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1.  Prognostic role of microRNA-205 in multiple human malignant neoplasms: a meta-analysis of 17 studies 
BMJ Open  2015;5(1):e006244.
MicroRNA-205 (miRNA-205) was revealed as an attractive prognostic tumour biomarker in recent studies. However, the results of different studies have been inconsistent. We conducted a meta-analysis to elucidate the precise predictive value of miRNA-205 in various human malignant neoplasms.
Data sources
Qualified studies were identified up to 5 June 2014 by performing online searches in PubMed, EMBASE and Web of Science, and additional quality evaluations.
Seventeen eligible studies with 4827 patients were ultimately enrolled in this meta-analysis.
Outcome measures
The heterogeneity between studies was assessed using I2 statistics. Pooled HRs with 95% CIs for patient survival and disease recurrence were calculated to investigate the correlation between miRNA-205 expression and cancer prognosis.
Our results indicate that elevated miRNA-205 was significantly associated with enhanced overall survival in the breast cancer subgroup (HR=0.78, 95% CI 0.67 to 0.91) and superior disease-free survival/recurrence-free survival in the adenocarcinoma subgroup (HR=0.68, 95% CI 0.49 to 0.94).
miRNA-205 is a promising biomarker for predicting the recurrence and progression of patients with adenocarcinomas or breast cancer. Owing to its complex roles, further relevant studies are warranted.
PMCID: PMC4305071  PMID: 25613953
2.  Centralized isolation of Helicobacter pylori from multiple centers and transport condition influences 
AIM: To evaluate the efficacy of centralized culture and possible influencing factors.
METHODS: From January 2010 to July 2012, 66452 patients with suspected Helicobacter pylori (H. pylori) infection from 26 hospitals in Zhejiang and Jiangsu Provinces in China underwent gastrointestinal endoscopy. Gastric mucosal biopsies were taken from the antrum for culture. These biopsies were transported under natural environmental temperature to the central laboratory in Hangzhou city and divided into three groups based on their transport time: 5, 24 and 48 h. The culture results were reported after 72 h and the positive culture rates were analyzed by a χ2 test. An additional 5736 biopsies from H. pylori-positive patients (5646 rapid urease test-positive and 90 14C-urease breath test-positive) were also cultured for quality control in the central laboratory setting.
RESULTS: The positive culture rate was 31.66% (21036/66452) for the patient samples and 71.72% (4114/5736) for the H. pylori-positive quality control specimens. In the 5 h transport group, the positive culture rate was 30.99% (3865/12471), and 32.84% (14960/45553) in the 24 h transport group. In contrast, the positive culture rate declined significantly in the 48 h transport group (26.25%; P < 0.001). During transportation, the average natural temperature increased from 4.67 to 29.14 °C, while the positive culture rate declined from 36.67% (1462/3987) to 24.12% (1799/7459). When the temperature exceeded 24 °C, the positive culture rate decreased significantly, especially in the 48 h transport group (23.17%).
CONCLUSION: Transportation of specimens within 24 h and below 24 °C is reasonable and acceptable for centralized culture of multicenter H. pylori samples.
PMCID: PMC4299348  PMID: 25624729
Centralized isolation; Helicobacter pylori; Influencing factor; Multiple centers; Personalized treatment
3.  Activation of Cannabinoid Receptor 2 Enhances Osteogenic Differentiation of Bone Marrow Derived Mesenchymal Stem Cells 
BioMed Research International  2015;2015:874982.
Bone marrow derived mesenchymal stem cells (BM-MSCs) are considered as the most promising cells source for bone engineering. Cannabinoid (CB) receptors play important roles in bone mass turnover. The aim of this study is to test if activation of CB2 receptor by chemical agonist could enhance the osteogenic differentiation and mineralization in bone BM-MSCs. Alkaline phosphatase (ALP) activity staining and real time PCR were performed to test the osteogenic differentiation. Alizarin red staining was carried out to examine the mineralization. Small interference RNA (siRNA) was used to study the role of CB2 receptor in osteogenic differentiation. Results showed activation of CB2 receptor increased ALP activity, promoted expression of osteogenic genes, and enhanced deposition of calcium in extracellular matrix. Knockdown of CB2 receptor by siRNA inhibited ALP activity and mineralization. Results of immunofluorescent staining showed that phosphorylation of p38 MAP kinase is reduced by knocking down of CB2 receptor. Finally, bone marrow samples demonstrated that expression of CB2 receptor is much lower in osteoporotic patients than in healthy donors. Taken together, data from this study suggested that activation of CB2 receptor plays important role in osteogenic differentiation of BM-MSCs. Lack of CB2 receptor may be related to osteoporosis.
