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1.  Cognitive trio: relationship with major depression and clinical predictors in Han Chinese women 
Psychological Medicine  2013;43(11):2265-2275.
Previous studies support Beck's cognitive model of vulnerability to depression. However, the relationship between his cognitive triad and other clinical features and risk factors among those with major depression (MD) has rarely been systematically studied.
The three key cognitive symptoms of worthlessness, hopelessness and helplessness were assessed during their lifetime worst episode in 1970 Han Chinese women with recurrent MD. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
Compared to patients who did not endorse the cognitive trio, those who did had a greater number of DSM-IV A criteria, more individual depressive symptoms, an earlier age at onset, a greater number of episodes, and were more likely to meet diagnostic criteria for melancholia, postnatal depression, dysthymia and anxiety disorders. Hopelessness was highly related to all the suicidal symptomatology, with ORs ranging from 5.92 to 6.51. Neuroticism, stressful life events (SLEs) and a protective parental rearing style were associated with these cognitive symptoms.
During the worst episode of MD in Han Chinese women, the endorsement of the cognitive trio was associated with a worse course of depression and an increased risk of suicide. Individuals with high levels of neuroticism, many SLEs and high parental protectiveness were at increased risk for these cognitive depressive symptoms. As in Western populations, symptoms of the cognitive trio appear to play a central role in the psychopathology of MD in Chinese women.
PMCID: PMC3807662  PMID: 23425530
Cognitive trio; Han Chinese women; major depression; suicide; symptoms
2.  The structure of the symptoms of major depression: exploratory and confirmatory factor analysis in depressed Han Chinese women 
Psychological Medicine  2013;44(7):1391-1401.
The symptoms of major depression (MD) are clinically diverse. Do they form coherent factors that might clarify the underlying nature of this important psychiatric syndrome?
Symptoms at lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ⩾30 years with recurrent DSM-IV MD. Exploratory factor analysis (EFA) and confirmatoryfactor analysis (CFA) were performed in Mplus in random split-half samples.
The preliminary EFA results were consistently supported by the findings from CFA. Analyses of the nine DSM-IV MD symptomatic A criteria revealed two factors loading on: (i) general depressive symptoms; and (ii) guilt/suicidal ideation. Examining 14 disaggregated DSM-IV criteria revealed three factors reflecting: (i) weight/appetite disturbance; (ii) general depressive symptoms; and (iii) sleep disturbance. Using all symptoms (n = 27), we identified five factors that reflected: (i) weight/appetite symptoms; (ii) general retarded depressive symptoms; (iii) atypical vegetative symptoms; (iv) suicidality/hopelessness; and (v) symptoms of agitation and anxiety.
MD is a clinically complex syndrome with several underlying correlated symptom dimensions. In addition to a general depressive symptom factor, a complete picture must include factors reflecting typical/atypical vegetative symptoms, cognitive symptoms (hopelessness/suicidal ideation), and an agitated symptom factor characterized by anxiety, guilt, helplessness and irritability. Prior cross-cultural studies, factor analyses of MD in Western populations and empirical findings in this sample showing risk factor profiles similar to those seen in Western populations suggest that our results are likely to be broadly representative of the human depressive syndrome.
PMCID: PMC3967839  PMID: 23920138
Atypical symptoms; China; cognitive symptoms; depression; factor analysis
5.  Immune Response to Tissue Restricted Self-Antigens Induces Airway Inflammation and Fibrosis Following Murine Lung Transplantation 
Immune responses against lung-associated self-antigens (self-Ags) are hypothesized to play a role in the development of chronic lung graft rejection. We determined whether immune responses to lung self-Ags, K-alpha-1-tubulin (Kα1T) and Collagen V (Col-V) in the absence of alloimmunity, could promote airway inflammation and fibrosis. Following syngeneic murine orthotopic lung transplantation (LTx) we administered antibodies (Abs) to either Kα1T or Col-V or in combination to both of these self-Ags. As compared to recipients of isotype control Abs Kα1T Abs and/or Col-V Abs-treated recipients had marked lung graft cellular infiltration and bronchiolar fibrosis, This inflammation was also associated the accumulation of Kα1T and Col-V specific IFN-γ+ and IL-17+ T cells. Notably, the administration of Abs to Kα1T led to cellular and humoral immune responses to Col-V prior to development of fibrosis, and vice versa, indicating that epitope spreading can occur rapidly in an alloantigen independent manner. Collectively, these data support a model of chronic lung transplant rejection where the progressive loss of self-tolerance through epitope spreading promotes airway fibrosis. Strategies that target autoreactive Abs may be useful to inhibit chronic rejection of lung grafts.
