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1.  Ingredients of Huangqi decoction slow biliary fibrosis progression by inhibiting the activation of the transforming growth factor-beta signaling pathway 
Huangqi decoction was first described in Prescriptions of the Bureau of Taiping People's Welfare Pharmacy in Song Dynasty (AD 1078), and it is an effective recipe that is usually used to treat consumptive disease, anorexia, and chronic liver diseases. Transforming growth factor beta 1 (TGFβ1) plays a key role in the progression of liver fibrosis, and Huangqi decoction and its ingredients (IHQD) markedly ameliorated hepatic fibrotic lesions induced by ligation of the common bile duct (BDL). However, the mechanism of IHQD on hepatic fibrotic lesions is not yet clear. The purpose of the present study is to elucidate the roles of TGFβ1 activation, Smad-signaling pathway, and extracellular signal-regulated kinase (ERK) in the pathogenesis of biliary fibrosis progression and the antifibrotic mechanism of IHQD.
A liver fibrosis model was induced by ligation of the common bile duct (BDL) in rats. Sham-operation was performed in control rats. The BDL rats were randomly divided into two groups: the BDL group and the IHQD group. IHQD was administrated intragastrically for 4 weeks. At the end of the fifth week after BDL, animals were sacrificed for sampling of blood serum and liver tissue. The effect of IHQD on the TGFβ1 signaling pathway was evaluated by western blotting and laser confocal microscopy.
Decreased content of hepatic hydroxyproline and improved liver function and histopathology were observed in IHQD rats. Hepatocytes, cholangiocytes, and myofibroblasts in the cholestatic liver injury released TGFβ1, and activated TGFβ1 receptors can accelerate liver fibrosis. IHQD markedly inhibited the protein expression of TGFβ1, TGFβ1 receptors, Smad3, and p-ERK1/2 expression with no change of Smad7 expression.
IHQD exert significant therapeutic effects on BDL-induced fibrosis in rats through inhibition of the activation of TGFβ1-Smad3 and TGFβ1-ERK1/2 signaling pathways.
PMCID: PMC3419610  PMID: 22471627
Ingredients of Huangqi decoction; Cholestatic liver fibrosis; Transforming growth factor beta 1; Smad-signaling pathway, Extracellular signal-regulated kinase
2.  Preventive effects of 1,25-(OH)2VD3 against ConA-induced mouse hepatitis through promoting vitamin D receptor gene expression 
Acta Pharmacologica Sinica  2010;31(6):703-708.
To investigate the immunosuppressive effects of 1,25-dihydroxyvitamin D3 (1,25-(OH)2VD3) on concanavalin A (ConA)-induced hepatitis and elucidate the action mechanism.
Female BALB/C mice were intravenously administered ConA (20 mg/kg) to induce acute immunological liver injury. Liver damage was evaluated in respect to serum alanine transaminase (ALT) level and liver histological changes. The proliferation of splenocytes was measured by using [3H]-thymidine incorporation. The cytokine level in the cultured splenocyte supernatant was determined by using enzyme-linked immunosorbent assays (ELISAs). The percentage of different splenic T cell subtypes was analyzed by using flow cytometry. The expression of splenic vitamin D receptor (VDR) mRNA and protein was detected by using real-time qRT-PCR and Western blot, respectively.
1,25-(OH)2VD3 (2.5 μg/kg, ip) significantly decreased the serum ALT levels and markedly attenuated the histological liver damage. The beneficial effect of 1,25-(OH)2VD3 was associated with: (i) inhibition of CD4+ T cell activation; (ii) reduction of interferon-γ (IFN-γ) and elevation of both IL-4 and IL-5 in supernatants of cultured splenocytes; and (iii) elimination of activated T cells by increasing VDR mRNA and protein expression in the spleen.
1,25-(OH)2VD3 had a significant protective effect against ConA-induced hepatitis, and its mechanism of action was associated with down-regulation of T cell-mediated immunity and up-regulation of VDR gene expression.
