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2.  Heat Shock Protein 90β Stabilizes Focal Adhesion Kinase and Enhances Cell Migration and Invasion in Breast Cancer Cells 
Experimental cell research  2014;326(1):78-89.
Focal adhesion kinase (FAK) acts as a regulator of cellular signaling and may promote cell spreading, motility, invasion and survival in malignancy. Elevated expression and activity of FAK frequently correlate with tumor cell metastasis and poor prognosis in breast cancer. However, the mechanisms by which the turnover of FAK is regulated remain elusive. Here we report that heat shock protein 90β (HSP90β) interacts with FAK and the middle domain (amino acids 233–620) of HSP90β is mainly responsible for this interaction. Furthermore, we found that HSP90β regulates FAK stability since HSP90β inhibitor 17-AAG triggers FAK ubiquitylation and subsequent proteasome-dependent degradation. Moreover, disrupted FAK-HSP90β interaction induced by 17-AAG contributes to attenuation of tumor cell growth, migration, and invasion. Together, our results reveal how HSP90β regulates FAK stability and identifies a potential therapeutic strategy to breast cancer.
doi:10.1016/j.yexcr.2014.05.018
PMCID: PMC4120946  PMID: 24880126
HSP90β; FAK; breast cancer; metastasis; ubiquitin
3.  Early detection of an epidemic erythromelalgia outbreak using Baidu search data 
Scientific Reports  2015;5:12649.
Dozens of epidemic erythromelalgia (EM) outbreaks have been reported in China since the mid-twentieth century, and the most recent happened in Foshan City, Guangdong Province early 2014. This study compared the daily case counts of this recent epidemic EM outbreak from February 11 to March 3 with Baidu search data for the same period. After keyword selection, filtering and composition, the most correlated lag of the EM Search Index was used for comparison and linear regression model development. This study also explored the spatial distribution of epidemic EM in China during this period based on EM Search Index. The EM Search Index at lag 2 was most significantly associated with daily case counts in Foshan (ρ = 0.863, P < 0.001). It captured an upward trend in the outbreak about one week ahead of official report and the linear regression analysis indicated that every 1.071 increase in the EM Search Index reflected a rise of 1 EM cases 2 days earlier. The spatial analysis found that the number of EM Search Indexes increased in the middle of Guangdong Province and South China during the outbreak period. The EM Search Index may be a good early indicator of an epidemic EM outbreak.
doi:10.1038/srep12649
PMCID: PMC4517510  PMID: 26218589
4.  Rational Design of CXCR4 Specific Antibodies with Elongated CDRs 
Journal of the American Chemical Society  2014;136(30):10557-10560.
The bovine antibody (BLV1H12) which has an ultralong heavy chain complementarity determining region 3 (CDRH3) provides a novel scaffold for antibody engineering. By substituting the extended CDRH3 of BLV1H12 with modified CXCR4 binding peptides that adopt a β-hairpin conformation, we generated antibodies specifically targeting the ligand binding pocket of CXCR4 receptor. These engineered antibodies selectively bind to CXCR4 expressing cells with binding affinities in the low nanomolar range. In addition, they inhibit SDF-1-dependent signal transduction and cell migration in a transwell assay. Finally, we also demonstrate that a similar strategy can be applied to other CDRs and show that a CDRH2-peptide fusion binds CXCR4 with a Kd of 0.9 nM. This work illustrates the versatility of scaffold-based antibody engineering and could greatly expand the antibody functional repertoire in the future.
doi:10.1021/ja5042447
PMCID: PMC4120998  PMID: 25041362
5.  Activation of transcription factor AP-1 in response to thermal injury in rat small intestine and IEC-6 cells 
BMC Gastroenterology  2015;15:83.
Background
Our previous studies indicated that heat stress can cause significant damage to the intestinal epithelium and induce differential expression of many genes in rat small intestine. The transcription factors AP-1 and NF-κB, which act as important mediators by binding to specific DNA sequences within gene promoters, regulate the transcription of genes associated with immune regulation, stress response and cell fate.
Methods
To determine whether AP-1 and NF-κB are involved in hyperthermia-induced injury in rat small intestine and IEC-6 cells, we investigated their activity, and the expression of related proteins, by electrophoretic mobility shift assays and western blotting, respectively.
Results
Heat stress resulted in severe damage to the epithelium of the small intestine. The cell morphology and viability were obviously altered when IEC-6 cell was exposed to hyperthermia. AP-1 was activated in the small intestine of heat-stressed rats, as was phosphorylation of the JNK signaling pathway. In IEC-6 cell line, AP-1 activation in groups exposed to 42 °C for 1 h, 2 h and 4 h was significantly increased. In contrast, NF-κB was not activated in both in vivo and in vitro models.
