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1.  p38α MAPK Regulates Lineage Commitment and OPG Synthesis of Bone Marrow Stromal Cells to Prevent Bone Loss under Physiological and Pathological Conditions 
Stem Cell Reports  2016;6(4):566-578.
Summary
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are capable of differentiating into osteoblasts, chondrocytes, and adipocytes. Skewed differentiation of BM-MSCs contributes to the pathogenesis of osteoporosis. Yet how BM-MSC lineage commitment is regulated remains unclear. We show that ablation of p38α in Prx1+ BM-MSCs produced osteoporotic phenotypes, growth plate defects, and increased bone marrow fat, secondary to biased BM-MSC differentiation from osteoblast/chondrocyte to adipocyte and increased osteoclastogenesis and bone resorption. p38α regulates BM-MSC osteogenic commitment through TAK1-NF-κB signaling and osteoclastogenesis through osteoprotegerin (OPG) production by BM-MSCs. Estrogen activates p38α to maintain OPG expression in BM-MSCs to preserve the bone. Ablation of p38α in BM-MSCs positive for Dermo1, a later BM-MSC marker, only affected osteogenic differentiation. Thus, p38α mitogen-activated protein kinase (MAPK) in Prx1+ BM-MSCs acts to preserve the bone by promoting osteogenic lineage commitment and sustaining OPG production. This study thus unravels previously unidentified roles for p38α MAPK in skeletal development and bone remodeling.
Highlights
•p38α deletion in Prx1+ BM-MSCs led to osteoporosis and cartilage anomaly•p38α controls proliferation and tri-lineage differentiation of Prx1+ BM-MSCs•p38α regulates osteoclastogenesis through OPG production by BM-MSCs•The BM-MSC p38-OPG axis participates in estrogen deficiency-induced osteoporosis
In this article, Li, Liu, and colleagues reveal that p38α MAPK regulates Prx1+BM-MSC cell fate decision. p38α is required for proper BM-MSC osteogenic commitment, via the TAK1-NF-κB pathway, to maintain proper bone formation, and for OPG synthesis by BM-MSCs to constrain osteoclastogenesis and bone resorption. Moreover, estrogen appears to go through the p38-OPG pathway to preserve the bone.
doi:10.1016/j.stemcr.2016.02.001
PMCID: PMC4834033  PMID: 26947973
2.  An Engineered Rare Codon Device for Optimization of Metabolic Pathways 
Scientific Reports  2016;6:20608.
Rare codons generally arrest translation due to rarity of their cognate tRNAs. This property of rare codons can be utilized to regulate protein expression. In this study, a linear relationship was found between expression levels of genes and copy numbers of rare codons inserted within them. Based on this discovery, we constructed a molecular device in Escherichia coli using the rare codon AGG, its cognate tRNA (tRNAArg (CCU)), modified tRNAAsp (GUC → CCU), and truncated aspartyl-tRNA synthetase (TDRS) to switch the expression of reporter genes on or off as well as to precisely regulate their expression to various intermediate levels. To underscore the applicability of our work, we used the rare codon device to alter the expression levels of four genes of the fatty acid synthesis II (FASII) pathway (i.e. fabZ, fabG, fabI, and tesA’) in E. coli to optimize steady-state kinetics, which produced nearly two-fold increase in fatty acid yield. Thus, the proposed method has potential applications in regulating target protein expression at desired levels and optimizing metabolic pathways by precisely tuning in vivo molar ratio of relevant enzymes.
doi:10.1038/srep20608
PMCID: PMC4745014  PMID: 26852704
3.  The application of color Doppler flow imaging in the diagnosis and therapeutic effect evaluation of erectile dysfunction 
Asian Journal of Andrology  2015;18(1):118-122.
We aim to investigate the correlations between hemodynamic parameters, penile rigidity grading, and the therapeutic effects of phosphodiesterase type 5 inhibitors using color Doppler flow imaging after intracavernosal injection in patients with erectile dysfunction. This study involved 164 patients. After intracavernosal injection with a mixture of papaverine (60 mg), prostaglandin E1 (10 μg), and lidocaine (2%, 0.5–1 ml), the penile vessels were assessed using color Doppler flow imaging. Penile rigidity was classified based on the Erection Hardness Score system as Grades 4, 3, 2 or 1 (corresponding to Schramek Grades V to II). Then, the patients were given oral sildenafil (50–100 mg) and scored according to the International Index of Erectile Function (IIEF-5) questionnaire. The number of patients with penile rigidities of Schramek Grades II to V was 14, 18, 21, and 111, respectively. The IIEF-5 score was positively correlated with the refilling index of the penile cavernosal artery (r = 0.79, P < 0.05), the peak systolic velocity (r = 0.45, P < 0.05), and penile rigidity (r = 0.75, P < 0.05), and was negatively correlated with the end diastolic velocity (r = −0.74, P < 0.05). For patients with erectile dysfunction, both the IIEF-5 score after sildenafil administration, which is correlated with penile rigidity, and the hemodynamic parameters detected using color Doppler flow imaging may predict the effects of phosphodiesterase type 5 inhibitor treatment and could provide a reasonable model for the targeted-treatment of erectile dysfunction.
doi:10.4103/1008-682X.155533
PMCID: PMC4736339  PMID: 25994651
color Doppler flow imaging; erectile dysfunction; hemodynamic parameters; penis rigidity; sildenafil
4.  NCOA1 promotes angiogenesis in breast tumors by simultaneously enhancing both HIF1α- and AP-1-mediated VEGFa transcription 
Oncotarget  2015;6(27):23890-23904.
