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1.  32k Da protein improve ovariectomy-induced bone loss in rats 
Prion  2013;7(4):335-340.
The objective of the present study was to systematically explore the effects of 32K Da protein (32KP) on postmenopausal osteoporosis. Eighty 3-mo-old female Sprague-Dawley rats were employed and randomly divided into one sham-operated group (SHAM) and five ovariectomy (OVX) subgroups as OVX (control), OVX with 17-ethinylestradiol (E2, 25 g/kg/day), OVX with 32KP of graded doses (50, 50, or 150 mg/kg/day). 32KP or E2 diet was fed on week 4 after operation, for 16 weeks. Bone mass, bone turnover and strength were evaluated by dual-energy X-ray absorptiometry (DEXA), biochemical markers and three-point bending test, respectively. Femur marrow cavity was observed by light microscopy via hematoxylin-eosin staining. It is observed that different dosage treatment of 32KP increased the body weight and prevented the loss of bone mass induced by OVX. The prevention effect against bone loss was presumably due to the altering of the rate of bone remodeling. The bone mineral density and bone calcium content in OVX rats were lower than that in the control group, suggesting that 32KP was able to prevent significant bone loss. In addition, the data from three point bending test and femur sections showed that 32KP treatment enhanced bone strength and reduced the marrow cavity of the femur in OVX rats. In the serum and urine assay, 32KP decreased urinary deoxypyridinoline and calcium concentrations; however, serum alkaline phosphatase activities were not inhibited. It suggested that amelioration of bone loss was changed via inhibition of bone reabsorption. Our findings indicated that 32KP might be a potential alternative drug for the prevention and treatment of postmenopausal osteoporosis.
doi:10.4161/pri.26020
PMCID: PMC3904320  PMID: 23924638
32k Da Protein; DEXA; biochemical markers; mechanical test; bone turnover
2.  Somatic cells regulate maternal mRNA translation and developmental competence of mouse oocytes 
Nature cell biology  2013;15(12):1415-1423.
Germ cells divide and differentiate in a unique local microenvironment under the control of somatic cells. Signals released in this niche instruct oocyte reentry into the meiotic cell cycle. Once initiated, the progression through meiosis and the associated program of maternal mRNA translation are thought to be cell-autonomous. Here we show that translation of a subset of maternal mRNAs critical for embryo development is under the control of somatic cell inputs. Translation of specific maternal transcripts increases in oocytes cultured in association with somatic cells and is sensitive to EGF-like growth factors that act only on the somatic compartment. In mice deficient in amphiregulin, decreased fecundity and oocyte developmental competence is associated with defective translation of a subset of maternal mRNAs. These somatic cell signals that affect translation require activation of the PI3K/AKT/mTOR pathway. Thus, mRNA translation depends on somatic cell cues that are essential to reprogram the oocyte for embryo development.
doi:10.1038/ncb2873
PMCID: PMC4066669  PMID: 24270888
3.  The Real-Time Dynamic Monitoring of microRNA Function in Cholangiocarcinoma 
PLoS ONE  2014;9(6):e99431.
Background
Although many studies have confirmed a relationship between microRNAs (miRNAs) and cholangiocarcinoma (CCA), the real-time dynamics of miRNA function have not been examined.
Methods
miRNA reporter constructs were generated using a recombinant adeno-associated virus vector, which contained complementary sequences for six miRNAs (miR-200a, miR-200b, miR-21, miR-146a, miR-155, and miR-221), along with two independent expression cassettes encoding the fluorescent reporter genes Fluc and Gluc. The spatio-temporal function of each miRNA was monitored both in CCA and control tissues.
Results
All miRNAs participated in CCA development, with distinct patterns of expression over time. The activity of miR-21 was significantly lower in female T3N0M0 CCA tissue relative to controls at three time points, yet was higher in two male T3N1M0 CCA tissues. The difference in miR-200b function between two male T3N1M0 CCA tissues and their corresponding controls peaked at 24 h, while function in a female T3N0M0 CCA was detected only at 72 h. The four remaining miRNAs (miR-200a, miR146a, miR-155, and miR-221) displayed patient-specific activity patterns in both CCA and control tissues.
Conclusion
Significant variability was observed in the temporal function of all six miRNAs, which may play an important role in the development of CCA.
doi:10.1371/journal.pone.0099431
PMCID: PMC4053425  PMID: 24918778
4.  Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy 
Angiogenesis  2013;16(4):985-992.
Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.
doi:10.1007/s10456-013-9374-5
PMCID: PMC4006695  PMID: 23912262
Acetylation; Hypoxia-induced factor; Ischemic retinopathy; Neovascularization; Retinal ganglion cell; Revascularization; Sirtuin1
5.  The Magnolia Bioactive Constituent 4-O-Methylhonokiol Protects against High-Fat Diet-Induced Obesity and Systemic Insulin Resistance in Mice 
Obesity is caused by a combination of both genetic and environmental risks. Disruption in energy balance is one of these risk factors. In the present study, the preventive effect on high-fat diet- (HFD-) induced obesity and insulin resistance in mice by Magnolia bioactive constituent 4-O-methylhonokiol (MH) was compared with Magnolia officinalis extract BL153. C57BL/6J mice were fed by normal diet or by HFD with gavage-administered vehicle, BL153, low-dose MH, and high-dose MH simultaneously for 24 weeks, respectively. Either MH or BL153 slightly inhibited body-weight gain of mice by HFD feeding although the food intake had no obvious difference. Body fat mass and the epididymal white adipose tissue weight were also mildly decreased by MH or BL153. Moreover, MH significantly lowered HFD-induced plasma triglyceride, cholesterol levels and activity of alanine transaminase (ALT), liver weight and hepatic triglyceride level, and ameliorated hepatic steatosis. BL153 only significantly reduced ALT and liver triglyceride level. Concurrently, low-dose MH improved HFD-induced hyperinsulinemia and insulin resistance. Furthermore, the infiltration of mast cells in adipose tissue was decreased in MH or in BL153 treatment. These results suggested that Magnolia bioactive constituent MH might exhibit potential benefits for HFD-induced obesity by improvement of lipid metabolism and insulin resistance.
doi:10.1155/2014/965954
PMCID: PMC4060163  PMID: 24991305
6.  Apoptosis Induction by the Total Flavonoids from Arachniodes exilis in HepG2 Cells through Reactive Oxygen Species-Mediated Mitochondrial Dysfunction Involving MAPK Activation 
Arachniodes exilis is used as a folk medicine in China and proved to have antibacterial, anti-inflammatory, and sedative activities. In the present study, the antitumor effect of the total flavonoids of A. exilis (TFAE) against HepG2 cells was evaluated. The results showed that TFAE inhibited the growth of HepG2 cells in a dosage- and time-dependent manner. Flow cytometry and Hoechst 33342 fluorescence staining results showed that TFAE could significantly increase the apoptosis ratio of HepG2 cells, which is accompanied with increased intracellular reactive oxygen species (ROS) production and decreased mitochondrial membrane potential (ΔΨm). Western blotting indicated that TFAE downregulated the ratio of Bcl-2/Bax, increased cytochrome c release, and activated the caspases-3 and -9. Further analysis showed that TFAE stimulated the mitogen-activated protein kinase (MAPK). However, treatment with NAC (reactive oxygen species scavenger) and MAPK-specific inhibitors (SP600125 and SB203580) could reverse the changes of these apoptotic-related proteins. These results suggested that TFAE possessed potential anticancer activity in HepG2 cells through ROS-mediated mitochondrial dysfunction involving MAPK pathway.
doi:10.1155/2014/906941
PMCID: PMC4058121  PMID: 24976852
7.  Fabrication and Electrical Properties of Stacked Graphene Monolayers 
Scientific Reports  2014;4:5065.
We develop a simple method to fabricate the two-stacked graphene monolayers and investigate the electronic transport in such a system. The independence of the two graphene monolayers gives rise to the asymmetric resistance-gate voltage curves and an eight-fold degeneracy of Landau level. The position of the maximum resistance of the transfer curves shifts towards higher gate voltage with increasing magnetic field, which is attributed to the magnetic field induced interlayer decoupling of the stacked graphene monolayers.
doi:10.1038/srep05065
PMCID: PMC4033920  PMID: 24861035
8.  Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE) Analysis Uncovers Broad Changes in Chromatin Structure Resulting from Hexavalent Chromium Exposure 
PLoS ONE  2014;9(5):e97849.
The ability of chromatin to switch back and forth from open euchromatin to closed heterochromatin is vital for transcriptional regulation and genomic stability, but its dynamic structure is subject to disruption by exposure to environmental agents such as hexavalent chromium. Cr(VI) exposure disrupts chromatin remodeling mechanisms and causes chromosomal damage through formation of free radicals, Cr-DNA adducts, and DNA-Cr-protein cross-links. In addition, acute, high-concentration, and chronic, low-concentration exposures to Cr(VI) lead to significantly different transcriptional and genomic stability outcomes. We used mouse hepatoma Hepa-1c1c7 cells to investigate how transcriptional responses to chromium treatment might correlate with structural chromatin changes. We used Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE) analysis coupled with deep sequencing to identify regions of the genome that may switch between open and closed chromatin in response to exposure to varying Cr(VI) concentrations. At either Cr(VI) concentration, chromatin domains surrounding binding sites for AP-1 transcription factors become significantly open, whereas BACH2 and CTCF binding sites are open solely at the low and high concentrations, respectively. Parallel gene expression profiling using RNA-seq indicates that the structural chromatin changes caused by Cr(VI) affect gene expression levels in the target areas that vary depending on Cr(VI) concentration, but show no correlation between global changes in the overall transcriptional response and Cr(VI) concentration. Our results suggest that FAIRE may be a useful technique to map chromatin elements targeted by DNA damaging agents for which there is no prior knowledge of their specificity, and to identify subsequent transcriptomic changes induced by those agents.
doi:10.1371/journal.pone.0097849
PMCID: PMC4023961  PMID: 24837440
9.  Effective and selective targeting of Ph+ leukemia cells using a TORC1/2 kinase inhibitor 
Nature medicine  2010;16(2):205-213.
