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author:("Wang, jisheng")
1.  Patch clamp apply in cardiomyocytes derived from patient’s iPS cells for individual anticancer therapy 
Cardiac side-effects of chemotherapy are old dogs for cancer patient at the beginning of cancer treatment. The deleterious side-effects of chemotherapy on the cardiovascular system have been deemed as a serious clinical issue for a long term, especially sudden cardiac death (SCD) due to QT prolongation. Since induced pluripotent stem cells has been firstly reported by Takahashi and Yamanaka in 2006, iPS has become a valuable research tool. Especially, cardiomyocytes have been successfully derived from human iPS cells which carry on corresponding genetic information of disease, and therefore show a great promise in drug screen on the diseasing model. In this study, we hypothesized that iPS cells created from patient with cancer and carried corresponding genetic alteration will provide a genetic background for sensitivity screening of anticancer drug, as well as side-effects of cardiovascular system.
PMCID: PMC4276230  PMID: 25550972
Patch clamp; iPS cells; individual anticancer therapy
2.  Impact of NPR-A expression in gastric cancer cells 
Background: The receptors for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPR-A), have been reported to be expressed in lung cancer, prostate cancer, ovarian cancer. NPR-A expression and signaling is important for tumor growth, its deficiency protect C57BL/6 mice from lung, skin, and ovarian cancers, and these result suggest that NPR-A is a new target for cancer therapy. Recently, NPR-A has been demonstrated to be expressed in pre-implantation embryos and in ES cells, it has a novel role in the maintenance of self-renewal and pluripotency of ES cells. However, the direct role of NPR-A signaling in gastric cancer remains unclear. Method: NPR-A expression was downregulated by transfection of shRNA. The proliferation of gastric cancer cells was measured by Hoechst 33342 stain. Cell proliferation and invasion were determined via BrdU and transwell assays, respectively. Results: Down-regulation of NPR-A expression by shNPR-A induced apoptosis, inhibited proliferation and invasion in AGS cells. The mechanism of shNPR-A-induced anti-AGS effects was linked to NPR-A-induced expression of KCNQ1, a gene to be overexpressed in AGS and significantly reduced by shNPR-A. Conclusion: Collectively, these results suggest that NPR-A promotes gastric cancer development in part by regulating KCNQ1. Our findings also suggest that NPR-A is a target for gastric cancer therapy.
PMCID: PMC4238555  PMID: 25419351
NPR-A; gastric cancer; KCNQ1
3.  Natriuretic peptide receptor A as a novel target for cancer 
The receptor for the cardiac hormone atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPR-A), has been reported to be expressed in lung cancer, prostate cancer and ovarian cancer. NPR-A expression and signaling is important for tumor growth; its deficiency protects C57BL/6 mice from lung, skin and ovarian cancers. This suggests that NPR-A is a new marker and a new target for cancer therapy. Recently, NPR-A has been demonstrated to be expressed in pre-implantation embryos and in embryonic stem cells, which has a novel role in the maintenance of self-renewal and pluripotency of embryonic stem cells. A nanoparticle-formulated interfering RNA for NPR-A attenuated B16 melanoma tumors in mice. Ectopic expression of a plasmid encoding NP73-102, the NH2-terminal peptide of the ANP prohormone which downregulates NPR-A expression, also suppressed lung metastasis of A549 cells in nude mice and tumorigenesis of Line 1 cells in immunocompetent BALB/c mice. These results suggest that NPR-A is involved in tumorigenesis and a new target for cancer therapy. This review focuses on structure, abnormal functions and carcinogenic mechanisms of NPR-A to investigate its role in tumorigenesis.
PMCID: PMC4049422  PMID: 24894887
NPR-A; Cancer; Target
4.  Expression of natriuretic peptide receptor-A in esophageal squamous cell carcinomas and the relationship with tumor invasion and migration 
The natriuretic peptide receptor-A (NPRA) has been investigated as a receptor of natriuretic peptides in the cardiovascular system. In this study, however, we analyze the expression status of NPRA and the relationship with tumor invasion in esophageal squamous cell carcinoma (ESCC) for the first time.
Western blots were used to examine the expression status of protein in human ESCC cell lines. Then, we used immunohistochemistry to detect the expression of NPRA in 45 ESCC specimens and 40 corresponding nontumor tissues. The clinical data were analyzed through statistical methods. Sh-RNA-NPRA was transfected into Eca109 cells to detect the relationship between NPRA and cell invasion through transwell assays.