Conclusion
These results reveal that AP-1 is likely to play an important role in regulating gene transcription in rat small intestine and IEC-6 cells during exposure to heat stress.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-015-0309-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-015-0309-z
PMCID: PMC4498520  PMID: 26162907
AP-1; NF-κB; Heat stress; Rat small intestine; IEC-6
6.  Photocurrent generation in lateral graphene p-n junction created by electron-beam irradiation 
Scientific Reports  2015;5:12014.
Graphene has been considered as an attractive material for optoelectronic applications such as photodetectors owing to its extraordinary properties, e.g. broadband absorption and ultrahigh mobility. However, challenges still remain in fundamental and practical aspects of the conventional graphene photodetectors which normally rely on the photoconductive mode of operation which has the drawback of e.g. high dark current. Here, we demonstrated the photovoltaic mode operation in graphene p-n junctions fabricated by a simple but effective electron irradiation method that induces n-type doping in intrinsic p-type graphene. The physical mechanism of the junction formation is owing to the substrate gating effect caused by electron irradiation. Photoresponse was obtained for this type of photodetector because the photoexcited electron-hole pairs can be separated in the graphene p-n junction by the built-in potential. The fabricated graphene p-n junction photodetectors exhibit a high detectivity up to ~3 × 1010 Jones (cm Hz1/2 W−1) at room temperature, which is on a par with that of the traditional III–V photodetectors. The demonstrated novel and simple scheme for obtaining graphene p-n junctions can be used for other optoelectronic devices such as solar cells and be applied to other two dimensional materials based devices.
doi:10.1038/srep12014
PMCID: PMC4495417  PMID: 26152225
7.  Brief Intervention to Increase Emergency Department Uptake of Combined Rapid HIV and Hepatitis C Screening Among a Drug Misusing Population 
Objectives
In this study, Increasing Viral Testing in the Emergency Department (InVITED), the authors investigated if a brief intervention about human immunodeficiency virus (HIV) and hepatitis C virus (HCV) risk-taking behaviors and drug use and misuse in addition to a self-administered risk assessment, as compared to a self-administered risk assessment alone, increased uptake of combined screening for HIV and HCV, self-perception of HIV/HCV risk, and beliefs and opinions on HIV/HCV screening.
Methods
InVITED was a randomized, controlled trial conducted at two urban emergency departments (EDs) from February 2011 to March 2012. ED patients who self-reported drug use within the past three months were invited to enroll. Drug misuse severity and need for a brief or more intensive intervention was assessed using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). Participants were randomly assigned to one of two study arms: a self-administered HIV/HCV risk assessment alone (control arm), or the assessment plus a brief intervention about their drug misuse and screening for HIV/HCV (intervention arm). Beliefs on the value of combined HIV/HCV screening, self-perception of HIV/HCV risk, and opinions on HIV/HCV screening in the ED were measured in both study arms before the HIV/HCV risk assessment (pre), after the assessment in the control arm, and after the brief intervention in the intervention arm (post). Participants in both study arms were offered free combined rapid HIV/HCV screening. Uptake of screening was compared by study arm. Multivariable logistic regression models were used to evaluate factors related to uptake of screening.
Results
Of the 395 participants in the study, the median age was 28 years (IQR 23 to 38 years), 44.8% were female, 82.3% had ever been tested for HIV, and 67.3% had ever been tested for HCV. Uptake of combined rapid HIV/HCV screening was nearly identical by study arm (64.5% vs. 65.2%; Δ = −0.7%; 95% CI = −10.1% to 8.7%). Of the 256 screened, none had reactive HIV antibody tests, but seven (2.7%) had reactive HCV antibody tests. Multivariable logistic regression analysis results indicated that uptake of screening was not related to study arm assignment, total ASSIST drug scores, need for an intervention for drug misuse, or HIV/HCV sexual risk assessment scores. However, uptake of screening was greater among participants who indicated placing a higher value on combined rapid HIV/HCV screening for themselves and all ED patients, and those with higher levels of perceived HIV/HCV risk. Uptake of combined rapid HIV/HCV screening was not related to changes in beliefs regarding the value of combined HIV/HCV screening or self-perceived HIV/HCV risk (post- vs. pre-risk assessment with or without a brief intervention). Opinions regarding the ED as a venue for combined rapid HIV/HCV screening were not related to uptake of screening.