PMCID: PMC4169463  PMID: 25220332
6.  Disruption of mGluR5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders 
Molecular psychiatry  2015;20(10):1161-1172.
Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv+) fast-spiking interneurons, have been proposed as underlying causes of several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv+ GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv+ interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv+ interneurons resulted in reduced numbers of Pv+ neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv+ neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders.
PMCID: PMC4583365  PMID: 26260494
7.  COUP-TFII regulates metastasis of colorectal adenocarcinoma cells by modulating Snail1 
Bao, Y | Gu, D | Feng, W | Sun, X | Wang, X | Zhang, X | Shi, Q | Cui, G | Yu, H | Tang, C | Deng, A
British Journal of Cancer  2014;111(5):933-943.
Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII, also known as NR2F2) promotes metastasis by functioning in the tumour microenvironment; however, the role of COUP-TFII in colorectal cancer remains unknown.
Human colon adenocarcinoma tissues were collected to test COUP-TFII expression. Wound-healing and cell invasion assay were used to evaluate migration and invasion of cells. Chicken ovalbumin upstream promoter-transcription factor II and related protein expression was assessed by immunostaining, immunoblotting and real-time PCR assay. Tamoxifen-inducible COUP-TFII knockout mice were employed to test COUP-TFII functions on colon cancer metastasis in vivo.
Elevated expression of COUP-TFII in colorectal adenocarcinoma tissue correlated with overexpression of the Snail1 transcription factor. High COUP-TFII expression correlated with metastasis and shorter patient survival. Chicken ovalbumin upstream promoter-transcription factor II regulated the migration and invasion of cancer cells. With Snail1, COUP-TFII inhibited expression of adherence molecules such as ZO-1, E-cadherin and β-catenin in colorectal cancer cells. Overexpression of COUP-TFII was required for cancer cells to metastasise in vivo. Chicken ovalbumin upstream promoter-transcription factor II regulated the transcription and expression of Snail1 by directly targeting the Snail1 promoter and regulated associated genes.
Chicken ovalbumin upstream promoter-transcription factor II was crucial for colorectal cancer metastasis and regulated cell migration and metastasis in conjunction with Snail1. Chicken ovalbumin upstream promoter-transcription factor II was found to be a biomarker associated with patient survival and colorectal cancer metastasis.
PMCID: PMC4150277  PMID: 25032732
COUP-TFII; colorectal adenocarcinoma; metastasis; Snail family transcription factors
8.  Cell Type-specific Translational Profiling in the Xenopus laevis Retina 
Translating Ribosome Affinity Purification (TRAP), a method recently developed to generate cell type-specific translational profiles, relies on creating transgenic lines of animals in which a tagged ribosomal protein is placed under regulatory control of a cell type-specific promoter. An antibody is then used to affinity purify the tagged ribosomes so that cell type-specific mRNAs can be isolated from whole tissue lysates.
Here, cell type-specific transgenic lines were generated to enable TRAP studies for retinal ganglion cells and rod photoreceptors in the Xenopus laevis retina. Using real time quantitative PCR for assessing expression levels of cell type-specific mRNAs, the TRAP method was shown to selectively isolate mRNAs expressed in the targeted cell and was efficient at purifying mRNAs expressed at both high and low levels. Statistical measures used to distinguish cell type-specific RNAs from low level background and non-specific RNAs showed TRAP to be highly effective in Xenopus.
TRAP can be used to purify mRNAs expressed in rod photoreceptors and retinal ganglion cells in Xenopus laevis. The generated transgenic lines will enable numerous studies into the development, disease and injury of the Xenopus laevis retina.
