. In this study, 954 Chinese male current smokers from a community-based chronic disease screening project in Guangzhou were interviewed with a structured questionnaire about socio-demographic status, smoking and other health-related behaviors. Blood was collected for DNA extraction and CYP2A6 genotyping. Hypertension was defined according to 2007 ESH-ESC Practice Guidelines. A multivariate logistic regression was performed to examine the interaction between smoking quantity and CYP2A6 genotypes on hypertension after adjusting for age, education level and other potential confounders. Multivariate analyses indicated that smoking more than 15 cigarettes per day significantly increased the risk of hypertension (odds ratio (OR)=1.59, 95% confidence interval (CI)=1.21-2.10) compared with smoking 1-15 cigarettes per day, and further suggested that smoking interacted with normal CYP2A6 metabolizer genotype to increase the risk of hypertension. Smokers consuming more than 15 cigarettes per day with normal CYP2A6 metabolizer genotypes had the highest risk of hypertension (OR=2.04, 95% CI=1.11-3.75) compared with those consuming 1-15 cigarettes per day with slower CYP2A6 metabolizer genotypes. These findings demonstrated that smoking quantity was positively associated with hypertension and that CYP2A6 genotypes may moderate this relationship.
doi:10.1038/jhh.2011.111
PMCID: PMC4128783  PMID: 22217675
cigarette smoking; CYP2A6; genetic polymorphisms; interaction
3.  KLF4 functions as an activator of the androgen receptor through reciprocal feedback 
Oncogenesis  2016;5(12):e282-.
In prostate cancer, Krüppel-like factor 4 (KLF4) depletion occurs frequently, suggesting a role as suppressor tumor. KLF4 is a transcription factor associated with androgen receptor (AR) expression; however, its cellular functions and signaling regulation mechanism remain largely unknown. In this study, we demonstrated that activated AR binds to the KLF4 promoter and enhances KLF4 expression, which reciprocally targets the AR promoter, thus sustaining KLF4 activity. Ectopic KLF4 expression in androgen-independent prostate cancer cells induced AR expression and decreased cell proliferation, invasion and bone metastasis. We previously showed that increased microRNA (miR)-1 expression is associated with reduced bone metastasis of prostate cancer cells. Here we observed that KLF4 targets the primary miR-1-2 stem-loop promoter and stimulates miR-1 expression. In clinical prostate cancer specimens, KLF4 levels were positively correlated with miR-1 and AR levels. These data suggest that the loss of KLF4 expression is one mechanistic link between aggressive prostate cancer progression and low canonical AR output through miR-1 inactivation.
doi:10.1038/oncsis.2016.79
PMCID: PMC5177777  PMID: 27991915
4.  Olfactomedin 4 deletion induces colon adenocarcinoma in ApcMin/+ mice 
Oncogene  2016;35(40):5237-5247.
Colon carcinogenesis is a multiple-step process involving the accumulation of a series of genetic and epigenetic alterations. The most commonly initiating event of intestinal carcinogenesis is mutation of the adenomatous polyposis coli (APC) gene, which leads to activation of the Wnt/β-catenin pathway. Olfactomedin 4 (OLFM4) has emerged as an intestinal stem-cell marker, but its biological function in the intestine remains to be determined. Here we show that Olfm4 deletion induced colon adenocarcinoma in the distal colon of ApcMin/+ mice. Mechanistically, we found that OLFM4 is a target gene of the Wnt/β-catenin pathway and can downregulate β-catenin signaling by competing with Wnt ligands for binding to Frizzled receptors, as well as by inhibition of the Akt-GSK-3β (Akt-glycogen synthase kinase-3β) pathway. We have shown that both Wnt and nuclear factor-κB (NF-κB) signaling were boosted in tumor tissues of Apc Olfm4 double-mutant mice. These data establish OLFM4 as a critical negative regulator of the Wnt/β-catenin and NF-κB pathways that inhibits colon-cancer development initiated by APC mutation. In addition, Olfm4 deletion significantly enhanced intestinal-crypt proliferation and inflammation induced by azoxymethane/dextran sodium sulfate. Thus, OLFM4 has an important role in the regulation of intestinal inflammation and tumorigenesis, and could be a potential therapeutic target for intestinal malignant tumors. Unlike the human colonic epithelium, the mouse colonic epithelium does not express OLFM4, but nevertheless, systemic OLFM4 deletion promotes colon tumorigenesis and that loss from mucosal neutrophils may have a role to play.
doi:10.1038/onc.2016.58
PMCID: PMC5057043  PMID: 26973250
5.  SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment 
Sun, Y | Zhu, D | Chen, F | Qian, M | Wei, H | Chen, W | Xu, J
Oncogene  2016;35(33):4321-4334.