Conclusions
Uptake of combined rapid HIV/HCV screening is high and considered valuable among drug using and misusing ED patients with little concern about the ED as a screening venue. The brief intervention investigated in this study does not appear to change beliefs regarding screening, self-perceived risk, or uptake of screening for HIV/HCV in this population. Initial beliefs regarding the value of screening and self-perceived risk for these infections predict uptake of screening.
doi:10.1111/acem.12419
PMCID: PMC4135533  PMID: 25125271
8.  Notch3 Pathway Alterations in Ovarian Cancer 
Cancer research  2014;74(12):3282-3293.
Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biological mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited OvCa growth and induced apoptosis. Importantly, we found that DNM-mediated endocytosis was required for selectively activating Jagged-1-mediated Notch3 signaling. Cleaved Notch3 expression was the critical determinant of response to Notch-targeted therapy. Collectively, these data identify previously unknown mechanisms underlying Notch3 signaling and identify new, biomarker-driven approaches for therapy.
doi:10.1158/0008-5472.CAN-13-2066
PMCID: PMC4058356  PMID: 24743243
9.  Prevalence of Obesity and Related Factors among Bouyei and Han Peoples in Guizhou Province, Southwest China 
PLoS ONE  2015;10(6):e0129230.
Objective
To investigate the prevalence of general and abdominal obesity and associated factors in Bouyei and Han peoples.
Design
A cross-sectional study was carried out in Guizhou province, southwest China in 2012, with multi-stage sampling to enroll 4551 participants aged 20 to 80 years. General and abdominal obesity were defined by World Health Organization (WHO) for Chinese. A design-based analysis was performed to evaluate prevalence of obesity and its related factors.
Results
Bouyei people had a significantly lower prevalence of general obesity (4.8% vs. 10.9%, p < 0.05) and abdominal obesity (13.6% vs. 26.8%, p < 0.05) than that in Han people. Prevalence of obesity increased with age until middle-age period and declined thereafter. Men aged 40–49 years group and women aged 50–59 years group have the highest prevalence of general obesity. Prevalence of abdominal obesity was higher than that of general obesity. Middle-age, Higher income, Han people were significantly associated with an increased risk of General/abdominal obesity.
Conclusions
Bouyei people had a lower prevalence of general and abdominal obesity than the Han people. Etiological studies should be conducted to determine underlying genetic factors and dietary factors.
doi:10.1371/journal.pone.0129230
PMCID: PMC4468129  PMID: 26075708
10.  Acute Interstitial Nephritis Following Multiple Asian Giant Hornet Stings 
Patient: Male, 42
Final Diagnosis: Acute interstitial nephritis
Symptoms: Difficulty breathing • headache • numbness • oliguria
Medication: Methylprednisolone
Clinical Procedure: Plasma exchange
Specialty: Nephrology
Objective:
Rare disease
Background:
The Asian giant hornet is the largest wasp species in the world. Its stings can cause acute interstitial nephritis and acute renal failure. From July to October, 2013, Asian giant hornet attacks have killed 42 people and injured 1675 people with their powerful venomous stings in Hanzhong, Ankang, and Shangluo, three cities in the southern part of Shaanxi Province, China.
Case Report:
We report here a case of a 42-year-old man with acute interstitial nephritis following multiple Asian giant hornet stings. On admission, the patient had difficulty breathing, headache, and numbness in both limbs (arm and leg). He was treated in the Emergency Department and Department of Nephrology with plasma exchange and dialysis within 24 hours after being stung. A kidney biopsy revealed acute interstitial nephritis with interstitial infiltrations of eosinophils and lymphocytes. After intensive treatment, his liver function recovered within 10 days. Along with oral methylprednisolone, his renal function recovered 1 month later.
Conclusions:
This case shows that acute interstitial nephritis happens several days after being stung. Since the number of deaths in southern Shaanxi province is much higher than other places, our report draws the attention of fellow clinicians to the acute interstitial nephritis following multiple Asian giant hornet stings.
doi:10.12659/AJCR.893734
PMCID: PMC4479185  PMID: 26076055
Acute Kidney Injury; Methylprednisolone; Wasp Venoms
11.  Inverted U-Shaped Relationship between Central Venous Pressure and Intra-Abdominal Pressure in the Early Phase of Severe Acute Pancreatitis: A Retrospective Study 
PLoS ONE  2015;10(6):e0128493.
Objective
Many studies have indicated that intra-abdominal pressure (IAP) is positively correlated with central venous pressure (CVP) in severe cases. However, although elevated IAP is common in patients with severe acute pancreatitis (SAP), its relationship with CVP remains unclear. Our study aimed to investigate the association of IAP with CVP in early-phase SAP patients.