PMCID: PMC4002975  PMID: 20523341
1,25-dihydroxyvitamin D3; concanavalin A; hepatitis; vitamin D receptor; interferon-γ; interleukin 4; interleukin 5
3.  Effects of Garlic Oil on the Migration of Neutrophil-Like Cell Studied by Using a Chemotactic Gradient Labchip 
We have designed and fabricated a novel chemotactic gradient Labchip for studying cell migration quantitatively. Owing to the great potential of garlic and its preparations in developing antiinflammatory drugs, the aim of the present study is to investigate the effect of garlic oil on the locomotion of a neutrophil-like cell by measuring the dynamic features of cell migration including migration direction, average migration speed, chemotactic index (CI), and motility index (MI) with the newly designed Labchip. We found that garlic oil treatment lowered the values of CI and MI and reduced the average speed of cell migration from 13 to 8 μm/min. The results indicate that garlic oil is a potential inhibitor for neutrophil-like cell migration and chemotactic responsiveness. By comparing with the effects of nocodazole and cytochalasin B, we also suggest that the antiinflammatory activity exhibited by garlic oil was mainly through inhibiting the assembly-disassembly processes of the cytoskeleton.
PMCID: PMC2862952  PMID: 20454631
4.  Multicenter clinical study on Fuzhenghuayu capsule against liver fibrosis due to chronic hepatitis B 
AIM: To study the efficacy and safety of Fuzhenghuayu capsule (FZHY capsule, a capsule for strengthening body resistance to remove blood stasis) against liver fibrosis due to chronic hepatitis B.
METHODS: Multicenter, randomized, double blinded and parallel control experiment was conducted in patients (aged from 18 to 65 years) with liver fibrosis due to chronic hepatitis B. Hepatic histologic changes and HBV markers were examined at wk 0 and 24 during treatment. Serologic parameters (HA, LM, P-III-P, IV-C) were determined and B ultrasound examination of the spleen and liver was performed at wk 0, 12 and 24. Liver function (liver function and serologic parameters for liver fibrosis) was observed at wk 0, 6, 12, 18 and 24. Blood and urine routine test, renal function and ECG were examined before and after treatment.
RESULTS: There was no significant difference between experimental group (110 cases) and control group (106 cases) in demographic features, vital signs, course of illness, history for drug anaphylaxis and previous therapy, liver function, serologic parameters for liver fibrosis, liver histologic examination (99 cases in experimental group, 96 cases in control group), HBV markers, and renal function. According to the criteria for liver fibrosis staging, mean score of fibrotic stage(s) in experimental group after treatment (1.80) decreased significantly compared to the previous treatment (2.33, P<0.05), but there was no significant difference in mean score of fibrotic stage(s) (2.11 and 2.14 respectively). There was a significant difference in reverse rate between experimental group (52%) and control group (23.3%) in liver biopsy. With marked effect on decreasing the mean value of inflammatory activity and score of inflammation (P<0.05), Fuzhenghuayu capsule had rather good effects on inhibiting inflammatory activity and was superior to that of Heluoshugan capsule. Compared to that of pretreatment, there was a significant decrease in HA, LM, P-III-P and IV-C content in experimental group after 12 and 24 wk of treatment. The difference in HA, LM, P-III-P and IV-C content between 12 and 24 wk of treatment and pretreatment in experimental group was significantly greater than that in control group (P<0.01-0.05). The effect, defined as two of four parameters lowering more than 30% of the baseline, was 72.7% in experimental group and 27.4% in control group (P<0.01). Obvious improvement in serum Alb, ALT, AST and GGT was seen in two groups. Compared to that of control group, marked improvement in GGT and Alb was seen in experimental group (P<0.05). The effective rate of improvement in serum ALT was 72.7% in experimental group and 59.4% in control group. No significant difference was seen in blood and urine routine and ECG before and after treatment. There was also no significant difference in stable rate in ALT and serologic parameters for liver fibrosis between experimental group and control group after 12 wk of withdrawal.
CONCLUSION: Fuzhenghuayu capsule has good therapeutic effects on alleviating liver fibrosis due to chronic hepatitis B without any adverse effect and is superior to that of Heluoshugan capsule.
PMCID: PMC4305655  PMID: 15902724
Chronic hepatitis B; Fuzhenghuayu capsule
5.  Epidemiological profile of Dupuytren’s disease in Taiwan (Ethnic Chinese): a nationwide population-based study 
The epidemiologic profile of ethnic Chinese patients with Dupuytren’s disease is unknown. We therefore investigated the epidemiology of Dupuytren’s disease using Taiwan’s National Health Insurance Research Database.
Patients who filed claims for treatment for Dupuytren’s disease between January 2000 and December 2011 were identified in the database. Age- and gender-specific incidences were estimated by dividing the incidence number by population data.