Most tumors initially respond to cytotoxic treatments, but acquired resistance often follows. The tumor microenvironment (TME) is a major barrier to clinical success by compromising therapeutic efficacy, and pathological relevance of multiple soluble factors released by a therapeutically remodeled TME remains largely unexplored. Here we show that the secreted frizzled-related protein 2 (SFRP2), a Wnt pathway modulator, is produced by human primary fibroblasts after genotoxic treatments. SFRP2 induction is remarkable in tumor stroma, with transcription mainly modulated by the nuclear factor-κB (NF-κB) complex, a property shared by several effectors of the DNA damage secretory program. Instead of directly altering canonical Wnt signaling, SFRP2 augments β-catenin activities initiated by WNT16B, another soluble factor from DNA-damaged stroma. WNT16B recognizes cancer cell surface receptors including frizzled (FZD) 3/4/6, a process enhanced by SFRP2, coordinated by the co-receptor LRP6 but subject to abrogation by DKK1. Importantly, we found WNT16B plays a central role in promoting advanced malignancies particularly acquired resistance by counteracting cell death, an effect that can be minimized by a neutralizing antibody co-administered with classical chemotherapy. Furthermore, DNA damage-triggered expression of WNT16B is systemic, imaged by significant induction among diverse solid organs and circulation in peripheral blood, thereby holding promise as not only a TME-derived anticancer target but also a novel biomarker for clinical evaluation of treatment efficacy. Overall, our study substantiates the biological complexity and pathological implication of a therapy-activated TME, and provides the proof of principle of co-targeting tumor and the TME to prevent acquired resistance, with the aim of improving intervention outcome in an era of precision medicine.
doi:10.1038/onc.2015.494
PMCID: PMC4994019  PMID: 26751775
6.  Study of cardiovascular function using a coupled left ventricle and systemic circulation model 
Journal of Biomechanics  2016;49(12):2445-2454.
To gain insight into cardio-arterial interactions, a coupled left ventricle-systemic artery (LV–SA) model is developed that incorporates a three-dimensional finite-strain left ventricle (LV), and a physiologically-based one-dimensional model for the systemic arteries (SA). The coupling of the LV model and the SA model is achieved by matching the pressure and the flow rate at the aortic root, i.e. the SA model feeds back the pressure as a boundary condition to the LV model, and the aortic flow rate from the LV model is used as the input for the SA model. The governing equations of the coupled system are solved using a combined immersed-boundary finite-element (IB/FE) method and a Lax–Wendroff scheme. A baseline case using physiological measurements of healthy subjects, and four exemplar cases based on different physiological and pathological scenarios are studied using the LV–SA model. The results of the baseline case agree well with published experimental data. The four exemplar cases predict varied pathological responses of the cardiovascular system, which are also supported by clinical observations. The new model can be used to gain insight into cardio-arterial interactions across a range of clinical applications.
doi:10.1016/j.jbiomech.2016.03.009
PMCID: PMC5038162  PMID: 27040388
Cardiovascular modelling; Left ventricle; Systemic circulation; Fluid–structure interaction; Cardio-arterial coupling
7.  Interactive Cohort Identification of Sleep Disorder Patients Using Natural Language Processing and i2b2 
Applied Clinical Informatics  2015;6(2):345-363.
Summary
Nationwide Children’s Hospital established an i2b2 (Informatics for Integrating Biology & the Bedside) application for sleep disorder cohort identification. Discrete data were gleaned from semistructured sleep study reports. The system showed to work more efficiently than the traditional manual chart review method, and it also enabled searching capabilities that were previously not possible.
Objective
We report on the development and implementation of the sleep disorder i2b2 cohort identification system using natural language processing of semi-structured documents.
Methods
We developed a natural language processing approach to automatically parse concepts and their values from semi-structured sleep study documents. Two parsers were developed: a regular expression parser for extracting numeric concepts and a NLP based tree parser for extracting textual concepts. Concepts were further organized into i2b2 ontologies based on document structures and in-domain knowledge.
Results
26,550 concepts were extracted with 99% being textual concepts. 1.01 million facts were extracted from sleep study documents such as demographic information, sleep study lab results, medications, procedures, diagnoses, among others. The average accuracy of terminology parsing was over 83% when comparing against those by experts. The system is capable of capturing both standard and non-standard terminologies. The time for cohort identification has been reduced significantly from a few weeks to a few seconds.
Conclusion
Natural language processing was shown to be powerful for quickly converting large amount of semi-structured or unstructured clinical data into discrete concepts, which in combination of intuitive domain specific ontologies, allows fast and effective interactive cohort identification through the i2b2 platform for research and clinical use.
doi:10.4338/ACI-2014-11-RA-0106
PMCID: PMC4493335  PMID: 26171080
Sleep disorder; cohort identification; natural language processing (NLP); i2b2; clinical ontology
8.  Assessing Specific Sexual Behavior: Instrument Development and Validation Techniques 
Through the use of multi-modal methods, the purpose of this study was to develop and assess measurement properties of an instrument evaluating specific sexual behaviors of college students and the role alcohol intoxication plays in one’s intention to participate in these behaviors. A modified version of N. Krause’s instrument development process was applied to create a behavior-specific instrument assessing oral, vaginal, and anal sex behaviors. The process included a review by expert scholars in relevant fields, cognitive interviews with the target population using screen-capture program Camtasia, piloting to assess measurement scales, and a formal investigation. The applied instrument development process employed screen capture software and web-based surveying in a cost-effective format suitable for mixed-method measurement development. The development and application of the instrument provides a clearer understanding of the relationship between alcohol use and sexual activity and aids in the development of effective public health interventions and policies.