Methods
In total, 116 SAP patients were included in this retrospective study. On the first day of hospitalization, blood samples were collected for biochemical examination and cytokine concentration monitoring. Additionally, a urinary catheter and right subclavian vein catheter were inserted for IAP and CVP measurement, respectively. Other routine clinical data were also recorded.
Results
Within 24 hours after hospitalization, CVP fluctuated and increased with increasing IAP up to 15.7 mmHg (P = 0.054) but decreased with increasing IAP when the IAP was > 15.7 mmHg (P < 0.001). After adjusting for abdominal perfusion pressure (APP) and mean arterial pressure (MAP), a similar distribution was observed. An inverted U-shaped trend between IAP and CVP was also present in the groups classified according to the patient’s sex, local complications, ascites, and serum amylase levels.
Conclusions
CVP and IAP have an inverted U-shaped relationship, with a peak at an IAP of 15.7 mmHg in the early phase of SAP. After this peak, CVP decreases as IAP increases. These results have crucial implications for clinical fluid resuscitation in SAP patients. In particular, because one CVP value might be correlated with different IAP values in patients with the same CVP, the volume of fluid needed might be different.
doi:10.1371/journal.pone.0128493
PMCID: PMC4459987  PMID: 26053865
12.  Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease 
Background
Aspirin-exacerbated respiratory disease (AERD) is an inflammatory condition of the respiratory tract and is characterized by overproduction of leukotrienes (LT) and large numbers of circulating granulocyte-platelet complexes. LT production can be suppressed by prostaglandin E2 (PGE2) and the cyclic AMP-dependent protein kinase A (PKA).
Objective
To determine if PGE2-dependent control of LT production by granulocytes is dysregulated in AERD.
Methods
Granulocytes from well-characterized patients with and without AERD were activated ex vivo and subjected to a range of functional and biochemical analyses.
Results
Granulocytes from subjects with AERD generated more LTB4 and cysteinyl LTs than did granulocytes from controls with aspirin-tolerant asthma and controls without asthma. When compared with controls, granulocytes from subjects with AERD had comparable levels of EP2 protein expression and PGE2-mediated cAMP accumulation, yet were resistant to PGE2-mediated suppression of LT generation. Percentages of platelet-adherent neutrophils correlated positively with LTB4 generation and inversely with responsiveness to PGE2-mediated suppression of LTB4. The PKA inhibitor H89 potentiated LTB4 generation by control granulocytes but was inactive in granulocytes from individuals with AERD and had no effect on platelet P-selectin induction. Both tonic PKA activity and levels of PKA catalytic gamma subunit protein were significantly lower in granulocytes from individuals with AERD relative to those from controls.
Conclusions
Impaired granulocyte PKA function in AERD may lead to dysregulated control of 5-lipoxygenase activity by PGE2, whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction.
doi:10.1016/j.jaci.2013.12.1034
PMCID: PMC4040319  PMID: 24486071
Samter’s triad; aspirin-exacerbated respiratory disease; AERD; aspirin triad; nonsteroidal anti-inflammatory drug; asthma; leukotriene; protein kinase A; prostaglandin E2; cyclic AMP
13.  Multiple Gaps in Care Common Among Newly Diagnosed HIV Patients 
AIDS care  2015;27(6):679-687.
The objective of this study was to identify frequency and predictors of gaps in care in a longitudinal cohort of HIV-infected patients in urban New England. We conducted a retrospective cohort study in Providence, RI of 581 newly diagnosed HIV-patients >18 entering into care from 2004-2010 and followed their care through the end of 2011. The outcome of interest was gaps in care, defined as an interruption of medical care for > 6 months. Time to the first gap was characterized using Kaplan-Meier (KM) curves. Anderson-Gill proportional hazards (AGPH) model was used to identify the risk factors of recurrent gaps in care. During the study period, 368 patients (63%) experienced at least 1 gap in care, 178 (30%) had ≥ 2 gaps, 84 (14.5%) had ≥ 3 gaps, and 21 (3.6%) died;77% of gaps were followed by a re-linkage with care The KM curves estimate that one quarter of patients (95%CI=22-29%) would experience ≥ 1 gap in care by year one; nearly one-half (CI=45-54%) by year two; and 90% (CI=93-96%) by year eight;. A prior gap was a strong predictor (HR=2.36; CI=2.16-2.58) of subsequent gaps; other predictors included age <25 (HR=1.29; CI=1.04-1.60), and no prescription of ART in first year of care (HR=1.23; CI=1.01-1.50). The results of this study suggest that a significant proportion of newly diagnosed HIV-infected patients will experience multiple gaps in care and yet re-engagement is possible. Interventions should focus on both prevention of gaps as well as re-engaging those lost to follow-up.
doi:10.1080/09540121.2015.1005002
PMCID: PMC4366312  PMID: 25634492
HIV; retention in care; treatment adherence; gaps
14.  Production of a fragment of glycoprotein G of herpes simplex virus type 2 and evaluation of its diagnostic potential 
Singapore Medical Journal  2015;56(6):346-352.
