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1.  Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates 
Millwood, Iona Y | Li, Liming | Smith, Margaret | Guo, Yu | Yang, Ling | Bian, Zheng | Lewington, Sarah | Whitlock, Gary | Sherliker, Paul | Collins, Rory | Chen, Junshi | Peto, Richard | Wang, Hongmei | Xu, Jiujiu | He, Jian | Yu, Min | Liu, Huilin | Chen, Zhengming | Li, Liming | Chen, Zhengming | Chen, Junshi | Collins, Rory | Wu, Fan | Peto, Richard | Chen, Zhengming | Lancaster, Garry | Yang, Xiaoming | Williams, Alex | Smith, Margaret | Yang, Ling | Chang, Yumei | Millwood, Iona | Chen, Yiping | Zhang, Qiuli | Lewington, Sarah | Whitlock, Gary | Guo, Yu | Zhao, Guoqing | Bian, Zheng | Wu, Lixue | Hou, Can | Pang, Zengchang | Wang, Shaojie | Zhang, Yun | Zhang, Kui | Liu, Silu | Zhao, Zhonghou | Liu, Shumei | Pang, Zhigang | Feng, Weijia | Wu, Shuling | Yang, Liqiu | Han, Huili | He, Hui | Pan, Xianhai | Wang, Shanqing | Wang, Hongmei | Hao, Xinhua | Chen, Chunxing | Lin, Shuxiong | Hu, Xiaoshu | Zhou, Minghao | Wu, Ming | Wang, Yeyuan | Hu, Yihe | Ma, Liangcai | Zhou, Renxian | Xu, Guanqun | Dong, Baiqing | Chen, Naying | Huang, Ying | Li, Mingqiang | Meng, Jinhuai | Gan, Zhigao | Xu, Jiujiu | Liu, Yun | Wu, Xianping | Gao, Yali | Zhang, Ningmei | Luo, Guojin | Que, Xiangsan | Chen, Xiaofang | Ge, Pengfei | He, Jian | Ren, Xiaolan | Zhang, Hui | Mao, Enke | Li, Guanzhong | Li, Zhongxiao | He, Jun | Liu, Guohua | Zhu, Baoyu | Zhou, Gang | Feng, Shixian | Gao, Yulian | He, Tianyou | Jiang, Li | Qin, Jianhua | Sun, Huarong | Liu, Liqun | Yu, Min | Chen, Yaping | Hu, Zhixiang | Hu, Jianjin | Qian, Yijian | Wu, Zhiying | Chen, Lingli | Liu, Wen | Li, Guangchun | Liu, Huilin | Long, Xiangquan | Xiong, Youping | Tan, Zhongwen | Xie, Xuqiu | Peng, Yunfang
Background Drinking alcohol has a long tradition in Chinese culture. However, data on the prevalence and patterns of alcohol consumption in China, and its main correlates, are limited.
Methods During 2004–08 the China Kadoorie Biobank recruited 512 891 men and women aged 30–79 years from 10 urban and rural areas of China. Detailed information on alcohol consumption was collected using a standardized questionnaire, and related to socio-demographic, physical and behavioural characteristics in men and women separately.
Results Overall, 76% of men and 36% of women reported drinking some alcohol during the past 12 months, with 33% of men and 2% of women drinking at least weekly; the prevalence of weekly drinking in men varied from 7% to 51% across the 10 study areas. Mean consumption was 286 g/week and was higher in those with less education. Most weekly drinkers habitually drank spirits, although this varied by area, and beer consumption was highest among younger drinkers; 37% of male weekly drinkers (12% of all men) reported weekly heavy drinking episodes, with the prevalence highest in younger men. Drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate. Among male weekly drinkers, each 20 g/day alcohol consumed was associated with 2 mmHg higher systolic blood pressure. Potential indicators of problem drinking were reported by 24% of male weekly drinkers.
Conclusion The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region. Alcohol consumption is associated with a number of unfavourable health behaviours and characteristics.
PMCID: PMC3733702  PMID: 23918852
Alcohol; drinking; cohort study; descriptive analysis; China
2.  Examining Two Sets of Introgression Lines in Rice (Oryza sativa L.) Reveals Favorable Alleles that Improve Grain Zn and Fe Concentrations 
PLoS ONE  2015;10(7):e0131846.
In the modern world, the grain mineral concentration (GMC) in rice (Oryza sativa L.) not only includes important micronutrient elements such as iron (Fe) and zinc (Zn), but it also includes toxic heavy metal elements, especially cadmium (Cd) and lead (Pb). To date, the genetic mechanisms underlying the regulation of GMC, especially the genetic background and G × E effects of GMC, remain largely unknown. In this study, we adopted two sets of backcross introgression lines (BILs) derived from IR75862 (a Zn-dense rice variety) as the donor parent and two elite indica varieties, Ce258 and Zhongguangxiang1, as recurrent parents to detect QTL affecting GMC traits including Fe, Zn, Cd and Pb concentrations in two environments. We detected a total of 22 loci responsible for GMC traits, which are distributed on all 12 rice chromosomes except 5, 9 and 10. Six genetic overlap (GO) regions affecting multiple elements were found, in which most donor alleles had synergistic effects on GMC. Some toxic heavy metal-independent loci (such as qFe1, qFe2 and qZn12) and some regions that have opposite genetic effects on micronutrient (Fe and Zn) and heavy metal element (Pb) concentrations (such as GO-IV) may be useful for marker-assisted biofortification breeding in rice. We discuss three important points affecting biofortification breeding efforts in rice, including correlations between different GMC traits, the genetic background effect and the G × E effect.
