Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia-reperfusion rats by activating Prkaca-mediated cAMP/PKA-MAPK pathway.

Ischemic stroke is one of the main causes of disability and death. However, recanalization of occluded cerebral arteries is effective only within a very narrow time window. Therefore, it is particularly important to find neuroprotective biological targets for cerebral artery recanalization. Here, gene expression profiles of datasets GSE160500 and GSE97537 were downloaded from the GEO database, which were related to ischemic stroke in rats. Olfactory receptor 78 (Olfr78) was screened, and which highly associated with Calcium signalling pathway and MAPK pathway. Interacting protein of Olfr78, Prkaca, was predicted by STRING, and their interaction was validated by Co-IP analysis. Then, a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a neuronal cell model stimulated by oxygen-glucose deprivation/reoxygenation (OGD/R) were constructed, and the results showed that expression of Olfr78 and Prkaca was downregulated in MCAO rats and OGD/R-stimulated neurons. Overexpression of Olfr78 or Prkaca inhibited the secretion of inflammatory factors, Ca2+ overload, and OGD/R-induced neuronal apoptosis. Moreover, Overexpression of Prkaca increased protein levels of cAMP, PKA and phosphorylated p38 in OGD/R-stimulated neurons, while SB203580, a p38 inhibitor, treatment inhibited activation of the cAMP/PKA-MAPK pathway and counteracted the effect of Olfr78 overexpression on improvement of neuronal functions. Meanwhile, overexpression of Olfr78 or Prkaca markedly inhibited neuronal apoptosis and improved brain injury in MCAO/R rats. In conclusion, overexpression of Olfr78 inhibited Ca2+ overload and reduced neuronal apoptosis in MCAO/R rats by promoting Prkaca-mediated activation of the cAMP/PKA-MAPK pathway, thereby improving brain injury in cerebral ischaemia-reperfusion.

Upregulation of LHPP by saRNA inhibited hepatocellular cancer cell proliferation and xenograft tumor growth.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide and no pharmacological treatment is available that can achieve complete remission of HCC. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a recently identified HCC tumor suppressor gene which plays an important role in the development of HCC and its inactivation and reactivation has been shown to result in respectively HCC tumorigenesis and suppression. Small activating RNAs (saRNAs) have been used to achieve targeted activation of therapeutic genes for the restoration of their encoded protein through the RNAa mechanism. Here we designed and validated saRNAs that could activate LHPP expression at both the mRNA and protein levels in HCC cells. Activation of LHPP by its saRNAs led to the suppression of HCC proliferation, migration and the inhibition of Akt phosphorylation. When combined with targeted anticancer drugs (e.g., regorafenib), LHPP saRNA exhibited synergistic effect in inhibiting in vitro HCC proliferation and in vivo antitumor growth in a xenograft HCC model. Findings from this study provides further evidence for a tumor suppressor role of LHPP and potential therapeutic value of restoring the expression of LHPP by saRNA for the treatment of HCC.

IFI35 regulates non-canonical NF-κB signaling to maintain glioblastoma stem cells and recruit tumor-associated macrophages.

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME). The symbiotic interactions between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAM) in the TME are critical for tumor progression. Here, we identified that IFI35, a transcriptional regulatory factor, plays both cell-intrinsic and cell-extrinsic roles in maintaining GSCs and the immunosuppressive TME. IFI35 induced non-canonical NF-kB signaling through proteasomal processing of p105 to the DNA-binding transcription factor p50, which heterodimerizes with RELB (RELB/p50), and activated cell chemotaxis in a cell-autonomous manner. Further, IFI35 induced recruitment and maintenance of M2-like TAMs in TME in a paracrine manner. Targeting IFI35 effectively suppressed in vivo tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Collectively, these findings reveal the tumor-promoting functions of IFI35 and suggest that targeting IFI35 or its downstream effectors may provide effective approaches to improve GBM treatment.

Programmed cell death 4 blocks autophagy and promotes dopaminergic neuronal injury in Parkinson's disease.