INTRODUCTION
Herpes simplex virus type 2 (HSV-2) is the most common cause of genital herpes. Glycoprotein G (gG) is a prototype antigen for type-specific serodiagnosis distinguishing between HSV type 1 (HSV-1) and HSV-2 infections. As immunological diagnosis kits for accurate differentiation between HSV-1 and HSV-2 antibodies can be expensive, there is a need to develop a convenient, sensitive, specific and cost-effective serodiagnostic kit.
METHODS
We successfully expressed a fragment of gG comprising residues 321–580 of HSV-2 with histidine tag (gG321–580His) in a Bac-to-Bac baculovirus expression system, which had an antigenicity similar to its native counterpart. An indirect enzyme-linked immunosorbent assay (ELISA) was developed using gG321–580His as the diagnostic antigen and evaluated by comparison with a commercial HerpeSelect 2 ELISA immunoglobulin G kit as reference.
RESULTS
In testing 318 field serum samples, the diagnostic relative sensitivity and specificity of the developed gG321–580His-ELISA test in qualitative comparison with the commercial kit were 93.81% and 96.74%, respectively, and the accuracy was 94.65%.
CONCLUSION
The study indicates that gG321–580His has a high diagnostic potential for HSV-2 virus serodiagnosis in humans.
doi:10.11622/smedj.2014197
PMCID: PMC4469854  PMID: 25532518
baculovirus expression system; glycoprotein G; herpes simplex virus type 2; immunodominant fragment; indirect enzyme-linked immunosorbent assay
15.  Hyperthermia combined with 5-fluorouracil promoted apoptosis and enhanced thermotolerance in human gastric cancer cell line SGC-7901 
OncoTargets and therapy  2015;8:1265-1270.
This study was designed to investigate the proliferation inhibition and apoptosis-promoting effect under hyperthermia and chemotherapy treatment, at cellular level. Human gastric cancer cell line SGC-7901 was cultivated with 5-fluorouracil at different temperatures. Cell proliferation and apoptosis were determined, and expression of Bcl-2 and HSP70 was measured at different treatments. Cell survival rates and inhibition rates in chemotherapy group, thermotherapy group, and thermo-chemotherapy group were drastically lower than the control group (P<0.05). For tumor cells in the thermo-chemotherapy group, survival rates and inhibition rates at three different temperatures were all significantly lower than those in chemotherapy group and thermotherapy group (P<0.05). 5-Fluorouracil induced apoptosis of SGC-7901 cells with a strong temperature dependence, which increased gradually with increase in temperature. At 37°C and 43°C there were significant differences between the thermotherapy group and chemotherapy group and between the thermo-chemotherapy group and thermotherapy group (P<0.01). The expression of Bcl-2 was downregulated and HSP70 was upregulated, with increase in temperature in all groups. Cell apoptosis was not significant at 46°C (P>0.05), which was probably due to thermotolerance caused by HSP70 accumulation. These results suggested that hyperthermia combined with 5-fluorouracil had a synergistic effect in promoting apoptosis and enhancing thermotolerance in gastric cancer cell line SGC-7901.
doi:10.2147/OTT.S78514
PMCID: PMC4455869  PMID: 26064061
gastric cancer; thermotherapy; 5-fluorouracil; Bcl-2; HSP70; thermotolerance
16.  Genetic Map Construction and Quantitative Trait Locus (QTL) Detection of Six Economic Traits Using an F2 Population of the Hybrid from Saccharina longissima and Saccharina japonica 
PLoS ONE  2015;10(5):e0128588.