PMCID: PMC4498612  PMID: 26161553
3.  Aging and Exercise Affect Hippocampal Neurogenesis via Different Mechanisms 
PLoS ONE  2015;10(7):e0132152.
The rate of neurogenesis is determined by 1) the number of neural stem/progenitor cells (NSCs), 2) proliferation of NSCs, 3) neuron lineage specification, and 4) survival rate of the newborn neurons. Aging lowers the rate of hippocampal neurogenesis, while exercise (Ex) increases this rate. However, it remains unclear which of the determinants are affected by aging and Ex. We characterized the four determinants in different age groups (3, 6, 9, 12, 21 months) of mice that either received one month of Ex training or remained sedentary. Bromodeoxyuridine (BrdU) was injected two hours before sacrificing the mice to label the proliferating cells. The results showed that the number of newborn neurons massively decreased (>95%) by the time the mice reached nine months of age. The number of NSC was mildly reduced during aging, while Ex delayed such decline. The proliferation rates were greatly decreased by the time the mice were 9-month-old and Ex could not improve the rates. The rates of neuron specification were decreased during aging, while Ex increased the rates. The survival rate was not affected by age or Ex. Aging greatly reduced newborn neuron maturation, while Ex potently enhanced it. In conclusion, age-associated decline of hippocampal neurogenesis is mainly caused by reduction of NSC proliferation. Although Ex increases the NSC number and neuron specification rates, it doesn't restore the massive decline of NSC proliferation rate. Hence, the effect of Ex on the rate of hippocampal neurogenesis during aging is limited, but Ex does enhance the maturation of newborn neurons.
PMCID: PMC4493040  PMID: 26147302
4.  Presepsin as a diagnostic marker for sepsis: evidence from a bivariate meta-analysis 
The diagnosis of sepsis remains a clinical challenge. Many studies suggest that presepsin plays a role in diagnosing sepsis, but the results remain controversial. This study aimed to identify the overall diagnostic accuracy of presepsin for sepsis through meta-analysis.
A systematic literature search was performed in PubMed and EMBASE to identify studies evaluating the diagnostic accuracy of presepsin in sepsis patients. Data were retrieved and the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (DOR) were calculated. A summary receiver operating characteristic curve and area under curve (AUC) were used to evaluate the overall diagnostic performance. The statistical analysis was performed using Stata 12.0 and Meta-DiSc 1.4 software.
Eleven publications with 3,106 subjects were included in the meta-analysis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and DOR were 0.83 (95% confidence interval [CI] 0.77–0.88), 0.81 (95% CI 0.74–0.87), 4.43 (95% CI 3.05–6.43), 0.21 (95% CI 0.14–0.30), and 21.56 (95% CI 10.59–43.88), respectively. The area under the curve was 0.89 (95% CI 0.86–0.92). Estimated positive and negative post-probability values for a sepsis prevalence of 20% were 53% and 5%, respectively. No publication bias was identified.
Based on currently available evidence, presepsin may have a valuable role in the diagnosis of sepsis, and its results should be interpreted carefully in the context of clinical condition and traditional markers.
PMCID: PMC4494627  PMID: 26170681
sepsis; presepsin; diagnosis; meta-analysis
5.  Chemokine Signaling Pathway Involved in CCL2 Expression in Patients with Rheumatoid Arthritis 
Yonsei Medical Journal  2015;56(4):1134-1142.
Rheumatoid arthritis (RA) is an inflammatory joint disorder, the progression of which leads to the destruction of cartilage and bone. Chemokines are involved in RA pathogenesis. In this study, we investigated the chemokine signaling pathway associated with CCL2 in peripheral blood (PB) and synovial tissues (ST) of RA patients based on our previous work about chemokine signaling pathway involved in the activation of CCL2 production in collagen-induced arthritis rat ST.
Materials and Methods
Total RNA was isolated from PB leukocytes and synovium of the knee joint in both RA patients and control populations. Real-time polymerase chain reaction was used to determine CCL4, CCR5, c-Jun, c-Fos, and CCL2 expressions. Serum level of CCL2 was assessed by enzyme-linked immunosorbent assay, and the production of CCL2 in ST was analyzed immunohistochemically.
The expressions of CCL4, CCR5, c-Jun, c-Fos, and CCL2 messenger RNA in RA patients were significantly higher than those in healthy controls, both in ST and on PB leukocyte. Serum CCL2 levels were elevated in RA patients. Histological examination of rheumatoid joints revealed extensive CCL2 expression in RA ST.
CCL2, CCL4, c-Jun, c-Fos, and CCR5 may play an important role in the recruitment of PB leukocytes into the RA joints. These data provide evidence that the chemokine signaling pathway is involved in CCL2 expression in RA patient tissues, which may contribute to chronic inflammation associated with RA. Targeting this signaling pathway may provide a novel therapeutic avenue in RA.