PMCID: PMC4536902  PMID: 23074098
Xenopus laevis; Translating ribosome affinity purification; TRAP; retina; rod photoreceptor cells; retinal ganglion cells; cell type-specific transgenic lines
9.  Quantitative analysis of clinically relevant mutations occurring in lymphoid cells harboring γ-retrovirus-encoded hsvtk suicide genes 
Gene therapy  2008;15(21):1454-1459.
The in vivo regulation of T lymphocyte activity by the activation of a suicide mechanism is an essential paradigm for the safety of adoptive cell therapies. In light of reports showing that γ-retroviral vector-encoded herpes simplex virus thymidine kinase (hsvtk) undergoes recombination, we undertook a thorough investigation of the genomic stability of SFG-based vectors using two variants of the wild-type hsvtk gene. In a large panel of independent clones, we demonstrate that both hsvtk genes undergo recombination with molecular signatures indicative of template switching in GC-rich regions displaying homology at the deletion junctions or RNA splicing. In the absence of ganciclovir selection, the frequency of recombination is 3% per retroviral replication cycle. Our results underscore the importance of the five nucleotide difference between the two hsvtk genes that account for the presence of recombinogenic hot spots in one variant and not the other, indicating that the probability of RNA splicing is influenced by minute nucleotide changes in sequences adjacent to the splice donor and acceptor sites. Furthermore, our mutational analysis in an unbiased panel of human lymphoid cells (that is, without immune or ganciclovir-mediated selective pressure) provides a robust in vitro assay to predict and quantify clinically relevant mutations in hsvtk suicide genes, which can be applied to studying and improving the stability of any transgene expressed in γ-retroviral or lentiviral vectors.
PMCID: PMC4528371  PMID: 18563185
γ-retroviral vector; hsvtk genes; variants; deletions; rearrangements; rate of mutation
10.  Metastatic Melanoma Induced Metabolic Changes in C57BL/6J Mouse Stomach Measured by 1H NMR Spectroscopy 
Wang, X | Hu, M | Liu, M | Hu, JZ
Metabolomics : open access  2014;4(2):1000135.
Melanoma is a malignant tumor of melanocytes with high capability of invasion and rapid metastasis to other organs. Malignant melanoma is the most common metastatic malignancy found in Gastrointestinal Tract (GI). In this work, the 1H NMR-based metabolomics approach is used to investigate the metabolite profile differences of stomach tissue extracts of metastatic B16-F10 melanoma and control groups in C57BL/6J mouse and to search for specific metabolite biomarker candidates. Principal Component Analysis (PCA), an unsupervised multivariate data analysis method, is used to detect possible outliers, while Orthogonal Projection to Latent Structure (OPLS), a supervised multivariate data analysis method, is employed to evaluate important metabolites responsible for discriminating the control and the melanoma groups. Both PCA and OPLS results reveal that the melanoma group can be well separated from its control group. Among the 50 identified metabolites, it is found that the concentrations of 19 metabolites are significantly changed with the levels of O-phosphocholine and hypoxanthine down-regulated while the levels of isoleucine, leucine, valine, isobutyrate, threonine, cadaverine, alanine, glutamate, glutamine, methionine, citrate, asparagine, tryptophan, glycine, serine, uracil, and formate up-regulated in the melanoma group. These significantly changed metabolites are associated with multiple biological pathways and may be potential biomarkers for metastatic melanoma in stomach.
PMCID: PMC4523238  PMID: 26246958
1H NMR Metabolomics; B16-F10 melanoma; Stomach; Metabolomics; Multivariate analysis; OPLS; PCA
11.  Association of Carotid Intima–media Thickness and Atherosclerotic Plaque with Periodontal Status 
Journal of Dental Research  2014;93(8):744-751.
