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1.  microRNA-106a modulates cisplatin sensitivity by targeting PDCD4 in human ovarian cancer cells 
Oncology Letters  2013;7(1):183-188.
microRNAs (miRNAs/miRs) are a cluster of short non-protein coding RNAs that negatively regulate gene expression, which is involved in fundamental cellular processes, including the response of tumor cells to chemotherapeutic agents. The present study investigated the role of miR-106a in the development of drug resistance in ovarian cancer cells. The expression of miR-106a in the ovarian cancer OVCAR3 cell line and the cisplatin (CDDP)-resistant ovarian cancer OVCAR3/CIS cell line was detected using stem-loop quantitative (q)PCR. The OVCAR3 and OVCAR3/CIS cells were transfected with mimics or inhibitors of miR-106a or with negative control (NC) RNA using lipofectamine 2000. Luciferase reporter assays were used to determine whether PDCD4 was a direct target of miR-106a in the OVCAR3 cells. The expression levels of the PDCD4 proteins were assessed using qRT-PCR and western blotting, respectively. Drug sensitivity was analyzed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, while apoptosis was determined by fluorescence-activating cell sorting analysis. The expression levels of miR-106a were upregulated in the CDDP-resistant ovarian cancer OVCAR3/CIS cell line compared with the parental OVCAR3 cell line. However, the PDCD4 protein levels were decreased in the OVCAR3/CIS cells compared with the OVCAR3 cells. The luciferase reporter assays revealed that PDCD4 was a direct miR-106a target in the OVCAR3 cells. Transfection of the OVCAR3/CIS cells with inhibitors of miR-106a enhanced the sensitivity of the OVCAR3/CIS cells to CDDP and increased CDDP-induced apoptosis. The expression of the PDCD4 protein and the sensitivity to CDDP was decreased in the OVCAR3 cells that were transfected with the mimics of miR-106a. The knockdown of PDCD4 expression using PDCD4-specific siRNAs in the OVCAR3 cells demonstrated that PDCD4 is a key signaling molecule in OVCAR3 cell CDDP-induced resistance. miR-106a may be involved in the development of drug resistance and the regulation of PDCD4 expression, at least in part, by modulating CDDP-induced apoptosis in ovarian cancer cells.
doi:10.3892/ol.2013.1644
PMCID: PMC3861584  PMID: 24348845
microRNA-106a; drug resistance; PDCD4; ovarian cancer
2.  Chromatin Remodeling Factor LSH is Upregulated by the LRP6-GSK3β-E2F1 Axis Linking Reversely with Survival in Gliomas 
Theranostics  2017;7(1):132-143.
The signaling pathway-based stratification in chromatin modification could predict clinical outcome more reliably than morphology-alone-based classification schemes in gliomas. Here we reported a role of the chromatin-remodeling factor lymphoid-specific helicase (LSH) in gliomas. Among astrocytomas of grade I to III and glioblastoma of grade IV, LSH were almost completely expressed in all cases, and strongly correlated with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Ectopic expression of LSH promoted tumor formation. Up-regulation of transcription factor E2F1 in astrocytomas and glioblastoma was associated with the progression of gliomas and correlated with LSH expression. Chromatin immunoprecipitation (ChIP) analysis showed transcription factor E2F1 were recruited to the promoter region of LSH, and depletion of E2F1 decreased LSH expression and cell growth. Moreover, glycogen synthase kinase-3β (GSK-3β), an intact complex of E2F1, were also highly expressed in astrocytomas and linked with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Inhibition of GSK3β increased the enrichment of E2F1 to the LSH promoter, in turn, increased LSH expression. Lipoprotein receptor-related protein 6 (LRP6), an upstream regulator of GSK3β signaling pathway, was highly expressed in gliomas. Knockdown of LRP6 decreased LSH expression through decrease of recruitment of E2F1 to the LSH promoter leading to inhibition of cell growth. Taken together, this study reveals evidence demonstrating a mechanism by which upregulated promoted gliomas. A mechanistic link between LSH expression and activation of the LPR6/ GSK3β/E2F1 axis in gliomas illustrates a novel role of LSH in malignant astrocytomas and glioblastoma.
doi:10.7150/thno.17032
PMCID: PMC5196891  PMID: 28042322
LSH; LRP6; E2F1; GSK3β; Astrocytomas; Gioblastoma.
3.  Mitochondrial co-chaperone protein Tid1 is required for energy homeostasis during skeletal myogenesis 
Background
Tid1 is a mitochondrial co-chaperone protein and its transcript is abundantly expressed in skeletal muscle tissues. However, the physiological function of Tid1 during skeletal myogenesis remains unclear.
Methods
In vitro induced differentiation assay of mouse myoblast C2C12 cells was applied to examine the physiological role of Tid1 during skeletal myogenesis. In addition, transgenic mice with muscle specific (HSA-Cre) Tid1 deletion were established and examined to determine the physiological function of Tid1 during skeletal muscle development in vivo.