Dysregulation of autophagy has previously been associated with the formation of toxic proteins, such as α-synuclein, in patients with Parkinson's disease (PD). In addition, it has been indicated that programmed cell death 4 (PDCD4) can inhibit autophagy in certain conditions, such as diabetic nephropathy, atherosclerosis and cardiac hypertrophy. Therefore, the hypothesis that PDCD4 can promote dopaminergic neuron damage through autophagy was proposed. To explore this hypothesis, the present study treated human neuroblastoma SK-N-SH cells with 1-methyl-4-phenylpyridinium (MPP+) to establish an in vitro model of PD. The potential effects of PDCD4 knockdown on lactate dehydrogenase (LDH) release, cell apoptosis, inflammatory response, oxidative stress and autophagy were then evaluated in this model of PD using an LDH assay kit, flow cytometry, western blotting, ELISA and immunofluorescence. The autophagy inhibitor 3-methyladenine (3-MA) was also applied to treat these cells, and its effects on these aforementioned parameters following PDCD4 knockdown were assessed. MPP+ was shown to increase the expression levels of PDCD4 in SK-N-SH cells. PDCD4 knockdown was revealed to suppress LDH release, cell apoptosis, secretion of inflammatory factors and oxidative stress. In addition, PDCD4 knockdown was demonstrated to enhance autophagy in cells treated with MPP+. By contrast, 3-MA treatment reversed the aforementioned effects of PDCD4 knockdown on cells, suggesting autophagy to be among the processes regulated by PDCD4 in SK-N-SH cells. The results of the present study suggested the existence of regulatory effects mediated by PDCD4 on autophagy in MPP+-induced SK-N-SH cells, offering potential future targets for PD therapy.

TFR1 knockdown alleviates iron overload and mitochondrial dysfunction during neural differentiation of Alzheimer's disease-derived induced pluripotent stem cells by interacting with GSK3B.

Iron metabolism disorders are implicated in the pathogenesis of Alzheimer's disease (AD). It was previously reported that transferrin receptor (TFR1) expression was upregulated in AD mouse model. However, the precise biological functions of TFR1 in AD progression remains unclear. Herein, we observed a gradual increase in TFR1 protein expression during the differentiation of AD patient-derived induced pluripotent stem cells (AD-iPS). TFR1 knockdown inhibited the protein expression of ferritin and ferritin heavy chain 1 (FTH1), enhanced the expression of ferroportin 1 (FPN1), and decreased intracellular levels of total iron, labile iron, and reactive oxygen species (ROS). Moreover, TFR1 knockdown improved mitochondrial membrane potential (MMP), increased adenosine triphosphate (ATP) content, downregulated mitochondrial fission proteins, and upregulated mitochondrial fusion proteins. TFR1 knockdown alleviated iron overload and mitochondrial dysfunction in neural cells differentiated from AD-iPS, while TFR1 overexpression showed the opposite results. Additionally, TFR1interacted with glycogen synthase kinase 3 beta (GSK3B) and promoted GSK3B expression. GSK3B overexpression reversed the inhibitory effects of TFR1 knockdown on iron overload and mitochondrial dysfunction in AD-iPS differentiated neural cells. In conclusion, TFR1 knockdown alleviated iron overload and mitochondrial dysfunction in neural cells differentiated from AD-iPS by promoting GSK3B expression. Our findings provide a potential therapeutic target for the treatment of AD.

Comparative outcomes of catheter-directed thrombolysis versus AngioJet pharmacomechanical catheter-directed thrombolysis for treatment of acute iliofemoral deep vein thrombosis.