PMCID: PMC4825870  PMID: 27066593
sexuality; sexual behavior; alcohol use; instrument development; instrument validation; college students
9.  Prehospital Aspirin Use Is Associated with Reduced Risk of Acute Respiratory Distress Syndrome in Critically Ill Patients: A Propensity-Adjusted Analysis 
Critical care medicine  2015;43(4):801-807.
Objectives
Platelet activation plays an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). In our prior study of 575 patients at high risk for ARDS, concurrent statin and aspirin use was associated with reduced ARDS. However, the largest study (n=3855) to date found no significant benefit of prehospital aspirin in a lower risk population when adjusted for the propensity for aspirin use. We aimed to determine whether prehospital aspirin use is associated with decreased ARDS in patients at high risk for ARDS after adjusting for the propensity to receive aspirin.
Design
Secondary analysis of patients enrolled prospectively in the Validating Acute Lung Injury Markers for Diagnosis (VALID) study.
Patients
A total of 1149 critically ill patients (age ≥ 40) admitted to the medical or surgical intensive care units of an academic tertiary care hospital including 575 previously reported patients as well as additional patients who were enrolled after completion of the prior statin and aspirin study.
Intervention
None
Measurements and Results
Of 1149 patients, 368 (32%) developed ARDS during the first four ICU days and 287 (25%) patients had prehospital aspirin use. Patients with prehospital aspirin had significantly lower incidence of ARDS (27% vs. 34%, p=0.034). In a multivariable, propensity-adjusted analysis including age, gender, race, sepsis and APACHE II, prehospital aspirin use was associated with a decreased risk of ARDS (OR 0.66, 95% CI 0.46-0.94) in the entire cohort and in a subgroup of 725 patients with sepsis (OR 0.60, 95% CI 0.41-0.90).
Conclusions
In this selected cohort of critically ill patients, prehospital aspirin use was independently associated with a decreased risk of ARDS even after adjusting for the propensity of pre-hospital aspirin use. These findings support the need for prospective clinical trials to determine whether aspirin may be beneficial for the prevention of clinical ARDS.
doi:10.1097/CCM.0000000000000789
PMCID: PMC4359645  PMID: 25559436
10.  Hepatitis B virus infection is associated with gastric cancer in China: an endemic area of both diseases 
British Journal of Cancer  2015;112(7):1283-1290.
Background:
Hepatitis B virus (HBV) infection was demonstrated to be a risk factor of several cancers of the digestive system. In addition, liver cirrhosis, which could possibly result from chronic HBV infection, was associated with a higher risk of gastric cancer. However, the association of HBV infection and gastric cancer has not been investigated.
Methods:
A retrospective case–control study with 580 cases and 580 controls matched for age, sex and year of diagnosis was conducted. The associations between gastric cancer and HBV infection were explored with univariate and multivariate unconditional logistic regression analysis.
Results:
Hepatitis B surface antigen (HBsAg) was positively associated with gastric cancer (AOR (95% CI): 1.49 (1.06–2.10)). This association remained significant in patients without family history of gastric cancer (AOR (95% CI): (1.06–2.11)). For HBsAg-negative population, being anti-HBc positive/anti-HBs negative, which possibly indicated occult HBV infection, was also found to have some associations with gastric cancer. In addition, some synergistic effects between HBV infection and blood type A in gastric cancer were identified.
Conclusions:
The HBV infection was positively related with gastric cancer, especially for patients without family history of gastric cancer. Further prospective studies are warranted to confirm this relationship.
doi:10.1038/bjc.2014.406
PMCID: PMC4385949  PMID: 25695484
hepatitis B virus; gastric cancer; risk factor; ABO blood group
11.  A new insight into high-strength Ti62Nb12.2Fe13.6Co6.4Al5.8 alloys with bimodal microstructure fabricated by semi-solid sintering 
Scientific Reports  2016;6:23467.
It is well known that semi-solid forming could only obtain coarse-grained microstructure in a few alloy systems with a low melting point, such as aluminum and magnesium alloys. This work presents that semi-solid forming could also produce novel bimodal microstructure composed of nanostructured matrix and micro-sized (CoFe)Ti2 twins in a titanium alloy, Ti62Nb12.2Fe13.6Co6.4Al5.8. The semi-solid sintering induced by eutectic transformation to form a bimodal microstructure in Ti62Nb12.2Fe13.6Co6.4Al5.8 alloy is a fundamentally different approach from other known methods. The fabricated alloy exhibits high yield strength of 1790 MPa and plastic strain of 15.5%. The novel idea provides a new insight into obtaining nano-grain or bimodal microstructure in alloy systems with high melting point by semi-solid forming and into fabricating high-performance metallic alloys in structural applications.
doi:10.1038/srep23467
PMCID: PMC4814828  PMID: 27029858
12.  Which measures of adiposity predict subsequent left ventricular geometry? Evidence from the Bogalusa Heart Study 
Background and aims
Left ventricular (LV) hypertrophy increases the risk of future cardiovascular events. The relationship between obesity in young adulthood and later LV geometry is unknown. We examined the association between long-term changes in measures of adiposity and subsequent LV geometry among 1073 young adults from the Bogalusa Heart Study.