Nuclear receptor coactivator 1 (NCOA1) is overexpressed in a subset of breast cancer and its increased expression positively correlates with disease recurrence and metastasis. Although NCOA1 is known to promote breast cancer metastasis through working with multiple transcription factors to upregulate the expression of Twist1, ITGA5, CSF-1, SDF1 and CXCR4, the role of NCOA1 in breast tumor angiogenesis has not been investigated. In this study, we found that the microvascular density (MVD) was significantly decreased and increased in Ncoa1-knockout and NCOA1-overexpressing mammary tumors, respectively, in several breast cancer mouse models. Knockout or knockdown of NCOA1 in breast cancer cell lines also markedly compromised their capability to induce angiogenesis in Matrigel plugs embedded subcutaneously in mice, while this compromised capability could be rescued by VEGFa treatment. At the molecular level, NCOA1 upregulates VEGFa expression in both mouse mammary tumors and cultured breast cancer cells, and it does so by associating with both c-Fos, which is recruited to the AP-1 site at bp −938 of the VEGFa promoter, and HIF1α, which is recruited to the HIF1α-binding element at bp −979 of the VEGFa promoter, to enhance VEGFa transcription. In 140 human breast tumors, high NCOA1 protein correlates with high MVD and patients with both high NCOA1 and high MVD showed significantly shorter survival time. In summary, this study revealed a novel mechanism that NCOA1 potentiates breast cancer angiogenesis through upregulating HIF1α and AP-1-mediated VEGFa expression, which reinforces the rational of targeting NCOA1 in controlling breast cancer progression and metastasis.
PMCID: PMC4695159  PMID: 26287601
NCOA1; VEGFa; transcriptional regulation; breast cancer
5.  Evidence of Distinct Populations of Hepatitis C Virus in the Liver and Plasma of Patients Co-Infected With HIV and HCV 
Journal of medical virology  2014;86(8):1332-1341.
Viral diversity is an important predictor of hepatitis C virus (HCV) treatment response and may influence viral pathogenesis. HIV influences HCV variability in the plasma; however, limited data on viral variability are available from distinct tissue/cell compartments in patients co-infected with HIV and HCV. Thus, this exploratory study evaluated diversity of the hypervariable region 1 (HVR1) of HCV in the plasma and liver for 14 patients co-infected with HIV and HCV. Median intra-patient genetic distances and entropy values were similar in the plasma and liver compartments. Positive immune selection pressure was observed in the plasma for five individuals and in the liver for three individuals. Statistical evidence supporting viral compartmentalization was found in five individuals. Linear regression identified ALT (P = 0.0104) and AST (P = 0.0130) as predictors of viral compartmentalization. A total of 12 signature amino acids that distinguish liver from plasma E1/HVR1 were identified. One signature amino acid was shared by at least two individuals. These findings suggest that HCV compartmentalization is relatively common among patients co-infected with HIV and HCV. These data also imply that evaluating viral diversity, including drug resistance patterns, in the serum/plasma only may not adequately represent viruses replicating with in the liver and, thus, deserves careful consideration in future studies.
doi:10.1002/jmv.23968
PMCID: PMC4562016  PMID: 24788693
HIV; HCV; co-infection; diversity; quasispecies; compartmentalization
6.  Is minimally invasive esophagectomy effective for preventing anastomotic leakages after esophagectomy for cancer? A systematic review and meta-analysis 
Background
Compared with open esophagectomy (OE), minimally invasive esophagectomy (MIE) proves to have clear benefits in reducing the risk of pulmonary complications for patients with resectable esophageal cancer. The objectives of our study were to explore the superiority of MIE in reducing the occurrence of anastomotic leakages (ALs) when compared to OE.
Methods
A systematic review and meta-analysis was performed to assess the superiority of MIE on the occurrence of ALs over OE, by searching many sources (through December, 2014) such as Medline, Embase, Wiley Online Library, and Cochrane Library. Fixed-effects model was used to calculate summary odds ratios (ORs) to quantify associations between OE and MIE groups. Cochran’s Q and I2 statistics were used to evaluate heterogeneity among studies.
Results
Among a total of 43 studies involving 5537 patients included in the meta-analysis, 2527 (45.6 %) cases underwent MIE and 3010 (54.4 %) cases underwent OE. Compared to patients undergoing OE, patients undergoing MIE did not have statistical significance in reduced occurrence of ALs (OR = 0.97, 95 % CI = 0.80–1.17). Insignificant reduced occurrence of ALs was not associated with anastomotic location (OR = 0.90, 95 % CI = 0.71–1.13) or anastomotic procedure (OR = 1.02, 95 % CI = 0.79–1.30).
Conclusions
More proofs are needed to clarify the strengths or weaknesses of MIE in preventing anastomotic leakages after esophagectomy for cancer. A largely randomized, controlled trial should be undertaken to resolve this contentious issue urgently.
doi:10.1186/s12957-015-0661-z
PMCID: PMC4560054  PMID: 26338060
Minimally invasive esophagectomy; Open esophagectomy; Anastomotic leakages
7.  Protective Effect of RNase on Unilateral Nephrectomy-Induced Postoperative Cognitive Dysfunction in Aged Mice 
PLoS ONE  2015;10(7):e0134307.
Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially for elderly patients. Administration of RNase has been reported to exhibit neuroprotective effects in acute stroke. However, the potential role of RNase on POCD is unknown. Therefore, we sought to investigate whether RNase treatment could mitigate unilateral nephrectomy induced-cognitive deficit in aged mice. In the present study, twelve-month-old mice were administered RNase or an equal amount of normal saline perioperatively. All mice underwent Morris Water Maze (MWM) training 3 times per day for 7 days to acclimatize them to the water maze before surgical operation, and testing on days 1, 3 and 7 after surgery. We found that perioperative administration of RNase: 1) attenuated unilateral nephrectomy-induced cognitive impairment at day 3 after surgery; 2) reduced the hippocampal cytokines mRNA production and serum cytokines protein production at day 1 and day 7 (for MCP-1) after surgery, and; 3) inhibited hippocampal apoptosis as indicated by cleaved caspase-3 western blot and TUNEL staining at day 1 after surgery. In addition, a trend decrease of total serum RNA levels was detected in the RNase treated group after surgery compared with the untreated group. Further, our protocol of RNase administration had no impact on the arterial blood gas analysis right after surgery, kidney function and mortality rate at the observed days postoperatively. In conclusion, perioperative RNase treatment attenuated unilateral nephrectomy-induced cognitive impairment in aged mice.
doi:10.1371/journal.pone.0134307
PMCID: PMC4520469  PMID: 26225860
8.  Foxp1 Regulates the Proliferation of Hair Follicle Stem Cells in Response to Oxidative Stress during Hair Cycling 
PLoS ONE  2015;10(7):e0131674.
Hair follicle stem cells (HFSCs) in the bugle circularly generate outer root sheath (ORS) through linear proliferation within limited cycles during anagen phases. However, the mechanisms controlling the pace of HFSC proliferation remain unclear. Here we revealed that Foxp1, a transcriptional factor, was dynamically relocated from the nucleus to the cytoplasm of HFSCs in phase transitions from anagen to catagen, coupled with the rise of oxidative stress. Mass spectrum analyses revealed that the S468 phosphorylation of Foxp1 protein was responsive to oxidative stress and affected its nucleocytoplasmic translocation. Foxp1 deficiency in hair follicles led to compromised ROS accrual and increased HFSC proliferation. And more, NAC treatment profoundly elongated the anagen duration and HFSC proliferation in Foxp1-deficient background. Molecularly, Foxp1 augmented ROS levels through suppression of Trx1-mediated reductive function, thereafter imposing the cell cycle arrest by modulating the activity of p19/p53 pathway. Our findings identify a novel role for Foxp1 in controlling HFSC proliferation with cellular dynamic location in response to oxidative stress during hair cycling.
doi:10.1371/journal.pone.0131674
PMCID: PMC4501748  PMID: 26171970
9.  Associations of deregulation of mir-365 and its target mRNA TTF-1 and survival in patients with NSCLC 
microRNA (mir)-365 exerts tumor suppressor function by targeting thyroid transcription factor-1 (TTF-1) in lung cancer cells. The purpose of the present study was to assess mir-365 and its target mRNA TTF-1 in lung cancer and their correlations with patients’ survival. Quantitative real-time PCR was used to examine the expression levels of mir-365 and TTF-1 in tumor tissue and its adjacent noncancerous tissue of 126 patients with non-small cell lung cancer (NSCLC). Our results showed that mir-365 was significantly decreased in tumor tissue than that in normal tissue (P=0.006), however, TTF-1 was significantly increased in tumor tissue than in normal tissue (P<0.001). Besides, significant correlations between decreased mir-365 and advanced tumor-node-metastasis (TNM) stage (P=0.001) and regional lymph node involvement (P=0.037) was observed. The similar result was also found between increased TTF-1 and TNM stage (P=0.003). Furthermore, mir-365 downregulation or TTF-1 upregulation were associated with poor outcome of patients than mir-365 upregulation or TTF-1 downregulation (for mir-365: P<0.001; for TTF-1: P=0.002). Of note, combination of decreased mir-365 and increased TTF-1 had worst overall survival (P<0.001). In conclusion, aberrant expression of mir-365/TTF-1 may be involved in the tumor development in patients with NSCLC. Moreover, mir-365 and TTF-1 could jointly predict the prognosis of patients and their combination may serve as a biomarker to predict risk of poor survival in NSCLC patients. Mir-365/TTF-1 might serve as a potential therapeutic target for clinical treatment of NSCLC.
PMCID: PMC4440055  PMID: 26045746
microRNA-365; NKX2-1; non-small cell lung cancer; prognostic; outcome
10.  Tumor-induced myeloid-derived suppressor cells promote tumor progression through oxidative metabolism in human colorectal cancer 
Background
Expansions of myeloid-derived suppressor cells (MDSCs) have been identified in human solid tumors, including colorectal cancer (CRC). However, the nature of these tumor-associated MDSCs and their interactions with tumor cells in CRC are still poorly understood.
Methods
The percentages and phenotype of MDSCs in peripheral blood and tumorous and paraneoplastic tissues from CRC patients, as well as the clinical relevance of these MDSCs, were assessed. Age-matched healthy donors were included as controls. The interaction between MDSCs and T cells or tumor cells was investigated in a coculture system in vitro, and the molecular mechanism of the effect of MDSCs on T cells or tumor cells was evaluated.