Targeting the mammalian target of rapamycin (mTOR) is a promising strategy for cancer therapy. However, the mTOR kinase functions in two complexes, TORC1 and TORC2, neither of which is fully inhibited by the allosteric inhibitor rapamycin or analogs. We compared rapamycin with the active-site TORC1/2 inhibitor PP242, in acute leukemia models harboring the Philadelphia chromosome (Ph) translocation. We demonstrate that PP242, but not rapamycin, causes death of mouse and human leukemia cells. In vivo, PP242 delays leukemia onset and augments the effects of current front-line tyrosine kinase inhibitors, more effectively than rapamycin. Surprisingly, PP242 has much weaker effects than rapamycin on proliferation and function of normal lymphocytes. PI-103, a less selective TORC1/2 inhibitor that also targets phosphoinositide 3-kinase, is more immunosuppressive than PP242. These findings establish that Ph+ transformed cells are more sensitive than normal lymphocytes to selective TORC1/2 inhibitors, and support the development of such inhibitors for leukemia therapy.
doi:10.1038/nm.2091
PMCID: PMC4017764  PMID: 20072130
10.  VITREAL LEVELS OF ERYTHROPOIETIN ARE INCREASED IN PATIENTS WITH RETINAL VEIN OCCLUSION AND CORRELATE WITH VITREAL VEGF AND THE EXTENT OF MACULAR EDEMA 
Retina (Philadelphia, Pa.)  2010;30(9):1524-1529.
Purpose
This study compares vitreal levels of erythropoietin (EPO) in patients with retinal vein occlusion (RVO) with control subjects. In addition, it investigates different RVO disease parameters (time of vein occlusion, patient age, vitreal vascular endothelial growth factor (VEGF) levels, and extent of central macular edema) for possible correlations with vitreal EPO levels.
Methods
Serum and vitreal EPO were measured from 6 patients with branch retinal vein occlusion, 6 patients with central retinal vein occlusion, and 12 control subjects (10 macular puckers and 2 macular holes).
Results
Serum EPO levels (9.8 ± 4.9 mU/mL) did not differ between the RVO and control groups and were significantly lower than vitreal EPO levels in all groups. Vitreal EPO was elevated both in branch RVO (91 ± 59 mU/mL) and central RVO (182 ± 70 mU/mL) compared with controls (35 ± 24 mU/mL). Increased vitreal EPO correlated with higher vitreal VEGF (r = 0.64, P = 0.0008) and more pronounced central macular edema (r = 0.66, P = 0.001).
Conclusion
The results from this study indicate that EPO is locally expressed in the retina and that it is upregulated together with VEGF in RVO eyes. Because of its role both in neuroprotection and angiogenesis, ocular EPO might represent an interesting target to investigate in patients with RVO, especially in light of the current anti-VEGF treatments.
doi:10.1097/IAE.0b013e3181d37539
PMCID: PMC4016716  PMID: 20664492
erythropoietin; EPO; retinal vein occlusion; VEGF; macular edema; CME
11.  CD36-Mediated Hematoma Absorption following Intracerebral Hemorrhage: Negative Regulation by TLR4 Signaling 
The Journal of Immunology Author Choice  2014;192(12):5984-5992.
Promoting hematoma absorption is a novel therapeutic strategy for intracerebral hemorrhage (ICH); however, the mechanism of hematoma absorption is unclear. The present study explored the function and potential mechanism of CD36 in hematoma absorption using in vitro and in vivo ICH models. Hematoma absorption in CD36-deficient ICH patients was examined. Compared with patients with normal CD36 expression, CD36-deficient ICH patients had slower hematoma adsorption and aggravated neurologic deficits. CD36 expression in perihematomal tissues in wild-type mice following ICH was increased, whereas the hematoma absorption in CD36−/− mice was decreased. CD36−/− mice also showed aggravated neurologic deficits and increased TNF-α and IL-1β expression levels. The phagocytic capacity of CD36−/− microglia for RBCs was also decreased. Additionally, the CD36 expression in the perihematoma area after ICH in TLR4−/− and MyD88−/− mice was significantly increased, and hematoma absorption was significantly promoted, which was significantly inhibited by an anti-CD36 Ab. In vitro, TNF-α and IL-1β significantly inhibited the microglia expression of CD36 and reduced the microglia phagocytosis of RBCs. Finally, the TLR4 inhibitor TAK-242 upregulated CD36 expression in microglia, promoted hematoma absorption, increased catalase expression, and decreased the H2O2 content. These results suggested that CD36 mediated hematoma absorption after ICH, and TLR4 signaling inhibited CD36 expression to slow hematoma absorption. TLR4 inhibition could promote hematoma absorption and significantly improve neurologic deficits following ICH.