Results
Expression of Tid1 protein was upregulated in the differentiated C2C12 cells, and the HSA-Tid1f/f mice displayed muscular dystrophic phenotype. The expression of myosin heavy chain (MyHC), the protein served as the muscular development marker, was reduced in HSA-Tid1f/f mice at postnatal day (P)5 and P8. The protein levels of ATP sensor (p-AMPK) and mitochondrial biogenesis protein (PGC-1α) were also significantly reduced in HSA-Tid1f/f mice. Moreover, Tid1 deficiency induced apoptotic marker Caspase-3 in muscle tissues of HSA-Tid1f/f mice. Consistent with the in vivo finding, we observed that downregulation of Tid1 not only reduced the ATP production but also abolished the differentiation ability of C2C12 cells by impairing the mitochondrial activity.
Conclusion
Together, our results suggest that Tid1 deficiency reduces ATP production and abolishes mitochondrial activity, resulting in energy imbalance and promoting apoptosis of muscle cells during myogenesis. It will be of importance to understand the function of Tid1 during human muscular dystrophy in the future.
Electronic supplementary material
The online version of this article (doi:10.1186/s13287-016-0443-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13287-016-0443-8
PMCID: PMC5143475  PMID: 27927223
Skeletal muscle; Co-chaperone; ATP; AMPK and PGC-1α
4.  Human Infection with Novel Spotted Fever Group Rickettsia Genotype, China, 2015 
Emerging Infectious Diseases  2016;22(12):2153-2156.
Only 4 species of spotted fever group rickettsiae have been detected in humans in China. However, phylogenetic analysis of samples from 5 ill patients in China indicated infection with a novel spotted fever group Rickettsia, designated Rickettsia sp. XY99. Clinical signs resembled those of severe fever with thrombocytopenia syndrome.
doi:10.3201/eid2212.160962
PMCID: PMC5189162  PMID: 27869588
Spotted fever group rickettsiae; rickettsiosis; rickettsia; human infection; ticks; vector-borne infections; China
5.  Traditional Chinese Medicine Huannao Yicong Decoction Extract Decreases Tau Hyperphosphorylation in the Brain of Alzheimer's Disease Model Rats Induced by Aβ1–42 
Objective. Huannao Yicong Decoction (HYD, 还脑益聪方) has been shown to improve the learning and memory capabilities of Alzheimer's disease (AD) subjects. However, the underlying mechanism remains to be determined. Methods. Sixty Sprague-Dawley rats were divided equally and randomly into five different groups including control, positive control, and HYD granules of low dose, medium dose, and high dose by daily gavage. The sham-treated rats were also given the same volume of sterile water by gavage. Twelve SD rats were treated with the same amount of physiological saline. Twelve weeks later, learning and memory capabilities, Aβ content of the right brain and the expression of glycogen synthase kinase-3β (GSK-3β), total tau protein kinase (TTBK1), and cyclin-dependent kinase-5 (CDK-5) were tested. Results. Our results showed that high dose HYD treatment significantly improved the learning and memory capability of the AD rats and decreased the expression of TTBK1, GSK-3β, and CDK-5 in the hippocampal CA1 region. Conclusions. HYD treatment for 12 weeks significantly improved spatial learning and memory and effectively inhibited Aβ deposition, likely via reducing tau protein kinase expression and thus tau hyperphosphorylation and inflammatory injury. Taken together, these results suggest that HYD could be an effective treatment for AD.
doi:10.1155/2016/6840432
PMCID: PMC5153479  PMID: 28018474
6.  Comparison of Experimental Diabetic Periodontitis Induced by Porphyromonas gingivalis in Mice 
Journal of Diabetes Research  2016;2016:4840203.
Periodontitis is one of the severe complications in diabetic patients and gingival epithelium plays an initial role on the onset and progression of this disease. However the potential mechanism is yet sufficiently understood. Meanwhile, the research on the correlational experimental animal models was also insufficient. Here, we established periodontitis with type 2 diabetes in db/db and Tallyho/JngJ (TH) mice and periodontitis with type 1 diabetes in streptozotocin induced diabetes C57BL/6J (STZ-C57) mice by oral infection of periodontal pathogen Porphyromonas gingivalis W50. We demonstrated that periodontal infected mice with high blood glucose levels showed dramatically more alveolar bone loss than their counterparts, in which infected db/db mice exhibited the most bone defects. No contrary impact could be observed between this periodontal infection and onset and severity of diabetes. The expressions of PTPN2 were inhibited whereas the expression of JAK1, STAT1, and STAT3 increased dramatically in gingival epithelia and the serum TNF-α also significantly increased in the mice with diabetic periodontitis. Our results indicated that the variations of inflammation-related protein expressions in gingival epithelia might lead to the phenotype differences in the mice with diabetic periodontitis.
doi:10.1155/2016/4840203
PMCID: PMC5141310  PMID: 27995146
7.  Transcriptome Profiling of Watermelon Root in Response to Short-Term Osmotic Stress 
PLoS ONE  2016;11(11):e0166314.