Saccharina (Laminaria) is one of the most important economic seaweeds. Previously, four genetic linkage maps of Saccharina have been constructed and five QTLs have been identified. However, they were not enough for its breeding. In this work, Saccharina longissima (♀) and Saccharina japonica (♂), which showed obvious differences in morphology and genetics, were applied in hybridization to yield the F2 mapping population with 102 individuals. Using these 102 F2 hybrids, the genetic linkage map of Saccharina was constructed by MapMaker software based on 37 amplified fragment length polymorphisms (AFLPs), 22 sequence-related amplified polymorphisms (SRAPs) and 139 simple sequence repeats (SSRs) markers. Meanwhile, QTL analysis was performed for six economic traits. The linkage map constructed in this research consisted of 422 marker loci (137 AFLPs, 57 SRAPs and 228 SSRs), which formed 45 linkage groups (LGs) with an average marker space of 7.92 cM; they spanned a total length of 2233.1 cM, covering the whole estimated genome size. A total of 29 QTLs were identified for six economic traits, which explained 1.06 to 64.00% of phenotypic variation, including three QTLs for frond length (FL) and raw weight (RW), five QTLs for frond width (FW), two QTLs for frond fascia width (FFW) and frond thickness (FT), and fourteen QTLs for base shape (BS). The results of this research will improve the breeding efficiency and be beneficial for marker-assisted selection (MAS) schemes in Saccharina breeding.
doi:10.1371/journal.pone.0128588
PMCID: PMC4444332  PMID: 26010152
17.  Bcl-xL Genetic Modification Enhanced the Therapeutic Efficacy of Mesenchymal Stem Cell Transplantation in the Treatment of Heart Infarction 
Stem Cells International  2015;2015:176409.
Objectives. Low survival rate of mesenchymal stem cells (MSCs) severely limited the therapeutic efficacy of cell therapy in the treatment of myocardial infarction (MI). Bcl-xL genetic modification might enhance MSC survival after transplantation. Methods. Adult rat bone marrow MSCs were modified with human Bcl-xL gene (hBcl-xL-MSCs) or empty vector (vector-MSCs). MSC apoptosis and paracrine secretions were characterized using flow cytometry, TUNEL, and ELISA in vitro. In vivo, randomized adult rats with MI received myocardial injections of one of the three reagents: hBcl-xL-MSCs, vector-MSCs, or culture medium. Histochemistry, TUNEL, and echocardiography were carried out to evaluate cell engraftment, apoptosis, angiogenesis, scar formation, and cardiac functional recovery. Results. In vitro, cell apoptosis decreased 43%, and vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), and plate-derived growth factor (PDGF) increased 1.5-, 0.7-, and 1.2-fold, respectively, in hBcl-xL-MSCs versus wild type and vector-MSCs. In vivo, cell apoptosis decreased 40% and 26% in hBcl-xL-MSC group versus medium and vector-MSC group, respectively. Similar results were observed in cell engraftment, angiogenesis, scar formation, and cardiac functional recovery. Conclusions. Genetic modification of MSCs with hBcl-xL gene could be an intriguing strategy to improve the therapeutic efficacy of cell therapy in the treatment of heart infarction.
doi:10.1155/2015/176409
PMCID: PMC4436513  PMID: 26074971
18.  Two new amides from a halotolerant fungus, Myrothecium sp. GS-17 
The Journal of Antibiotics  2014;68(4):267-270.
Two new amides, named N-acetyl-2,4,10,17-tetrahydroxyheptadecylamine (1) and N-acetyl-3,5,11,18-tetrahydroxyoctadecyl-2-amine (2), were isolated from a halotolerant fungus, Myrothecium sp. GS-17. Their structures were identified on the basis of spectroscopic characteristics. The cancer cell cytotoxicities of two compounds were evaluated, and compound 2 exhibited weak cytotoxicity in HL-60 cell line.
doi:10.1038/ja.2014.136
PMCID: PMC4418385  PMID: 25269461
19.  Upregulated Ras/Raf/ERK1/2 signaling pathway: a new hope in the repair of spinal cord injury 
Neural Regeneration Research  2015;10(5):792-796.
An increasing number of studies report that the Ras/Raf/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway has a death-promoting apoptotic function in neural cells. We hypothesized that the Ras/Raf/ERK1/2 signaling pathway may be abnormally regulated in rat injured spinal cord models. The weight drop method was used to establish rat spinal cord injury at T9. Western blot analysis and immunohistochemical staining revealed Ras expression was dramatically elevated, and the phosphorylations of A-Raf, B-Raf and C-Raf were all upregulated in the injured spinal cord. Both mitogen-activated protein kinase kinase 1/2 and ERK1/2, which belong to the Ras/Raf signaling kinases, were upregulated. These results indicate that Ras/Raf/ERK1/2 signaling may be upregulated in injured spinal cord and are involved in recovery after spinal cord injury.
doi:10.4103/1673-5374.156984
PMCID: PMC4468773  PMID: 26109956
nerve regeneration; Ras/Raf/Erk1/2 signaling pathway; spinal cord injury; apoptosis; repair; regulation; inhibition; neural regeneration
20.  Multicolor Fluorescent Biosensor for Multiplexed Detection of DNA 
Analytical Chemistry  2014;86(10):5009-5016.