Studies have suggested an association between clinical/subclinical atherosclerosis and periodontal status. The purpose of this study was to investigate the association among maximal carotid intima–media thickness (cIMT), atherosclerotic plaque, and periodontal status in Chinese elderly patients. A cross-sectional study was conducted of 847 participants (age, 70.64 ± 9.03 yr) with ≥10 teeth. A questionnaire survey, routine biochemical tests, a periodontal examination, and maximal cIMT measurement were performed for each. Traditional risk factors for atherogenesis were considered in the statistical analysis. Mean plaque index, which reflects oral hygiene, was correlated with maximal cIMT and atherosclerotic plaque in the study sample overall (β = 0.068, p < .001; OR = 2.051, p < .001) and in euglycemic participants (β = 0.066, p = .008; odds ratio = 2.122, p = .009). In hyperglycemic participants, multiple linear regression analysis (p = .006) and multivariate logistic regression analysis (p = .025) revealed a linear and dose-dependent association between mean clinical attachment loss and maximal cIMT after adjustment for traditional risk factors. Each 1-mm increase in mean clinical attachment loss corresponded to a 0.018-mm increase in maximal cIMT. The risk of atherosclerotic plaque increased by 18.3% with each 1-mm increase in mean clinical attachment loss. Other indicators of periodontal exposure, including percentage of sites with attachment loss ≥ 3 to 5 mm (3%-5%), were also correlated with cIMT and atherosclerotic plaque in hyperglycemic patients. In this elderly population, a linear and dose-dependent association among mean clinical attachment loss, attachment loss 3% to 5%, maximal cIMT, and atherosclerotic plaque was verified in those with hyperglycemia. Poor oral hygiene was correlated with maximal cIMT and atherosclerotic plaque in all participants, including those with normal blood glucose.
PMCID: PMC4293759  PMID: 24935064
atherosclerosis; periodontitis; periodontal attachment loss; oral hygiene; hyperglycemia; cardiovascular diseases
12.  Effects of L-tryptophan, Fructan, and Casein on Reducing Ammonia, Hydrogen Sulfide, and Skatole in Fermented Swine Manure 
The effects of daily dietary Bacillus subtilis (Bs), and adding L-tryptophan, fructan, or casein to fecal fermentation broths were investigated as means to reduce the production of noxious gas during manure fermentation caused by ammonia, hydrogen sulfide (H2S), and 3-methylindole (skatole). Eighty swine (50.0±0.5 kg) were equally apportioned to an experimental group given Bs in daily feed, or a control group without Bs. After 6 weeks, fresh manure was collected from both groups for fermentation studies using a 3×3 orthogonal array, in which tryptophan, casein, and fructan were added at various concentrations. After fermentation, the ammonia, H2S, L-tryptophan, skatole, and microflora were measured. In both groups, L-tryptophan was the principle additive increasing skatole production, with significant correlation (r = 0.9992). L-tryptophan had no effect on the production of ammonia, H2S, or skatole in animals fed Bs. In both groups, fructan was the principle additive that reduced H2S production (r = 0.9981). Fructan and Bs significantly interacted in H2S production (p = 0.014). Casein was the principle additive affecting the concentration of ammonia, only in the control group. Casein and Bs significantly interacted in ammonia production (p = 0.039). The predominant bacteria were Bacillus spp. CWBI B1434 (26%) in the control group, and Streptococcus alactolyticus AF201899 (36%) in the experimental group. In summary, daily dietary Bs reduced ammonia production during fecal fermentation. Lessening L-tryptophan and increasing fructan in the fermentation broth reduced skatole and H2S.
PMCID: PMC4478490  PMID: 26104530
Swine Manure; L-tryptophan; Fructan; Casein; Ammonia; H2S; Skatole; B. subtilis
13.  Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy 
Cell Death and Differentiation  2014;21(8):1209-1217.