Results
We discovered that CRC patients had elevated levels of CD33+CD11b+HLA-DR− MDSCs in primary tumor tissues and in peripheral blood, and the elevated circulating MDSCs were correlated with advanced TNM stages and lymph node metastases. Radical resection significantly decreases the proportions of circulating MDSCs and CD4+CD25highFOXP3+ regulatory T cells. In vitro, CRC cells mediate the promotion of MDSC induction. Moreover, these tumor-induced MDSCs could suppress T cell proliferation and promote CRC cell growth via cell-to-cell contact. Such effects could be abolished by the inhibition of oxidative metabolism, including the production of nitric oxide (NO), and reactive oxygen species (ROS).
Conclusions
Our results reveal the functional interdependence between MDSCs, T cells and cancer cells in CRC pathogenesis. Understanding the impact of MDSCs on T cells and tumor cells will be helpful to establish an immunotherapeutic strategy in CRC patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0410-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0410-7
PMCID: PMC4357065  PMID: 25638150
Myeloid-derived suppressor cells; Colorectal carcinoma; Radical resection
11.  Tamoxifen Inhibits ER-negative Breast Cancer Cell Invasion and Metastasis by Accelerating Twist1 Degradation 
Twist1 is a transcription factor driving epithelial-mesenchymal transition, invasion and metastasis of breast cancer cells. Mice with germ-line Twist1 knockout are embryonic lethal, while adult mice with inducible Twist1 knockout have no obvious health problems, suggesting that Twist1 is a viable therapeutic target for the inhibition of invasion and metastasis of breast cancer in adult patients. In this study, we expressed a luciferase protein or a Twist1-luciferase fusion protein in HeLa cells as part of a high throughput system to screen 1280 compounds in the Library of Pharmacologically Active Compounds (LOPAC) from Sigma-Aldrich for their effects on Twist1 protein expression. One of the most interesting compounds identified is tamoxifen, a selective estrogen receptor (ER) modulator used to treat ER-positive breast cancer. Tamoxifen treatment significantly accelerated Twist1 degradation in multiple cell lines including HEK293 human kidney cells, 4T1 and 168FARN mouse mammary tumor cells with either ectopically or endogenously expressed Twist1. Tamoxifen-induced Twist1 degradation could be blocked by the MG132 proteasome inhibitor, suggesting that tamoxifen induces Twist1 degradation through the ubiquitination-proteasome pathway. However, tamoxifen-induced Twist1 degradation was independent of Twist1 mRNA expression, estrogen signaling and MAPK-mediated Twist1 phosphorylation in these cells. Importantly, tamoxifen also significantly inhibited invasive behavior in Matrigel and lung metastasis in SCID-bg mice of ER-negative 4T1 mammary tumor cells, which depend on endogenous Twist1 to invade and metastasize. These results indicate that tamoxifen can significantly accelerate Twist1 degradation to suppress cancer cell invasion and metastasis, suggesting that tamoxifen can be used not only to treat ER-positive breast cancers but also to reduce Twist1-mediated invasion and metastasis in ER-negative breast cancers.
doi:10.7150/ijbs.11380
PMCID: PMC4400392  PMID: 25892968
Breast cancer; Twist1; tamoxifen; Twist1 degradation; lung metastasis
12.  A Single Hot Event Stimulates Adult Performance but Reduces Egg Survival in the Oriental Fruit Moth, Grapholitha molesta 
PLoS ONE  2014;9(12):e116339.
Climate warming is expected to increase the exposure of insects to hot events (involving a few hours at extreme high temperatures). These events are unlikely to cause widespread mortality but may modify population dynamics via impacting life history traits such as adult fecundity and egg hatching. These effects and their potential impact on population predictions are still largely unknown. In this study, we simulated a single hot event (maximum of 38°C lasting for 4 h) of a magnitude increasingly found under field conditions and examined its effect in the oriental fruit moth, Grapholitha molesta. This hot event had no impact on the survival of G. molesta adults, copulation periods or male longevity. However, the event increased female lifespan and the length of the oviposition period, leading to a potential increase in lifetime fecundity and suggesting hormesis. In contrast, exposure of males to this event markedly reduced the net reproductive value. Male heat treatment delayed the onset of oviposition in the females they mated with, as well as causing a decrease in the duration of oviposition period and lifetime fecundity. Both male and female stress also reduced egg hatch. Our findings of hormetic effects on female performance but concurrent detrimental effects on egg hatch suggest that hot events have unpredictable consequences on the population dynamics of this pest species with implications for likely effects associated with climate warming.
doi:10.1371/journal.pone.0116339
PMCID: PMC4281249  PMID: 25551751
13.  GB Virus C (GBV-C) Infection in Hepatitis C Virus (HCV) Seropositive Women with or at Risk for HIV Infection 
PLoS ONE  2014;9(12):e114467.
Background
GB virus C (GBV-C) may have a beneficial impact on HIV disease progression; however, the epidemiologic characteristics of this virus are not well characterized. Behavioral factors and gender may lead to differential rates of GBV-C infection; yet, studies have rarely addressed GBV-C infections in women or racial/ethnic minorities. Therefore, we evaluated GBV-C RNA prevalence and genotype distribution in a large prospective study of high-risk women in the US.