doi:10.4049/jimmunol.1400054
PMCID: PMC4049082  PMID: 24808360
12.  Effects of Angiogenic Factors, Antagonists, and Podocyte Injury on Development of Proteinuria in Preeclampsia 
Reproductive Sciences  2013;20(5):579-588.
Proteinuria is universal to all patients with preeclampsia. We examined the urinary podocytes in women with preeclampsia (n = 14), gestational hypertension (n = 14), and normal pregnancy. Maternal serum and urinary concentrations of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and the antiangiogenic factor soluble fms-like tyrosine kinase 1 (sFlt-1) were detected. These concentrations were used to evaluate the urinary excretion of podocytes and the alteration of angiogenic factors and to assess their relationships to proteinuria in preeclampsia. Our studies suggest that the urinary podocyte number and angiogenic factors are correlated with random urine albumin/creatinine ratio and blood pressure. Receiver–operating characteristic (ROC) curves of serum and urinary PlGF and the PlGF/sFlt-1 ratio as well as the presence of podocyturia confirmed their usefulness in distinguishing preeclamptic and normotensive pregnant women. In addition, combinations of serum or urinary PlGF or podocyturia tests in parallel or in series provided the best clue for identifying patients with preeclampsia. We considered that the dysregulation of angiogenic factors and its subsequent podocyte injury may contribute to the mechanism of proteinuria development in preeclampsia.
doi:10.1177/1933719112459227
PMCID: PMC3713540  PMID: 22991381
angiogenic factors; preeclampsia; proteinuria; podocyte
13.  Association of Cardiac Troponin T With Left Ventricular Structure and Function in CKD 
Background
Serum cardiac troponin T (cTnT) is associated with increased risk of heart failure and cardiovascular death in several population settings. We evaluated associations of cTnT with cardiac structural and functional abnormalities in a cohort of chronic kidney disease (CKD) patients without heart failure.
Study Design
Cross-sectional.
Setting & Participants
Chronic Renal Insufficiency Cohort (CRIC; N= 3,243)
Predictor
The primary predictor was cTnT. Secondary predictors included demographic and clinical characteristics, hemoglobin level, high-sensitivity C-reactive protein, and estimated glomerular filtration rate using cystatin C.
Outcomes
Echocardiography was used to determine left ventricular (LV) mass and LV systolic and diastolic function.
Measurements
Circulating cTnT was measured in stored sera using the highly sensitive assay. Logistic and linear regression models were used to examine associations of cTnT with each echocardiographic outcome.
Results
cTnT was detectable in 2,735 (84%) persons; the median was 13.3 (IQR, 7.7–23.8) pg/mL. Compared with undetectable cTnT (<3.0 pg/mL), the highest quartile (23.9 – 738.7 pg/mL) was associated with approximately two times as likely to experience LV hypertrophy (OR, 2.43; 95% CI, 1.44–4.09) in the fully adjusted model. cTnT had a more modest association with LV systolic dysfunction; as a log-linear variable, a significant association was present in the fully adjusted model (OR of 1.4 [95% CI, 1.1–1.7] per 1-log unit; p<0.01). There was no significant independent association between cTnT and LV diastolic dysfunction. When evaluated as a screening test, cTnT functioned only modestly for LV hypertrophy and concentric hypertrophy detection (area under the curve, 0.64 for both) with weaker areas under the curve for the other outcomes.
Limitations
The presence of coronary artery disease was not formally assessed using either noninvasive or angiographic techniques in this study.
Conclusions
In this large CKD cohort without heart failure, detectable cTnT had a strong association with LV hypertrophy, a more modest association with LV systolic dysfunction, and no association with diastolic dysfunction. These findings indicate that circulating cTnT levels in CKD are predominantly an indicator of pathological LV hypertrophy.
doi:10.1053/j.ajkd.2012.11.034
PMCID: PMC3627820  PMID: 23291148
Troponin T; left ventricular structure; chronic kidney disease
14.  cAMP PULSING OF DENUDED MOUSE OOCYTES INCREASES MEIOTIC RESUMPTION VIA ACTIVATION OF AMP-ACTIVATED PROTEIN KINASE 
Reproduction (Cambridge, England)  2009;138(5):759-770.