PMCID: PMC4479845  PMID: 26069140
CCL2; leukocytes; rheumatoid; arthritis; synovial membrane
6.  Benign Multiple Sclerosis is Associated with Reduced Thinning of the Retinal Nerve Fiber and Ganglion Cell Layers in Non-Optic-Neuritis Eyes 
Background and Purpose
It is exceedingly difficult to differentiate benign multiple sclerosis (BMS) from relapsing-remitting multiple sclerosis (RRMS) based on clinical characteristics, neuroimaging, and cerebrospinal fluid tests. Optical coherence tomography (OCT) allows quantification of retinal structures, such as the retinal nerve fiber layer (RNFL) thickness, at the optic disc and the ganglion cell layer (GCL) at the macula, on a micrometer scale. It can also be used to trace minor alterations and the progression of neurodegeneration, help predict BMS, and influence the choice of therapy. To utilize OCT to detect the extent of changes of the optic disk and macular microstructure in patients with BMS and RRMS compared to healthy controls (HCs), with special focus on changes related to the presence/absence of optic neuritis (ON).
Spectral-domain OCT was applied to examine eyes from 36 patients with multiple sclerosis (MS), comprising 11 with BMS and 25 with RRMS, and 34 HCs.
The RNFL and GCL were significantly thinner in eyes previously affected by ON, irrespective of the type of MS (i.e., BMS or RRMS), than in HCs. Significant thinning of the GCL was also observed in non-ON RRMS (and not non-ON BMS) compared to HCs. Correspondingly, a significant association between disease duration and thinning rates of the RNFL and GCL was observed only in non-ON RRMS (-0.54±0.24 and -0.43±0.21 µm/year, mean±SE; p<0.05 for both), and not in non-ON BMS (-0.11±0.27 and -0.24±0.24 µm/year).
The RNFL and GCL were thinner in both ON- and non-ON MS, but the change was more pronounced in ON MS, irrespective of the MS subtype studied herein. GCL thinning and the thinning rate of both the GCL and RNFL were less pronounced in non-ON BMS than in non-ON RRMS. These findings may help to predict the course of BMS.
PMCID: PMC4507378  PMID: 26022460
benign multiple sclerosis; optic neuritis; optical coherence tomography; retinal nerve fiber layer; macular ganglion cell layer
7.  Cancer risk among patients with type 2 diabetes mellitus: a population-based prospective study in China 
Scientific Reports  2015;5:11503.
Evidence indicates an increased cancer risk among type 2 diabetes mellitus (T2DM) patients, yet studies in mainland China are scarce. Based on Diabetes Surveillance System linking to Cancer Surveillance System of Zhejiang Province in China, we explored the cancer risk among T2DM patients. Totally, 327,268 T2DM patients were identified and followed from January 1, 2007 to December 31, 2013. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were reported. Overall cancer risk was found significantly increased with an SIR of 1.15 (95% CI 1.12–1.19) and 1.25 (95% CI 1.21–1.30) in males and females, respectively. Regarding specific cancer sites, risks of liver, colon, rectum, pancreas, and kidney were significantly increased with SIRs of 1.26 (95% CI 1.16–1.36), 1.47 (95% CI 1.29–1.67), 1.25 (95% CI 1.09–1.43), 2.81 (95% CI 2.50–3.16) and 1.61 (95% CI 1.28–2.03) in males, 1.53 (95% CI 1.35–1.73), 1.33 (95% CI 1.15–1.54), 1.29 (95% CI 1.10–1.51), 3.62 (95% CI 3.20–4.09) and 1.71 (95% CI 1.28–2.29) in females, respectively. A significant increased SIR was noted for prostate (1.80, 95% CI 1.58–2.06). Significant increased SIRs for lung (1.32, 95% CI 1.20–1.44) and stomach (1.16, 95% CI 1.03–1.30) were observed in females. We suggested an increased cancer risk among T2DM patients.
PMCID: PMC4469976  PMID: 26082067
8.  Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase 
Science translational medicine  2014;6(266):266ra170.
Doxorubicin is a highly effective anti-cancer chemotherapy agent, but its usage is limited by its cardiotoxicity. To develop a drug that prevents the cardiac toxicity of doxorubicin while preserving its anti-tumor potency, we established a doxorubicin-induced cardiomyopathy model in zebrafish that recapitulated the cardiomyocyte apoptosis and contractility decline observed in patients. Using this model, we screened 3000 compounds and discovered that visnagin (VIS) and diphenylurea (DPU) rescue cardiac performance and circulatory defects caused by doxorubicin treatment in zebrafish. VIS and DPU reduced doxorubicin-induced apoptosis in cultured cardiomyocytes and in vivo in zebrafish and mouse hearts. Furthermore, VIS treatment improved cardiac contractility in doxorubicin-treated mice. Importantly, VIS and DPU caused no reduction in the chemotherapeutic efficacy of doxorubicin in several cultured tumor lines or in zebrafish and mouse xenograft models. Using affinity chromatography, we discovered that VIS binds to mitochondrial malate dehydrogenase (MDH2), one of the key enzymes in the tricarboxylic acid cycle. As with VIS, treatment with the MDH2 inhibitors mebendazole, thyroxine, and iodine prevented doxorubicin cardiotoxicity, as did treatment with malate itself, suggesting that modulation of MDH2 activity is responsible for VIS’s cardioprotective effects. Taken together, this study identified VIS and DPU as potent cardioprotective compounds and implicates MDH2 as a previously undescribed, druggable target for doxorubicin-induced cardiomyopathy.