OBJECTIVE: The objective of this study was to compare the outcomes of pharmacomechanical thrombolysis and thrombectomy (PCDT) plus catheter-directed thrombolysis (CDT) vs CDT alone for the treatment of acute iliofemoral deep vein thrombosis (DVT) and summarize the clinical experience, safety outcomes, and short- and long-term efficacy. METHODS: We performed a 4-year retrospective, case-control study. A total of 95 consecutive patients with acute symptomatic iliofemoral deep vein thrombosis (DVT) with a symptom duration of ≤7 days involving the iliac and/or common femoral veins underwent endovascular interventions. The patients were divided into two groups according to their clinical indications: PCDT plus CDT vs CDT alone. Statistical analyses were used to compare the clinical characteristics and outcomes between the two groups. Additionally, the patients were followed up for 3 to 36 months after treatment, and the proportions of post-thrombotic syndrome (PTS) and moderate to severe PTS were analyzed using the Kaplan-Meier survival method. RESULTS: A total of 95 consecutive patients were analyzed in this retrospective study, of whom, 51 underwent CDT alone and 44 underwent PCDT plus CDT. Between the two groups, in terms of immediate-term efficacy and safety, significant differences were found in the catheter retention time (60.64 ± 12.04 hours vs 19.42 ± 4.04 hours; P < .001), dosages of urokinase required (5.82 ± 0.81 million units vs 1.80 ± 0.64 million units; P < .001), the detumescence rate at 24 hours postoperatively (48.46% ± 8.62% vs 76.79% ± 7.98%; P = .026), the descent velocity of D-dimer per day (2266.28 ± 1358.26 µg/L/D vs 3842.34 ± 2048.02 µg/L/D; P = .018), total hospitalization stay (6.2 ± 1.40 days vs 3.8 ± 0.70 days; P = .024), number of postoperative angiograms (2.4 ± 0.80 vs 1.2 ± 0.30; P = .042), and grade III venous patency (>95% lysis: 54.5% vs 68.6%; P = .047). Furthermore, during the follow-up period, significant differences were found in the incidence of PTS (Villalta scale ≥5 or a venous ulcer: 47.0% vs 27.7%; P = .037), and the incidence proportion of moderate to severe PTS at 12 months (15.7% vs 4.5%; P = .024) and 24 months (35.3% vs 11.4%; P = .016). CONCLUSIONS: Compared with CDT alone, in the iliofemoral DVT subgroup with a symptom duration of ≤7 days, PCDT plus CDT could significantly relieve early leg symptoms, shorten the hospitalization stay, reduce bleeding complications, promote long-term venous patency, and decrease the occurrence of PTS and the incidence proportion of moderate to severe PTS. Thus, the short- and long-term outcomes both support the superiority of PCDT plus CDT vs CDT in this subgroup.

BRAP silencing protects against neuronal inflammation, oxidative stress and apoptosis in cerebral ischemia-reperfusion injury by promoting PON1 expression.

BACKGROUND: BRCA1 associated protein (BRAP) participates in the regulation of myocardial infarction and atherosclerosis. But the function of BRAP in cerebral ischemia-reperfusion (CIR) injury has not been elucidated yet. METHODS: BRAP expression in PC12 cells in response to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment was examined with Western blot assay. PC12 cells underwent OGD/R-treatment and were subsequently transfected with pcDNA-BRAP or sh-BRAP, followed by determination of viability, lactate dehydrogenase (LDH) production, apoptosis, inflammatory cytokine secretion, and oxidative stress marker protein levels. Paraoxonase 1 (PON1) promoter methylation was evaluated with methylation-specific PCR assay. the effect of BRAP/PON1 axis on CIR injury was investigated by rescue experiments. Additionally, sh-BRAP was injected into a middle cerebral artery occlusion (MCAO) rat model, and the changes of neurological damage were evaluated. RESULTS: BRAP overexpression exacerbated OGD/R-induced viability reduction, LDH production, apoptosis, inflammatory cytokine secretion and oxidative stress in PC12 neuronal cells. In contrast, BRAP silencing showed the opposite results. Mechanistically, BRAP reduced PON1 expression by promoting DNA methyl transferase1 (DNMT1)-mediated PON1 promoter methylation. PON1 silencing reversed BRAP-mediated neuroprotection. Additionally, BRAP silencing alleviated CIR-induced neurological damage in MCAO rats. CONCLUSION: BRAP silencing suppressed OGD/R-induced neuronal apoptosis, inflammation, and oxidative stress, and alleviated CIR-induced neurological damage in MCAO rats through facilitating PON1 expression.

Analgesic and hemodynamic effects of two injection approaches of dexmedetomidine in elderly cholecystolithiasis patients undergoing laparoscopic cholecystectomy: a retrospective study of 150 patients.

This retrospective study investigated the effects of three dexmedetomidine (Dex) injection approaches on analgesic and hemodynamics in elderly cholecystolithiasis patients undergoing laparoscopic cholecystectomy. The clinical data of 150 elderly patients with cholecystolithiasis were collected, and they were divided into the Dex A (n=50), Dex B (n=50), and Dex C (n=50) cohorts. Patient's heart rate (HR) and mean arterial pressure (MAP) were collected at T0, T1, and T2 for blood gas analysis. The difference in oxygen content between cerebral arterial and venous blood (Da-jvO2) was calculated. The duration of surgery, occurrence of cardiovascular and respiratory suppression, and the time of spontaneous respiratory recovery and extubation were recorded. At T2, T3, and T4, HR and MAP in the Dex C group were smaller than Dex A group and Dex B group (Dex C

Sterol regulatory element-binding protein 2 maintains glioblastoma stem cells by keeping the balance between cholesterol biosynthesis and uptake.