Results
438 hepatitis C virus (HCV) seropositive women, including 306 HIV-infected and 132 HIV-uninfected women, from the HIV Epidemiologic Research Study were evaluated for GBV-C RNA. 347 (79.2%) women were GBV-C RNA negative, while 91 (20.8%) were GBV-C RNA positive. GBV-C positive women were younger than GBV-C negative women. Among 306 HIV-infected women, 70 (22.9%) women were HIV/GBV-C co-infected. Among HIV-infected women, the only significant difference between GBV-negative and GBV-positive women was age (mean 38.4 vs. 35.1 years; p<0.001). Median baseline CD4 cell counts and plasma HIV RNA levels were similar. The GBV-C genotypes were 1 (n = 31; 44.3%), 2 (n = 36; 51.4%), and 3 (n = 3; 4.3%). The distribution of GBV-C genotypes in co-infected women differed significantly by race/ethnicity. However, median CD4 cell counts and log10 HIV RNA levels did not differ by GBV-C genotype. GBV-C incidence was 2.7% over a median follow-up of 2.9 (IQR: 1.5, 4.9) years, while GBV-C clearance was 35.7% over a median follow-up of 2.44 (1.4, 3.5) years. 4 women switched genotypes.
Conclusions
Age, injection drug use, a history of sex for money or drugs, and number of recent male sex partners were associated with GBV-C infection among all women in this analysis. However, CD4 cell count and HIV viral load of HIV/HCV/GBV-C co-infected women were not different although race was associated with GBV-C genotype.
doi:10.1371/journal.pone.0114467
PMCID: PMC4262414  PMID: 25493916
14.  Upregulation of microRNA-23a/b promotes tumor progression and confers poor prognosis in patients with gastric cancer 
Background and purpose: To investigate the clinical significance of microRNA (miR)-23a and miR-23b expression in human gastric cancer (GC). Methods: Quantitative RT-PCR was performed to detect the expression changes of miR-23a and miR-23b in 160 human GC tissues and paired normal mucosa. The associations between miR-23a and miR-23b expression, and the selected clinicopathological characteristics and patients’ prognosis were also evaluated. Results: MiR-23a (GC vs. Normal: 3.98 ± 1.23 vs. 2.29 ± 1.12, P < 0.001) and miR-23b (GC vs. Normal: 3.70 ± 1.24 vs. 1.58 ± 1.18, P < 0.001) expression were both increased dramatically when compared with paired normal mucosa. Notably, the expression levels of miR-23a in GC tissues were positively correlated with those of miR-23b (Spearman correlation coefficient r = 0.77, P < 0.001). Then, the coexpression of miR-23a and miR-23b (miR-23a-high/miR-23b-high) in GC tissues was significantly associated with the advanced TNM stage (P < 0.001), the presence of lymph node metastasis (P = 0.008) and the great depth of invasion (P = 0.02). Furthermore, both univariate and multivariate analyses showed that miR-23a/miR-23b co-expression was an independent predictor for unfavorable overall survival. Conclusions: These results suggest that the dysregulation of miR-23a and miR-23b may be implicated in the progression of human GC. Combined expression of miR-23a and miR-23b appears to be a valuable marker for prognosis of this disease.
PMCID: PMC4314044  PMID: 25674252
Gastric cancer; microRNA-23a; microRNA-23b; clinicopathological feature; overall survival
15.  Ablation of Tak1 in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice 
Scientific Reports  2014;4:7158.
Tak1 is a MAPKKK that can be activated by growth factors and cytokines such as RANKL and BMPs and its downstream pathways include NF-κB and JNK/p38 MAPKs. Tak1 is essential for mouse embryonic development and plays critical roles in tissue homeostasis. Previous studies have shown that Tak1 is a positive regulator of osteoclast maturation, yet its roles in bone growth and remodeling have not been assessed, as mature osteoclast-specific Tak1 deletion with Cstk-Cre resulted in runtedness and postnatal lethality. Here we generated osteoclast progenitor (monocyte)-specific Tak1 knockout mice and found that these mice show normal body weight, limb size and fertility, and osteopetrosis with severity similar to that of RANK or RANKL deficient mice. Mechanistically, Tak1 deficiency altered the signaling of NF-κB, p38MAPK, and Smad1/5/8 and the expression of PU.1, MITF, c-Fos, and NFATc1, suggesting that Tak1 regulates osteoclast differentiation at multiple stages via multiple signaling pathways. Moreover, the Tak1 mutant mice showed defects in skull, articular cartilage, and mesenchymal stromal cells. Ex vivo Tak1−/− monocytes also showed enhanced ability in promoting osteogenic differentiation of mesenchymal stromal cells. These findings indicate that Tak1 functions in osteoclastogenesis in a cell-autonomous manner and in osteoblastogenesis and chondrogenesis in non-cell-autonomous manners.
doi:10.1038/srep07158
PMCID: PMC4241509  PMID: 25418008
16.  miR-429 inhibits migration and invasion of breast cancer cells in vitro 
International Journal of Oncology  2014;46(2):531-538.