We identified 1,078 patients with Dupuytren’s disease (681 men, 397 women; male/female ratio: 1:1.72). The annual incidence rate ranged from 0.39-0.63/105 for men and 0.14-0.44/105 for women. A trend analysis revealed a rising trend in the annual incidence from 2001 to 2011 (p = 0.0199). The prevalence rate increased steadily from 0.46/105 in 2000 to 4.52/105 in 2011 (p = 0.0186). The mean age at onset was significantly higher in men than in women (60.7 ± 18.4 vs. 53.7 ± 15.5 years). Peak age at onset for men was 70–79 (28.1%) and for women was 50–59 (33.5%). Men > 60 years old had higher incidence rates than did women (incidence rate ratios: 2.0, 4.5, and 6.6 for those 60–69, 70–79, and ≥ 80, respectively). Hypertension (29.6%), diabetes mellitus (21.9%), hyperlipidemia (14.8%), ischemic heart disease (10.5%), and chronic obstructive pulmonary disease (8.0%) were the most common comorbidities.
The incidence and prevalence of Dupuytren’s disease and the male/female ratio were significantly lower in ethnic Chinese than in Western ethnic groups. Moreover, the age at onset was significantly lower in ethnic Chinese women. However, the incidences of three comorbidities (hypertension, diabetes mellitus, and hyperlipidemia) were similar to those in other ethnicities.
Electronic supplementary material
The online version of this article (doi:10.1186/s12891-015-0476-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4324654
Dupuytren’s disease; Epidemiology; Ethnic; Chinese
6.  Gastric De Novo Muc13 Expression and Spasmolytic Polypeptide-Expressing Metaplasia during Helicobacter heilmannii Infection 
Infection and Immunity  2014;82(8):3227-3239.
Helicobacter heilmannii is a zoonotic bacterium that has been associated with gastric disease in humans. In this study, the mRNA expression of mucins in the stomach of BALB/c mice was analyzed at several time points during a 1-year infection with this bacterium, during which gastric disease progressed in severity. Markers for acid production by parietal cells and mucous metaplasia were also examined. In the first 9 weeks postinfection, the mRNA expression of Muc6 was clearly upregulated in both the antrum and fundus of the stomach of H. heilmannii-infected mice. Interestingly, Muc13 was upregulated already at 1 day postinfection in the fundus of the stomach. Its expression level remained high in the stomach over the course of the infection. This mucin is, however, not expressed in a healthy stomach, and high expression of this mucin has so far only been described in gastric cancer. In the later stages of infection, mRNA expression of H+/K+-ATPase α/β and KCNQ1 decreased, whereas the expression of Muc4, Tff2, Dmbt1, and polymeric immunoglobulin receptor (pIgR) increased starting at 16 weeks postinfection onwards, suggesting the existence of spasmolytic polypeptide-expressing metaplasia in the fundus of the stomach. Mucous metaplasia present in the mucosa surrounding low-grade mucosa-associated lymphoid tissue (MALT) lymphoma-like lesions was also histologically confirmed. Our findings indicate that H. heilmannii infection causes severe gastric pathologies and alterations in the expression pattern of gastric mucins, such as Muc6 and Muc13, as well as disrupting gastric homeostasis by inducing the loss of parietal cells, resulting in the development of mucous metaplasia.
PMCID: PMC4136228  PMID: 24866791
7.  Body Mass Index and Risk of Breast Cancer: A Nonlinear Dose-Response Meta-Analysis of Prospective Studies 
Scientific Reports  2014;4:7480.
The role of Body Mass Index (BMI) for Breast Cancer (BC) remains to be great interest for a long time. However, the precise effect of nonlinear dose-response for BMI and BC risk is still unclear. We conducted a dose-response meta-analysis to quantitatively assess the effect of BMI on BC risk. Twelve prospective studies with 4,699 cases identified among 426,199 participants and 25 studies of 22,809 cases identified among 1,155,110 participants in premenopausal and postmenopausal groups, respectively, were included in this meta-analysis. Significant non-linear dose-response (P < 0.001) association was identified between BMI and BC risk in postmenopausal women. Individuals with BMI of 25, 30, and 35 kg/m2 yielded relative risks (RRs) of 1.02 [95% confidence interval (CI): 0.98–1.06], 1.12 (95% CI: 1.01–1.24), and 1.26 (95% CI: 1.07–1.50), respectively, when compared to the mean level of the normal BMI range. However, inverse result though not significant was observed in premenopausal women. In conclusion, the results of this meta-analysis highlighted that obesity contributed to increased BC risk in a nonlinear dose-response manner in postmenopausal women, and it is important to realize that body weight control may be a crucial process to reduce BC susceptibility.