Osmotic stress adversely affects the growth, fruit quality and yield of watermelon (Citrullus lanatus (Thunb.) Matsum. & Nakai). Increasing the tolerance of watermelon to osmotic stress caused by factors such as high salt and water deficit is an effective way to improve crop survival in osmotic stress environments. Roots are important organs in water absorption and are involved in the initial response to osmosis stress; however, few studies have examined the underlying mechanism of tolerance to osmotic stress in watermelon roots. For better understanding of this mechanism, the inbred watermelon accession M08, which exhibits relatively high tolerance to water deficits, was treated with 20% polyethylene glycol (PEG) 6000. The root samples were harvested at 6 h after PEG treatment and untreated samples were used as controls. Transcriptome analyses were carried out by Illumina RNA sequencing. A total of 5246 differentially expressed genes were identified. Gene ontology enrichment and biochemical pathway analyses of these 5246 genes showed that short-term osmotic stress affected osmotic adjustment, signal transduction, hormone responses, cell division, cell cycle and ribosome, and M08 may repress root growth to adapt osmotic stress. The results of this study describe the watermelon root transcriptome under osmotic stress and propose new insight into watermelon root responses to osmotic stress at the transcriptome level. Accordingly, these results allow us to better understand the molecular mechanisms of watermelon in response to drought stress and will facilitate watermelon breeding projects to improve drought tolerance.
doi:10.1371/journal.pone.0166314
PMCID: PMC5115733  PMID: 27861528
8.  Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria 
ACS Medicinal Chemistry Letters  2015;6(11):1145-1149.
Peroxidic antimalarial agents including the sequiterpene artemisinins and the synthetic 1,2,4-trioxolanes function via initial intraparasitic reduction of an endoperoxide bond. By chemically coupling this reduction to release of a tethered drug species it is possible to confer two distinct pharmacological effects in a parasite-selective fashion, both in vitro and in vivo. Here we demonstrate the trioxolane-mediated delivery of the antimalarial agent mefloquine in a mouse malaria model. Selective partitioning of the trioxolane–mefloquine conjugate in parasitized erythrocytes, combined with effective exclusion of the conjugate from brain significantly reduced brain exposure as compared to mice directly administered mefloquine. These studies suggest the potential of trioxolane-mediated drug delivery to mitigate off-target effects of existing drugs, including the adverse neuropsychiatric effects of mefloquine use in therapeutic and chemoprophylactic settings.
doi:10.1021/acsmedchemlett.5b00296
PMCID: PMC4645246  PMID: 26617969
antimalarial; trioxolane; mefloquine; drug delivery
9.  Evaluation of Lethal Giant Larvae as a Schistosomiasis Vaccine Candidate 
BioMed Research International  2016;2016:4680812.
Schistosomiasis is a neglected tropical disease of humans, and it is considered to be the second most devastating parasitic disease after malaria. Eggs produced by normally developed female worms are important in the transmission of the parasite, and they responsible for the pathogenesis of schistosomiasis. The tumor suppressor gene lethal giant larvae (lgl) has an essential function in establishing apical-basal cell polarity, cell proliferation, differentiation, and tissue organization. In our earlier study, downregulation of the lgl gene induced a significant reduction in the egg hatching rate of Schistosoma japonicum (Sj) eggs. In this study, the Sjlgl gene was used as a vaccine candidate against schistosomiasis, and vaccination achieved and maintained a stable reduction of the egg hatching rate, which is consistent with previous studies, in addition to reducing the worm burden and liver egg burden in some trials.
doi:10.1155/2016/4680812
PMCID: PMC5120214  PMID: 27957496
10.  The association between oxidized low-density lipoprotein antibodies and hematological diseases 
Background
The aim of the study is to compare the profiles of antibodies (IgM and IgG) against oxidized low-density lipoprotein (oxLDL) of hematological diseases.
Methods
The serum antibodies of oxLDL-IgM and oxLDL-IgG for 446 cases with hematological diseases and 90 patients with primary hypertension and 90 healthy controls were measured by enzyme-linked immunosorbent assay (ELISA) in a cross-section survey. The association of serum oxLDL-LgM and oxLDL-IgG with hematological diseases was analyzed by multiple linear regression model.
Results
Comparing with the hypertension or normal groups, the levels of TCH, TG, LDL-c, HDL-c, oxLDL, and oxLDL-IgG were lower and the levels of ADP and oxLDL-IgM were higher in the hematological diseases group. The levels of oxLDL-IgG antibodies titer were different among hematological diseases group. The results of correlation and multiple regression analysis showed that the seven hematological disease subgroups were positively related to the oxLDL-IgM antibody titer but negatively related to the oxLDL-IgG antibody titer, having been adjusted for potential confounding factors such as age, SBP, DBP, BMI, TCH, TG, ADP, oxLDL, HDL-c, LDL-C.