Accumulating evidence indicates that microRNAs (miRNAs) are involved in regulating cancer invasion and metastasis, and an increasing number of research demonstrates that miRNAs can promote or inhibit cell motility depending on genetic background of different cancers and the microenvironment. In the present study, we established an in vivo bone metastasis model of breast cancer by injecting MDA-MB-231 cells into the left ventricle of nude mice, and then screened the differentially expressed miRNAs between parental and bone-metastatic MDA-MB-231 cells using miRNA array. The results revealed that decreased expression of miR-429 was probably involved in negatively regulating bone metastasis of breast cancer cells. On the other hand, overexpression of miR-429 in MDA-MB-231 cells remarkably suppressed invasion in vitro. We identified ZEB1 and CRKL as potential targets of miR-429 by analyzing combined results from in silico search and global expression array of the same RNA samples. Immunoblot assay confirmed that miR-429 reduced their expression at protein level. Taken together, our results offer an opportunity for further understanding of the recondite mechanisms underlying the bone metastasis of breast cancer.
doi:10.3892/ijo.2014.2759
PMCID: PMC4277243  PMID: 25405387
miR-429; ZEB1; CRKL; breast cancer bone metastasis
17.  Increased HIF-1alpha expression in tumor cells and lymphocytes of tumor microenvironments predicts unfavorable survival in esophageal squamous cell carcinoma patients 
The expression of hypoxia-induced factor (HIF)-1α is up-regulated in tumor microenvironments under hypoxia condition. However, the prognostic significance of HIF-1α in esophageal squamous cell carcinoma (ESCC) is still elusive. We measured the HIF-1α expression by immunochemistry in tumor specimens from 136 resected ESCC; in the current study, the HIF-1α expression in tumor cells was significantly associated with tumor stage (P = 0.003) and lymph node metastasis (P = 0.006); whereas the HIF-1α expression in tumor-infiltrating lymphocytes (TILs) had no relationship with patients’ clinicopathological parameters. Patients with high HIF-1α expression in tumor cells or in TILs showed worse survival related to those with low HIF-1α expression. Multivariate analysis demonstrated that expression of HIF-1α in TILs was an independent factor for DFS (P = 0.007) and OS (P = 0.013). Additionally, the expression of HIF-1α in tumor cells was an independent factor for DFS (P = 0.037) and OS (P = 0.033) in locoregional ESCC patients, whereas the expression of HIF-1α in TILs was an independent factor for DFS (P = 0.048) and OS (P = 0.039) in metastatic ESCC patients. Correlation analysis revealed that expressions of HIF-1α in tumor cells and in TILs were positively correlated, and patients with combined high HIF-1α in both tumor cells and TILs had the worst survivals (P < 0.05). These findings suggest that the HIF-1α expressions in different cell populations of ESCC microenvironments have different clinical relevance and prognostic impact on patients.
PMCID: PMC4129000  PMID: 25120765
Esophageal squamous cell carcinoma; HIF-1α; tumor microenvironments; clinical prognosis; tumor-infiltrating lymphocytes
18.  A New Criterion to Evaluate Water Vapor Interference in Protein Secondary Structural Analysis by FTIR Spectroscopy 
Second derivative and Fourier self-deconvolution (FSD) are two commonly used techniques to resolve the overlapped component peaks from the often featureless amide I band in Fourier transform infrared (FTIR) curve-fitting approach for protein secondary structural analysis. Yet, the reliability of these two techniques is greatly affected by the omnipresent water vapor in the atmosphere. Several criteria are currently in use as quality controls to ensure the protein absorption spectrum is negligibly affected by water vapor interference. In this study, through a second derivative study of liquid water, we first argue that the previously established criteria cannot guarantee a reliable evaluation of water vapor interference due to a phenomenon that we refer to as sample’s absorbance-dependent water vapor interference. Then, through a comparative study of protein and liquid water, we show that a protein absorption spectrum can still be significantly affected by water vapor interference even though it satisfies the established criteria. At last, we propose to use the comparison between the second derivative spectra of protein and liquid water as a new criterion to better evaluate water vapor interference for more reliable second derivative and FSD treatments on the protein amide I band.
doi:10.3390/ijms150610018
PMCID: PMC4100137  PMID: 24901531
FTIR spectroscopy; vibrational spectroscopy; protein secondary structure; second derivative; Fourier self-deconvolution
19.  Current Situation and Associated Factors of Withdrawing or Withholding Life Support to Patients in an Intensive Care Unit of Cancer Center in China 
PLoS ONE  2014;9(5):e98545.
Objectives
To investigate the current situation and analyze the associated factors of withdrawing or withholding life support in the intensive care unit (ICU) of our cancer center.
Methods
Three hundred and twenty-two cancer patients in critical status were admitted to our ICU in 2010 and 2011. They were included in the study and were classified into two groups: withdrawing or withholding life support (WWLS), and full life support (FLS). Demographic information and clinical data were collected and compared between the two groups. Factors associated with withdrawing or withholding life support were analyzed with univariate and multivariate logistic regression analysis.
Results
Eighty-two of the 322 cases (25.5% of all) made the decisions to withdraw or withhold life support. Emergency or critical condition at hospital admission, higher scores of Acute Physiology and Chronic Health Evaluation II (APACHE II) in 12 hours after ICU admission, financial difficulties and humanistic care requirements are important factors associated with withdrawing or withholding life support.