BACKGROUND: Glioblastomas (GBMs) display striking dysregulation of metabolism to promote tumor growth. Glioblastoma stem cells (GSCs) adapt to regions of heterogeneous nutrient availability, yet display dependency on de novo cholesterol biosynthesis. The transcription factor Sterol Regulatory Element-Binding Protein 2 (SREBP2) regulates cholesterol biosynthesis enzymes and uptake receptors. Here, we investigate adaptive behavior of GSCs under different cholesterol supplies. METHODS: In silico analysis of patient tumors demonstrated enrichment of cholesterol synthesis associated with decreased angiogenesis. Comparative gene expression of cholesterol biosynthesis enzymes in paired GBM specimens and GSCs were performed. In vitro and in vivo loss-of-function genetic and pharmacologic assays were conducted to evaluate the effect of SREBP2 on GBM cholesterol biosynthesis, proliferation, and self-renewal. Chromatin immunoprecipitation quantitative real-time PCR was leveraged to map the regulation of SREBP2 to cholesterol biosynthesis enzymes and uptake receptors in GSCs. RESULTS: Cholesterol biosynthetic enzymes were expressed at higher levels in GBM tumor cores than in invasive margins. SREBP2 promoted cholesterol biosynthesis in GSCs, especially under starvation, as well as proliferation, self-renewal, and tumor growth. SREBP2 governed the balance between cholesterol biosynthesis and uptake in different nutrient conditions. CONCLUSIONS: SREBP2 displays context-specific regulation of cholesterol biology based on its availability in the microenvironment with induction of cholesterol biosynthesis in the tumor core and uptake in the margin, informing a novel treatment strategy for GBM.

Optimal cut-off value of serum procalcitonin in predicting bacterial infection induced acute exacerbation in chronic obstructive pulmonary disease: A prospective observational study.

OBJECTIVE: To explore the optimal cut-off value of serum procalcitonin (PCT) level in predicting bacterial infection in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: 204 hospitalized patients with AECOPD were enrolled in this study. Their diagnoses and treatments followed routine protocols in Fu-Xing Hospital affiliated to Capital Medical University, Beijing, China. Extra blood samples were taken for serum PCT level testing and the results were blinded to the treating physicians. On discharge, clinical data were collected and the treating physicians made comprehensive analyses to determine whether the AECOPD were triggered by respiratory tract bacterial infection or non-bacterial causes according to the "new diagnostic criteria" defined in this study. In the AECOPD patients with bacterial infection, treating physicians decided whether they had bacterial pneumonia based on imaging studies. Receiver operating characteristic curve (ROC) was used to analyze the accuracy of serum PCT level in predicting bacterial infection. RESULTS: In the 173 AECOPD patients who did not have pneumonia, 115 had evidences of bacterial infection while 58 did not. The median PCT levels were 0.1(0.08, 0.18) ng/ml and 0.07 (0.05, 0.08) ng/ml for each group, which were statistically different. The proposed optimal cut-off value of serum PCT level in predicting bacterial infection was 0.08 ng/mL according to this study, with a sensitivity of 81%, specificity of 67% and area under the ROC curve (AUC) of 0.794. There were 31 AECOPD patients diagnosed with pneumonia, their median PCT level was 0.23 ng/mL. CONCLUSIONS: The serum PCT levels slightly increased in the majority of hospitalized patients with AECOPD compared with reference range. When PCT level was ≥0.08 ng/mL, AECOPD was more likely to be caused by bacterial infection. A significantly elevated PCT levels may indicate combination of AECOPD and bacterial pneumonia.

NDRG4 Alleviates Aß1-40 Induction of SH-SY5Y Cell Injury via Activation of BDNF-Inducing Signalling Pathways.