PMCID: PMC4317596
4.  Partial remission of acute myeloid leukemia complicating multiple myeloma following COAP chemotherapy: A case report 
Oncology Letters  2015;9(3):1303-1306.
A 77-year-old male was admitted to hospital after complaining of fever and a cough for three days. A diagnosis of multiple myeloma was confirmed following M protein identification and a bone marrow biopsy. The patient received chemotherapy regimens of bortezomib plus dexamethasone, cyclophosphamide, thalidomide and dexamethasone, and thalidomide and dexamethasone, and was prescribed thalidomide (100 mg/d) to be taken orally for maintenance therapy. After a further two years the patient was subsequently diagnosed with acute myeloid leukemia. Chemotherapy regimens of cytarabine, aclacinomycin and daunorubicin, homoharringtonine and etoposide, and mitoxantrone and cytarabine resulted in no remission. Partial remission was obtained with a course of ifosfamide, vindesine, cytarabine and prednisone chemotherapy. This therapy may be an alternative treatment for secondary leukemia, particularly in elderly patients.
PMCID: PMC4315064  PMID: 25663902
acute myeloid leukemia; multiple myeloma; partial remission; COAP
5.  Genome Sequence of a Novel Recombinant Coxsackievirus A6 Strain from Shanghai, China, 2013 
Genome Announcements  2015;3(1):e01347-14.
A novel recombinant coxsackievirus A6 (CVA6) strain was isolated during a coxsackievirus A6 outbreak in Shanghai, China, in 2013. Genomic sequence and similarity plot analysis showed that the novel CVA6 strain shared higher similarity with a recent CVA4 strain rather than the recent CVA6 strain in the 2C and 3′ untranslated regions (UTRs).
PMCID: PMC4290982  PMID: 25573929
6.  Molecular characteristics of the HSP70 gene and its differential expression in female and male golden apple snails (Pomacea canaliculata) under temperature stimulation 
Cell Stress & Chaperones  2013;19(4):579-589.
Heat-shock protein 70 (HSP70) is one of the most important heat-shock proteins that helps organisms to modulate stress response via over-expression. The HSP70 gene from Pomacea canaliculata was cloned using the RACE approach; the gene is 2,767 bp in length and contains an open reading frame of 1,932 bp, which is encoded by a polypeptide of 643 amino acids. BLAST analysis showed that the predicted amino acid sequence of the P. canaliculata HSP70 gene shared a relatively high similarity with that of other known eukaryotic species that display conserved HSP characteristics. The phylogeny demonstrated a separate clustering of the apple snail HSP70 with other constitutive members from other mollusk species. Quantitative real-time RT-PCR was used to detect the differential expression of HSP70 in both sexes of P. canaliculata at different temperature conditions. These results showed that HSP70 transcript levels decreased slightly under cold shock and increased significantly under heat-shock conditions in both sexes compared to normal temperatures (26 °C). Under cold-shock treatment, the sex effect was not significant. With heat treatment, HSP70 expression could be induced at 36 °C in both females and males, and it peaked at 42 and 39 °C in females and males, respectively. In addition, a clear time-dependent HSP70 expression pattern of the apple snail exposed to the same high temperature (36 °C) was observed at different time points. The maximal induction of HSP70 expression appeared at 12 and 48 h in males and females after heat shock, respectively. The maximal induction in females was significantly higher compared to males under heat stimulus. Taken together, these results strongly suggested that males were more susceptible to heat than females and provided useful molecular information for the ecological adaptability of P. canaliculata against extreme environmental stress.
PMCID: PMC4041941  PMID: 24368711
Pomacea canaliculata; HSP70; Gene expression; Temperature stress
7.  The Value of Routine Biopsy during Percutaneous Kyphoplasty for Vertebral Compression Fractures 
PLoS ONE  2014;9(12):e115417.