PMCID: PMC4360984  PMID: 25504881
9.  High-level expression, purification, and enzymatic characterization of truncated human plasminogen (Lys531-Asn791) in the methylotrophic yeast Pichia pastoris 
BMC Biotechnology  2015;15:50.
Plasmin is a serine protease that plays a critical role in fibrinolysis, which is a process that prevents blood clots from growing and becoming problematic. Recombinant human microplasminogen (rhμPlg) is a derivative of plasmin that solely consists of the catalytic domain of human plasmin and lacks the five kringle domains found in the native protein. Developing an industrial production method that provides high yields of this protein with high purity, quality, and potency is critical for preclinical research.
The human microplasminogen gene was cloned into the pPIC9K vector, and the recombinant plasmid was transformed into Pichia pastoris strain GS115. The concentration of plasmin reached 510.1 mg/L of culture medium. Under fermentation conditions, the yield of rhμPlg was 1.0 g/L. We purified rhμPlg to 96 % purity by gel-filtration and cation-exchange chromatography. The specific activity of rhμPlg reached 23.6 U/mg. The Km of substrate hydrolysis by recombinant human microplasmin was comparable to that of human plasmin, while rhμPlm had higher kcat/Km values than plasmin. The high purity and activity of the rhμPlg obtained here will likely prove to be a valuable tool for studies of its application in thrombotic diseases and vitreoretinopathies.
Reliable rhμPlg production (for use in therapeutic applications) is feasible using genetically modified P. pastoris as a host strain. The successful expression of rhμPlg in P. pastoris lays a solid foundation for its downstream application.
Electronic supplementary material
The online version of this article (doi:10.1186/s12896-015-0179-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4460660  PMID: 26054637
Truncated plasminogen; Plasmin; Pichia pastoris; Purification; rhμPlg
11.  Epidemiological characterization and prognostic factors in patients with confirmed cerebral cryptococcosis in central Taiwan 
Cryptococcal meningitis is a deadly fungal infection. This study aimed to characterize the epidemiology of cerebral cryptococcosis and to define its prognostic factors.
This cross-sectional study collected clinical information from cryptococcal meningitis patients with confirmed cerebral cryptococcosis from 2006 to 2012 at the Changhua Christian Healthcare System to access prognostic factors.
Fifty-nine adult cryptococcal meningitis patients were studied. The incidence at Changhua Christian Healthcare System was approximately 170 episodes per 100,000 patients within the studied period. Forty-one of 59 cryptococcal meningitis patients developed complications. Overall, 12 of 59 patients died, for a three-month mortality rate of 20.3 %. Prognostic factors positively associated with the three-month mortality included age (>55 years), patient delay, prolonged delay by the doctor in administering antifungal agent therapy, duration of intensive care unit stay, chronic lung disease, cryptococcemia, headache, altered mental status, positive blood cultures, and high cerebrospinal fluid opening pressure (≥250 mm H2O).
We strongly recommend early administration of an antifungal agent to each suspected cryptococcal meningitis patient to decrease both the delay by doctors in administering therapy and the mortality risk. Aggressive and supportive care for severe cryptococcal meningitis patients is critical to decrease overall mortality from this infection.
PMCID: PMC4487963  PMID: 26136773
Cryptococcus neoformans; Cryptococcus gattii Cryptococcosis; Meningitis; Outcome; Risk Assessment
12.  Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients 
Glutamate dehydrogenase (GDH) is a key enzyme that catalyzes the final reaction of the glutamine metabolic pathway, and has been reported implicated in tumor growth and metastasis. However, it’s clinical significance and role in colorectal cancer (CRC) pathogenesis is largely unknown.
The expression of GDH was determined by qPCR, western blot and immunohistochemistry in CRC cells and samples. The correlation of GDH expression with clinicopathologic features and prognosis was analyzed. The functional role of GDH in CRC cell proliferation, motility and metastasis was evaluated.
We found that GDH was up-regulated both in colorectal cancer and metastatic lesions (n = 104). Patients with high GDH expression had poorer overall survival (HR 2.32; 95% CI 1.26-4.26; P = 0.007) and poorer disease-free survival rates (HR 2.48; 95% CI 1.25-4.92; P = 0.009) than those with low GDH expression. Furthermore, we showed that GDH expression was an independent prognostic factor for CRC. In addition, over-expression of GDH promoted cell proliferation, migration and invasion in vitro, whereas loss function of GDH did the opposite. Finally, we demonstrated that the promotion of CRC progression by GDH correlated with activation of STAT3 mediated epithelial-mesenchymal transition (EMT) induction.
These results indicate that GDH plays a critical role in CRC progression, and may provide a novel metabolism therapeutic target for CRC treatment.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0500-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4490642  PMID: 25947346
Colorectal cancer; Prognosis; GDH; STAT3; EMT
13.  Use of Medications and Lifestyles of Hypertensive Patients with High Risk of Cardiovascular Disease in Rural China 
PLoS ONE  2015;10(5):e0124484.