We explored the functions and mechanisms of N-myc downstream-regulated gene 4 (NDRG4) in an amyloid beta 1-40 induced Alzheimer's disease cell model. The levels of total and phosphorylated Tau protein were significantly up-regulated and cell activity was decreased with increasing Aß1-40 treatment in SH-SY5Y cells. The expression of NDRG4 mRNA and protein levels were significantly decreased that induced by Aß1-40 in these cells. NDRG4 overexpression significantly alleviated Aß1-40-induced SH-SY5Y apoptosis rates and caspases-3/7 activities. Equally, Reactive oxygen species, Mitochondrial membrane potential and Microscale malondialdehyde levels were significantly down-regulated, and Superoxide dismutase activity was increased by NDRG4 overexpression. BDNF protein level and phosphorylation levels of AKT and ERK1/2 were enhanced by NDRG4 overexpression. We also determined that the inhibitory effects of NDRG4 on cell apoptosis and Reactive oxygen species release were partially reversed by BDNF silencing, and by application of the PI3K specific inhibitor (LY294002) or ERK inhibitor (PD98059). These data indicate that NDRG4 attenuates Aß1-40-induced cell apoptosis and Reactive oxygen species release release, as well as oxidative stress injury. These effects may be mediated through BDNF-induced PI3K/AKT and MEK/ERK pathways.

Immunogenicity and protective potency of Norovirus GII.17 virus-like particle-based vaccine.

OBJECTIVES: Noroviruses (NoVs) are major cause of acute viral gastroenteritis in worldwide, and the lack of a cell culture system that must be considered the virus like particles (VLPs) are used as an effective vaccine development. MATERIALS AND METHODS: In the present study, we investigated the expression of the major capsid protein (VP1) of the Genogroup II, genotype 17 (GII.17) NoV, using recombinant baculovirus system in insect cells, as well as a saliva binding blockade assay to detect their protective potency. RESULTS: Our results showed that GII.17 VLPs could be successfully generated in sf9 insect cells, and electron microscopic revealed that GII.17 VLPs appeared as spherical particles with a - 35 nm diameter. Immunized mice with purified VLPs produced GII.17 specific sera and could efficiently block GII.17 VLPs binding to the saliva histo-blood group antigens (HBGAs). CONCLUSIONS: Together, these results suggested that GII.17 VLPs represent a promising vaccine candidate against NoV GII.17 infection and strongly support further preclinical and clinical studies.

Rational design, synthesis and structure-activity relationship of novel substituted oxazole isoxazole carboxamides as herbicide safener.

A series of novel substituted oxazole isoxazole carboxamides derivatives were designed on the basis of active subunit combination. Forty-four novel compounds were synthesized by an efficient one-pot procedure under microwave irradiation. The bioactivity was evaluated as herbicide safener against the injury of chlorsulfuron. It was found that most of the synthesized compounds displayed remarkable protection against chlorsulfuron via enhanced glutathione content and glutathione S transferase activity. Especially compound I-11 exhibited better bioactivity than the safeners isoxadifen-ethyl and R-28725. Molecular docking simulations suggested that the target compounds could compete with chlorsulfuron in the active site of acetolactate synthase, which could explain the protective effects of safeners. The present work demonstrates that the target compounds containing oxazole isoxazole groups could be considered as potential candidates for developing novel safeners in the future.

Subtly Manipulated Expression of ZmmiR156 in Tobacco Improves Drought and Salt Tolerance Without Changing the Architecture of Transgenic Plants.

Plants in the juvenile state are more tolerant to adverse conditions. Constitutive expression of MicroRNA156 (miR156) prolonged the juvenile phase and increased resistance to abiotic stress, but also affected the architecture of transgenic plants. In this study, we investigated the possibility of subtle manipulation of miR156 expression in flowering plants, with the goal to increase tolerance to abiotic stress without altering the normal growth and development of transgenic plants. Transgenic tobacco plants expressing ZmmiR156 from maize were generated, driven either by the cauliflower mosaic virus (CaMV) 35S promoter or the stress-inducible ZmRab17 promoter. Expression of ZmmiR156 led to improved drought and salt tolerance in both 35S::MIR156 and Rab17::MIR156 transgenic plants, as shown by more vigorous growth, greater biomass production and higher antioxidant enzyme expression after a long period of drought or salt treatment, when compared to wild type and transgenic vector control plants. However, constitutive expression of ZmmiR156 also resulted in retarded growth, increased branching and delayed flowering of transgenic plants. These undesirable developmental changes could be mitigated by using the stress-inducible ZmRab17 promoter. Furthermore, under drought or salt stress conditions, expression of ZmmiR156 reduced the transcript level of NtSPL2 and NtSPL9, the genes potentially targeted by ZmmiR156, as well as that of CP1, CP2, and SAG12, the senescence-associated genes in tobacco. Collectively, our results indicate that ZmmiR156 can be temporally manipulated for the genetic improvement of plants resistant to various abiotic stresses.