In esophageal squamous cells, the expression of NPRA was strongly detected in the cytoplasm, while undetectable or very weak in the nucleus. The positive rates of NPRA in cancer tissues are significantly higher than that in nontumor tissues (P <0.05). Clinicopathological analyses revealed that increased NPRA expression correlated with differentiation and TNM stage (P <0.05), while it showed no statistically significant association with age, gender, and lymph node metastasis. In analysis of prognosis, we found that highly.Transwell assays showed that NPRA promoted Eca109 cell migration and invasion in vitro and may be involved in MMP2 and MMP9 activation.
NPRA protein is highly expressed in ESCC tissues and could promote Eca109 cell migration and invasion in vitro.
PMCID: PMC4038370  PMID: 24885858
natriuretic peptide receptor-A; NPRA; esophageal squamous cell carcinoma; ESCC; MMP; invasion; migration
5.  Histologic Tumor Involvement of Superior Mesenteric Vein/Portal Vein Predicts Poor Prognosis in Patients with Stage II Pancreatic Adenocarcinoma Treated with Neoadjuvant Chemoradiation 
Cancer  2011;118(15):3801-3811.
Studies have shown that superior mesenteric vein/portal vein (SMV/PV) resection with pancreaticoduodenectomy (PD) is safe and feasible for patient with pancreatic adenocarcinoma (PAC). However, the prognostic significance of tumor involvement of the resected vein in patients who received neoadjuvant therapy is unclear.
We evaluated 225 consecutive patients with stage II PAC who received neoadjuvant therapy and PD with or without SMV/PV resection. The resected SMV/PV was entirely submitted for histologic assessment and reviewed in all cases. Tumor involvement of the SMV/PV was correlated with clinicopathologic features and survival.
Among the 225 patients, SMV/PV resection was performed in 85 patients. Histologic tumor involvement of the resected SMV/PV was identified in 57 patients. Histologic tumor involvement of the SMV/PV was associated with larger tumor size, higher rates of positive margin and local/distant recurrence. By multivariate analysis, tumor involvement of the SMV/PV was an independent predictor of both disease-free survival (DFS) and overall survival (OS). However, addition of venous resection to PD itself had no impact on either DFS or OS compared to those with PD alone.
Tumor involvement of the SMV/PV is an independent predictor of both DFS and OS in patients with stage II PAC treated with neoadjuvant therapy and PD. Complete histologic evaluation of the resected SMV/PV is important for the prognosis in patients with PAC who received neoadjuvant therapy and PD.
PMCID: PMC3310937  PMID: 22180096
pancreatic adenocarcinoma; survival; prognosis; SMV/PV
6.  Atrial natriuretic peptide modulates the proliferation of human gastric cancer cells via KCNQ1 expression 
Oncology Letters  2013;6(2):407-414.
Atrial natriuretic peptide (ANP) and brain NP (BNP) belong to the NP family that regulates mammalian blood volume and blood pressure. ANP signaling through NP receptor A (NPR-A)/cyclic guanosine 3′5′-monophosphate (cGMP)/ cGMP-dependent protein kinase (PKG) activates various downstream effectors involved in cell growth, apoptosis, proliferation and inflammation. Evidence has shown the critical role of plasma K+ channels in the regulation of tumor cell proliferation. However, the role of ANP in the proliferation of gastric cancer cells is not clear. In the present study, the expression of NPR-A in the human gastric cancer cell line, AGS, and the effect of ANP on the proliferation of AGS cells were investigated using western blotting, immunofluorescence, qPCR and patch clamp assays. The K+ current was also analyzed in the effect of ANP on the proliferation of AGS cells. NPR-A was expressed in the human gastric cancer AGS cell line. Lower concentrations of ANP promoted the proliferation of the AGS cells, although higher concentrations decreased their proliferation. Significant increases in the levels of cGMP activity were observed in the AGS cells treated with 10−10, 10−9 and 10−8 M ANP compared with the controls, but no significant differences were observed in the 10−7 and 10−6 M ANP groups. The patch clamp results showed that 10−9 M ANP significantly increased the tetraethylammonium (TEA)- and 293B-sensitive K+ current, while 10−6 M ANP significantly decreased the TEA- and 293B-sensitive K+ current. The results showed that 10−10 and 10−9 M ANP significantly upregulated the expression of potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) at the protein and mRNA levels, although 10−7 and 10−6 M ANP significantly downregulated the expression of KCNQ1. The data indicated that lower and higher concentrations of ANP have opposite effects on the proliferation of AGS cells through cGMP-dependent or -independent pathways. KCNQ1 upregulation and downregulation by lower and higher concentrations of ANP, respectively, have separate effects on the promotion and inhibition of proliferation.