Hypertension, with a global prevalence of 40%, is a risk factor for cardiovascular diseases (CVD). We conducted an exploratory study in Zhejiang China to understand the prevention of CVD among hypertensive patients with a 10 year CVD risk of 20% or higher. We assessed current practices in a rural ‘township hospital’ (a primary care facility), and compared them with international evidence-based practice.
A questionnaire survey was conducted to examine the use of modern drugs (antihypertensive drugs, statins and aspirin) and traditional drugs, compliance to medications and lifestyle among 274 hypertensive patients aged 40-74, with a CVD risk of 20% or higher (using the Asian Equation).
The majority (72%) were diagnosed with hypertension at township hospitals. Only 15% of study participants used two anti-hypertensive drugs, 0.7% took statin and 2.9% aspirin. Only 2.9% combined two types of modern drugs, while 0.4% combined three types (antihypertensives, statins and aspirin). Herbal compounds, sometimes with internationally rarely recommended drugs such as Reserpine were taken by 44%. Analysis of drug adherence showed that 9.8% had discontinued their drug therapy by themselves. 16% had missed doses and these were on less anti-hypertensive drugs than those who did not (t=-5.217, P=0.003). Of all participants, 28% currently smoked, 39% drank regularly and only 21% exercised frequently. The average salt intake per day was 7.1 (±3.8) g, while the national recommended level is 6g.
The study revealed outdated and inadequate treatment and health education for hypertensive patients, especially for those who have high risk scores for CVD. There is a need to review the community-based guidelines for hypertension management. Health providers and patients should make a transition from solely treating hypertension, towards prevention of CVD. Health system issues need addressing including improving rural health insurance cover and primary care doctors’ capacity to manage chronic disease patients.
PMCID: PMC4416726  PMID: 25932640
14.  Association between sugar-sweetened beverages and type 2 diabetes: A meta-analysis 
Many studies have been carried out to examine the association between sugar-sweetened beverages and the incident of type 2 diabetes, but results are mixed. The aim of the present study was to estimate the association between sugar-sweetened beverage intake and the risk of type 2 diabetes.
Materials and Methods
PubMed, Springer Link and Elsevier databases were searched up to July 2014. Prospective studies published on the association between sugar-sweetened beverage intake and the risk of type 2 diabetes were included. The pooled relative risks (RRs) and 95% confidence intervals (CIs) for highest versus lowest category of sugar-sweetened beverages were estimated using a random-effects model.
The pooled effect estimate of sugar-sweetened beverage intake was 1.30 (95% confidence interval [CI] 1.21–1.39) for type 2 diabetes; stratified by geographic region of the studies, the pooled effect estimates were 1.34 (95% CI 0.74–2.43), 1.30 (95% CI 1.20–1.40), 1.29 (95% CI 1.09–1.53) in Asia, the USA and Europe,respectively; the pooled effect estimates were 1.26 (95% CI 1.16–1.36) with adjusting body mass index and 1.38 (95% CI 1.23–1.56) without adjusting body mass index.
Our findings suggested that sugar-sweetened beverage intake was associated with an increased risk of type 2 diabetes, and the association was attenuated by adjustment for body mass index. Specifically, the associations were also found to be significantly positive in the USA and Europe.
PMCID: PMC4420570  PMID: 25969723
Meta-analysis; Sugar-sweetened beverages; Type 2 diabetes
15.  Primary mediastinal giant liposarcoma with smooth muscle and neural differentiation: A case report 
Oncology Letters  2015;9(6):2667-2669.
Liposarcoma has previously been described in Western studies, however, such cases are rarely reported in the mediastinum. In addition, the presence of a liposarcoma with smooth muscle and neural differentiation has not been previously reported. Thus, the present study describes the rare case of a 28-year-old Chinese male admitted to our hospital with the symptoms of chest tightness and shortness of breath due to a recurrent fibrolipoma in the mediastinum. The resected tumor measured 23 cm at its largest diameter, with histopathological and immunohistochemical features indicating a well-differentiated liposarcoma accompanied by smooth muscle and neural differentiation. Following the resection, the patient underwent radiation treatment and remains alive with no evidence of disease recurrence at two months post-surgery. To the best of our knowledge, the present study is the first to report a case of liposarcoma with smooth muscle and neural differentiation, which indicates that liposarcomas could potentially originate from stem cells. The present study highlights the fact that pathologists must carefully investigate the histopathological characteristics of liposarcomas in order to obtain an accurate diagnosis.
PMCID: PMC4473669  PMID: 26137125
liposarcoma; mediastinum; differentiation; smooth muscle; neural
16.  Advanced squamous lung carcinoma in a patient experiencing long-term survival following repeated responses to gemcitabine and cisplatin chemotherapy: A case report 
Oncology Letters  2015;9(6):2874-2878.
The cisplatin and gemcitabine regimen is one of the most effective regimens against advanced non-small-cell lung cancer. However, tumors that are initially sensitive to chemotherapy treatment may acquire drug resistance. Excision repair cross complementation 1 gene (ERCC1) is involved in the repair of DNA damage caused by cisplatin, and ribonucleotide reductase M1 subunit (RRM1) is associated with gemcitabine resistance in tumor cells. The current study reports the case of a patient with advanced squamous cell lung carcinoma exhibiting low ERCC1 and RRM1 expression levels, who experienced long-term survival following repeated responses to gemcitabine and cisplatin chemotherapy. This case indicates that selected patients may benefit from multiple courses of gemcitabine and cisplatin chemotherapy, and the sustained clinical benefits suggest that further investigation into individualized therapy is merited.