PMCID: PMC4265780  PMID: 25504309
8.  HSPD1 Interacts with IRF3 to Facilitate Interferon-Beta Induction 
PLoS ONE  2014;9(12):e114874.
The production of IFN- I (IFN-α/β) is one of the earliest and most important host-protective responses. Interferon regulatory factor 3 (IRF3) is a critical transcriptional factor in the IFN-β signaling pathway. Although significant progress has been achieved in the regulation of IRF3, the process may be more complicated than previously considered. In the present study, heat shock protein 60 (HSP60, HSPD1) was identified as a novel IRF3-interacting protein. Overexpression of HSPD1 facilitated the phosphorylation and dimerization of IRF3 and enhanced IFN-β induction induced by SeV infection. In contrast, knockdown of endogenous HSPD1 significantly inhibited the signaling pathway. Furthermore, HSPD1 enhanced activation of the IFN-β promoter mediated by RIG-I, MDA-5, MAVS, TBK1 and IKKε but not IRF3/5D, a mock phosphorylated form of IRF3. The present study indicated that HSPD1 interacted with IRF3 and it contributed to the induction of IFN-β.
PMCID: PMC4266637  PMID: 25506707
9.  Neurotropin Suppresses Inflammatory Cytokine Expression and Cell Death through Suppression of NF-κB and JNK in Hepatocytes 
PLoS ONE  2014;9(12):e114071.
Inflammatory response and cell death in hepatocytes are hallmarks of chronic liver disease, and, therefore, can be effective therapeutic targets. Neurotropin® (NTP) is a drug widely used in Japan and China to treat chronic pain. Although NTP has been demonstrated to suppress chronic pain through the descending pain inhibitory system, the action mechanism of NTP remains elusive. We hypothesize that NTP functions to suppress inflammatory pathways, thereby attenuating disease progression. In the present study, we investigated whether NTP suppresses inflammatory signaling and cell death pathways induced by interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) in hepatocytes. NTP suppressed nuclear factor-κB (NF-κB) activation induced by IL-1β and TNFα assessed by using hepatocytes isolated from NF-κB-green fluorescent protein (GFP) reporter mice and an NF-κB-luciferase reporter system. The expression of NF-κB target genes, Il6, Nos2, Cxcl1, ccl5 and Cxcl2 induced by IL-1β and TNFα was suppressed after NTP treatment. We also found that NTP suppressed the JNK phosphorylation induced by IL-1β and TNFα. Because JNK activation contributes to hepatocyte death, we determined that NTP treatment suppressed hepatocyte death induced by IL-1β and TNFα in combination with actinomycin D. Taken together, our data demonstrate that NTP attenuates IL-1β and TNFα-mediated inflammatory cytokine expression and cell death in hepatocytes through the suppression of NF-κB and JNK. The results from the present study suggest that NTP may become a preventive or therapeutic strategy for alcoholic and non-alcoholic fatty liver disease in which NF-κB and JNK are thought to take part.
PMCID: PMC4254918  PMID: 25470242
10.  Comparative Transcriptome Analysis to Reveal Genes Involved in Wheat Hybrid Necrosis 
Wheat hybrid necrosis is an interesting genetic phenomenon that is found frequently and results in gradual death or loss of productivity of wheat. However, the molecular basis and mechanisms of this genetic phenomenon are still not well understood. In this study, the transcriptomes of wheat hybrid necrosis F1 and its parents (Neimai 8 and II469) were investigated using digital gene expression (DGE). A total of 1300 differentially expressed genes were identified, indicating that the response to hybrid necrosis in wheat is complicated. The assignments of the annotated genes based on Gene Ontology (GO) revealed that most of the up-regulated genes belong to “universal stress related”, “DNA/RNA binding”, “protein degradation” functional groups, while the down-regulated genes belong to “carbohydrate metabolism” and “translation regulation” functional groups. These findings suggest that these pathways were affected by hybrid necrosis. Our results provide preliminarily new insight into the underlying molecular mechanisms of hybrid necrosis and will help to identify important candidate genes involved in wheat hybrid necrosis.