cAMP plays a critical role in the control of oocyte maturation, as a high level of cAMP maintains oocyte arrest at the first meiotic prophase. Yet this study shows that pulsing meiotically arrested denuded oocytes (DO) with cAMP induces oocyte maturation through the activation of AMP-activated protein kinase (PRKA). Short term (3 h) pulsing of meiotically arrested oocytes with forskolin, an adenyl cyclase (AC) activator, increased oocyte cAMP, led to elevated AMP and induced oocyte meiotic resumption compared to oocytes continuously cultured in the control medium with or without forskolin. Western analysis showed that GV-stage oocytes after forskolin pulsing contained increased levels of phospho-acetyl CoA carboxylase (pACACA), a primary substrate of PRKA. Pulsing oocytes with the PDE-sensitive cAMP analog, 8-Bromo-cAMP (8-Br-cAMP), also increased pACACA and pPRKA levels in GV-stage oocytes and induced oocyte meiotic resumption. Moreover, the PRKA inhibitors, compound C and araA, prevented 8-Br-cAMP pulsing-induced maturation. The lack of effect on meiotic induction and PRKA activation when oocytes were pulsed with the PDE-resistant activators of cAMP-dependent protein kinase, Sp-cAMP-AM and Sp-5,6-DCI-cBIMPS, suggests that cAMP degradation is required for pulsing-induced maturation. Pulsing oocytes with the Epac (exchange protein directly activated by cAMP)-specific activator, 8-CPT-2′-O-Me-cAMP, had no stimulatory effect on oocyte maturation, suggesting Epac is not involved in the pulsing-induced maturation. Taken together, these data support the idea that a transient increase in oocyte cAMP can induce meiotic resumption via activation of PRKA.
doi:10.1530/REP-08-0535
PMCID: PMC3995479  PMID: 19700529
15.  Anti-EGFR and anti-VEGF agents: Important targeted therapies of colorectal liver metastases 
Colorectal liver metastasis (CLM) is common worldwide. Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials, and are now becoming standards for patients with CLM. The development and application of anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies represents significant advances in the treatment of this disease. However, new findings continue to emerge casting doubt on the efficacy of this approach. The Kirsten rat sarcoma viral oncogene (KRAS) has been proven to be a crucial predictor of the success of anti-EGFR treatment in CLM. Whereas a recent study summarized several randomized controlled trials, and showed that patients with the KRAS G13D mutation significantly benefited from the addition of cetuximab in terms of progress-free survival (PFS, 4.0 mo vs 1.9 mo, HR = 0.51, P = 0.004) and overall survival (OS, 7.6 mo vs 5.7 mo, HR = 0.50, P = 0.005). Some other studies also reported that the KRAS G13D mutation might not be absolutely predictive of non-responsiveness to anti-EGFR therapy. At the same time, “new” RAS mutations, including mutations in neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) and exons 3 and 4 of KRAS, have been suggested to be predictors of a poor treatment response. This finding was first reported by the update of the PRIME trial. The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations, panitumumab-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)4 treatment led to inferior PFS (HR = 1.28, 95%CI: 0.79-2.07) and OS (HR = 1.29, 95%CI: 0.79-2.10), which was consistent with the findings in patients with KRAS mutations in exon 2. Then, the update of the PEAK trial and the FIRE-III trial also supported this finding, which would reduce candidates for anti-EGFR therapy but enhance the efficacy. In first-line targeted combination therapy, the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-VII trial. Also, bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966 trial. By the update and further analysis of the COIN trial and the NORDIC-VII trial, cetuximab plus FOLFOX was reported to be reliable again. But bevacizumab plus oxaliplatin-based chemotherapy was still controversial. In addition, some trials have reported that bevacizumab is not suitable for conversion therapy. The results of the FIRE-III trial showed that cetuximab led to a significant advantage over bevacizumab in response rate (72% vs 63%, P = 0.017) for evaluable population. With the balanced allocation of second-line treatment, the FIRE-III trial was expected to provide evidence for selecting following regimens after first-line progression. There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM, although the combined regimen is often administered based on experience. Combination therapy with more than one targeted agent has been proven to provide no benefit, and even was reported to be harmful as first-line treatment by four large clinical trials. However, recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment. The mechanism of antagonism between different targeted agents deserves further study, and may also provide greater understanding of the development of resistance to targeted agents.
doi:10.3748/wjg.v20.i15.4263
PMCID: PMC3989962  PMID: 24764664
Oncology; Colorectal cancer; Liver metastases; Chemotherapy; Targeted therapy
16.  Association of Serum Phosphorus Variability with Coronary Artery Calcification among Hemodialysis Patients 
PLoS ONE  2014;9(4):e93360.