A Prediction Model with a Combination of Variables for Diagnosis of Lung Cancer.

BACKGROUND Multivariate models with a combination of variables can predict disease more accurately than a single variable employed alone. We developed a logistic regression model with a combination of variables and evaluated its ability to predict lung cancer. MATERIAL AND METHODS The exhaled breath from 57 patients with lung cancer and 72 healthy controls without cancer was collected. The VOCs of exhaled breath were examined qualitatively and quantitatively by a novel electronic nose (Z-nose4200 equipment). The VOCs in the 2 groups were compared using the Mann-Whitney U test, and the baseline data were compared between the 2 groups using the chi-square test or ANOVA. Variables from VOCs and baseline data were selected by stepwise logistic regression and subjected to a prediction model for the diagnosis of lung cancer as combined factors. The receiver operating characteristic (ROC) curve was used to evaluate the predictive ability of this prediction model. RESULTS Nine VOCs in exhaled breath of lung cancer patients differed significantly from those of healthy controls. Four variables - age, hexane, 2,2,4,6,6-pentamethylheptane, and 1,2,6-trimethylnaphthalene - were entered into the prediction model, which could effectively separate the lung cancer samples from the control samples with an accuracy of 82.8%, a sensitivity of 76.0%, and a specificity of 94.0%. CONCLUSIONS The profile of VOCs in exhaled breath contained distinguishable biomarkers in the patients with lung cancers. The prediction model with 4 variables appears to provide a new technique for lung cancer detection.

Modified Glasgow prognostic score might be a prognostic factor for hepatocellular carcinoma: a meta-analysis.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the fifth-most common cancer. Recent studies have demonstrated that there was a relationship between modified Glasgow prognostic score (mGPS) and survival of HCC. However, the results were inconsistent. EVIDENCE ACQUISITION: The following databases were searched for relevant articles published until June 2016: PubMed; EMBASE; Web of Science and the China National Knowledge Infrastructure. The strength of association between mGPS and OS of HCC was estimated by pooled HRs with corresponding 95% CIs. EVIDENCE SYNTHESIS: Seven studies with 2047 HCC patients were included in this meta-analysis. The mGPS was an independent marker of poor prognosis in patients with HCC (HR=2.21; 95% CI: 1.73-2.82; I2=51%). In the subgroup analysis of study design, both prospective studies (HR=1.68; 95% CI: 1.35-2.11; I2=0%) and retrospective studies (HR=2.64; 95% CI: 1.92-3.62; I2=39%) with higher mGPS had shorter OS. The patients with resectable HCC and high mGPS also showed shorter OS (HR=2.33; 95% CI: 1.65-3.29; I2=63%). In the subgroup analysis by sample size, both large sample size studies (HR=2.56; 95% CI: 1.50-4.38; I2=72%) and small sample size studies (HR=2.00; 95% CI: 1.62-2.48; I2=0%) showed the same results. CONCLUSIONS: In conclusion, this meta-analysis suggested that mGPS might be an independent prognostic factor for HCC.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) with intracranial Epstein-Barr virus infection: A Case Report.

BACKGROUND: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disorder in the central nervous system (CNS) with distinct clinical, radiological, and pathological features. The pathophysiology of CLIPPERS still remains unclear and the reports are quite few. Although the radiological lesions were reported to be located predominantly in the pons, brachium pontis, and cerebellum, other adjacent structures such as the white matter and spinal cord were very recently reported as involved regions in CLIPPERS. In this study, we report a case of CLIPPERS presenting with intracranial Epstein-Barr virus (EBV) infection and diffuse white matter involvement. CASE SUMMARY: A 37-year-old male was diagnosed with mediastinal Hodgkin's lymphoma (lymphocyte predominance type) at the age of 26, and then obtained complete remission after treatment and remained free of relapse for 11 years. He was admitted with 7 months' history of mental disorder, and 20 days' history of gait and limb ataxia, dysphagia, and cough. The diagnosis of CLIPPERS was established based on the findings of punctate and nodular enhancing lesions in the bilateral pons, the basal ganglia, the mid-brain, the pontine brachium, and diffuse white matter in magnetic resonance imaging (MRI), together with CD3 T-lymphocytic inflammatory infiltration in perivascular and parenchymal area revealed by bilateral parietal lobe brain biopsy. Also, our patient exhibited a good response to steroid therapy and remained free of relapse for 5 months. Importantly, we found intracranial Epstein-Barr virus infection in this patient. CONCLUSION: CLIPPERS might be an autoimmune disorder, and intracranial EBV-infection raises the possibility that EBV-associated autoimmunity is associated with CLIPPERS pathogenesis.