Methods and results
Echocardiography-measured LV geometry was classified into normal (N = 796), concentric remodeling (N = 124), eccentric hypertrophy (N = 99), and concentric hypertrophy (N = 54) by integrating relative wall thickness and LV mass index. The mean age of our population was 38 years when the LV geometry was measured. Body mass index (BMI) increased by a mean of 4.9 kg/m2 over a median of 20 years, waist circumference (WC) by 10.9 cm over 17 years, waist/hip ratio by 0.02 over 10 years, waist/height ratio by 0.06 over 17 years, abdominal height by 0.9 cm over 10 years, body fat (BF) percentage by 12.7% over 20 years, and Visceral Adiposity Index by 0.30 over 17 years. In polytomous logistic regression models corrected for multiple comparisons, participants with one-standard-deviation increases in BMI,WC, waist/height ratio, and BF had 2.00 (95% confidence interval (CI): 1.53–2.61), 1.33 (1.06–1.68), 1.35 (1.07–1.70), and 1.60 (1.26–2.03) times the risk of eccentric hypertrophy, respectively, after adjustment for demographic, lifestyle, metabolic risk factors, and follow-up time. Likewise, the rates of change in BMI, WC, waist/height ratio, and BF were associated with eccentric hypertrophy. There was no association with concentric remodeling or concentric hypertrophy.
Conclusions
Our findings suggest that increases in BMI, WC, waist/height ratio, and BF were strong predictors of eccentric hypertrophy in middle age.
doi:10.1016/j.numecd.2014.11.001
PMCID: PMC4417354  PMID: 25534865
Left ventricular geometry; Obesity; Epidemiology
13.  Characterizing the Activation of the Wnt Signaling Pathway in Hilar Cholangiocarcinoma Using a Tissue Microarray Approach 
Hilar cholangiocarcinoma (HCCA) is an invasive hepatic malignancy that is difficult to biopsy; therefore, novel markers of HCCA prognosis are needed. Here, the level of canonical Wnt activation in patients with HCCA, intrahepatic cholangiocarcinoma (IHCC), and congenital choledochal cysts (CCC) was compared to understand the role of Wnt signaling in HCCA. Pathology specimens from HCCA (n=129), IHCC (n=31), and CCC (n=45) patients were used to construct tissue microarrays. Wnt2, Wnt3, β-catenin, TCF4, c-Myc, and cyclin D1 were detected by immunohistochemistry. Parallel correlation analysis was used to analyze differences in protein levels between the HCCA, IHCC, and CCC groups. Univariate and multivariate analyses were used to determine independent predictors of successful resection and prognosis in the HCCA group. The protein levels of Wnt2, β-catenin, TCF4, c-Myc, and cyclin D1 were significantly higher in HCCA compared to IHHC or CCC. Wnt signaling activation (Wnt2+, Wnt3+, nuclear β-catenin+, nuclear TCF4+) was significantly greater in HCCA tissues than CCC tissues. Univariable analyses indicated that expression of cyclin D1 as well as Wnt signaling activation, and partial Wnt activation (Wnt2+ or Wnt3+ and nuclear β-catenin+ or nuclear TCF4+) predicted successful resection, but only cyclin D1 expression remained significant in multivariable analyses. Only partial Wnt activation was an independent predictor of survival time. Proteins in the canonical Wnt signaling pathway were present at higher levels in HCCA and correlated with tumor resecility and patient prognosis. These results suggest that Wnt pathway analysis may be a useful marker for clinical outcome in HCCA.
doi:10.4081/ejh.2016.2536
PMCID: PMC4800245  PMID: 26972709
Hilar cholangiocarcinoma; Wnt signaling pathway; tissue microarray; β-catenin; c-Myc; cyclin D1
14.  Attenuation of the programmed cell death-1 pathway increases the M1 polarization of macrophages induced by zymosan 
Chen, W | Wang, J | Jia, L | Liu, J | Tian, Y
Cell Death & Disease  2016;7(2):e2115-.
Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals on interaction with its 2 ligands, PD-L1 and PD-L2. We assessed the contribution of the PD-1 pathway to regulating the polarization of macrophages that promote inflammation induced by zymosan. We found that PD-1−/− mice developed robust peritonitis with more abundant infiltration of M1 macrophages, accompanied by higher levels of pro-inflammation factors, especially monocyte chemotactic protein-1 (MCP-1) compared with wild-type controls ex vivo and in vitro. Our results indicated that PD-1 deficiency promotes M1 rather than M2 polarization of macrophages by enhancing the expression of p-STAT1/p-NF-κB p65 and downregulating p-STAT6. We found that PD-1 engagement followed by zymosan stimulation might primarily attenuate the phosphorylation of tyrosine residue in PD-1 receptor/ligand and the recruitment of SHP-2 to PD-1 receptor/ligand, leading to the reduction of M1 type cytokine production.
doi:10.1038/cddis.2016.33
PMCID: PMC4849159  PMID: 26913605
15.  Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation 
Oncogenesis  2016;5(2):e198-.
Although carcinoma-associated fibroblasts (CAFs) in tumor microenvironments have a critical role in immune cell modulation, their effects on the generation of regulatory dendritic cells (DCs) are still unclear. In this study, we initially show that CAFs derived from hepatocellular carcinoma (HCC) tumors facilitate the generation of regulatory DCs, which are characterized by low expression of costimulatory molecules, high suppressive cytokines production and enhanced regulation of immune responses, including T-cell proliferation impairment and promotion of regulatory T-cell (Treg) expansion via indoleamine 2,3-dioxygenase (IDO) upregulation. Our findings also indicate that STAT3 activation in DCs, as mediated by CAF-derived interleukin (IL)-6, is essential to IDO production. Moreover, IDO inhibitor, STAT3 and IL-6 blocking antibodies can reverse this hepatic CAF-DC regulatory function. Therefore, our results provide new insights into the mechanisms by which CAFs induce tumor immune escape as well as a novel cancer immunotherapeutic approach (for example, targeting CAFs, IDO or IL-6).
doi:10.1038/oncsis.2016.7
PMCID: PMC5154347  PMID: 26900950
16.  CRISPR/Cas9 facilitates investigation of neural circuit disease using human iPSCs: mechanism of epilepsy caused by an SCN1A loss-of-function mutation 
Liu, J | Gao, C | Chen, W | Ma, W | Li, X | Shi, Y | Zhang, H | Zhang, L | Long, Y | Xu, H | Guo, X | Deng, S | Yan, X | Yu, D | Pan, G | Chen, Y | Lai, L | Liao, W | Li, Z
Translational Psychiatry  2016;6(1):e703-.
Mutations in SCN1A, the gene encoding the α subunit of Nav1.1 channel, can cause epilepsies with wide ranges of clinical phenotypes, which are associated with the contrasting effects of channel loss-of-function or gain-of-function. In this project, CRISPR/Cas9- and TALEN-mediated genome-editing techniques were applied to induced pluripotent stem cell (iPSC)-based-disease model to explore the mechanism of epilepsy caused by SCN1A loss-of-function mutation. By fluorescently labeling GABAergic subtype in iPSC-derived neurons using CRISPR/Cas9, we for the first time performed electrophysiological studies on SCN1A-expressing neural subtype and monitored the postsynaptic activity of both inhibitory and excitatory types. We found that the mutation c.A5768G, which led to no current of Nav1.1 in exogenously transfected system, influenced the properties of not only Nav current amount, but also Nav activation in Nav1.1-expressing GABAergic neurons. The two alterations in Nav further reduced the amplitudes and enhanced the thresholds of action potential in patient-derived GABAergic neurons, and led to weakened spontaneous inhibitory postsynaptic currents (sIPSCs) in the patient-derived neuronal network. Although the spontaneous excitatory postsynaptic currents (sEPSCs) did not change significantly, when the frequencies of both sIPSCs and sEPSCs were further analyzed, we found the whole postsynaptic activity transferred from the inhibition-dominated state to excitation in patient-derived neuronal networks, suggesting that changes in sIPSCs alone were sufficient to significantly reverse the excitatory level of spontaneous postsynaptic activity. In summary, our findings fill the gap of our knowledge regarding the relationship between SCN1A mutation effect recorded on exogenously transfected cells and on Nav1.1-expressing neurons, and reveal the physiological basis underlying epileptogenesis caused by SCN1A loss-of-function mutation.
doi:10.1038/tp.2015.203
PMCID: PMC5068877  PMID: 26731440
17.  Aberrant expression of microRNAs as biomarker for schizophrenia: from acute state to partial remission, and from peripheral blood to cortical tissue 
Translational Psychiatry  2016;6(1):e717-.