Coronary artery calcification (CAC) is associated with increased mortality in patients on maintenance hemodialysis (MHD), but the pathogenesis of this condition is not well understood. We evaluated the relationship of CAC score (CACs) and variability in serum phosphorus in MHD patients. Seventy-seven adults on MHD at Huashan Hospital (Shanghai) were enrolled in July, 2010. CAC of all the patients were measured by computed tomography and CACs was calculated by the Agatston method at the entry of enrollment. Patients were divided into three categories according to their CACs (0∼10, 11∼400, and >400). Blood chemistry was recorded every 3 months from January 2008 to July 2010. Phosphorus variation was defined by the standard deviation (SD) or coefficient of variation (CV) and it was calculated from the past records. The ordinal multivariate logistic regression analysis was used to analyze the predictors of CAC. The mean patient age (± SD) was 61.7 years (±11.3) and 51% of patients were men. The mean CACs was 609.6 (±1062.9), the median CACs was 168.5, and 78% of patients had CACs more than 0. Multivariate analysis indicated that female gender (OR = 0.20, 95% CI = 0.07–0.55), age (OR = 2.31, 95% CI = 1.32–4.04), serum fibroblast growth factor 23 (OR = 2.25, 95% CI = 1.31–3.85), SD-phosphorus calculated from the most recent 6 measurements (OR = 2.12; 95% CI = 1.23–3.63), and CV-phosphorus calculated from the most recent 6 measurements (OR = 1.90, 95% CI = 1.16–3.11) were significantly and independently associated with CACs. These associations persisted for phosphorus variation calculated from past 7, 8, 9, 10, and 11 follow-up values. Variability of serum phosphorus may contribute significantly to CAC and keeping serum phosphorus stable may decrease coronary calcification and associated morbidity and mortality in MHD patients.
doi:10.1371/journal.pone.0093360
PMCID: PMC3991577  PMID: 24747427
17.  Association between the Polymorphism rs3217927 of CCND2 and the Risk of Childhood Acute Lymphoblastic Leukemia in a Chinese Population 
PLoS ONE  2014;9(4):e95059.
CyclinD proteins, the ultimate recipients of mitogenic and oncogenic signals, play a crucial role in cell-cycle regulation. CyclinD2, one of the cyclinD family, is overexpressed in T-acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia and involved in the pathogenesis of leukemias. Recent reports indicated that CCND2 polymorphisms are associated with human cancer risk, thusly we hypothesized that CCND2 gene polymorphisms may contribute to childhood ALL susceptibility. We selected the polymorphism rs3217927 located in the 3′UTR region of CCND2 to assess its associations with childhood ALL risk in a case-control study. A significant difference was found in the genotype distributions of rs3217927 polymorphism between cases and controls (P = 0.019) and homozygous GG genotype may be an increased risk factor for childhood ALL (adjusted OR  =  1.84, 95% CI  =  1.14 —2.99). Furthermore, this increased risk was more pronounced with GG genotype among high-risk ALL (adjusted OR  = 1.95, 95% CI  =  1.04–3.67), low-risk ALL (adjusted OR  =  2.09, 95% CI  =  1.13–3.87), B-phenotype ALL patients (adjusted OR  =  1.78, 95% CI  =  1.08–2.95) and T-phenotype ALL patients (adjusted OR  =  2.87, 95% CI  =  1.16–7.13). Our results provide evidence that CCND2 polymorphism rs3217927 may be involved in the etiology of childhood ALL, and the GG genotype of rs3217927 may modulate the genetic susceptibility to childhood ALL in the Chinese population. Further functional studies and investigations in larger populations should be conducted to validate our findings.
doi:10.1371/journal.pone.0095059
PMCID: PMC3990598  PMID: 24743557
18.  Diethyl [(4-nitrobenzamido)(phen­yl)meth­yl]phospho­nate 
In the title compound, C18H21N2O6P, the dihedral angle between the benzene and phenyl rings is 85.1 (2)°. In the crystal, mol­ecules are linked via pairs of N—H⋯O(=P) hydrogen bonds, forming inversion dimers with graph-set notation R 2 2(10). One of the ethyl groups is disordered over two sets of sites, with occupancies 0.746 (11) and 0.254 (11).
doi:10.1107/S1600536814007776
PMCID: PMC4011288  PMID: 24860356
19.  Polyinosinic-Polycytidylic Acid Has Therapeutic Effects against Cerebral Ischemia/Reperfusion Injury through the Downregulation of TLR4 Signaling via TLR3 
The Journal of Immunology Author Choice  2014;192(10):4783-4794.