The mitochondrial phosphate carrier (PiC) is critical for ATP synthesis by serving as the primary means for mitochondrial phosphate import across the inner membrane. In addition to its role in energy production, PiC is hypothesized to have a role in cell death as either a component or a regulator of the mitochondrial permeability transition pore (MPTP) complex. Here, we have generated a mouse model with inducible and cardiac-specific deletion of the Slc25a3 gene (PiC protein). Loss of PiC protein did not prevent MPTP opening, suggesting it is not a direct pore-forming component of this complex. However, Slc25a3 deletion in the heart blunted MPTP opening in response to Ca2+ challenge and led to a greater Ca2+ uptake capacity. This desensitization of MPTP opening due to loss or reduction in PiC protein attenuated cardiac ischemic-reperfusion injury, as well as partially protected cells in culture from Ca2+ overload induced death. Intriguingly, deletion of the Slc25a3 gene from the heart long-term resulted in profound hypertrophy with ventricular dilation and depressed cardiac function, all features that reflect the cardiomyopathy observed in humans with mutations in SLC25A3. Together, these results demonstrate that although the PiC is not a direct component of the MPTP, it can regulate its activity, suggesting a novel therapeutic target for reducing necrotic cell death. In addition, mice lacking Slc25a3 in the heart serve as a novel model of metabolic, mitochondrial-driven cardiomyopathy.
PMCID: PMC4085527  PMID: 24658400
14.  Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis 
Cell Death and Differentiation  2014;21(8):1303-1312.
Non-alcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA) and hepatocyte lipoapoptosis. This lipoapoptosis requires increased JNK phosphorylation and activation of the pro-apoptotic BH3-only proteins Bim and PUMA. Kelch-like ECH-associated protein (Keap)-1 is a BTB/Kelch protein that can regulate the expression of Bcl-2 protein and control apoptotic cell death. Yet, the role of Keap1 in hepatocyte lipotoxicity is unclear. Here we demonstrate that Keap1 protein was rapidly degraded in hepatocytes, through autophagy in a p62-dependent manner, in response to the toxic saturated FFA palmitate, but not following incubation with the non-toxic FFA oleic acid. Stable knockdown of Keap1 expression, using shRNA technology, in hepatocarcinoma cell lines induced spontaneous cell toxicity that was associated with JNK1-dependent upregulation of Bim and PUMA protein levels. Also, Keap1 knockdown further sensitized hepatocytes to lipoapoptosis by palmitate. Likewise, primary hepatocytes isolated from liver-specific Keap1−/− mice displayed higher Bim and PUMA protein levels and demonstrated increased sensitivity to palmitate-induced apoptosis than wild-type mouse hepatocytes. Finally, stable knockdown of Bim or PUMA expression prevented cell toxicity induced by loss of Keap1. These results implicate p62-dependent autophagic degradation of Keap1 by palmitate as a mechanism contributing to hepatocyte lipoapoptosis.
PMCID: PMC4085536  PMID: 24769730
15.  Using next-generation RNA sequencing to identify imprinted genes 
Heredity  2014;113(2):156-166.
Genomic imprinting is manifested as differential allelic expression (DAE) depending on the parent-of-origin. The most direct way to identify imprinted genes is to directly score the DAE in a context where one can identify which parent transmitted each allele. Because many genes display DAE, simply scoring DAE in an individual is not sufficient to identify imprinted genes. In this paper, we outline many technical aspects of a scheme for identification of imprinted genes that makes use of RNA sequencing (RNA-seq) from tissues isolated from F1 offspring derived from the pair of reciprocal crosses. Ideally, the parental lines are from two inbred strains that are not closely related to each other. Aspects of tissue purity, RNA extraction, library preparation and bioinformatic inference of imprinting are all covered. These methods have already been applied in a number of organisms, and one of the most striking results is the evolutionary fluidity with which novel imprinted genes are gained and lost within genomes. The general methodology is also applicable to a wide range of other biological problems that require quantification of allele-specific expression using RNA-seq, such as cis-regulation of gene expression, X chromosome inactivation and random monoallelic expression.
PMCID: PMC4105452  PMID: 24619182
16.  Decreased autophagy: a major factor for cardiomyocyte death induced by β1-adrenoceptor autoantibodies 
Wang, L | Hao, H | Wang, J | Wang, X | Zhang, S | Du, Y | Lv, T | Zuo, L | Li, Y | Liu, H
Cell Death & Disease  2015;6(8):e1862-.