Percutaneous kyphoplasty (PKP) is now widely performed to treat VCF, which is usually caused by osteoporosis. Previous researches have reported unsuspected malignancies found by biopsy. However, the safety and cost-effective profiles of routine biopsy during PKP are unclear. The purpose of this study was to evaluate the feasibility of routine biopsy during PKP in treatment of VCF.
Ninety-three patients (September 2007–November 2010) undergoing PKP without biopsy were reviewed as the control group. One hundred and three consecutive patients (November 2010–September 2013) undergoing PKP with biopsy of every operated vertebral level were prospectively enrolled as the biopsy group. The rate of unsuspected lesions was reported, and the severe adverse events, surgical duration, cement leakage rate and pain control were compared between the two groups.
No statistically significant differences were found between the two groups, regarding the severe adverse events, surgical duration, cement leakage rate and pain control. Four unsuspected lesions were found in the biopsy group, three of which were malignancies with a 2.9% (3/103) unsuspected malignancy rate. The economic analysis showed that routine biopsy was cost-effective in finding new malignancies comparing with a routine cancer screening campaign.
Routine biopsy during PKP was safe and cost-effective in finding unsuspected malignancies. We advocate routine biopsy in every operated vertebral level during PKP for VCF patients.
PMCID: PMC4272288  PMID: 25526360
8.  Selective Nickel- and Manganese-Catalyzed Decarboxylative Cross Coupling of Some α,β-Unsaturated Carboxylic Acids with Cyclic Ethers 
Scientific Reports  2014;4:7446.
A nickel- and manganese-catalyzed decarboxylative cross coupling of α, β-unsaturated carboxylic acids with cyclic ethers such as tetrahydrofuran and 1, 4-dioxane was developed. Oxyalkylation was achieved when nickel acetate was used as catalyst, while manganese acetate promoted the reaction of alkenylation.
PMCID: PMC4264008  PMID: 25502282
9.  Microglia/macrophage polarization dynamics in white matter after traumatic brain injury 
Mononuclear phagocytes are a population of multi-phenotypic cells and have dual roles in brain destruction/reconstruction. The phenotype-specific roles of microglia/macrophages in traumatic brain injury (TBI) are, however, poorly characterized. In the present study, TBI was induced in mice by a controlled cortical impact (CCI) and animals were killed at 1 to 14 days post injury. Real-time polymerase chain reaction (RT–PCR) and immunofluorescence staining for M1 and M2 markers were performed to characterize phenotypic changes of microglia/macrophages in both gray and white matter. We found that the number of M1-like phagocytes increased in cortex, striatum and corpus callosum (CC) during the first week and remained elevated until at least 14 days after TBI. In contrast, M2-like microglia/macrophages peaked at 5 days, but decreased rapidly thereafter. Notably, the severity of white matter injury (WMI), manifested by immunohistochemical staining for neurofilament SMI-32, was strongly correlated with the number of M1-like phagocytes. In vitro experiments using a conditioned medium transfer system confirmed that M1 microglia-conditioned media exacerbated oxygen glucose deprivation–induced oligodendrocyte death. Our results indicate that microglia/macrophages respond dynamically to TBI, experiencing a transient M2 phenotype followed by a shift to the M1 phenotype. The M1 phenotypic shift may propel WMI progression and represents a rational target for TBI treatment.
PMCID: PMC3851898  PMID: 23942366
inflammation; macrophage; microglia; polarization; white matter injury
10.  Therapeutic detoxification of quercetin against carbon tetrachloride-induced acute liver injury in mice and its mechanism*  
This study observes the therapeutic detoxification of quercetin, a well-known flavonoid, against carbon tetrachloride (CCl4) induced acute liver injury in vivo and explores its mechanism. Quercetin decreased CCl4-increased serum activities of alanine and aspartate aminotransferases (ALT/AST) when orally taken 30 min after CCl4 intoxication. The results of a histological evaluation further evidenced the ability of quercetin to protect against CCl4-induced liver injury. Quercetin decreased the CCl4-increased malondialdehyde (MDA) and reduced the glutathione (GSH) amounts in the liver. It also reduced the enhanced immunohistochemical staining of the 4-hydroxynonenal (4-HNE) in the liver induced by CCl4. Peroxiredoxin (Prx) 1, 2, 3, 5, 6, thioredoxin reductase 1 and 2 (TrxR1/2), thioredoxin 1 and 2 (Trx1/2), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) all play critical roles in maintaining cellular redox homeostasis. Real-time polymerase chain reaction (PCR) results demonstrated that quercetin reversed the decreased mRNA expression of all those genes induced by CCl4. In conclusion, our results demonstrate that quercetin ameliorates CCl4-induced acute liver injury in vivo via alleviating oxidative stress injuries when orally taken after CCl4 intoxication. This protection may be caused by the elevation of the antioxidant capacity induced by quercetin.