PMCID: PMC4284769  PMID: 25522166
Triticumaestivum; hybrid necrosis; digital gene expression; transcriptome
11.  Emerging role of HMGB1 in fibrotic diseases 
High-mobility group box 1 (HMGB1) is originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be passively released from necrotic cells or actively secreted into the extracellular milieu under appropriate signal stimulation. Extracellular HMGB1 is a multifunctional cytokine that contributes to the process of infection, injury, inflammation, apoptosis, and immune responses by binding to specific cell-surface receptors. Recently, emerging studies indicate that HMGB1 is closely involved in fibrotic disorders including cystic fibrosis, liver fibrosis and pulmonary fibrosis, while HMGB1 signal inhibitions protect against the experimental models of fibrotic diseases. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses. This review focuses on the crucial role of HMGB1 in the pathogenesis of fibrotic diseases and inhibition of which may represent a promising clinical approach for treating tissue fibrosis.
PMCID: PMC4302638  PMID: 25284457
high-mobility group box 1; cystic fibrosis; liver fibrosis; renal fibrosis; pulmonary fibrosis; myocardial fibrosis
12.  Increased expression of melanoma stem cell marker CD271 in metastatic melanoma to the brain 
Human melanoma contains multipotent stem cells that express the neural crest stem cell marker CD271. CD271-expressing melanoma cells in murine xenografts give rise to metastatic tumor. However, a comprehensive clinical investigation of its role in different stages of melanomagenesis has not been well studied. We studied CD271 expression with immunohistochemistry in 11 cases of banal melanocytic nevus, 9 cases of primary cutaneous melanoma, 10 cases of primary mucosal melanoma, 5 cases of metastatic melanoma in regional lymph nodes, and 11 cases of metastatic melanoma in the brain. In addition, 9 cases of metastatic, high-grade adenocarcinomas from breast and lung to the brain were studied as controls. The staining was scored based on the number of positive cells and analyzed by student t-test. All banal melanocytic nevi showed negative to equivocal staining. Primary cutaneous melanomas showed variable patterns, mucosal melanomas were mostly negative, and metastases to lymph nodes ranged from negative to moderate positivity. In contrast, all 11 cases of metastatic melanoma to the brain showed moderate (4 cases) to strong positivity (7 cases). Metastases from lung and breast origin were used as controls and showed negative to weakly positive staining in all but one case. Statistically, CD271 has significantly increased expression in metastatic melanoma to the brain when compared to the other groups studied (P < 0.05). The findings suggest that CD271 expression is specifically increased in metastatic melanoma to the brain. Further prospective study for the role of CD271 in prediction of melanoma brain metastasis as well as prognosis assessment will be of great clinical significance.
PMCID: PMC4313973
Melanoma; metastatic melanoma; CD271; tumor stem cells; melanoma prognosis
13.  Inhibition of itch-related responses by selectively ablated serotonergic signals at the rostral ventromedial medulla in mice 
Descending control of nociceptive processing in the rostral ventromedial medulla (RVM) has been implicated in the inhibition and facilitation of spinal nociceptive transmission. Here we investigated the contribution of serotonergic (5-HT) pathway at the RVM to pruritic behavior. Selective lesion of the descending serotonergic pathway by intra-RVM injection of focal neurotoxin 5,7-dihydroxytryptamine (2 μg/0.5 μl) attenuated pruritic behavior at the 30-min observation period following an intradermal microinjection of compound 48/80 (100 μg/100 μl) in the nape of the neck. Intradermal microinjection of compound 48/80 resulted in a dramatic increase in itch behavior between naive group and saline group. 5,7-DHT-treated mice showed profound scratching deficits after intradermal injection of compound 48/80. 5,7-DHT treatment resulted in a significant decrease in the number of 5-HT positive neurons in the RVM by using intracisternal injection of the serotonin neurotoxin 5,7-DHT. These findings demonstrate that pruritic behavior is dependent in part on descending facilitation via the RVM, and identify a modulatory role of serotonergic pathway at the RVM for pruritic behavior.
PMCID: PMC4314012
Itch; serotonergic signals; the rostral ventromedial medulla
14.  TERT promoter mutations are associated with distant metastases in upper tract urothelial carcinomas and serve as urinary biomarkers detected by a sensitive castPCR 
Oncotarget  2014;5(23):12428-12439.
TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies.