Development of efficient methods for highly sensitive and rapid screening of specific oligonucleotide sequences is essential to the early diagnosis of serious diseases. In this work, an aggregated cationic perylene diimide (PDI) derivative was found to efficiently quench the fluorescence emission of a variety of anionic oligonucleotide-labeled fluorophores that emit at wavelengths from the visible to NIR region. This broad-spectrum quencher was then adopted to develop a multicolor biosensor via a label-free approach for multiplexed fluorescent detection of DNA. The aggregated perylene derivative exhibits a very high quenching efficiency on all ssDNA-labeled dyes associated with biosensor detection, having efficiency values of 98.3 ± 0.9%, 97 ± 1.1%, and 98.2 ± 0.6% for FAM, TAMRA, and Cy5, respectively. An exonuclease-assisted autocatalytic target recycling amplification was also integrated into the sensing system. High quenching efficiency combined with autocatalytic target recycling amplification afforded the biosensor with high sensitivity toward target DNA, resulting in a detection limit of 20 pM, which is about 50-fold lower than that of traditional unamplified homogeneous fluorescent assay methods. The quencher did not interfere with the catalytic activity of nuclease, and the biosensor could be manipulated in either preaddition or postaddition manner with similar sensitivity. Moreover, the proposed sensing system allows for simultaneous and multicolor analysis of several oligonucleotides in homogeneous solution, demonstrating its potential application in the rapid screening of multiple biotargets.
doi:10.1021/ac500618v
PMCID: PMC4033642  PMID: 24731194
21.  The Relationship of Serum Macrophage Inhibitory Cytokine – 1 Levels with Gray Matter Volumes in Community-Dwelling Older Individuals 
PLoS ONE  2015;10(4):e0123399.
Using circulating inflammatory markers and magnetic resonance imaging (MRI), recent studies have associated inflammation with brain volumetric measures. Macrophage Inhibitory Cytokine–1 (MIC-1/GDF15) is a divergent transforming growth factor – beta (TGF-β) superfamily cytokine. To uncover the underlying mechanisms of the previous finding of a negative association between MIC-1/GDF15 serum levels and cognition, the present study aimed to examine the relationship of circulating MIC-1/GDF15 levels with human brain gray matter (GM) volumes, in a community-dwelling sample aged 70–90 years over two years (Wave 1: n = 506, Wave 2: n = 327), of which the age-related brain atrophy had been previously well defined. T1-weighted MRI scans were obtained at both waves and analyzed using the FMRIB Software Library and FreeSurfer. The results showed significantly negative associations between MIC-1/GDF15 serum levels and both subcortical and cortical GM volumes. GM volumes of the whole brain, cortex, temporal lobe, thalamus and accumbens showed significant mediating effects on the associations between MIC-1/GDF15 serum levels and global cognition scores. Increases in MIC-1/GDF15 serum levels were associated with decreases in cortical and subcortical GM volume over two years. In conclusion, MIC-1/GDF15 serum levels were inversely associated with GM volumes both cross-sectionally and longitudinally.
doi:10.1371/journal.pone.0123399
PMCID: PMC4395016  PMID: 25867953
22.  Species-dependent neuropathology in transgenic SOD1 pigs 
Cell Research  2014;24(4):464-481.
Mutations in the human copper/zinc superoxide dismutase 1 (hSOD1) gene cause familial amyotrophic lateral sclerosis (ALS). It remains unknown whether large animal models of ALS mimic more pathological events seen in ALS patients via novel mechanisms. Here, we report the generation of transgenic pigs expressing mutant G93A hSOD1 and showing hind limb motor defects, which are germline transmissible, and motor neuron degeneration in dose- and age-dependent manners. Importantly, in the early disease stage, mutant hSOD1 did not form cytoplasmic inclusions, but showed nuclear accumulation and ubiquitinated nuclear aggregates, as seen in some ALS patient brains, but not in transgenic ALS mouse models. Our findings revealed that SOD1 binds PCBP1, a nuclear poly(rC) binding protein, in pig brain, but not in mouse brain, suggesting that the SOD1-PCBP1 interaction accounts for nuclear SOD1 accumulation and that species-specific targets are key to ALS pathology in large mammals and in humans.
doi:10.1038/cr.2014.25
PMCID: PMC3975503  PMID: 24577199
neurodegeneration; motor neurons; nuclear inclusions; SOD1; PCBP1
23.  Crosstalk between EphA2 and BRaf/CRaf is a Key Determinant of Response to Dasatinib 
Purpose
EphA2 is an attractive therapeutic target due to its diverse roles in cancer growth and progression. Dasatinib is a multi-kinase inhibitor that targets EphA2 and other kinases. However, reliable predictive markers and a better understanding of the mechanisms of response to this agent are needed.