Conclusions
Here we show that oxLDL-IgG antibodies titer were lower and of oxLDL-IgM titer were higher than hypertension and healthy individuals. Also oxLDL-IgG titer were different among hematological diseases group.
doi:10.1186/s12944-016-0360-y
PMCID: PMC5101799  PMID: 27825356
Oxidized low-density lipoprotein; Autoantibody; Hematological diseases; oxLDL-IgG antibody; oxLDL-IgM antibody
11.  Over-Expression of the Mycobacterial Trehalose-Phosphate Phosphatase OtsB2 Results in a Defect in Macrophage Phagocytosis Associated with Increased Mycobacterial-Macrophage Adhesion 
Trehalose-6-phosphate phosphatase (OtsB2) is involved in the OtsAB trehalose synthesis pathway to produce free trehalose and is strictly essential for mycobacterial growth. We wished to determine the effects of OtsB2 expression on mycobacterial phenotypes such as growth, phagocytosis and survival in macrophages. Mycobacterium bovis-bacillus calmette-guerin (BCG) over-expressing OtsB2 were able to better survive in stationary phase. Over-expression of OtsB2 led to a decrease in phagocytosis but not survival in THP-1 macrophage-like cells, and this was not due to a decrease in general macrophage phagocytic activity. Surprisingly, when we investigated macrophage–mycobacterial interactions by flow cytometry and atomic force microscopy, we discovered that BCG over-expressing OtsB2 have stronger binding to THP-1 cells than wild-type BCG. These results suggest that altering OtsB2 expression has implications for mycobacterial host–pathogen interactions. Macrophage–mycobacteria phagocytic interactions are complex and merit further study.
doi:10.3389/fmicb.2016.01754
PMCID: PMC5095139  PMID: 27867377
Mycobacterium bovis-BCG; OtsB2; trehalose; macrophage; phagocytosis; adhesion
12.  Association of Lp-PLA2-A and early recurrence of vascular events after TIA and minor stroke 
Neurology  2015;85(18):1585-1591.
Objective:
To determine the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) measured in the acute period and the short-term risk of recurrent vascular events in patients with TIA or minor stroke.
Methods:
We measured Lp-PLA2 activity (Lp-PLA2-A) in a subset of 3,201 participants enrolled in the CHANCE (Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events) trial. Participants with TIA or minor stroke were enrolled within 24 hours of symptom onset and randomized to single or dual antiplatelet therapy. In the current analysis, the primary outcome was defined as the composite of ischemic stroke, myocardial infarction, or death within 90 days.
Results:
The composite endpoint occurred in 299 of 3,021 participants (9.9%). The population average Lp-PLA2-A level was 209 ± 59 nmol/min/mL (95% confidence interval [CI] 207–211). Older age, male sex, and current smoking were associated with higher Lp-PLA2-A levels. Lp-PLA2-A was significantly associated with the primary endpoint (adjusted hazard ratio 1.07, 95% CI 1.01–1.13 for every 30 nmol/min/mL increase). Similar results were seen for ischemic stroke alone. Adjustment for low-density lipoprotein cholesterol attenuated the association between Lp-PLA2-A and the primary endpoint (adjusted hazard ratio 1.04, 95% CI 0.97–1.11 for every 30 nmol/min/mL increase).
Conclusions:
Higher levels of Lp-PLA2-A in the acute period are associated with increased short-term risk of recurrent vascular events.
doi:10.1212/WNL.0000000000001938
PMCID: PMC4642142  PMID: 26311748
13.  Severe Fever with Thrombocytopenia Syndrome Complicated by Co-infection with Spotted Fever Group Rickettsiae, China 
Emerging Infectious Diseases  2016;22(11):1957-1960.
During 2013–2015 in central China, co-infection with spotted fever group rickettsiae was identified in 77 of 823 patients infected with severe fever with thrombocytopenia syndrome virus. Co-infection resulted in delayed recovery and increased risk for death, prompting clinical practices in the region to consider co-infection in patients with severe fever with thrombocytopenia syndrome.
doi:10.3201/eid2211.161021
PMCID: PMC5088031  PMID: 27767921
spotted fever group rickettsiae; SFGR; severe fever with thrombocytopenia syndrome; SFTS; severe fever with thrombocytopenia syndrome virus; SFTSV; viruses; bacteria; zoonoses; epidemiologic characteristics; clinical features; laboratory findings; co-infection; complications; ticks; tick bites; tick-borne pathogen; human infection; China; vector-borne infections
14.  Lack of Mimivirus Detection in Patients with Respiratory Disease, China 
Emerging Infectious Diseases  2016;22(11):2011-2012.
doi:10.3201/eid2211.160687
PMCID: PMC5088041  PMID: 27331870
mimivirus; viruses; pneumonia; epidemiology; respiratory disease; respiratory infections; China
15.  The Association between Impaired Glucose Regulation and Prognosis of Chinese Patients with Intracerebral Hemorrhage 
Scientific Reports  2016;6:36220.