Cardiomyocyte death is one major factor in the development of heart dysfunction, thus, understanding its mechanism may help with the prevention and treatment of this disease. Previously, we reported that anti-β1-adrenergic receptor autoantibodies (β1-AABs) decreased myocardial autophagy, but the role of these in cardiac function and cardiomyocyte death is unclear. We report that rapamycin, an mTOR inhibitor, restored cardiac function in a passively β1-AAB-immunized rat model with decreased cardiac function and myocardial autophagic flux. Next, after upregulating or inhibiting autophagy with Beclin-1 overexpression/rapamycin or RNA interference (RNAi)-mediated expression of Beclin-1/3-methyladenine, β1-AAB-induced autophagy was an initial protective stress response before apoptosis. Then, decreased autophagy contributed to cardiomyocyte death followed by decreases in cardiac function. In conclusion, proper regulation of autophagy may be important for treating patients with β1-AAB-positive heart dysfunction.
PMCID: PMC4558518  PMID: 26313913
17.  MicroRNA-26a supports mammalian axon regeneration in vivo by suppressing GSK3β expression 
Cell Death & Disease  2015;6(8):e1865-.
MicroRNAs are emerging to be important epigenetic factors that control axon regeneration. Here, we report that microRNA-26a (miR-26a) is a physiological regulator of mammalian axon regeneration in vivo. We demonstrated that endogenous miR-26a acted to target specifically glycogen synthase kinase 3β (GSK3β) in adult mouse sensory neurons in vitro and in vivo. Inhibition of endogenous miR-26a in sensory neurons impaired axon regeneration in vitro and in vivo. Moreover, the regulatory effect of miR-26a was mediated by increased expression of GSK3β because downregulation or pharmacological inhibition of GSK3β fully rescued axon regeneration. Our results also suggested that the miR-26a-GSK3β pathway regulated axon regeneration at the neuronal soma by controlling gene expression. We provided biochemical and functional evidences that the regeneration-associated transcription factor Smad1 acted downstream of miR-26a and GSK3β to control sensory axon regeneration. Our study reveals a novel miR-26a-GSK3β-Smad1 signaling pathway in the regulation of mammalian axon regeneration. Moreover, we provide the first evidence that, in addition to inhibition of GSK3β kinase activity, maintaining a lower protein level of GSK3β in neurons by the microRNA is necessary for efficient axon regeneration.
PMCID: PMC4558520  PMID: 26313916
18.  Retina Is Protected by Neuroserpin from Ischemic/Reperfusion-Induced Injury Independent of Tissue-Type Plasminogen Activator 
PLoS ONE  2015;10(7):e0130440.
The purpose of the present study was to investigate the potential neuroprotective effect of neuroserpin (NSP) on acute retinal ischemic/reperfusion-induced (IR) injury. An IR injury model was established by elevating intraocular pressure (IOP) for 60 minutes in wild type and tPA-deficient (tPA-/-) mice. Prior to IR injury, 1 μL of 20 μmol/L NSP or an equal volume of bovine serum albumin (BSA) was intravitreally administered. Retinal function was evaluated by electroretinograph (ERG) and the number of apoptotic neurons was determined via TUNEL labeling. Caspase-3, -8, -9,poly (ADP-ribose) polymerase (PARP)and their cleaved forms were subsequently analyzed. It was found that IR injury significantly damaged retinal function, inducing apoptosis in the retina, while NSP attenuated the loss of retinal function and significantly reduced the number of apoptotic neurons in both wild type and tPA-/- mice. The levels of cleaved caspase-3, cleaved PARP (the substrate of caspase-3) and caspase-9 (the modulator of the caspase-3), which had increased following IR injury, were significantly inhibited by NSP in both wild type and tPA-/- mice. NSP increased ischemic tolerance in the retina at least partially by inhibiting the intrinsic cell death signaling pathway of caspase-3. It was therefore concluded that the protective effect of neuroserpin maybe independent from its canonical interaction with a tissue-type plasminogen activator.
PMCID: PMC4503687  PMID: 26176694
19.  Hemodynamics in the Cephalic Arch of a Brachiocephalic Fistula 
Medical engineering & physics  2014;36(7):822-830.