PMCID: PMC4322995  PMID: 25474136
Cancer biomarkers; Promoter mutations; Telomerase; TERT; UTUC
15.  A minimally invasive posterior lumbar interbody fusion using percutaneous long arm pedicle screw system for degenerative lumbar disease 
The aim of this study is to evaluate the therapeutic efficacy of patients with lumbar degeneration and instability treated with percutaneous pedicle screw fixation and minimally invasive lumbar interbody fusion. Twenty-one patients were selected in our hospital from November, 2012 to March, 2013. The patients with an average age 55.62 years, including 8 vertebral spondylolisthesis, 4 lumbar intervertebral disc herniation, and 9 lumbar spinal canal stenosis cases. All the patients were managed to take the lumbar MRI and radiographs. The comparison of preoperative and postoperative (3 days, 2 weeks, 3 months) VAS and ODI score were analyzed. The results indicated that VAS scores were 7.14 ± 0.79 before operation, and 5.19 ± 0.81 in 3 days after operation, 4 ± 0.84 after 2 weeks, and 2.67 ± 0.66 after 3 months. The pain was relieved, and the postoperative VAS score was lower than that before treatment (P < 0.05). ODI score was 55.8 ± 11.4 before operation, 47.38 ± 9.38 after 3 days, 41.38 ± 8.09 after 2 weeks, 35.76 ± 4.50 after 3 months. ODI score was obviously decreased (P < 0.05). In conclusion, percutaneous pedicle screw fixation combined with minimally invasive interbody fusion is a safe, effective, feasible minimally invasive spine operation, with worthy for spreading.
PMCID: PMC4276162  PMID: 25550904
Percutaneous pedicle screw fixation; minimally invasive; lumbar degeneration
16.  A Functional p53 Responsive Polymorphism in KITLG, rs4590952, Does not Affect the Risk of Breast Cancer 
Scientific Reports  2014;4:6371.
Recently, a functional polymorphism in KITLG, rs4590952, was identified to be associated with testicular cancer susceptibility through increasing the p53-dependent KITLG expression and disrupting the function of p53. We performed a hospital-based case-control study, including 1241 breast cancer (BC) patients and 1259 cancer-free controls, to investigate the role of this polymorphism in the risk of BC in Chinese Han population. However, no significant association between rs4590952 and BC risk was identified in allelic model with the odds ratio (OR) of 1.04 (95% confidence interval (CI) = 0.73–1.46, P = 0.839) or in any other genetic models. When performed stratified analysis according to the Estrogen Receptor (ER) and Progesterone Receptor (PR) status, rs4590952 was neither associated with ER+/PR+ nor ER−PR− subgroups. Our results suggested that rs4590952 was not associated with the risk of BC in Chinese population, implying that heterogeneous distinct mechanisms might exist in the etiology of different cancers.
PMCID: PMC4163669  PMID: 25220285
17.  Multi-Slice Computed Tomography 5-Minute Delayed Scan is Superior to Immediate Scan after Contrast Media Application in Characterization of Intracranial Tuberculosis 
The aim of this study was to determine whether the diagnosis of intracranial tuberculosis (TB) can be improved when multi-slice computed tomography (MSCT) scans are taken with a 5-min delay after contrast media application.
Pre- and post-contrast CT scans of the head were obtained from 30 patients using a 16-slice spiral CT. Dual-phase acquisition was performed immediately and 5 min after contrast agent injection. Diagnostic values of different images were compared using a scoring system applied by 2 experienced radiologists.
We found 526 lesions in 30 patients, including 22 meningeal thickenings, 235 meningeal tuberculomas/tubercles, and 269 parenchymal tuberculomas/tubercles. Images obtained with 5-min delayed scan time were superior in terms of lesion size and meningeal thickening outlining in all disease types (P<0.01). The ability to distinguish between vascular sections from the cerebral sulcus and tubercle was also improved (P<0.01).
Image acquisition with 5-min delay after contrast agent injection should be performed as a standard scanning protocol to diagnose intracranial TB.
PMCID: PMC4160133  PMID: 25183433
Medicare Part C; Tomography; Spiral Computed; Tuberculosis; Central Nervous System
18.  Androgen-producing steroid cell ovarian tumor in a young woman and subsequent spontaneous pregnancy 
To describe the presentation and fertility sparing treatment of a young woman found to have a steroid cell tumor not otherwise specified (NOS) and her spontaneous pregnancy and delivery shortly after surgery.
A 20-year-old Hispanic female presented with hirsuitism, virilization, and elevated androgen levels (testosterone 328 ng/dL) and was wrongly diagnosed with polycystic ovarian syndrome. Four months later she sought a second opinion. Her androgens were as follows: testosterone level 485 ng/dL, androstenedione 1,738 ng/dL and DHEA 1,459 ng/dL. She had normal levels of progesterone, estradiol, and DHEA-SO4. On transvaginal ultrasound she had a solid-appearing right ovarian mass. She underwent fertility sparing surgery with a laparoscopic right oophorectomy.