PMCID: PMC4265558  PMID: 25471833
Hepatotoxicity; Oxidative stress; Peroxiredoxin (Prx); Nuclear factor erythroid 2-related factor 2 (Nrf2); TrxR; Trx; HO-1
11.  Cell membrane damage is involved in the impaired survival of bone marrow stem cells by oxidized low-density lipoprotein 
Cell therapy with bone marrow stem cells (BMSCs) remains a viable option for tissue repair and regeneration. A major challenge for cell therapy is the limited cell survival after implantation. This study was to investigate the effect of oxidized low-density lipoprotein (ox-LDL, naturally present in human blood) on BMSC injury and the effect of MG53, a tissue repair protein, for the improvement of stem cell survival. Rat bone marrow multipotent adult progenitor cells (MAPCs) were treated with ox-LDL, which caused significant cell death as reflected by the increased LDH release to the media. Exposure of MAPCs to ox-LDL led to entry of fluorescent dye FM1-43 measured under confocal microscope, suggesting damage to the plasma membrane. Ox-LDL also generated reactive oxygen species (ROS) as measured with electron paramagnetic resonance spectroscopy. While antioxidant N-acetylcysteine completely blocked ROS production from ox-LDL, it failed to prevent ox-LDL-induced cell death. When MAPCs were treated with the recombinant human MG53 protein (rhMG53) ox-LDL induced LDH release and FM1-43 dye entry were significantly reduced. In the presence of rhMG53, the MAPCs showed enhanced cell survival and proliferation. Our data suggest that membrane damage induced by ox-LDL contributed to the impaired survival of MAPCs. rhMG53 treatment protected MAPCs against membrane damage and enhanced their survival which might represent a novel means for improving efficacy for stem cell-based therapy for treatment of diseases, especially in setting of hyperlipidemia.
PMCID: PMC4302650  PMID: 25256620
mesenchymal stem cells; ox-LDL; MG53; membrane damage; cell survival
12.  Patch clamp apply in cardiomyocytes derived from patient’s iPS cells for individual anticancer therapy 
Cardiac side-effects of chemotherapy are old dogs for cancer patient at the beginning of cancer treatment. The deleterious side-effects of chemotherapy on the cardiovascular system have been deemed as a serious clinical issue for a long term, especially sudden cardiac death (SCD) due to QT prolongation. Since induced pluripotent stem cells has been firstly reported by Takahashi and Yamanaka in 2006, iPS has become a valuable research tool. Especially, cardiomyocytes have been successfully derived from human iPS cells which carry on corresponding genetic information of disease, and therefore show a great promise in drug screen on the diseasing model. In this study, we hypothesized that iPS cells created from patient with cancer and carried corresponding genetic alteration will provide a genetic background for sensitivity screening of anticancer drug, as well as side-effects of cardiovascular system.
PMCID: PMC4276230  PMID: 25550972
Patch clamp; iPS cells; individual anticancer therapy
13.  Crystallization and preliminary crystallographic analysis of 2-aminophenol 1,6-dioxygenase complexed with substrate and with an inhibitor 
The crystallization of 2-aminophenol 1,6-dioxygenase in complexes with its substrate and with an inhibitor is reported.