This study aimed at observing the influence of impaired glucose regulation (IGR) on 1-year outcomes in patients with intracerebral hemorrhage (ICH). Patients hospitalized for ICH from 2008 to 2009 were recruited consecutively at 35 centres across China. A standard oral glucose tolerance test at day 14 ± 3 after stroke onset or before discharge was performed to identify IGR. The outcomes were death (modified Rankin scale [mRS] score of 6), dependency (mRS score of 2 to 5) and poor outcome (mRS score of 2 to 6) at 1 year. Cox proportion hazard model for death and logistic regression model for dependency and poor outcome were performed to investigate the influence of IGR on 1-year outcomes. A total of 288 non-diabetic ICH patients were included in this analysis, among which 150 (52.1%) were IGR. IGR was associated with 1-year dependency (adjusted odds ratio [OR] 2.18, 95% confidence interval [CI], 1.19–3.99; P = 0.01) and poor outcome (adjusted OR 2.17; 95% CI, 1.24–3.80; P = 0.007) of patients with ICH. However, IGR showed no significant association with 1-year death (adjusted hazard ratio 1.49, 95% CI, 0.60–3.67; P = 0.39). IGR was independently associated with 1-year poor outcome of ICH in Chinese patients, with more important influence on dependency than death.
doi:10.1038/srep36220
PMCID: PMC5086982  PMID: 27796374
16.  Predicting malignant transformation of esophageal squamous cell lesions by combined biomarkers in an endoscopic screening program 
World Journal of Gastroenterology  2016;22(39):8770-8778.
AIM
To determine the association of p53, carcinoembryonic antigen (CEA) and CA19-9 protein expression with esophageal carcinogenesis.
METHODS
An iodine staining endoscopic screening program of esophageal lesions was carried out in the high-incidence area of Feicheng County, China. Seventy-seven patients with basal cell hyperplasia (BCH), 247 with low-grade dysplasia (LGD), 51 with high-grade dysplasia (HGD), 134 with invasive cancer, and 80 normal controls diagnosed by mucous membrane biopsy pathology were enrolled. Immunohistochemical detection of p53, CEA and CA19-9 proteins was performed. In the ROC curve analysis, the expression of a single biomarker and the expression of a combination of biomarkers were used to predict the risk of these four esophageal lesions.
RESULTS
The positive rates of p53 protein expression in invasive cancer, HGD, LGD, BCH and the normal control groups were 53.0%, 52.9%, 35.6%, 27.3% and 20.0%, respectively; the positive rates of CA19-9 protein expression were 44.0%, 33.3%, 16.5%, 9.2% and 6.2%, respectively; the positive rates of CEA protein expression were 74.6%, 60.8%, 23.3%, 23.7% and 16.2%, respectively. The positive rates of the combined expression of the three biomarkers were 84.3%, 76.5%, 47.6%, 42.9% and 27.5%, respectively. In the receiver operating characteristic curves of the combination of the three biomarkers, the specificity was 88.8% for the normal controls, and the sensitivity was 58.2% for invasive cancer, 25.5% for HGD, 11.2% for LGD, and 6.5% for BCH.
CONCLUSION
p53, CEA and CA19-9 protein expression was correlated with esophageal carcinogenesis, and testing for the combination of these biomarkers is useful for identifying high-risk patients with precancerous lesions.
doi:10.3748/wjg.v22.i39.8770
PMCID: PMC5075551  PMID: 27818592
Esophageal squamous cell cancer; Esophageal squamous cell dysplasia; p53; Carcinoembryonic antigen; CA19-9; Immunohistochemistry; Prediction
17.  A retrospective clinical study of 98 adult idiopathic primary intraventricular hemorrhage cases 
Medicine  2016;95(42):e5089.
Abstract
The aim of the study is to define the clinical features, risk factors, treatment and prognosis of idiopathic primary intraventricular hemorrhage (IPIVH).
We retrospectively collected the data of consecutively admitted patients who were diagnosed and treated for IPIVH in our hospital from January 2010 to December 2014. The clinical information, treatment, and prognosis at the 6-month follow-up were analyzed.
Among the 3798 cases of spontaneous intracranial hemorrhage (ICH), 98 IPIVH (2.58%) patients were recruited for the study. The study population consisted of 60 males and 38 females, with an average age (± standard deviation, SD) of 51.20 ± 15.48 years. The initial symptoms were headache (75 cases) and impaired consciousness (23 cases). The surgical treatments included hematoma evacuation under a microscope or an endoscope in 8 cases (8.16%), external ventricular drainage (EVD) in 11 cases (11.22%), lumbar drainage (LD) in 10 cases (10.20%), and a combination of EVD and LD in 11 cases (11.22%). In total, 4 patients died in the hospital (4.08%). At the 6-month follow-up, 73 patients (74.49%) had an improved outcome (modified Rankin scale [mRS] < 3), and 21 patients (21.43%) had a poor outcome (mRS ≥ 3 points) at the end of the 6-month follow-up.