PMCID: PMC3789098  PMID: 24137337
atrial natriuretic peptide; KCNQ1; proliferation; gastric cancer
7.  An 11 kg Phyllodes tumor of the breast in combination with other multiple chronic diseases: Case report and review of the literature 
Oncology Letters  2013;6(1):150-152.
Phyllodes tumors (PTs) of the breast are a rare type of tumor that account for <1% of breast tumors in females and usually present as a large lump of 3–5 cm in size. Surgery is the first line of treatment for PTs, and chemotherapy and irradiation may be useful in certain patients but not all. In the present study, the case of a 63-year-old female patient with a huge PT in the left breast is described. On physical examination, the patient presented with a huge mass of ∼45 cm in diameter, weighing ∼11 kg, and a composite of multiple chronic diseases. The breast and pectoris major and minor were excised. Post-operatively, the patient recovered well and to date there has been no evidence of local recurrence or distant metastasis.
PMCID: PMC3742775  PMID: 23946794
breast; phyllodes tumor; chronic diseases; cancer
8.  Multiple phytohormone signalling pathways modulate susceptibility of tomato plants to Alternaria alternata f. sp. lycopersici  
Journal of Experimental Botany  2013;64(2):637-650.
Three phytohormone molecules – ethylene (ET), jasmonic acid (JA) and salicylic acid (SA) – play key roles in mediating disease response to necrotrophic fungal pathogens. This study investigated the roles of the ET, JA, and SA pathways as well as their crosstalk during the interaction between tomato (Solanum lycopersicum) plants and a necrotrophic fungal pathogen Alternaria alternata f. sp. lycopersici (AAL). Both the ET and JASMONIC ACID INSENSITIVE1 (JAI1) receptor-dependent JA signalling pathways are necessary for susceptibility, while SA response promotes resistance to AAL infection. In addition, the role of JA in susceptibility to AAL is partly dependent on ET biosynthesis and perception, while the SA pathway enhances resistance to AAL and antagonizes the ET response. Based on these results, it is proposed that ET, JA, and SA each on their own can influence the susceptibility of tomato to AAL. Furthermore, the functions of JA and SA in susceptibility to the pathogen are correlated with the enhanced or decreased action of ET, respectively. This study has revealed the functional relationship among the three key hormone pathways in tomato defence against AAL.
PMCID: PMC3542053  PMID: 23264518
AAL; ethylene; hormonal interactions; jasmonic acid; salicylic acid; tomato
9.  The changes of Th17 cells and the related cytokines in the progression of human colorectal cancers 
BMC Cancer  2012;12:418.
The role of Th17 cells in colorectal tumorigenesis and development still remains unclear, despite the fact that it has been established in the pathogenesis of autoimmune diseases.
We first analyzed Th17 cells and Treg cells using flow cytometry in the circulation of colorectal adenoma (CRA) and colorectal carcinoma (CRC) patients and healthy controls, and the frequency of Th17 cells in peripheral blood mononuclear cells (PBMCs) stimulated by anti-CD3 plus anti-CD28 and treated by IL-1β, IL-6, and TGF-β in different concentrations. We then detected cytokines IL-1β, IL-6, IL-17A, IL-21, IL-23 or TGF-β by ELISA in sera and supernatants from both normal and tumor tissues cultured ex vivo.
It was found that the percentage of Th17 and Treg cells increased in the circulation of both CRA and CRC patients; the increase of Th17 cells in the circulation occurred in early stages, whereas the increase of Treg cells in the circulation and the increase of Th17 cells in tumor tissues occurred in advanced stages. The subsequent cytokine profiling showed that, along CRC progression, IL-1β, IL-17A and IL-23 underwent a similar change, while IL-6 in CRC exhibited an opposite change, with Th17 cells. In addition, high levels of TGF-β and IL-17A were detected in tumor tissues rather than in normal mucosa. The in vitro experiment further demonstrated that IL-1β, IL-6 or TGF-β modulated Th17 cell expansion in PBMC.
Our study reveals a unique change of Th17 cells, which is regulated possibly by IL-1β, IL-6 and TGF-β in the progression of CRC.
PMCID: PMC3488332  PMID: 22994684
Colorectal adenoma; Colorectal cancer; Th17 cells; Treg cells; Cytokines
10.  Eight RGS and RGS-like Proteins Orchestrate Growth, Differentiation, and Pathogenicity of Magnaporthe oryzae 
PLoS Pathogens  2011;7(12):e1002450.