Based on our previous finding of a seven-miRNA (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) signature as a potential biomarker for schizophrenia, this study aimed to examine if hospitalization could affect expressions of these miRNAs. We compared their expression levels between acute state and partial remission state in people with schizophrenia (n=48) using quantitative PCR method. Further, to examine whether the blood and brain show similar expression patterns, the expressions of two miRNAs (hsa-miR-34a and hsa-miR-548d) were examined in the postmortem brain tissue of people with schizophrenia (n=25) and controls (n=27). The expression level of the seven miRNAs did not alter after ~2 months of hospitalization with significant improvement in clinical symptoms, suggesting the miRNAs could be traits rather than state-dependent markers. The aberrant expression seen in the blood of hsa-miR-34a and hsa-miR-548d were not present in the brain samples, but this does not discount the possibility that the peripheral miRNAs could be clinically useful biomarkers for schizophrenia. Unexpectedly, we found an age-dependent increase in hsa-miR-34a expressions in human cortical (Brodmann area 46 (BA46)) but not subcortical region (caudate putamen). The correlation between hsa-miR-34a expression level in BA46 and age was much stronger in the controls than in the cases, and the corresponding correlation in the blood was only seen in the cases. The association between the miRNA dysregulations, the disease predisposition and aging warrants further investigation. Taken together, this study provides further insight on the candidate peripheral miRNAs as stable biomarkers for the diagnostics of schizophrenia.
doi:10.1038/tp.2015.213
PMCID: PMC5068884  PMID: 26784971
18.  Overexpression of myeloid differentiation protein 88 in mice induces mild cardiac dysfunction, but no deficit in heart morphology 
Cardiac remodeling involves changes in heart shape, size, structure, and function after injury to the myocardium. The proinflammatory adaptor protein myeloid differentiation protein 88 (MyD88) contributes to cardiac remodeling. To investigate whether excessive MyD88 levels initiate spontaneous cardiac remodeling at the whole-organism level, we generated a transgenic MyD88 mouse model with a cardiac-specific promoter. MyD88 mice (male, 20-30 g, n=∼80) were born at the expected Mendelian ratio and demonstrated similar morphology of the heart and cardiomyocytes with that of wild-type controls. Although heart weight was unaffected, cardiac contractility of MyD88 hearts was mildly reduced, as shown by echocardiographic examination, compared with wild-type controls. Moreover, the cardiac dysfunction phenotype was associated with elevation of ANF and BNP expression. Collectively, our data provide novel evidence of the critical role of balanced MyD88 signaling in maintaining physiological function in the adult heart.
doi:10.1590/1414-431X20154794
PMCID: PMC4681416  PMID: 26628395
Cardiac dysfunction; Cardiac remodeling; Transgenic mice; Myeloid differentiation protein 88
19.  Pre-Chemoradiotherapy FDG PET/CT cannot Identify Residual Metabolically-Active Volumes within Individual Esophageal Tumors 
Objective
To study whether subvolumes with a high pre-chemoradiotherapy (CRT) FDG uptake could identify residual metabolically-active volumes (MAVs) post-CRT within individual esophageal tumors. Accurate identification will allow simultaneous integrated boost to these subvolumes at higher risk to improve clinical outcomes.
Methods
Twenty patients with esophageal cancer were treated with CRT plus surgery and underwent FDG PET/CT scans before and after CRT. The two scans were rigidly registered. Seven MAVs pre-CRT and four MAVs post-CRT within a tumor were defined with various SUV thresholds. The similarity and proximity between the MAVs pre-CRT and post-CRT were quantified with three metrics: fraction of post-CRT MAV included in pre-CRT MAV, volume overlap and centroid distance.
Results
Eight patients had no residual MAV. Six patients had local residual MAV (SUV ≥2.5 post-CRT) within or adjoining the original MAV (SUV ≥2.5 pre-CRT). On average, less than 65% of any post-CRT MAVs was included in any pre-CRT MAVs, with a low volume overlap <45%, and large centroid distance >8.6 mm. In general, subvolumes with higher FDG-uptake pre-CRT or post-CRT had lower volume overlap and larger centroid distance. Six patients had new distant MAVs that were determined to be inflammation from radiation therapy.
Conclusions
Pre-CRT PET/CT cannot reliably identify the residual MAVs within individual esophageal tumors. Simultaneous integrated boost to subvolumes with high FDG uptake pre-CRT may not be feasible.
doi:10.4172/2155-9619.1000226
PMCID: PMC4652953  PMID: 26594591
18F-FDG PET/CT; Esophageal cancer; Radiation therapy
20.  MicroRNA-183 promotes proliferation and invasion in oesophageal squamous cell carcinoma by targeting programmed cell death 4 
British Journal of Cancer  2014;111(10):2003-2013.
Background:
Dysregulated microRNAs (miRNAs) can serve as oncogenes or suppressors and are associated with many cancers, including oesophageal squamous cell carcinoma (ESCC).
Methods:
An alignment miRNA array was used to identify differentially expressed miRNAs in ESCC tissues. The expression of miR-183 and programmed cell death 4 (PDCD4) in oesophageal tissues from ESCC and early oesophageal carcinoma patients was examined by quantitative reverse transcriptase PCR and western blotting. A luciferase assay was performed to confirm miR-183 target genes. The effects of miR-183 on ESCC cells and the associated mechanisms were established by in vitro experiments.