PMCID: PMC4473694  PMID: 26137163
non-small-cell lung cancer; squamous lung carcinoma; gemcitabine; cisplatin
17.  Differences in onset timing between the vastus medialis and lateralis during concentric knee contraction in individuals with genu varum or valgum 
Journal of Physical Therapy Science  2015;27(4):1207-1210.
[Purpose] The purpose of this study was to investigate the difference in onset timing between the vastus medialis and lateralis among the different knee alignments, as well as the best isokinetic angular velocity for an isokinetic concentric contraction. [Subjects] Fifty-two adults (20 with genu varum, 12 genu valgum, and 20 controls) were enrolled in this study. Subjects with > 4 cm between the medial epicondyles of the knee were placed in the genu varum group, whereas subjects with > 4 cm between the medial malleolus of the ankle were placed in the genu valgum group. [Methods] Surface electromyography was used to measure the onset times of the vastus medialis and vastus lateralis during concentric contractions at 30, 60, and 90°/sec. [Results] The vastus lateralis showed more delayed firing than the vastus medialis in the genu varum group, whereas vastus medialis firing was delayed more than that of the vastus lateralis in the genu valgum group. No differences in onset timing were observed between the vastus medialis and lateralis according the different angular velocities during concentric contractions in all three groups. [Conclusion] Genu varum and valgum affect quadriceps firing. Therefore, selective rehabilitation training of the quadriceps femoris should be considered to prevent pain or knee malalignment deformities.
PMCID: PMC4434011  PMID: 25995590
Quadriceps muscle; Genu varum; Genu valgum
18.  Polysaccharide Hydrogel Combined with Mesenchymal Stem Cells Promotes the Healing of Corneal Alkali Burn in Rats 
PLoS ONE  2015;10(3):e0119725.
Corneal chemical burns are common ophthalmic injuries that may result in permanent visual impairment. Although significant advances have been achieved on the treatment of such cases, the structural and functional restoration of a chemical burn-injured cornea remains challenging. The applications of polysaccharide hydrogel and subconjunctival injection of mesenchymal stem cells (MSCs) have been reported to promote the healing of corneal wounds. In this study, polysaccharide was extracted from Hardy Orchid and mesenchymal stem cells (MSCs) were derived from Sprague-Dawley rats. Supplementation of the polysaccharide significantly enhanced the migration rate of primarily cultured rat corneal epithelial cells. We examined the therapeutic effects of polysaccharide in conjunction with MSCs application on the healing of corneal alkali burns in rats. Compared with either treatment alone, the combination strategy resulted in significantly better recovery of corneal epithelium and reduction in inflammation, neovascularization and opacity of healed cornea. Polysaccharide and MSCs acted additively to increase the expression of anti-inflammatory cytokine (TGF-β), antiangiogenic cytokine (TSP-1) and decrease those promoting inflammation (TNF-α), chemotaxis (MIP-1α and MCP-1) and angiogenesis (VEGF and MMP-2). This study provided evidence that Hardy Orchid derived polysaccharide and MSCs are safe and effective treatments for corneal alkali burns and that their benefits are additive when used in combination. We concluded that combination therapy with polysaccharide and MSCs is a promising clinical treatment for corneal alkali burns and may be applicable for other types of corneal disorder.
PMCID: PMC4366244  PMID: 25789487
19.  Cyproheptadine, an antihistaminic drug, inhibits proliferation of hepatocellular carcinoma cells by blocking cell cycle progression through the activation of P38 MAP kinase 
BMC Cancer  2015;15:134.
Hepatocellular carcinoma (HCC) is a major cause of cancer deaths worldwide. However, current chemotherapeutic drugs for HCC are either poorly effective or expensive, and treatment with these drugs has not led to satisfactory outcomes. In a 2012 case report, we described our breakthrough finding in two advanced HCC patients, of whom one achieved complete remission of liver tumors and the other a normalized α-fetoprotein level, along with complete remission of their lung metastases, after the concomitant use of thalidomide and cyproheptadine. We assumed the key factor in our effective therapy to be cyproheptadine. In this study, we investigated the antiproliferative effects and molecular mechanisms of cyproheptadine.
The effect of cyproheptadine on cell proliferation was examined in human HCC cell lines HepG2 and Huh-7. Cell viability was assayed with Cell Counting Kit-8; cell cycle distribution was analyzed by flow cytometry. Mechanisms underlying cyproheptadine-induced cell cycle arrest were probed by western blot analysis.
Cyproheptadine had a potent inhibitory effect on the proliferation of HepG2 and Huh-7 cells but minimal toxicity in normal hepatocytes. Cyproheptadine induced cell cycle arrest in HepG2 cells in the G1 phase and in Huh-7 cells at the G1/S transition. The cyproheptadine-induced G1 arrest in HepG2 cells was associated with an increased expression of HBP1 and p16, whereas the G1/S arrest in Huh-7 cells was associated with an increase in p21 and p27 expression and a dramatic decrease in the phosphorylation of the retinoblastoma protein. Additionally, cyproheptadine elevated the percentage of Huh-7 cells in the sub-G1 population, increased annexin V staining for cell death, and raised the levels of PARP and its cleaved form, indicating induction of apoptosis. Finally, cyproheptadine-mediated cell cycle arrest was dependent upon the activation of p38 MAP kinase in HepG2 cells and the activation of both p38 MAP kinase and CHK2 in Huh-7 cells.