The care and outcome of patients with end stage renal disease (ESRD) on chronic hemodialysis is directly dependent on their hemodialysis access. A brachiocephalic fistula (BCF) is commonly placed in the elderly and in patients with a failed lower-arm, or radiocephalic, fistula. However, there are numerous complications such that the BCF has an average patency of only 3.6 years. A leading cause of BCF dysfunction and failure is stenosis in the arch of the cephalic vein near its junction with the axillary vein, which is called cephalic arch stenosis (CAS). Using a combined clinical and computational investigation, we seek to improve our understanding of the cause of CAS, and to develop a means of predicting CAS risk in patients with a planned BCF access. This paper details the methodology used to determine the hemodynamic consequences of the post-fistula environment and illustrates detailed results for a representative sample of patient-specific anatomies, including a single, bifurcated, and trifurcated arch. It is found that the high flows present due to fistula creation lead to secondary flows in the arch owing to its curvature with corresponding low wall shear stresses. The abnormally low wall shear stress locations correlate with the development of stenosis in the singular case that is tracked in time for a period of one year.
PMCID: PMC4063319  PMID: 24695337
brachiocephalic; fistula; cephalic arch; intimal hyperplasia; stenosis
20.  Patterns of Symptom Burden During Radiation Therapy or Concurrent Chemoradiation for Head and Neck Cancer: A Prospective Analysis Using the MD Anderson Symptom Inventory–Head and Neck Module 
Cancer  2014;120(13):1975-1984.
We performed a prospective longitudinal study to profile patient-reported symptoms during radiation therapy (RT) or concurrent chemoradiation (CCRT) for head and neck cancer. The goals were to understand the onset and trajectory of specific symptoms and their severity, identify clusters, and to facilitate symptom interventions and clinical trial design.
Participants in this questionnaire-based study received RT or CCRT. They completed the MD Anderson Symptom Inventory—Head and Neck Module before and weekly during treatment. Symptom scores were compared between treatment groups, and hierarchical cluster analysis was used to depict clustering of symptoms at treatment end. Variables thought to predict symptom severity were assessed using a multivariate mixed model.
Among the 149 patients studied, most (47%) had oropharyngeal tumors, and nearly half received CCRT. Overall symptom severity (P<0.001) and symptom interference (P<0.0001) became progressively more severe and were more severe for those receiving CCRT. On multivariate analysis, baseline performance status (P<0.001) and receipt of CCRT (P<0.04) correlated with higher symptom severity. Fatigue, drowsiness, lack of appetite, problem with mouth/throat mucus, and problem tasting food were more severe for those receiving CCRT. Both local and systemic symptom clusters were identified.
Our findings from this prospective longitudinal study identified a pattern of local and systemic symptoms, symptom clusters, and symptom interference that was temporally distinct and marked by increased magnitude and a shift in individual symptom rank order during the treatment course. These inform us about symptom intervention needs, and are a benchmark for future symptom intervention clinical trials.
PMCID: PMC4095802  PMID: 24711162
Symptoms; patient-reported outcomes; radiation; chemoradiation; head and neck cancer
21.  Human Papillomavirus (HPV)-associated Oral Cancers and Treatment Strategies 
Journal of Dental Research  2014;93(7 Suppl):29S-36S.
Human papillomavirus (HPV) is known to be associated with several types of human cancer, including cervical, vulvar, vaginal, penile, anal, and head-and-neck cancers. Among these cancers, HPV-associated head-and-neck cancers, inclusive of oropharyngeal squamous cell carcinoma (OSCC) and oral cavity squamous cell carcinomas (OCSCC), have recently risen dramatically in men under 50 years old. Within 20 years, the percentage of HPV-positive OSCC in total OSCC went from less than 20% to more than 70% in the United States and some European countries. This article reviews the incidence trend and pathogenesis of HPV-associated head-and-neck cancers as well as current treatment modalities for the disease.
PMCID: PMC4107541  PMID: 24663683
head-and-neck cancer; oropharyngeal squamous cell carcinoma (OSCC); treatment of head-and-neck cancers; HPV vaccine; oral pathology; oral neoplasia
22.  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.