IPIVH is rare in clinical practice, and hypertension is the most common risk factor. Furthermore, the treatment of IPIVH is still controversial. Hematoma evacuation under a microscope or an endoscope, EVD, LD and a combination of EVD and LD could be surgical options for the treatment of IPIVH patients. The outcomes for IPIVH patients could be relatively favorable with individualized treatment.
doi:10.1097/MD.0000000000005089
PMCID: PMC5079321  PMID: 27759637
etiology; hypertension; intracerebral hemorrhage; primary intraventricular hemorrhage; prognosis; stroke; treatment
18.  Substance P Promotes the Proliferation, but Inhibits Differentiation and Mineralization of Osteoblasts from Rats with Spinal Cord Injury via RANKL/OPG System 
PLoS ONE  2016;11(10):e0165063.
Spinal cord injury (SCI) causes a significant amount of bone loss, which results in osteoporosis (OP). The neuropeptide substance P (SP) and SP receptors may play important roles in the pathogenesis of OP after SCI. To identify the roles of SP in the bone marrow mesenchymal stem cell derived osteoblasts (BMSC-OB) in SCI rats, we investigated the expression of neurokinin-1 receptors (NK1R) in BMSC-OB and the effects of SP on bone formation by development of BMSC-OB cultures. Sixty young male Sprague-Dawley rats were randomized into two groups: SHAM and SCI. The expression of NK1R protein in BMSC-OB was observed using immunohistochemistry and Western blot analysis. The dose- and time-dependent effects of SP on the proliferation, differentiation and mineralization of BMSC-OB and the expression of osteoblastic markers by in vitro experiments. The expression of NK1R in BMSC-OB was observed on plasma membranes and in cytoplasm. One week after osteogenic differentiation, the expression of NK1R was significantly increased after SCI at mRNA and protein levels. However, this difference was gradually attenuated at 2 or 3 weeks later. SP have the function to enhance cell proliferation, inhibite cell differentiation and mineralization at a proper concentration and incubation time, and this effect would be inhibited by adding SP or NK1R antagonist. The expression of RANKL/OPG was significantly increased in tibiae after SCI. Similarly, the RANKL/OPG expression in SCI rats was significantly increased when treating with 10−8 M SP. SP plays a very important role in the pathogenesis of OP after SCI. The direct effect of SP may lead to increased bone resorption through the RANKL/OPG axis after SCI. In addition, high expression of SP also results in the suppression of osteogenesis in SCI rats. Then, the balance between bone resorption and bone formation was broken and finally osteoporosis occurred.
doi:10.1371/journal.pone.0165063
PMCID: PMC5072631  PMID: 27764190
19.  Selective Degeneration of Entorhinal-CA1 Synapses in Alzheimer's Disease via Activation of DAPK1 
The Journal of Neuroscience  2016;36(42):10843-10852.
Excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) form functional excitatory synapses with CA1 parvalbumin inhibitory neurons (CA1PV) and undergo selective degeneration in the early stages of Alzheimer's disease (AD). Here, we show that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PV synaptic loss and improves spatial learning and memory in AD mice. This study demonstrates that activation of DAPK1 in ECIIPN contributes to a memory loss in AD and hence warrants a promising target for the treatment of AD.
SIGNIFICANCE STATEMENT Our recent study reported that excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) target to CA1 parvalbumin-type inhibitory neurons (CA1PV) at a direct pathway and are one of the most vulnerable brain cells that are selectively degenerated in the early stage of Alzheimer's disease (AD). Our present study shows that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PV synaptic loss and improves spatial learning and memory in the early stage of AD. These data not only demonstrate a crucial molecular event for synaptic degeneration but also provide a therapeutic target for the treatment of AD.
doi:10.1523/JNEUROSCI.2258-16.2016
PMCID: PMC5083012  PMID: 27798139
Alzheimers’ disease; DAPK1; learning and memory; synaptic degeneration
20.  Prognosis for recipients with hepatocellular carcinoma of salvage liver transplantation versus those of primary liver transplantation: a retrospective single-center study 
SpringerPlus  2016;5(1):1809.
Purpose
The prognosis for recipients with hepatocellular carcinoma (HCC) of salvage liver transplantation (SLT) versus those of primary liver transplantation (PLT) remains controversial. The objective of this study was to evaluate the clinical features and survival rate of SLT recipients.
Methods
Three hundred seventy-one patients with HCC transplanted at Shanghai General Hospital, China, between October 2001 and October 2011 were separated into PLT (n = 295) and SLT (n = 76) groups. Patient characteristics and survival curves were studied by univariate and multivariate analysis. A Milan criteria-stratified survival analysis was conducted.