Antiproliferative activity and apoptosis inducing effects of nitric oxide donating derivatives of evodiamine.

The first series of nitric oxide donating derivatives of evodiamine were designed and prepared. NO releasing ability of all target derivatives was evaluated in BGC-823, Bel-7402 and L-02 cells. The cytotoxicity was evaluated against three human tumor cell lines (Bel-7402, A549 and BGC-823) and normal human liver cells L-02. The nitrate derivatives 11a and 11b only exhibited moderate activity and furoxan-based derivatives 13a-c, 14a and 14b showed promising activity. 13c showed good cytotoxic selectivity between tumor and normal liver cells and was further investigated for its apoptotic properties on human hepatocarcinoma Bel-7402 cells. The molecular mode of action revealed that 13c caused cell-cycle arrest at S phase and induced apoptosis in Bel-7402 cells through mitochondria-related caspase-dependent pathways.

Association Study of Single-Nucleotide Polymorphisms of STAT2/STAT3/IFN-γ Genes in Cervical Cancer in Southern Chinese Han Women.

OBJECTIVE: Interferon-γ (IFN-γ) and signal transducers and activators of transcription (STATs) each play an important role in carcinogenesis associated with viral infection. Cervical cancer is almost invariably associated with infection by human papillomavirus (HPV), and previous studies suggested that dysregulation of the signal pathway involved in IFN-γ and STATs is associated. Our objective was to evaluate the association of SNPs in STAT2, STAT3, and IFN-γ with cervical cancer susceptibility in Chinese Han women in Hunan province. MATERIALS AND METHODS: Genomic DNA was extracted from peripheral blood samples of 234 cervical cancer patients and 216 healthy female controls. STAT2 and STAT3 genotyping was performed using polymerase chain reaction-restriction enzyme (PCR-RE) analysis. IFN-γ genotyping was detected by PCR-amplification of specific allele (PASA). RESULTS: For STAT2 rs2066807 polymorphisms, there was no significant difference of genotype distribution (P=0.827) and allele frequencies (P=0.830, OR=1.09, 95% CI: 0.51-2.31) between cases and controls. For STAT3 rs957970 polymorphisms, there was no significant difference of genotype distribution (P=0.455) and allele frequencies (P=0.560, OR=0.92, 95% CI: 0.71-1.20) between cases and controls. For IFN-γ +874A/T polymorphisms, there was no significant difference of genotype distribution (P=0.652) and allele frequencies (P=0.527, OR=1.12, 95% CI: 0.79-1.59) between cases and controls. CONCLUSION: These results suggest that polymorphisms in STAT2, STAT3 and IFN-γ genes are not likely to be strong predictors of cervical cancer in Han women in southern China.

Detection of mitochondrial DNA mutations by high-throughput sequencing in the blood of breast cancer patients.

Mitochondrial DNA mutations have been identified in serveral types of cancer. In breast cancer, germline and somatic mitochondrial DNA (mtDNA) mutations have been identified. A number of mtDNA mutations in breast cancer have been identified in protein-coding regions (in protein-coding genes, such as ND2, COX3, ND4, ND5 and CytB). Mutations in these structure proteins cause impaired electron transport function and lead to electron leakage and increased reactive oxygen species (ROS) production, which in turn increases oxidative stress and oxidative damage to the mitochondria, as well as to cells. These data establish an association between mtDNA mutations and breast cancer; however, there is no reliable prediction of breast cancer predisposition or progression based on mtDNA mutation patterns thus far. In this study, we used high-throughput sequencing to detect mtDNA mutations in the blood of breast cancer patients. Some of these mutations may be used as potential markers for breast cancer diagnosis.