A previous study identified MoRgs1 as an RGS protein that negative regulates G-protein signaling to control developmental processes such as conidiation and appressorium formation in Magnaporthe oryzae. Here, we characterized additional seven RGS and RGS-like proteins (MoRgs2 through MoRgs8). We found that MoRgs1 and MoRgs4 positively regulate surface hydrophobicity, conidiation, and mating. Indifference to MoRgs1, MoRgs4 has a role in regulating laccase and peroxidase activities. MoRgs1, MoRgs2, MoRgs3, MoRgs4, MoRgs6, and MoRgs7 are important for germ tube growth and appressorium formation. Interestingly, MoRgs7 and MoRgs8 exhibit a unique domain structure in which the RGS domain is linked to a seven-transmembrane motif, a hallmark of G-protein coupled receptors (GPCRs). We have also shown that MoRgs1 regulates mating through negative regulation of Gα MoMagB and is involved in the maintenance of cell wall integrity. While all proteins appear to be involved in the control of intracellular cAMP levels, only MoRgs1, MoRgs3, MoRgs4, and MoRgs7 are required for full virulence. Taking together, in addition to MoRgs1 functions as a prominent RGS protein in M. oryzae, MoRgs4 and other RGS and RGS-like proteins are also involved in a complex process governing asexual/sexual development, appressorium formation, and pathogenicity.
Author Summary
Regulator of G-protein signaling (RGS) proteins play pivotal roles in modulating heterotrimeric G-protein signal transduction cascades that enable eukaryotic cells to perceive external cues and elicit appropriate physiological and biochemical responses. A previous study for one of the RGS proteins, MoRgs1, has demonstrated that these important roles also exist in the rice blast pathogen Magnaporthe oryzae. To further study functions of RGS proteins in this pathogen, we have characterized additional seven RGS and RGS-like proteins. This has been the largest number of RGS and RGS-like proteins ever discovered from a single fungal organism. We provided evidence to demonstrate that, in addition to MoRgs1 functioning as a prominent RGS protein, other RGS and RGS-like proteins are also involved in a complex process to control asexual/sexual development, appressorium differentiation and penetration, and pathogenicity of M. oryzae.
PMCID: PMC3248559  PMID: 22241981
11.  Two Phosphodiesterase Genes, PDEL and PDEH, Regulate Development and Pathogenicity by Modulating Intracellular Cyclic AMP Levels in Magnaporthe oryzae 
PLoS ONE  2011;6(2):e17241.
Cyclic AMP (cAMP) signaling plays an important role in regulating multiple cellular responses, such as growth, morphogenesis, and/or pathogenicity of eukaryotic organisms such as fungi. As a second messenger, cAMP is important in the activation of downstream effector molecules. The balance of intracellular cAMP levels depends on biosynthesis by adenylyl cyclases (ACs) and hydrolysis by cAMP phosphodiesterases (PDEases). The rice blast fungus Magnaporthe oryzae contains a high-affinity (PdeH/Pde2) and a low-affinity (PdeL/Pde1) PDEases, and a previous study showed that PdeH has a major role in asexual differentiation and pathogenicity. Here, we show that PdeL is required for asexual development and conidial morphology, and it also plays a minor role in regulating cAMP signaling. This is in contrast to PdeH whose mutation resulted in major defects in conidial morphology, cell wall integrity, and surface hydrophobicity, as well as a significant reduction in pathogenicity. Consistent with both PdeH and PdeL functioning in cAMP signaling, disruption of PDEH only partially rescued the mutant phenotype of ΔmagB and Δpka1. Further studies suggest that PdeH might function through a feedback mechanism to regulate the expression of pathogenicity factor Mpg1 during surface hydrophobicity and pathogenic development. Moreover, microarray data revealed new insights into the underlying cAMP regulatory mechanisms that may help to identify potential pathogenicity factors for the development of new disease management strategies.
PMCID: PMC3046207  PMID: 21386978
12.  Expenditures for the care of HIV-infected patients in rural areas in China's antiretroviral therapy programs 
BMC Medicine  2011;9:6.
The Chinese government has provided health services to those infected by the human immunodeficiency virus (HIV) under the acquired immunodeficiency syndrome (AIDS) care policy since 2003. Detailed research on the actual expenditures and costs for providing care to patients with AIDS is needed for future financial planning of AIDS health care services and possible reform of HIV/AIDS-related policy. The purpose of the current study was to determine the actual expenditures and factors influencing costs for untreated AIDS patients in a rural area of China after initiating highly active antiretroviral therapy (HAART) under the national Free Care Program (China CARES).
A retrospective cohort study was conducted in Yunnan and Shanxi Provinces, where HAART and all medical care are provided free to HIV-positive patients. Health expenditures and costs in the first treatment year were collected from medical records and prescriptions at local hospitals between January and June 2007. Multivariate linear regression was used to determine the factors associated with the actual expenditures in the first antiretroviral (ARV) treatment year.