Our results demonstrate that a non-classical p38 MAP kinase function, regulation of cell cycle checkpoints, is one of the underlying mechanisms promoted by cyproheptadine to suppress the proliferation of HCC cells. These results provide evidence for the drug’s potential as a treatment option for liver cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1137-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4383201  PMID: 25886177
Hepatocellular carcinoma; Cyproheptadine; Cell cycle arrest; Apoptosis; p38 MAP kinase
20.  Deficiency of the Novel Exopolyphosphatase Rv1026/PPX2 Leads to Metabolic Downshift and Altered Cell Wall Permeability in Mycobacterium tuberculosis 
mBio  2015;6(2):e02428-14.
Mycobacterium tuberculosis can persist for decades in the human host. Stringent response pathways involving inorganic polyphosphate [poly(P)], which is synthesized and hydrolyzed by polyphosphate kinase (PPK) and exopolyphosphatase (PPX), respectively, are believed to play a key regulatory role in bacterial persistence. We show here that M. tuberculosis poly(P) accumulation is temporally linked to bacillary growth restriction. We also identify M. tuberculosis Rv1026 as a novel exopolyphosphatase with hydrolytic activity against long-chain poly(P). Using a tetracycline-inducible expression system to knock down expression of Rv1026 (ppx2), we found that M. tuberculosis poly(P) accumulation leads to slowed growth and reduced susceptibility to isoniazid, increased resistance to heat and acid pH, and enhanced intracellular survival during macrophage infection. By transmission electron microscopy, the ppx2 knockdown strain exhibited increased cell wall thickness, which was associated with reduced cell wall permeability to hydrophilic drugs rather than induction of drug efflux pumps or altered biofilm formation relative to the empty vector control. Transcriptomic and metabolomic analysis revealed a metabolic downshift of the ppx2 knockdown characterized by reduced transcription and translation and a downshift of glycerol-3-phosphate levels. In summary, poly(P) plays an important role in M. tuberculosis growth restriction and metabolic downshift and contributes to antibiotic tolerance through altered cell wall permeability.
The stringent response, involving the regulatory molecules inorganic polyphosphate [poly(P)] and (p)ppGpp, is believed to mediate Mycobacterium tuberculosis persistence. In this study, we identified a novel enzyme (Rv1026, PPX2) responsible for hydrolyzing long-chain poly(P). A genetically engineered M. tuberculosis strain deficient in the ppx2 gene showed increased poly(P) levels, which were associated with early bacterial growth arrest and reduced susceptibility to the first-line drug isoniazid, as well as increased bacterial survival during exposure to stress conditions and within macrophages. Relative to the control strain, the mutant showed increased thickness of the cell wall and reduced drug permeability. Global gene expression and metabolite analysis revealed reduced expression of the transcriptional and translational machinery and a shift in carbon source utilization. In summary, regulation of the poly(P) balance is critical for persister formation in M. tuberculosis.
PMCID: PMC4453511  PMID: 25784702
21.  Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility 
Science (New York, N.Y.)  2014;345(6193):216-220.
Circulating tumor cells (CTCs) are present at low concentrations in the peripheral blood of patients with solid tumors. It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations. In a proof-of-concept study, we established CTC cultures from six patients with estrogen receptor–positive breast cancer. Three of five CTC lines tested were tumorigenic in mice. Genome sequencing of the CTC lines revealed preexisting mutations in the PIK3CA gene and newly acquired mutations in the estrogen receptor gene (ESR1), PIK3CA gene, and fibroblast growth factor receptor gene (FGFR2), among others. Drug sensitivity testing of CTC lines with multiple mutations revealed potential new therapeutic targets. With optimization of CTC culture conditions, this strategy may help identify the best therapies for individual cancer patients over the course of their disease.
PMCID: PMC4358808  PMID: 25013076
22.  Specifically targeted delivery of protein to phagocytic macrophages 
Macrophages play important roles in the pathogenesis of various diseases, and are important potential therapeutic targets. Furthermore, macrophages are key antigen-presenting cells and important in vaccine design. In this study, we report on the novel formulation (bovine serum albumin [BSA]-loaded glucan particles [GMP-BSA]) based on β-glucan particles from cell walls of baker’s yeast for the targeted delivery of protein to macrophages. Using this formulation, chitosan, tripolyphosphate, and alginate were used to fabricate colloidal particles with the model protein BSA via electrostatic interactions, which were caged and incorporated BSA very tightly within the β-glucan particle shells. The prepared GMP-BSA exhibited good protein-release behavior and avoided protein leakage. The particles were also highly specific to phagocytic macrophages, such as Raw 264.7 cells, primary bone marrow-derived macrophages, and peritoneal exudate macrophages, whereas the particles were not taken up by nonphagocytic cells, including NIH3T3, AD293, HeLa, and Caco-2. We hypothesize that these tightly encapsulated protein-loaded glucan particles deliver various types of proteins to macrophages with notably high selectivity, and may have broad applications in targeted drug delivery or vaccine design against macrophages.