Gross and histological pathology confirmed a benign steroid cell tumor NOS. She had rapid normalization of all androgens 13 days after surgery. She had spontaneous resumption of menses 4 months later. She conceived despite using emergency contraception approximately 9 months following surgery and delivered a healthy boy at term without complication.
Prompt evaluation for an androgen producing tumor should be performed when testosterone levels are greater than 200 ng/dL. Pregnancy following removal of this rare tumor has not previously been reported.
PMCID: PMC3800527  PMID: 23868533
Virilization; Steroid cell tumor not otherwise specified; Pregnancy; Androgen tumor; Elevated testosterone; Fertility preservation
19.  Edited Magnetic Resonance Spectroscopy Detects an Age-related Decline in Brain GABA Levels 
NeuroImage  2013;78:75-82.
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. Although measurements of GABA levels in vivo in the human brain using edited proton magnetic resonance spectroscopy (1H-MRS) have been established for some time, it is has not been established how regional GABA levels vary with age in the normal human brain. In this study, 49 healthy men and 51 healthy women aged between 20 and 76 years were recruited and J-difference edited spectra were recorded at 3 Tesla to determine the effect of age on GABA levels, and to investigate whether there are regional and gender differences in GABA in mesial frontal and parietal regions.
Because the signal detected at 3.02 ppm using these experimental parameters is also expected to contain contributions from both macromolecules (MM) and homocarnosine, in this study the signal is labeled GABA+ rather than GABA. Significant negative correlations were observed between age and GABA+ in both regions studied (GABA+/Cr: frontal region, r = -0.68, p< 0.001, parietal region, r = -0.54, p< 0.001; GABA+/NAA: frontal region, r = -0.58, p< 0.001, parietal region, r = -0.49, p< 0.001). The decrease in GABA+ with age in the frontal region was more rapid in women than men. Evidence of a measureable decline in GABA is important in considering the neurochemical basis of the cognitive decline that is associated with normal aging.
PMCID: PMC3716005  PMID: 23587685
Proton MRS; GABA; Normal brain; Aging
20.  Selective Ablation of Tumor-Associated Macrophages (TAMs) Suppresses Metastasis and Angiogenesis 
Cancer science  2013;104(9):1217-1225.
Tumor-associated macrophages (TAMs) play a critical role in promoting tumor development and metastasis. In this study, we found that legumain, an asparaginyl endopeptidase, was highly expressed on the surface of TAMs. A doxorubicin-based prodrug specifically activated by legumain selectively ablated TAMs and resulted in a significant reduction of angiogenic factors and related tumor vessel growth. Treatment with the prodrug also suppressed circulating tumor cells and myeloid immune suppressor Gr-1+ /CD11b+ cells in tumor-bearing animals. After selective ablation of TAMs by the prodrug, the tumor growth and metastases were greatly inhibited in murine tumor models. These results indicate that legumain-activated prodrugs targeting TAMs in tumors may represent a novel anti-cancer strategy.
PMCID: PMC3766435  PMID: 23691974
tumor-associated macrophage; legumain; prodrug; angiogenesis; metastasis
21.  Induction of Caspase-3-like activity in Rice following release of cytochrome-f from the chloroplast and subsequent interaction with the Ubiquitin-Proteasome System 
Scientific Reports  2014;4:5989.
It has been known that the process of leaf senescence is accompanied by programmed cell death (PCD), and the previous study indicated that dark-induced senescence in detached leaves from rice led to the release of cytochrome f (Cyt f) from chloroplast into the cytoplasm. In this study, the effects of Cyt f on PCD were studied both in vitro and in vivo. In a cell-free system, purified Cyt f activated caspase-3-like protease and endonuclease OsNuc37, and induced DNA fragmentation. Furthermore, Cyt f-induced caspase-3-like activity could be inhibited by MG132, which suggests that the activity was attributed to the 26S proteasome. Conditional expression of Cyt f in the cytoplasm could also activate caspase-3-like activity and DNA fragmentation. Fluorescein diacetate staining and annexin V-FITC/PI double staining demonstrated that Cyt f expression in cytoplasm significantly increased the percentage of PCD protoplasts. Yeast two-hybrid screening showed that Cyt f might interact with E3-ubiquitin ligase and RPN9b, the subunits of the ubiquitin proteasome system (UPS), and other PCD-related proteins. Taken together, these results suggest that the released Cyt f from the chloroplast into the cytoplasm might activate or rescue caspase-3-like activity by interacting with the UPS, ultimately leading to the induction of PCD.