Conclusions
Withdrawing or withholding life support is not uncommon in critically ill cancer patients in China. Characteristics and associated factors of the decision-making are related to the current medical system, medical resources and traditional culture of the country.
doi:10.1371/journal.pone.0098545
PMCID: PMC4037202  PMID: 24870360
20.  Differentiation-Associated Genes Regulated by c-Jun and Decreased in the Progression of Esophageal Squamous Cell Carcinoma 
PLoS ONE  2014;9(5):e96610.
Transcription factor c-Jun plays a key role in controlling epithelium cell proliferation, apoptosis and differentiation. However, molecular mechanism and biological functions of c-Jun in squamous differentiation and the progression of esophageal squamous cell carcinoma (ESCC) remain elusive. In this study, we found that c-Jun bound directly to the promoter region, and activated the transcription of differentiation-associated genes including cystatin A, involucrin and SPRR3 in vivo. Ectopic expression of c-Jun enhanced SPRR3 transactivation in KYSE450 cells. Conversely, TAM67, a dominant negative mutant of c-Jun, inhibited SPRR3 transactivation. c-Jun increased expression of SPPR3 mainly via a PKC/JNK pathway in response to TPA in KYSE450 cells. Furthermore, c-Jun was remarkably reduced in esophageal cancer. Interestingly, cystatin A, involucrin and SPRR3 were significantly downregulated as well, and associated with differentiation grade. Expression of c-Jun was correlated with the expression of these genes in normal epithelium and ESCC. Importantly, the expression of these genes was remarkably decreased during the malignant transformation from normal epithelium to low-grade intraepithelial neoplasia (LGIN) or high-grade intraepithelial neoplasia (HGIN). The expression of cystatin A and involucrin was significantly reduced from LGIN to HGIN. These results suggest c-Jun was involved in the regulation of differentiation-associated genes in ESCC. These genes might serve as the potential markers in distinguishing normal epithelium from esophageal squamous intraepithelial neoplasia.
doi:10.1371/journal.pone.0096610
PMCID: PMC4010476  PMID: 24796531
21.  Constitutive Activation of Ectodermal β-Catenin Induces Ectopic Outgrowths at Various Positions in Mouse Embryo and Affects Abdominal Ventral Body Wall Closure 
PLoS ONE  2014;9(3):e92092.
Vertebrate limbs originate from the lateral plate mesoderm (LPM) and the overlying ectoderm. While normal limb formation in defined regions has been well studied, the question of whether other positions retain limb-forming potential has not been fully investigated in mice. By ectopically activating β-catenin in the ectoderm with Msx2-cre, we observed that local tissue outgrowths were induced, which either progressed into limb-like structure within the inter-limb flank or formed extra tissues in other parts of the mouse embryo. In the presumptive abdominal region of severely affected embryos, ectopic limb formation was coupled with impaired abdominal ventral body wall (AVBW) closure, which indicates the existence of a potential counterbalance of limb formation and AVBW closure. At the molecular level, constitutive β-catenin activation was sufficient to trigger, but insufficient to maintain the ectopic expression of a putative limb-inducing factor, Fgf8, in the ectoderm. These findings provide new insight into the mechanism of limb formation and AVBW closure, and the crosstalk between the Wnt/β-catenin pathway and Fgf signal.
doi:10.1371/journal.pone.0092092
PMCID: PMC3960177  PMID: 24647475
22.  Overexpression of Cystatin SN positively affects survival of patients with surgically resected esophageal squamous cell carcinoma 
BMC Surgery  2013;13:15.
Background
Cystatin SN is a secreted protein and a cysteine proteinase inhibitor. It has been considered to be a tumor marker for gastrointestinal tract cancer in several functional researches. However, the clinicopathological and prognostic significance of Cystatin SN expression in esophageal squamous cell carcinoma (ESCC) has not been elucidated.
Methods
In our study, the expression of Cystatin SN was detected in 209 surgically resected ESCC tissues and 170 peritumoral normal esophageal mucosae by immunohistochemistry. The prognostic significance of Cystatin SN expression was analysed with Kaplan-Meier plots and the Cox proportional hazards regression models.
Results
The results showed that the immunostaining of Cystatin SN in ESCC tissues was less intense than that in the normal control tissue (P < 0.001). Compared with patients with low tumoral Cystatin SN expression, ESCC patients with tumors high-expression Cystatin SN exhibited increased disease-free survival (DFS) and overall survival (OS) (P < 0.001 and P < 0.001, respectively). Furthermore, the expression level of Cystatin SN could further stratify the ESCC patients by survival (DFS and OS) in the stage II subgroup (P < 0.001 and P < 0.001, respectively). Multivariate analyses showed that Cystatin SN expression, N status and differentiation were independent and significant predictors of survival.
Conclusions
We concluded that ESCC patients whose tumors express high levels of Cystatin SN have favourable survival compared with those patients with low Cystatin SN expression. Tumoral Cystatin SN expression may be an independent predictor of survival for patients with resectable ESCCs.
doi:10.1186/1471-2482-13-15
PMCID: PMC3699386  PMID: 23711283
Esophageal squamous cell carcinoma; Cystatin SN; Immunohistochemistry; Prognosis
23.  Misexpression of Pknox2 in Mouse Limb Bud Mesenchyme Perturbs Zeugopod Development and Deltoid Crest Formation 
PLoS ONE  2013;8(5):e64237.