Dioxygen activation implemented by nonhaem FeII enzymes containing the 2-­His-1-carboxylate facial triad has been extensively studied in recent years. Extradiol dioxygenase is the archetypal member of this superfamily and catalyzes the oxygenolytic ring opening of catechol analogues. Here, the crystallization and preliminary X-ray analysis of 2-aminophenol 1,6-dioxygenase, an enzyme representing a minor subset of extradiol dioxygenases that catalyze the fission of 2-aminophenol rather than catecholic compounds, is reported. Crystals of the holoenzyme with FeII and of complexes with the substrate 2-aminophenol and the suicide inhibitor 4-nitrocatechol were grown using the cocrystallization method under the same conditions as used for the crystallization of the apoenzyme. The crystals belonged to space group C2 and diffracted to 2.3–2.7 Å resolution; the crystal that diffracted to the highest resolution had unit-cell parameters a = 270.24, b = 48.39, c = 108.55 Å, β = 109.57°. All X-ray data sets collected from diffraction-quality crystals were suitable for structure determination.
PMCID: PMC3515376  PMID: 23143244
2-aminophenol 1,6-dioxygenase; extradiol dioxygenases; 2-aminophenol; catechol
14.  HMGB1 mediates hyperglycaemia-induced cardiomyocyte apoptosis via ERK/Ets-1 signalling pathway 
Apoptosis is a key event involved in diabetic cardiomyopathy. The expression of high mobility group box 1 protein (HMGB1) is up-regulated in diabetic mice. However, the molecular mechanism of high glucose (HG)-induced cardiomyocyte apoptosis remains obscure. We aimed to determine the role of HMGB1 in HG-induced apoptosis of cardiomyocytes. Treating neonatal primary cardiomyocytes with HG increased cell apoptosis, which was accompanied by elevated levels of HMGB1. Inhibition of HMGB1 by short-hairpin RNA significantly decreased HG-induced cell apoptosis by reducing caspase-3 activation and ratio of Bcl2-associated X protein to B-cell lymphoma/leukemia-2 (bax/bcl-2). Furthermore, HG activated E26 transformation-specific sequence-1 (Ets-1), and HMGB1 inhibition attenuated HG-induced activation of Ets-1 via extracellular signal-regulated kinase 1/2 (ERK1/2) signalling. In addition, inhibition of Ets-1 significantly decreased HG-induced cardiomyocyte apoptosis. Similar results were observed in streptozotocin-treated diabetic mice. Inhibition of HMGB1 by short-hairpin RNA markedly decreased myocardial cell apoptosis and activation of ERK and Ets-1 in diabetic mice. In conclusion, inhibition of HMGB1 may protect against hyperglycaemia-induced cardiomyocyte apoptosis by down-regulating ERK-dependent activation of Ets-1.
PMCID: PMC4224563  PMID: 25210949
high glucose; cardiomyocyte; apoptosis; diabetes; HMGB1; Ets-1
15.  Visualization analysis of research hotspots based on CiteSpace II: taking medical devices as an example 
Biomedical engineering has been one of the hottest fields in biology and engineering. As an important branch, the medical device has achieved significant progress in the past decades. As a useful method in evaluative bibliometrics, mapping knowledge has been used to explore the trend of one field. In the present study, we retrieve literatures about the medical device from the Web of Science™ (2004–2013), and acquire 26,793 related records, then analyze time range, region distribution, and main research directions of the literatures, and try to use keywords combined with mapping knowledge to explore the main trends of the medical device, and then aim to provide more information for medical device research. Through the study, we discover: 1) the publications regarding medical devices show an upward trend over the past decade in general; 2) the percentage of publications in the USA (38.49%) is the highest all over the world; 3) engineering (20.64%) is the hottest research direction, and takes up about one-fifth of the total publications; 4) the Journal of the American Medical Association and The New England Journal of Medicine are among the two journals that are the most highly cited, followed by Science and The Lancet; and 5) keywords of the medical device include in vitro, quality-of-life, outcomes, management, mortality, depression, and so on. With the help of mapping knowledge, we dig out some hot topics of medical devices and provide more information through trend analysis, and we discover that our findings are related to previous research and further research can enlarge the number of records and optimize the algorithm. We provide a systematic approach for researchers to keep abreast of the development and state of the research of medical devices.