Results:
We identified 51 upregulated miRNAs and 17 downregulated miRNAs in our array, and miR-183 was one of the most upregulated miRNAs. An inverse correlation between miR-183 and PDCD4 levels was found in ESCC tissues. Upregulated expression of miR-183 was not correlated with tumour stage or lymphatic metastasis in ESCC patients. The luciferase assay confirmed that miR-183 directly interacted with the PDCD4 mRNA 3′-untranslated region in ESCC cells. Overexpression of miR-183 led to decreased PDCD4 protein levels and promoted ESCC cell proliferation and invasion. Inhibition of the PI3K/Akt signalling pathway increased PDCD4 protein levels and decreased miR-183 expression in ESCC cells.
Conclusions:
MiR-183 promotes ESCC cell proliferation and invasion by directly targeting PDCD4, which suggests that it is involved in the pathogenesis of ESCC.
doi:10.1038/bjc.2014.485
PMCID: PMC4229630  PMID: 25211657
microRNA-183; oesophageal squamous cell carcinoma; oesophageal intraepithelial neoplasia; programmed cell death 4; tumour progression
21.  Effect of flaxseed on the fatty acid profile of egg yolk and antioxidant status of their neonatal offspring in Huoyan geese 
Animal  2015;9(11):1749-1755.
The aim of this study was to evaluate the effects of geese’s maternal diet supplemented with flaxseed on the fatty acid profiles of egg yolks and the antioxidant status of their offspring. A total of 288 female Huoyan geese (42 weeks old) were randomly allotted to four experimental groups in this 56-day experiment and fed on diets containing flaxseed at 0% (control), 5%, 10% and 15%, respectively. There were nine replicate pens per treatment, with eight geese per replicate pen. The concentration of α-linolenic acid (linear, P<0.01), EPA (20:5n-3; linear, P<0.01), DHA (22:6n-3; quadratic, P=0.03) and n-3 polyunsaturated fatty acid (PUFA) (linear, P<0.01) levels in the yolk lipids increased with increasing dietary flaxseed levels. Yolk palmitic acid (16:0, linear, P=0.05), saturated fatty acid (linear, P=0.04) level and total n-6/n-3 ratio (P<0.01) decreased in a linear fashion as dietary flaxseed levels increased. Increasing dietary flaxseed levels linearly decreased (P=0.01) the total cholesterol in egg yolks. After hatching, three 1-day-old gosling were selected randomly from each replicate to determine blood characteristics and liver antioxidant status. Aspartate aminotransferase activity (linear, P=0.03), total triglycerides (linear, P=0.02) and total cholesterol (linear, P=0.05) contents in blood linearly decreased as the levels of flaxseed increased. A linear dose response to maternal dietary flaxseed was detected for the activities of the goslings’ liver enzymes catalase (linear, P=0.01), superoxide dismutase (linear, P<0.01) and glutathione peroxidase (linear, P<0.01). The malondialdehyde (quadratic, P=0.03) and alkaline phosphatase content in the livers of goslings decreased as flaxseed supplementation levels increased. In conclusion, the dietary addition of flaxseed up to 15%, in the maternal diet resulted in increased n-3 PUFA levels in egg yolks and improved the antioxidant status of offspring in a dose-dependent manner.
doi:10.1017/S1751731115001287
PMCID: PMC4609985  PMID: 26173627
antioxidant status; flaxseed; n-3 polyunsaturated fatty acid; goose
22.  Arizona Alzheimer's Registry: Strategy and Outcomes of a Statewide Research Recruitment Registry 
BACKGROUND
The Arizona Alzheimer's Consortium (AAC) created the Arizona Alzheimer's Registry, a screening and referral process for people interested in participating in Alzheimer's disease related research. The goals of the Registry were to increase awareness of Alzheimer's disease research and accelerate enrollment into AAC research studies.
METHODS
Participation was by open invitation to adults 18 and older. Those interested provided consent and completed a written questionnaire. A subset of Registrants underwent an initial telephone cognitive assessment. Referral to AAC sites was based on medical history, telephone cognitive assessment, and research interests.
RESULTS
A total of 1257 people consented and 1182 underwent an initial cognitive screening. Earned media (38.7%) was the most effective recruitment strategy. Participants had a mean age of 68.1 (SD 10.6), 97% were Caucasian, had 15.2 (SD 2.7) mean years of education, and 60% were female. 30% reported a family history of dementia and 70% normal cognition. Inter-rater agreement between self-reported memory status and the initial telephone cognitive assessment had a kappa of 0.31-0.43. 301 were referred to AAC sites.
CONCLUSION
IThe Registry created an infrastructure and process to screen and refer a high volume of eager Registrants. These methods were found to be effective at prescreening individuals for studies, which facilitated AAC research recruitment. The established infrastructure and experiences gained from the Registry have served as the prototype for the web-based Alzheimer's Prevention Registry, a national registry focusing on Alzheimer's disease prevention research.
doi:10.14283/jpad.2014.1
PMCID: PMC4610410  PMID: 26491650
Alzheimer's disease; registry; prevention; recruitment
23.  Prevalence and risk factors of diabetes and impaired fasting glucose among university applicants in Eastern China: findings from a population-based study 
Aims
To investigate the prevalence and risk factors of diabetes and impaired fasting glucose among urban university applicants in Eastern China.