Five ARV regimens are commonly used in China CARES: zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP), stavudine (D4T) + 3TC + efavirenz (EFV), D4T + 3TC + NVP, didanosine (DDI) + 3TC + NVP and combivir + EFV. The mean annual expenditure per person for ARV medications was US$2,242 (US$1 = 7 Chinese Yuan (CNY)) among 276 participants. The total costs for treating all adverse drug events (ADEs) and opportunistic infections (OIs) were US$29,703 and US$23,031, respectively. The expenses for treatment of peripheral neuritis and cytomegalovirus (CMV) infections were the highest among those patients with ADEs and OIs, respectively. On the basis of multivariate linear regression, CD4 cell counts (100-199 cells/μL versus <100 cells/μL, P = 0.02; and ≥200 cells/μL versus <100 cells/μL, P < 0.004), residence in Mangshi County (P < 0.0001), ADEs (P = 0.04) and OIs (P = 0.02) were significantly associated with total expenditures in the first ARV treatment year.
This is the first study to determine the actual costs of HIV treatment in rural areas of China. Costs for ARV drugs represented the major portion of HIV medical expenditures. Initiating HAART in patients with higher CD4 cell count levels is likely to reduce treatment expenses for ADEs and OIs in patients with AIDS.
PMCID: PMC3025874  PMID: 21241494
13.  Self-reported prevalence of childhood allergic diseases in three cities of China: a multicenter study 
BMC Public Health  2010;10:551.
Several studies conducted during the 1990s indicated that childhood allergic diseases were increasing worldwide, but more recent investigations in some Western countries have suggested that the trend is stabilizing or may even be reversing. However, few data are available on the current status of allergic disease prevalence in Chinese children. The aim of the present study was to investigate the prevalence rates of asthma, allergic rhinitis, and eczema in children of three major cities of China, to determine the status of allergic diseases among Chinese children generally, and to evaluate the prevalence of allergic diseases in children of different ages.
We conducted a cross-sectional survey between October 2008 and May 2009 in three major cities of China (Beijing, Chongqing, and Guangzhou) to evaluate the prevalence rates of childhood allergic diseases including asthma, allergic rhinitis, and eczema, using a questionnaire of the International Study of Asthma and Allergies in Childhood (ISAAC) group. A total of 24,290 children aged 0-14 years were interviewed, using a multi-stage sampling method. To acquire data on children aged 3-14 years, we visited schools and kindergartens. To access children too young to attend school or kindergarten, we extended our survey to community health service centers. Each questionnaire was completed by a parent or guardian of a child after an informed consent form was signed.
Of the 24,290 children in our study, 12,908 (53.14%) were males and 11,382 (46.86%) females; 10,372 (42.70%) were from Beijing, 9,846 (40.53%) from Chongqing, and 4,072 (16.77%) from Guangzhou. Our survey indicated that in Beijing, Chongqing, and Guangzhou, the prevalence rates of asthma were 3.15%, 7.45%, and 2.09%, respectively; the rates of allergic rhinitis were 14.46%, 20.42%, and 7.83%; and the rates of eczema were 20.64%, 10.02%, and 7.22%. The prevalence of allergic diseases varied with age. Asthma was relatively less common both in children aged under 2 years, and in those aged 9 years or more, in each of the three cities. The prevalence of allergic rhinitis was also lower in children younger than 2 years. The prevalence of eczema fell with age.
A marked increase in the prevalence rates of allergic diseases in China (compared with earlier data) was evident. Further studies exploring the precise causes of this increase are warranted.
PMCID: PMC2944377  PMID: 20836838
15.  Primary adenomyoepithelioma of tonsil 
We present a case of adenomyoepithlioma (AME) arising from the tonsil. AME is an uncommon tumor that typically arises in breast, but rarely found in salivary glands, lung, and skin. Its biological features have not been thoroughly characterized. Here we describe a primary AME originating from the tonsil. The pathologic changes were characterized by hypercellularity, the dominance of both epithelial and myoepithelial cells. Malignancy was evidenced by the presence of a high mitotic rate and invasive growth. The epithelial cells express high levels of cytokeratin and epithelial membrane antigen (EMA). The myoepithelial cells show positive staining for calponin, p63, vimentin, and S-100. A thorough review of the literature indicates that this is likely the first reported case of AME from the tonsil. Following descriptions of the diagnosis, treatment, and prognosis of this specific case, pathologic and clinical characteristics of AME from other tissues are also compiled and discussed.
PMCID: PMC3161342  PMID: 20356364

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