Results
The proportions of reoperation (11.8 vs. 5.4 %, P = 0.047) and early postoperative mortality (11.8 vs. 4.7 %, P = 0.032) were higher in the SLT group than in the PLT group. Recurrence free survival (RFS) rate and overall survival (OS) rate had no statistically significant differences after stratification using Milan criteria between the PLT group and SLT group. Alphafetoprotein >400 ng/mL (P = 0.011), microscopic vascular invasion (MVI) (P < 0.001), tumor node metastasis (TNM) staging (P = 0.006), and out of Milan criteria (P < 0.001) were independent risk factors for RFS, while MVI (P < 0.001), TNM staging (P = 0.009), and out of Milan criteria (P = 0.003) were factors for OS. In the multivariate logistic regression analysis, HCC recurrence was associated with MVI (OR = 4.196 [2.538–6.936], P < 0.001), and out of Milan criteria (OR = 2.704 [1.643–4.451], P < 0.001).
Conclusions
Our retrospective, single-center study demonstrated that SLT increases surgical difficulty; however, it has good post-transplantation OS and is a feasible alternative after HCC recurrence within Milan criteria.
doi:10.1186/s40064-016-3441-5
PMCID: PMC5069219  PMID: 27818858
Salvage liver transplantation; Primary liver transplantation; Hepatocellular carcinoma; Prognosis
21.  Fabricating customized hydrogel contact lens 
Scientific Reports  2016;6:34905.
Contact lenses are increasingly used in laboratories for in vivo animal retinal imaging and pre-clinical studies. The lens shapes often need modification to optimally fit corneas of individual test subjects. However, the choices from commercially available contact lenses are rather limited. Here, we report a flexible method to fabricate customized hydrogel contact lenses. We showed that the fabricated hydrogel is highly transparent, with refractive indices ranging from 1.42 to 1.45 in the spectra range from 400 nm to 800 nm. The Young’s modulus (1.47 MPa) and hydrophobicity (with a sessile drop contact angle of 40.5°) have also been characterized experimentally. Retinal imaging using optical coherence tomography in rats wearing our customized contact lenses has the quality comparable to the control case without the contact lens. Our method could significantly reduce the cost and the lead time for fabricating soft contact lenses with customized shapes, and benefit the laboratorial-used contact lenses in pre-clinical studies.
doi:10.1038/srep34905
PMCID: PMC5066254  PMID: 27748361
22.  Radiation-induced osteosarcoma of the maxilla and mandible after radiotherapy for nasopharyngeal carcinoma 
Background
The increasing incidence of radiation-induced osteosarcoma of the maxilla and mandible (RIOSM) has become a significant problem that can limit long-term survival. The purpose of this study was to analyze the association of clinicopathologic characteristics with treatment outcomes and prognostic factors of patients who developed RIOSM after undergoing radiotherapy for nasopharyngeal carcinoma (NPC).
Methods
We reviewed the medical records of 53,760 NPC patients admitted to Sun Yat-sen University Cancer Center during the period August 1964 to August 2012. Of these patients, 47 who developed RISOM and met inclusion criteria were included in this study. Two of these 47 patients refused treatment and were then excluded.
Results
For all patients treated for NPC at Sun Yat-sen University Cancer Center during the study period, the total incidence of RIOSM after radiotherapy was 0.084% (47/53,760). Two patients (4.4%) had metastases at the diagnosis of RIOSM. Thirty-nine of the 45 (86.7%) patients underwent surgery for RIOSM; most patients (24/39; 61.5%) who underwent resection had gross clear margins, with 15 patients (38.5%) having either a gross or microscopic positive margin. All patients died. The 1-, 2-, and 3-year overall survival (OS) rates for the entire cohort of 45 patients were 53.3%, 35.6% and 13.5%, respectively. The independent prognostic factors associated with high OS rate were tumor size and treatment type.
Conclusions
RISOM after radiotherapy for NPC is aggressive and often eludes early detection and timely intervention. Surgery combined with postoperative chemotherapy might be an effective treatment to improve patient survival.
doi:10.1186/s40880-016-0153-8
PMCID: PMC5059957  PMID: 27729091
Radiation-induced osteosarcoma; Maxilla and mandible; Nasopharyngeal carcinoma; Prognosis
23.  Zoledronate induces autophagic cell death in human umbilical vein endothelial cells via Beclin-1 dependent pathway activation 
Molecular Medicine Reports  2016;14(5):4747-4754.