PMCID: PMC4216033  PMID: 25368536
visualization analysis; medical device; CiteSpace; hotspot
16.  Impact of NPR-A expression in gastric cancer cells 
Background: The receptors for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPR-A), have been reported to be expressed in lung cancer, prostate cancer, ovarian cancer. NPR-A expression and signaling is important for tumor growth, its deficiency protect C57BL/6 mice from lung, skin, and ovarian cancers, and these result suggest that NPR-A is a new target for cancer therapy. Recently, NPR-A has been demonstrated to be expressed in pre-implantation embryos and in ES cells, it has a novel role in the maintenance of self-renewal and pluripotency of ES cells. However, the direct role of NPR-A signaling in gastric cancer remains unclear. Method: NPR-A expression was downregulated by transfection of shRNA. The proliferation of gastric cancer cells was measured by Hoechst 33342 stain. Cell proliferation and invasion were determined via BrdU and transwell assays, respectively. Results: Down-regulation of NPR-A expression by shNPR-A induced apoptosis, inhibited proliferation and invasion in AGS cells. The mechanism of shNPR-A-induced anti-AGS effects was linked to NPR-A-induced expression of KCNQ1, a gene to be overexpressed in AGS and significantly reduced by shNPR-A. Conclusion: Collectively, these results suggest that NPR-A promotes gastric cancer development in part by regulating KCNQ1. Our findings also suggest that NPR-A is a target for gastric cancer therapy.
PMCID: PMC4238555  PMID: 25419351
NPR-A; gastric cancer; KCNQ1
18.  Covered versus uncovered self-expandable metallic stents for palliation of malignant gastric outlet obstruction: a systematic review and meta-analysis 
BMC Gastroenterology  2014;14(1):170.
Self-expandable metallic stents (SEMSs) are widely used for palliation of malignant gastric outlet obstruction (GOO). There are two types of SEMS, covered and uncovered, each with its own advantages and disadvantages. We aimed to compare the efficacy and safety between uncovered and covered SEMSs in the palliation of malignant gastric outlet obstruction.
Databases including PubMed, EMBASE, the Cochrane Library, the Science Citation Index and momentous meeting abstracts were searched and evaluated by two reviewers independently.
Nine trials involving 849 patients were analyzed. Meta-analysis showed there was no significant difference in technical success rate (RR 1.0, 95% CI [0.98, 1.01]), clinical success rate (RR 1.04, 95% CI [0.98, 1.11]), post-stenting dysphagia score (WMD −0.01, 95% CI [−0.52, 0.50]), stent patency (WMD −0.31, 95% CI [−1.73, 1.11]), overall complications (RR 1.07, 95% CI [0.87, 1.32]) and reintervention rate (RR 1.30, 95% CI [0.92, 1.83]) between covered and uncovered SEMSs group. However, covered SEMSs were associated with higher migration rate (RR 3.48, 95% CI [2.16, 5.62], P < 0.00001) and lower obstruction rate (RR 0.42, 95% CI [0.24, 0.73], P = 0.002).
In the palliative treatment of malignant gastric outlet obstruction, both covered and uncovered SEMSs are safely and effective. Covered stents can reduce the risk of restenosis, whereas uncovered stents are effective in decreasing stent migration.
PMCID: PMC4190394  PMID: 25270550
Covered SEMSs; Uncovered SEMSs; Gastric outlet obstruction; Meta-analysis
19.  Nanoencapsulation Enhances Epigallocatechin-3-Gallate Stability and Its Anti-atherogenic Bioactivities in Macrophages 
Journal of agricultural and food chemistry  2013;61(38):10.1021/jf4023004.
We have successfully synthesized (−)-epigallocatechin-3-gallate (EGCG) encapsulated nanostructured lipid carriers (NLCE) and chitosan coated NLCE (CSNLCE) using natural lipids, surfactant, chitosan and EGCG. Nanoencapsulation dramatically improved EGCG stability. CSNLCE significantly increased EGCG content in THP-1 derived macrophages compared with nonencapsulated EGCG. As compared to 10 μM of nonencapsulated EGCG, both NLCE and CSNLCE at the same concentration significantly decreased macrophage cholesteryl ester content. NLCE and CSNLCE significantly decreased mRNA levels and protein secretion of monocyte chemoattractant protein-1 (MCP-1) levels in macrophages, respectively. These data suggest that nanoencapsulated EGCG may have a potential to inhibit atherosclerotic lesion development through decreasing macrophage cholesterol content and MCP-1 expression.