PMCID: PMC4356666  PMID: 25784802
macrophage; targeted drug delivery; vaccine; glucan particle; yeast-cell wall
23.  Metabolic Phenotypes in Pancreatic Cancer 
PLoS ONE  2015;10(2):e0115153.
The aim of present study was to profile the glucose-dependent and glutamine- dependent metabolism in pancreatic cancer.
We performed Immunohistochemical staining of GLUT1, CAIX, BNIP3, p62, LC3, GLUD1, and GOT1. Based on the expression of metabolism-related proteins, the metabolic phenotypes of tumors were classified into two categories, including glucose- and glutamine-dependent metabolism. There were Warburg type, reverse Warburg type, mixed type, and null type in glucose-dependent metabolism, and canonical type, non-canonical type, mixed type, null type in glutamine-dependent metabolism.
Longer overall survival was associated with high expression of BNIP3 in tumor (p = 0.010). Shorter overall survival was associated with high expression of GLUT1 in tumor (P = 0.002) and GOT1 in tumor (p = 0.030). Warburg type of glucose-dependent metabolism had a highest percentage of tumors with nerve infiltration (P = 0.0003), UICC stage (P = 0.0004), and activated autophagic status in tumor (P = 0.0167). Mixed type of glucose-dependent metabolism comprised the highest percentage of tumors with positive marginal status (P<0.0001), lymphatic invasion (P<0.0001), and activated autophagic status in stroma (P = 0.0002). Mixed type and Warburg type had a significant association with shorter overall survival (P = 0.018). Non-canonical type and mixed type of glutamine-dependent metabolism comprised the highest percentage of tumors with vascular invasion (p = 0.0073), highest percentage of activated autophagy in tumors (P = 0.0034). Moreover, these two types of glutamine-dependent metabolism were significantly associated with shorter overall survival (P<0.001). Further analysis suggested that most of tumors were dependent on both glucose- and glutamine-dependent metabolism. After dividing the tumors according to the number of metabolism, we found that the increasing numbers of metabolism subtypes inversely associated with survival outcome.
Warburg type, non-canonical type and mixed types of glucose- and glutamine-dependent metabolism comprised of more metabolically active, biologically aggressive and poor prognostic tumors. Moreover, the increasing subtypes and categories of the metabolism in each tumor significantly associated with poor prognosis.
PMCID: PMC4342019  PMID: 25719198
24.  Dose-response models for selected respiratory infectious agents: Bordetella pertussis, group a Streptococcus, rhinovirus and respiratory syncytial virus 
Dose-response assessment is one step in quantitative microbial risk assessment (QMRA). Four infectious microbes capable of causing respiratory diseases important to public health, and for which dose-response functions have not been available are: Bordetella pertussis (whooping cough), group A Streptococcus (pharyngitis), rhinovirus (common cold) and respiratory syncytial virus (common cold). The objective of this study was to fit dose-response functions for these microbes to published experimental data.
Experimental infectivity data in human subjects and/or animal models were identified from the peer-reviewed literature. The exponential and beta-Poisson dose-response functions were fitted using the method of maximum likelihood, and models compared by Akaike’s Information Criterion.
Dose-response functions were identified for each appropriate data set for the four infectious microbes. Statistical and graphical measures of fit are presented.
With the fitted dose-response functions it will be possible to perform QMRA for these microbes. The dose-response functions, however, have a number of limitations associated with the route of exposure, use of animal hosts, and quality of fit. As a result, thoughtfulness must be used in selecting one dose-response function for a QMRA, and the function should be recognized as a significant source of uncertainty. Nonetheless, QMRA offers a transparent, systematic framework within which to understand the mechanisms of disease transmission, and evaluate interventions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0832-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4345006  PMID: 25880210
Risk assessment; Dose-response; Respiratory infections; Pharyngitis; Common cold
25.  Manifestations of Perihepatic Lymph Nodes in Acute Flare of Chronic Hepatitis B: Association with HBeAg Status and with HBeAg Seroconversion 
PLoS ONE  2015;10(2):e0117590.
It has been observed that enlargement of perihepatic lymph nodes may be seen in patients with chronic hepatitis B, particularly during acute flares of CHB. We hypothesized that there may be a correlation between the nodal change patterns in CHB patients with acute flare and HBeAg status. Perihepatic lymph node sizes of 87 patients with acute flares of CHB were documented, with a median follow up of 43 months. Patients were separated into 3 groups, HBeAg-positive with HBe seroconversion (group 1), HBeAg-positive without HBe seroconversion (group 2), and HBeAg-negative (group 3). Group 1 has the highest incidence of enlarged lymph nodes (92.3%) compared with group 2 (75.8%) and group 3 (46.8%) (p = 0.003). And if nodal width at acute flare was > 8mm and interval change of nodal width was >3mm, the incidence of HBeAg seroconversion will be 75% (p<0.001).
Larger perihepatic lymph nodes are seen in CHB acute flare patients with positive HBeAg and the magnitude of nodal width change may predict HBeAg seroconversion at recovery.
PMCID: PMC4331514  PMID: 25689069

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