Zoledronate has been reported to exhibit pro-apoptotic and anti-angiogenic effects in endothelial cells, which partially contributes to bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ). Zoledronate can also induce autophagic cell death. The present study hypothesized that Zoledronate may activate autophagy to exert pro-apoptotic effects in endothelial cells and aimed to investigate the effect of Zoledronate on human umbilical vein endothelial cells (HUVECs) and explore the underlying mechanisms. The current study demonstrated that Zoledronate induced autophagy in HUVECs in a dose-dependent manner, as demonstrated by increased levels of microtubule-associated proteins 1A/1B light chain 3B-II (LC3B-II) and Beclin-1, and decreased levels of sequestome 1 (SQSTM1). In addition, treatment with chloroquine further increased LC3B-II and increased SQSTM1 levels, indicating that Zoledronate induces autophagy by increasing autophagic activity. Flow cytometry and Hoechst 33258 staining revealed that inhibition of autophagy with 3-methyladenine markedly attenuated Zoledronate-induced apoptosis. Furthermore, genetic knockdown of Beclin-1 significantly inhibited autophagy and apoptosis induced by Zoledronate. The present study therefore demonstrated that Zoledronate may promote Beclin-1-mediated autophagy to induce endothelial cell apoptosis, and suggests that blocking autophagy may represent a novel approach for the prevention of BP-ONJ in patients receiving Zoledronate.
doi:10.3892/mmr.2016.5834
PMCID: PMC5102043  PMID: 27748838
zoledronate; autophagy; apoptosis; Beclin-1
24.  Gq-DREADD Selectively Initiates Glial Glutamate Release and Inhibits Cue-induced Cocaine Seeking 
Biological psychiatry  2015;78(7):441-451.
Background
Glial cells of the central nervous system directly influence neuronal activity by releasing neuroactive small molecules, including glutamate. Long-lasting cocaine-induced reductions in extracellular glutamate in the nucleus accumbens core (NAcore) affect synaptic plasticity responsible for relapse vulnerability.
Methods
We transduced NAcore astrocytes with an AAV viral vector expressing hM3Dq (Gq) DREADD under control of the glial fibrillary acidic protein (GFAP) promoter in 62 male Sprague Dawley rats, 4 dnSNARE mice and 4 wild type littermates. Using glutamate biosensors we measured NAcore glutamate levels following intracranial or systemic administration of clozapine-N-oxide (CNO), and tested the ability of systemic CNO to inhibit reinstated cocaine or sucrose seeking following self-administration (SA) and extinction training.
Results
Administration of CNO in GFAP-Gq-DREADD transfected animals increased NAcore extracellular glutamate levels in vivo. The glial origin of released glutamate was validated by an absence of CNO-mediated release in mice expressing a dominant-negative SNARE variant in glia. Also, CNO-mediated release was relatively insensitive to N-type calcium channel blockade. Systemic administration of CNO inhibited cue-induced reinstatement of cocaine seeking in rats extinguished from cocaine, but not sucrose SA. The capacity to inhibit reinstated cocaine-seeking was prevented by systemic administration of the group II metabotropic glutamate receptor (mGluR2/3) antagonist LY341495.
Conclusions
DREADD-mediated glutamate gliotransmission inhibited cue-induced reinstatement of cocaine seeking by stimulating release-regulating mGluR2/3 autoreceptors to inhibit cue-induced synaptic glutamate spillover.
doi:10.1016/j.biopsych.2015.02.016
PMCID: PMC4547911  PMID: 25861696
Cocaine; Glutamate; Astrocytes; DREADD; Reinstatement; Biosensor
25.  Dual specificity phosphatase 5 is a novel prognostic indicator for patients with advanced colorectal cancer 
American Journal of Cancer Research  2016;6(10):2323-2333.
Dual specificity phosphatase 5 (DUSP5) is a negative regulator of Mitogen-activated protein kinase (MAPK) signaling pathway and has recently been identified as a tumor suppressor in several human malignancies. However, its clinical significance in colorectal cancer (CRC) remains unclear. In this study, we aimed to investigate the potential utility of DUSP5 as a novel biomarker for progression indication and chemotherapy benefit in CRC patients. Through quantitative real time-polymerase chain reaction and western blot, we determined that DUSP5 expression is dramatically lower in CRC tissues than that in matched normal tissues. The statistical analysis based on immunohistochemistry revealed that DUSP5 expression is significantly correlated with tumor differentiation, TNM stage, lymph node metastasis and distant metastasis. For the whole study cohort, patients with high DUSP5 expression had a better CRC-specific and disease-free survival than those with low DUSP5 expression and DUSP5 expression is an independent prognostic factor for patient survival. In subgroup analysis, DUSP5 has no prognostic significance in low-risk stage II patients, but could predict treatment response in high-risk stage II and stage III/IV patients who received standard FOLFOX chemotherapy scheme. Finally, the correlation analysis suggested that DUSP5 expression is associated with Epithelial-to-Mesenchymal Transition (EMT) phenotype in CRC tissues, suggesting that downregulated DUSP5 may contribute to poor prognosis partly by involving EMT. Taken together, our study proposes that DUSP5 is a promising biomarker for predicting CRC progression and advanced patients with high DUSP5 expression appear to benefit from standard FOLFOX chemotherapy scheme.
PMCID: PMC5088295  PMID: 27822421
DUSP5; colorectal cancer; prognosis; EMT

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