PMCID: PMC3840090  PMID: 24020822
EGCG; nanostructured lipid carriers; atherosclerosis; macrophage; stability; uptake
20.  Genetic Features of Late Onset Primary Hemophagocytic Lymphohistiocytosis in Adolescence or Adulthood 
PLoS ONE  2014;9(9):e107386.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of uncontrolled immune activation leading to extreme inflammation. Primary HLH was once believed to be a disease that occurred only in infancy or young children, and was rarely diagnosed in adults. It is now understood that patients can develop primary HLH in their adolescence or adulthood. This study included 252 adolescent and adult patients with a clinical diagnosis of HLH from 35 general medical institutions across mainland China. All exons and 50 bp of flanking intronic sequence of six HLH-related genes (PRF1, UNC13D, STX11, STXBP2, SH2D1A, and BIRC4) were sequenced in these patients. We identified mutations in 18/252 (7.1%) of the patients, with changes in PRF1 being most common. Late-onset HLH often features viral infection and other predisposing factors. We conclude that late-onset primary HLH is not as rare as previously thought. Older patients should not be delayed to receive HLH-related genes testing when they are suspected with HLH.
PMCID: PMC4169386  PMID: 25233452
22.  Fission Yeast Pxd1 Promotes Proper DNA Repair by Activating Rad16XPF and Inhibiting Dna2 
PLoS Biology  2014;12(9):e1001946.
During DNA double-strand break repair, two structure-specific DNA nucleases are controlled by the same regulator Pxd1, but in opposite manners.
Structure-specific nucleases play crucial roles in many DNA repair pathways. They must be precisely controlled to ensure optimal repair outcomes; however, mechanisms of their regulation are not fully understood. Here, we report a fission yeast protein, Pxd1, that binds to and regulates two structure-specific nucleases: Rad16XPF-Swi10ERCC1 and Dna2-Cdc24. Strikingly, Pxd1 influences the activities of these two nucleases in opposite ways: It activates the 3′ endonuclease activity of Rad16-Swi10 but inhibits the RPA-mediated activation of the 5′ endonuclease activity of Dna2. Pxd1 is required for Rad16-Swi10 to function in single-strand annealing, mating-type switching, and the removal of Top1-DNA adducts. Meanwhile, Pxd1 attenuates DNA end resection mediated by the Rqh1-Dna2 pathway. Disabling the Dna2-inhibitory activity of Pxd1 results in enhanced use of a break-distal repeat sequence in single-strand annealing and a greater loss of genetic information. We propose that Pxd1 promotes proper DNA repair by differentially regulating two structure-specific nucleases.
Author Summary
Genome stability maintenance relies on DNA repair enzymes, among which are structure-specific nucleases that cleave DNA in a sequence-independent but structure-dependent manner. It is important to understand how the activities of such nucleases are controlled, because either insufficient or excessive cleavage of DNA could jeopardize genome integrity. In this study, we discovered a new regulator of two different structure-specific nucleases in the fission yeast Schizosaccharomyces pombe. The identified protein, which we named Pxd1, promotes the activity of the 3′ endonuclease Rad16, but restrains the activity of the 5′ endonuclease Dna2. In the absence of Pxd1, several Rad16-dependent DNA repair processes become defective. One of these processes is a DNA-repeat–mediated double-strand break repair pathway called single-strand annealing, which causes genomic deletions. When the Dna2-inhibitory activity of Pxd1 is impaired, Dna2-dependent end processing of double-strand breaks is enhanced and a more extensive deletion occurs during single-strand annealing. Thus, Pxd1 facilitates a potentially dangerous DNA repair process, but in the meantime minimizes its deleterious consequences. We propose that a dual-target regulator like Pxd1 is ideally suited for coordinating multiple enzymatic activities during DNA repair.