PMCID: PMC4207474  PMID: 24583643
receptor-interacting protein 1; metabolism; PGC-1α; glycolysis; oxidative phosphorylation; DNA damage
23.  Donor Height in Combination With Islet Donor Score Improves Pancreas Donor Selection for Pancreatic Islet Isolation and Transplantation 
Transplantation proceedings  2014;46(6):1972-1974.
To maximize the islet isolation yield for successful islet transplantation, the key task has been to identify an ideal pancreas donor. Since implementation of the islet donor score in donor selection, we have consistently obtained higher islet yields and transplantation rates. In this study, we tested whether assessing donor height as an independent variable in combination with the donor score could improve the pancreas donor selection. Donor and islet isolation information (n = 22) were collected and studied between 2011 and 2012. Pearson correlation analysis was used in statistical analysis. Donor height as an independent variable was significantly correlated to the weight of the pancreas, pre-Islet Equivalents (pre-IEQ), post-IEQ, and IDS (P <.05). When donor with height of 179 cm ± 3 was selected in combination with IDS > 80, the clinical islet transplantation rate reached 80%.
PMCID: PMC4435932  PMID: 25131085
24.  Suppression of epithelial–mesenchymal transition and apoptotic pathways by miR-294/302 family synergistically blocks let-7-induced silencing of self-renewal in embryonic stem cells 
Cell Death and Differentiation  2014;22(7):1158-1169.
The embryonic stem cell (ESC)-enriched miR-294/302 family and the somatic cell-enriched let-7 family stabilizes the self-renewing and differentiated cell fates, respectively. The mechanisms underlying these processes remain unknown. Here we show that among many pathways regulated by miR-294/302, the combinatorial suppression of epithelial–mesenchymal transition (EMT) and apoptotic pathways is sufficient in maintaining the self-renewal of ESCs. The silencing of ESC self-renewal by let-7 was accompanied by the upregulation of several EMT regulators and the induction of apoptosis. The ectopic activation of either EMT or apoptotic program is sufficient in silencing ESC self-renewal. However, only combined but not separate suppression of the two programs inhibited the silencing of ESC self-renewal by let-7 and several other differentiation-inducing miRNAs. These findings demonstrate that combined repression of the EMT and apoptotic pathways by miR-294/302 imposes a synergistic barrier to the silencing of ESC self-renewal, supporting a model whereby miRNAs regulate complicated cellular processes through synergistic repression of multiple targets or pathways.
PMCID: PMC4572863  PMID: 25501598
25.  Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells 
Cell Death and Differentiation  2015;22(7):1181-1191.
Tunneling nanotubes (TNTs) are F-actin-based membrane tubes that form between cells in culture and in tissues. They mediate intercellular communication ranging from electrical signalling to the transfer of organelles. Here, we studied the role of TNTs in the interaction between apoptotic and healthy cells. We found that pheochromocytoma (PC) 12 cells treated with ultraviolet light (UV) were rescued when cocultured with untreated PC12 cells. UV-treated cells formed a different type of TNT with untreated PC12 cells, which was characterized by continuous microtubule localized inside these TNTs. The dynamic behaviour of mCherry-tagged end-binding protein 3 and the accumulation of detyrosinated tubulin in these TNTs indicate that they are regulated structures. In addition, these TNTs show different biophysical properties, for example, increased diameter allowing dye entry, prolonged lifetime and decreased membrane fluidity. Further studies demonstrated that microtubule-containing TNTs were formed by stressed cells, which had lost cytochrome c but did not enter into the execution phase of apoptosis characterized by caspase-3 activation. Moreover, mitochondria colocalized with microtubules in TNTs and transited along these structures from healthy to stressed cells. Importantly, impaired formation of TNTs and untreated cells carrying defective mitochondria were unable to rescue UV-treated cells in the coculture. We conclude that TNT-mediated transfer of functional mitochondria reverse stressed cells in the early stages of apoptosis. This provides new insights into the survival mechanisms of damaged cells in a multicellular context.
PMCID: PMC4572865  PMID: 25571977

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