Method
The study uses data from the annual health examination among all students finishing high school who applied for university entrance in Changzhou City in 2012. In total, 6716 students aged 17–19 years had fasting blood glucose, alanine transaminase, height, weight and blood pressure measured. Impaired fasting glucose and diabetes were defined as fasting blood glucose ≥ 5.6 mmol/l (but < 7 mmol/l) and ≥ 7 mmol/l, respectively.
Results
The overall prevalence of impaired fasting glucose and diabetes was 2.40% and 0.13%, respectively (3.67% and 0.09% in boys; 1.09% and 0.18% in girls). In total, 20.9% of boys and 10.6% of girls were overweight/obese. High socio-economic status was associated with an increased risk of diabetes / impaired fasting glucose, but the association was significant only among boys (adjusted odds ratio 1.94, 95% CI 1.26–2.98). Alanine transaminase levels were significantly and positively related to diabetes / impaired fasting glucose risk. Overweight / obesity was significantly associated with increased risk of impaired fasting glucose/diabetes in girls, but not in boys. Moreover, the number of the above-mentioned risk factors (i.e. overweight/obesity, elevated alanine transaminase, pre-hypertension) was significantly and positively related to diabetes / impaired fasting glucose among both boys and girls.
Conclusions
Impaired fasting glucose was prevalent among urban university applicants, in particular boys and those of high socio-economic status in eastern China. Elevated levels of liver function enzyme appear to be the strongest risk factor for diabetes / impaired fasting glucose.
doi:10.1111/dme.12473
PMCID: PMC4167969  PMID: 24766092
24.  Inferring outcrossing in the homothallic fungus Sclerotinia sclerotiorum using linkage disequilibrium decay 
Heredity  2014;113(4):353-363.
The occurrence and frequency of outcrossing in homothallic fungal species in nature is an unresolved question. Here we report detection of frequent outcrossing in the homothallic fungus Sclerotinia sclerotiorum. In using multilocus linkage disequilibrium (LD) to infer recombination among microsatellite alleles, high mutation rates confound the estimates of recombination. To distinguish high mutation rates from recombination to infer outcrossing, 8 population samples comprising 268 S. sclerotiorum isolates from widely distributed agricultural fields were genotyped for 12 microsatellite markers, resulting in multiple polymorphic markers on three chromosomes. Each isolate was homokaryotic for the 12 loci. Pairwise LD was estimated using three methods: Fisher's exact test, index of association (IA) and Hedrick's D′. For most of the populations, pairwise LD decayed with increasing physical distance between loci in two of the three chromosomes. Therefore, the observed recombination of alleles cannot be simply attributed to mutation alone. Different recombination rates in various DNA regions (recombination hot/cold spots) and different evolutionary histories of the populations could explain the observed differences in rates of LD decay among the chromosomes and among populations. The majority of the isolates exhibited mycelial incompatibility, minimizing the possibility of heterokaryon formation and mitotic recombination. Thus, the observed high intrachromosomal recombination is due to meiotic recombination, suggesting frequent outcrossing in these populations, supporting the view that homothallism favors universal compatibility of gametes instead of traditionally believed haploid selfing in S. sclerotiorum. Frequent outcrossing facilitates emergence and spread of new traits such as fungicide resistance, increasing difficulties in managing Sclerotinia diseases.
doi:10.1038/hdy.2014.37
PMCID: PMC4181068  PMID: 24781807
25.  RILP suppresses invasion of breast cancer cells by modulating the activity of RalA through interaction with RalGDS 
Wang, Z | Zhou, Y | Hu, X | Chen, W | Lin, X | Sun, L | Xu, X | Hong, W | Wang, T
Cell Death & Disease  2015;6(10):e1923-.
RILP (Rab7-interacting lysosomal protein) is a key regulator for late endosomal/lysosomal trafficking, and probably a tumor suppressor in prostate cancer. However, the role of RILP in other cancers and the underlying mechanism for RILP in regulating the invasion of cancer cells remain to be investigated. In this study, we showed that overexpression of RILP in breast cancer cells inhibits the migration and invasion, whereas the depletion of RILP by RNAi-mediated knockdown promotes the migration and invasion. We identified RalGDS (Ral guanine nucleotide dissociation stimulator) as a novel interacting partner for RILP, and truncation analysis revealed the N-terminal region of RILP is responsible for interacting with the guanine nucleotide exchange factor (GEF) domain of RalGDS. Immunofluorescence microscopy revealed that RalGDS can be recruited to the late endosomal compartments by RILP. Further investigations indicated that the overexpression of RILP inhibits the activity of RalA, a downstream target of RalGDS. Our data suggest that RILP suppresses the invasion of breast cancer cells by interacting with RalGDS to inhibit its GEF activity for RalA.
doi:10.1038/cddis.2015.266
PMCID: PMC4632296  PMID: 26469971

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