PMCID: PMC4159138  PMID: 25203555
23.  Omega-3 polyunsaturated fatty acid supplementation improves neurologic recovery and attenuates white matter injury after experimental traumatic brain injury 
Dietary supplementation with omega-3 (ω-3) fatty acids is a safe, economical mean of preventive medicine that has shown protection against several neurologic disorders. The present study tested the hypothesis that this method is protective against controlled cortical impact (CCI). Indeed, mice fed with ω-3 polyunsaturated fatty acid (PUFA)-enriched diet for 2 months exhibited attenuated short and long-term behavioral deficits due to CCI. Although ω-3 PUFAs did not decrease cortical lesion volume, these fatty acids did protect against hippocampal neuronal loss after CCI and reduced pro-inflammatory response. Interestingly, ω-3 PUFAs prevented the loss of myelin basic protein (MPB), preserved the integrity of the myelin sheath, and maintained the nerve fiber conductivity in the CCI model. ω-3 PUFAs also directly protected oligodendrocyte cultures from excitotoxicity and blunted the microglial activation-induced death of oligodendrocytes in microglia/oligodendrocyte cocultures. In sum, ω-3 PUFAs elicit multifaceted protection against behavioral dysfunction, hippocampal neuronal loss, inflammation, and loss of myelination and impulse conductivity. The present report is the first demonstration that ω-3 PUFAs protect against white matter injury in vivo and in vitro. The protective impact of ω-3 PUFAs supports the clinical use of this dietary supplement as a prophylaxis against traumatic brain injury and other nervous system disorders.
PMCID: PMC3764381  PMID: 23801244
behavior (rodent); brain trauma; inflammation; neurodegeneration; white matter/oligodendrocytes
24.  A competitive formation of DNA:RNA hybrid G-quadruplex is responsible to the mitochondrial transcription termination at the DNA replication priming site 
Nucleic Acids Research  2014;42(16):10832-10844.
Human mitochondrial DNA contains a distinctive guanine-rich motif denoted conserved sequence block II (CSB II) that stops RNA transcription, producing prematurely terminated transcripts to prime mitochondrial DNA replication. Recently, we reported a general phenomenon that DNA:RNA hybrid G-quadruplexes (HQs) readily form during transcription when the non-template DNA strand is guanine-rich and such HQs in turn regulate transcription. In this work, we show that transcription of mitochondrial DNA leads to the formation of a stable HQ or alternatively an unstable intramolecular DNA G-quadruplex (DQ) at the CSB II. The HQ is the dominant species and contributes to the majority of the premature transcription termination. Manipulating the stability of the DQ has little effect on the termination even in the absence of HQ; however, abolishing the formation of HQs by preventing the participation of either DNA or RNA abolishes the vast majority of the termination. These results demonstrate that the type of G-quadruplexes (HQ or DQ) is a crucial determinant in directing the transcription termination at the CSB II and suggest a potential functionality of the co-transcriptionally formed HQ in DNA replication initiation. They also suggest that the competition/conversion between an HQ and a DQ may regulate the function of a G-quadruplex-forming sequence.
PMCID: PMC4176368  PMID: 25140009
25.  Prognostic role of microRNA-145 in various human malignant neoplasms: a meta-analysis of 18 related studies 
Recent studies show that microRNA-145 (miR-145) might be an attractive tumor biomarker of considerable prognostic value. To clarify the preliminary predictive value of miR-145 for prognosis in various malignant neoplasms, we conducted a meta-analysis of 18 relevant studies.
Eligible studies were identified by searching the online databases PubMed, EMBASE, and Web of Science up to March 2014. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for patient survival and disease progress were calculated to investigate the association with miR-145 expression.
In total, 18 eligible studies were included in this meta-analysis. Our results showed that upregulated miR-145 significantly predicted a favorable overall survival (OS) (HR = 0.47, 95% CI 0.31 to 0.72), but failed to show a significant relation with disease prognosis. In stratified analyses, high miR-145 expression predicted favorable OS in both Whites and Asians but the intensity of the association in Whites (HR = 0.67, 95% CI 0.47 to 0.95) was not as strong as in Asians (HR = 0.35, 95% CI 0.19 to 0.64). High miR-145 expression also predicted better progression-free survival (PFS) in Asians (HR = 0.43, 95% CI 0.21 to 0.89), but not in Whites. In addition, a significantly favorable OS associated with upregulated miR-145 expression was observed in both squamous cell (SCC) (HR = 0.34, 95% CI 0.13 to 0.93) and glioblastoma (HR = 0.72, 95% CI 0.52 to 0.99).
Our findings indicate that high miR-145 expression is better at predicting patient survival rather than disease progression for malignant tumors, especially for SCC and glioblastoma in Asians. Considering the insufficient evidence, further investigations and more studies are needed.
PMCID: PMC4249768  PMID: 25106061
Malignant neoplasm; miR-145; Prognosis; Overall survival; Progression-free survival

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