Experimental design
The effects of dasatinib on human uterine cancer cell lines were examined using a series of in vitro experiments, including MTT, Western blot, and plasmid transfection. In vivo, an orthotopic mouse model of uterine cancer was utilized to identify the biological effects of dasatinib. Molecular markers for response prediction and the mechanisms relevant to response to dasatinib were identified by using RPPA, immunoprecipitation, and double immunofluorescence staining.
Results
We show that high levels of CAV-1, EphA2 phosphorylation at S897 and the status of PTEN are key determinants of dasatinib response in uterine carcinoma. A set of markers essential for dasatinib response was also identified and includes CRaf, pCRafS338, pMAPKT202/Y204 (MAPK pathway), pS6S240/244, p70S6kT389 (mTOR pathway) and pAKTS473. A novel mechanism for response was discovered whereby high expression level of CAV-1 at the plasma membrane disrupts the BRaf/CRaf heterodimer and thus inhibits the activation of MAPK pathway during dasatinib treatment.
Conclusions
Our in vitro and in vivo results provide a new understanding of EphA2 targeting by dasatinib and identify key predictors of therapeutic response. These findings have implications for ongoing dasatinib-based clinical trials.
doi:10.1158/1078-0432.CCR-13-2141
PMCID: PMC3975695  PMID: 24486585
Dasatinib; EphA2; Caveolin-1 (CAV-1); Uterine Cancer
24.  CHRNA3 rs6495308 Genotype as an Effect Modifier of the Association between Daily Cigarette Consumption and Hypertension in Chinese Male Smokers 
Cigarette smoking is an important risk factor for hypertension. However, the effects on hypertension of the interaction between smoking and the genotype of the nicotinic acetylcholine receptor gene are unclear. The purpose of this study is to determine whether the CHRNA3 rs6495308 genotype affects the association between daily cigarette consumption and hypertension. We recruited 947 male smokers in southern China and used a questionnaire administered in face to face interviews to obtain information on their socio-demographic characteristics and smoking behavior. Blood samples were collected to test for CHRNA3 rs6495308 genotype variations. Three blood-pressure measurements were taken for each participant, and the average values recorded. We found that, compared with light smoking (<15 cigarettes per day), heavy smoking (≥15 cigarettes per day) yielded a greater risk of hypertension. We also observed that the interaction between daily cigarette consumption and the CHRNA3 rs6495308 genotype may affect hypertension. Heavy smokers with the homozygous mutant CHRNA3 rs6495308 genotype exhibited a significantly greater risk of hypertension than light smokers with wild-type CHRNA3 rs6495308 genotypes. The positive interaction between heavy smoking and the homozygous mutant CHRNA3 rs6495308 genotype was found to affect the likelihood of hypertension in Chinese male smokers.
doi:10.3390/ijerph120404156
PMCID: PMC4410239  PMID: 25874685
cigarette smoking; nicotine acetylcholine receptor; genotype; hypertension
25.  A large temperature fluctuation may trigger an epidemic erythromelalgia outbreak in China 
Scientific Reports  2015;5:9525.
Although erythromelalgia (EM) has been documented in the literature for almost 150 years, it is still poorly understood. To overcome this limitation, we examined the spatial distribution of epidemic EM, and explored the association between temperature fluctuation and epidemic EM outbreaks in China. We searched all peer-reviewed literature on primary epidemic EM outbreaks in China. A two-stage model was used to characterize the relationship between temperature fluctuation and epidemic EM outbreaks. We observed that epidemic EM outbreaks were reported from 13 provinces during 1960–2014 and they mainly occurred between February and March in southern China. The majority of EM cases were middle school students, with a higher incidence rate in female and resident students. The major clinical characteristics of EM cases included burning, sharp, tingling and/or stinging pain in toes, soles and/or dorsum of feet, fever, erythema and swelling. A large “V”-shaped fluctuation of daily average temperature (TM) observed during the epidemic EM outbreaks was significantly associated with the number of daily EM cases (β = 1.22, 95%CI: 0.66 ~ 1.79), which indicated that this “V”-shaped fluctuation of TM probably triggered the epidemic EM outbreaks.
doi:10.1038/srep09525
PMCID: PMC4377627  PMID: 25820221

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