Recent reports have shown that preconditioning with the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) protects against cerebral ischemia/reperfusion (I/R) injury. However, it is unclear whether poly(I:C) treatment after cerebral I/R injury is also effective. We used mouse/rat middle cerebral artery occlusion and cell oxygen-glucose deprivation models to evaluate the therapeutic effects and mechanisms of poly(I:C) treatment. Poly(I:C) was i.p. injected 3 h after ischemia (treatment group). Cerebral infarct volumes and brain edemas were significantly reduced, and neurologic scores were significantly increased. TNF-α and IL-1β levels were markedly decreased, whereas IFN-β levels were greatly increased, in the ischemic brain tissues, cerebral spinal fluid, and serum. Injuries to hippocampal neurons and mitochondria were greatly reduced. The numbers of TUNEL-positive and Fluoro-Jade B+ cells also decreased significantly in the ischemic brain tissues. Poly(I:C) treatment increased the levels of Hsp27, Hsp70, and Bcl2 and decreased the level of Bax in the ischemic brain tissues. Moreover, poly(I:C) treatment attenuated the levels of TNF-α and IL-1β in serum and cerebral spinal fluid of mice stimulated by LPS. However, the protective effects of poly(I:C) against cerebral ischemia were abolished in TLR3−/− and TLR4−/−mice. Poly(I:C) downregulated TLR4 signaling via TLR3. Poly(I:C) treatment exhibited obvious protective effects 14 d after ischemia and was also effective in the rat permanent middle cerebral artery occlusion model. The results suggest that poly(I:C) exerts therapeutic effects against cerebral I/R injury through the downregulation of TLR4 signaling via TLR3. Poly(I:C) is a promising new drug candidate for the treatment of cerebral infarcts.
doi:10.4049/jimmunol.1303108
PMCID: PMC4009499  PMID: 24729619
20.  Ectopic Expression of Activated Notch or SOX2 Reveals Similar and Unique Roles in the Development of the Sensory Cell Progenitors in the Mammalian Inner Ear 
The Journal of Neuroscience  2013;33(41):16146-16157.
Hearing impairment or vestibular dysfunction in humans often results from a permanent loss of critical cell types in the sensory regions of the inner ear, including hair cells, supporting cells, or cochleovestibular neurons. These important cell types arise from a common sensory or neurosensory progenitor, although little is known about how these progenitors are specified. Studies have shown that Notch signaling and the transcription factor Sox2 are required for the development of these lineages. Previously we and others demonstrated that ectopic activation of Notch can direct nonsensory cells to adopt a sensory fate, indicating a role for Notch in early specification events. Here, we explore the relationship between Notch and SOX2 by ectopically activating these factors in nonsensory regions of the mouse cochlea, and demonstrate that, similar to Notch, SOX2 can specify sensory progenitors, consistent with a role downstream of Notch signaling. However, we also show that Notch has a unique role in promoting the proliferation of the sensory progenitors. We further demonstrate that Notch can only induce ectopic sensory regions within a certain time window of development, and that the ectopic hair cells display specialized stereocilia bundles similar to endogenous hair cells. These results demonstrate that Notch and SOX2 can both drive the sensory program in nonsensory cells, indicating these factors may be useful in cell replacement strategies in the inner ear.
doi:10.1523/JNEUROSCI.3150-12.2013
PMCID: PMC3792456  PMID: 24107947
21.  Pallidal Index as Biomarker of Manganese Brain Accumulation and Associated with Manganese Levels in Blood: A Meta-Analysis 
PLoS ONE  2014;9(4):e93900.
Objective
The current study was designed to evaluate the sensitivity, feasibility, and effectiveness of the pallidal index (PI) serving as a biomarker of brain manganese (Mn) accumulation, which would be used as an early diagnosis criteria for Mn neurotoxicity.
Methods
The weighted mean difference (WMD) of the PI between control and Mn-exposed groups was estimated by using a random-effects or fixed-effects meta-analysis with 95% confidence interval (CI) performed by STATA software version 12.1. Moreover, the R package “metacor” was used to estimate correlation coefficients between PI and blood Mn (MnB).
Results
A total of eight studies with 281 occupationally Mn-exposed workers met the inclusion criteria. Results were pooled and performed with the Meta-analysis. Our data indicated that the PI of the exposed group was significantly higher than that of the control (WMD: 7.76; 95% CI: 4.86, 10.65; I2 = 85.7%, p<0.0001). A random effects model was used to perform meta-analysis. These findings were remarkably robust in the sensitivity analysis, and publication bias was shown in the included studies. Seven out of the eight studies reported the Pearson correlation (r) values. Significantly positive correlation between PI and MnB was observed (r = 0.42; 95% CI, 0.31, 0.52).
Conclusions
PI can be considered as a sensitive, feasible, effective and semi-quantitative index in evaluating brain Mn accumulation. MnB can also augment the evaluation of brain Mn accumulation levels in the near future. However, the results should be interpreted with caution.
doi:10.1371/journal.pone.0093900
PMCID: PMC3981755  PMID: 24718592
22.  Altered cholesterol homeostasis in aged macrophages linked to neovascular macular degeneration 
Cell metabolism  2013;17(4):471-472.