The TALE (Three Amino acid Loop Extension) family consisting of Meis, Pbx and Pknox proteins is a group of transcriptional co-factors with atypical homeodomains that play pivotal roles in limb development. Compared to the in-depth investigations of Meis and Pbx protein functions, the role of Pknox2 in limb development remains unclear. Here, we showed that Pknox2 was mainly expressed in the zeugopod domain of the murine limb at E10.5 and E11.5. Misexpression of Pknox2 in the limb bud mesenchyme of transgenic mice led to deformities in the zeugopod and forelimb stylopod deltoid crest, but left the autopod and other stylopod skeletons largely intact. These malformations in zeugopod skeletons were recapitulated in mice overexpressing Pknox2 in osteochondroprogenitor cells. Molecular and cellular analyses indicated that the misexpression of Pknox2 in limb bud mesenchyme perturbed the Hox10-11 gene expression profiles, decreased Col2 expression and Bmp/Smad signaling activity in the limb. These results indicated that Pknox2 misexpression affected mesenchymal condensation and early chondrogenic differentiation in the zeugopod skeletons of transgenic embryos, suggesting Pknox2 as a potential regulator of zeugopod and deltoid crest formation.
doi:10.1371/journal.pone.0064237
PMCID: PMC3661445  PMID: 23717575
24.  The expressions of MIF and CXCR4 protein in tumor microenvironment are adverse prognostic factors in patients with esophageal squamous cell carcinoma 
Background
Tumor-derived cytokines and their receptors usually take important roles in the disease progression and prognosis of cancer patients. In this survey, we aimed to detect the expression levels of MIF and CXCR4 in different cell populations of tumor microenvironments and their association with survivals of patients with esophageal squamous cell carcinoma (ESCC).
Methods
MIF and CXCR4 levels were measured by immunochemistry in tumor specimens from 136 resected ESCC. Correlation analyses and independent prognostic outcomes were determined using Pearson’s chi-square test and Cox regression analysis.
Results
The expression of CXCR4 in tumor cells was positively associated with tumor status (P = 0.045) and clinical stage (P = 0.044); whereas the expression of CXCR4 in tumor-infiltrating lymphocytes (TILs) and the expression of MIF in tumor cells and in TILs were not associated with clinical parameters of ESCC patients. High MIF expression in tumor cells or in TILs or high CXCR4 expression in tumor cells was significantly related to poor survival of ESCC patients (P < 0.05). Multivariate analysis showed that the expression of MIF or CXCR4 in tumor cells and the expression of MIF in TILs were adverse independent factors for disease-free survival (DFS) and overall survival (OS) in the whole cohort of patients (P < 0.05). Furthermore, the expression of MIF and CXCR4 in tumor cells were independent factors for reduced DFS and OS in metastatic/recurrent ESCC patients (P < 0.05). Interestingly, the expressions of MIF and CXCR4 in tumor cells and in TILs were significantly positively correlated (P < 0.05), and the combined MIF and CXCR4 expression in tumor cells was an independent adverse predictive factor for DFS and OS (P < 0.05).
Conclusion
The expressions of MIF and CXCR4 proteins in tumor cells and TILs have different clinically predictive values in ESCC.
doi:10.1186/1479-5876-11-60
PMCID: PMC3623724  PMID: 23497377
Esophageal squamous cell carcinoma; Tumor microenvironment; MIF; CXCR4; Prognosis
25.  Efficacy, Compliance and Reasons for Refusal of Postoperative Chemotherapy for Elderly Patients with Colorectal Cancer: A Retrospective Chart Review and Telephone Patient Questionnaire 
PLoS ONE  2013;8(2):e55494.
Background
Numerous clinical trials have demonstrated that elderly patients with colorectal cancer (CRC) can benefit from chemotherapy, yet compliance in real-world practice is low. The purpose of this study is to investigate the efficacy, compliance and reasons for refusal of postoperative chemotherapy for elderly patients with CRC and to provide corresponding strategies.
Patients and methods
The clinico-pathological and biochemical data of the chemotherapy group and chemo-refusing group were compared among 386 elderly patients (>70 years old) with CRC who underwent surgery. 226 patients received chemotherapy and 160 patients refused. Follow-up of the subjective reasons for refusal was investigated using the elderly caner patients' chemo-refusal reason questionnaire (ECPCRRQ) prepared by the authors and a group of psychologists. The questionnaire is administrated by telephone. A predictive model for 5-year disease-free survival (DFS) and 5-year overall survival (OS) was constructed by using Kaplan-Meier analysis, logistic and Cox regression.
Results
Among stage III patients, receiving chemotherapy was associated with a significantly higher OS (68%) compared to those who refused (OS50%) (HR: 2.05, 95%CI: 1.12–3.77, P = 0.02). The Chemo-refusal group had more female and elderly patients, significantly higher rate of severe complications, and lower body mass index (BMI). Follow-up phone questionnaire analysis showed the doctors’ uncertainty of chemotherapy benefit, economic difficulties, uncomfortable feeling, superstition of Traditional Chinese Medicine, concealing information and lack of social support were the main factors for elderly CRC patients to decline chemotherapy.
Conclusion
The receipt of post-operative chemotherapy in elderly patients with resected stage III CRC was associated with a more favorable survival. The low compliance rate (160/386) of postoperative chemotherapy was influenced by various subjective and objective factors.
doi:10.1371/journal.pone.0055494
PMCID: PMC3579821  PMID: 23451026

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