Abnormal lipid metabolism has been linked to age-related macular degeneration (AMD); choroidal neovascularization in late AMD commonly causes blindness. Sene et al. now demonstrate that in aged macrophages decreased ABCA1 expression, regulated by liver X receptor and miR-33, impairs export of intracellular cholesterol which promotes neovascular AMD (Sene et al., 2013).
doi:10.1016/j.cmet.2013.03.010
PMCID: PMC3669899  PMID: 23562072
23.  Intravitreal Injection of IGFBP-3 Restores Normal Insulin Signaling in Diabetic Rat Retina 
PLoS ONE  2014;9(4):e93788.
Diabetes-induced changes in growth factor binding protein 3 (IGFBP-3) and tumor necrosis factor alpha (TNFα) have been linked to decreased insulin receptor signaling in diabetic retinopathy. Our previous studies in retinas of diabetic rats have shown that Compound 49b, a novel β-adrenergic receptor agonist, prevented diabetic changes by increasing IGFBP-3 and decreasing TNFα, thus restoring insulin signaling and protection against diabetic retinopathy. The current study was designed to determine whether boosted expression of IGFBP-3 NB (a non-IGF-1 binding form of IGFBP-3) alone is sufficient to mimic the full actions of Compound 49b in protecting against diabetic retinopathy, as well as testing whether IGFBP-3 NB is linked to a restoration of normal insulin signal transduction. Two months after initiation of streptozotocin-induced diabetes, rats received a single intravitreal injection of IGFBP-3 NB plasmid in the right eye. Four days after injection, electroretinogram (ERG) analyses were performed prior to sacrifice. Whole retinal lysates from control, diabetic, diabetic + control plasmid, and diabetic+ IGFBP-3 NB were analyzed for IGFBP-3, TNFα, suppressor of cytokine signaling 3 (SOCS3), and insulin receptor signaling partners using Western blotting or ELISA. Data show that a single intraocular injection of IGFBP-3 NB in diabetic animals significantly reduced TNFα levels, concomitant with reductions in IRS-1Ser307, SOCS3, and pro-apoptotic markers, while restoring insulin receptor phosphorylation and increasing anti-apoptotic marker levels. These cellular changes were linked to restoration of retinal function. Our findings establish IGFBP-3 as a pivotal regulator of the insulin receptor/TNFα pathway and a potential therapeutic target for diabetic retinopathy.
doi:10.1371/journal.pone.0093788
PMCID: PMC3973588  PMID: 24695399
24.  IL-17 induces expression of vascular cell adhesion molecule through signaling pathway of NF-κB, but not Akt1 and TAK1 in vascular smooth muscle cells 
Interleukin 17 (IL-17) plays an important role in several autoimmune diseases. IL-17 can induce the expression of vascular cell adhesion molecule (VCAM-1) in aortic vascular smooth muscle cells (SMCs), which is important for the development of atherosclerosis. However, the signaling pathway of IL-17-induced VCAM-1 expression remains unclear. In this study, we reported that IL-17 induced expression of VCAM-1 in SMCs is dependent on NF-κB, but independent of Akt1 and TAK1. This is because knocking down Akt1 or TAK1 by siRNA did not reduce IL-17-induced activation of NF-κB and expression of VCAM-1, whereas knocking down NF-κB by siRNA markedly inhibited IL-17-mediated upregulation of VCAM-1 expression. In addition, IL-17-induced expression of VCAM-1 is partially dependent on activation of ERK1/2. Therefore, these signaling pathways of IL-17-mediated upregulation of VCAM-1 expression might be therapeutic targets for treatment of IL-17-mediated inflammation.
doi:10.1111/sji.12030
PMCID: PMC3683581  PMID: 23421430
IL-17; NF-κB; vascular smooth muscle cells; adhesion molecule
25.  Lymphomatoid granulomatosis involving the central nervous system: A case report and review of the literature 
Oncology Letters  2014;7(6):1843-1846.
Lymphomatoid granulomatosis (LYG) is a rare tumor with unknown etiology. Specific etiological factors for LYG are also unknown, although previous data indicates that LYG is an Epstein-Barr virus-associated B-cell proliferation associated with an exuberant T-cell reaction. According to the 2008 WHO classification, LYG is characterized by B-cell proliferation of B-lymphoma cells. Generally, treatment options for LYG are similar to those for diffuse large B-cell lymphoma. Unfortunately, LYG is a chemotherapy-resistant disease in certain patients and has a poor prognosis. The current study presents the case of a 19-year-old male patient with pulmonary LYG. The patient exhibited progressive disease following one cycle of chemotherapy with cyclophosphamide, adriamycin, vincristine and prednisone, and nodular lesions in the brain were diagnosed. Radiotherapy was delivered to the whole brain, however, this treatment did not prevent progression of the disease and the patient succumbed three months after initial presentation. An overview of the literature with regard to the etiology, clinical features, diagnosis and treatment options for LYG is also presented in the current case study.
doi:10.3892/ol.2014.2002
PMCID: PMC4049686  PMID: 24932245
lymphomatoid granulomatosis; lymphoma; chemotherapy

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