PMCID: PMC4125987  PMID: 25103621
22.  Association of the ST3GAL4 rs11220462 polymorphism and serum lipid levels in the Mulao and Han populations 
A previous genome-wide association study has displayed the association of the ST3 beta-galactoside alpha-2,3-sialytransferase 4 (ST3GAL4) gene variant and lipid traits in the individuals of European ancestry, but the reproducibility of this association has not been detected in the Chinese population. The present study was undertaken to detect the association of ST3GAL4 rs11220462 single nucleotide polymorphism (SNP) and several environmental factors with serum lipid profiles in the Mulao and Han populations.
A total of 700 unrelated individuals of Mulao nationality and 694 subjects of Han nationality were randomly selected from our previous stratified randomized samples. Genotypes of the SNP were determined via polymerase chain reaction and restriction fragment length polymorphism in combination with gel electrophoresis, and then verified by direct sequencing.
Serum apolipoprotein (Apo) B levels were higher and the ApoAI/ApoB ratio was lower in Mulao than in Han (P < 0.05-0.01). There were no significant differences in the genotypic and allelic frequencies of the ST3GAL4 rs11220462 SNP between the two ethnic groups or between males and females. The A allele carriers in both Mulao males and females had higher total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and ApoB levels than the A allele non-carriers (P < 0.05-0.01). The subjects with AA genotype in Han males but not in females had higher TC and triglyceride (TG) levels than the subjects with AG or GG genotype (P < 0.01 for each). Multiple linear regression analyses showed that the levels of TC, LDL-C and ApoB in Mulao females; TC and LDL-C in Mulao males; and TC in Han males were correlated with the genotypes (P < 0.05-0.001). Serum lipid parameters were also associated with several environmental factors in both ethnic groups (P < 0.05 -0.001).
The association of ST3GAL4 rs11220462 SNP and serum lipid levels was different between the Mulao and Han populations, suggesting that there may be a racial/ethnic-specific association, and/or sex-specific association between the ST3GAL4 rs11220462 SNP and serum lipid parameters in some ethnic groups.
PMCID: PMC4237880  PMID: 25086711
Lipids; ST3 beta-galactoside alpha-2,3-sialytransferase 4; Single nucleotide polymorphism; Environmental factors
23.  PAX1/SOX1 DNA methylation and cervical neoplasia detection: a Taiwanese Gynecologic Oncology Group (TGOG) study 
Cancer Medicine  2014;3(4):1062-1074.
We aimed to determine whether PAX1/SOX1 methylation could be translated to clinical practice for cervical neoplasia detection when used alone and in combination with current cytology-based Pap screening. We conducted a multicenter case–control study in 11 medical centers in Taiwan from December 2009 to November 2010. Six hundred seventy-six patients were included in the analysis, including 330 in the training set and 346 in the testing set. Multiplex quantitative methylation-specific polymerase chain reaction (PCR) was performed with a TaqMan probe system using a LightCycler 480 Real-Time PCR System (Roche). The level of human papilloma virus (HPV) was analyzed using a Hybrid Capture 2 system (Digene). Receiver operating characteristic curves were generated to obtain the best cutoff values from the training data set. The sensitivities, specificities, and accuracies were validated in the testing set. The sensitivities for methylated (m) PAX1m and SOX1m and HPV testing for detecting CIN3+ lesions were 0.64, 0.71, and 0.89, and the specificities were 0.91, 0.77, and 0.68, respectively. Combined parallel testing of PAX1m/SOX1m tests with Pap smearing showed superior specificity (0.84/0.71 vs. 0.66, respectively) and similar sensitivity (0.93/0.96 vs. 0.97) to the combination of Pap smear results and HPV testing. Thus, combined parallel testing using Pap smears and PAX1 or SOX1 methylation tests may provide better performance than a combination of Pap smears with HPV testing in detection for cervical neoplasia.
PMCID: PMC4303175  PMID: 24799352
Cervical cancer screening; DNA methylation; PAX1; SOX1
24.  Late Eocene to early Oligocene quantitative paleotemperature record: Evidence from continental halite fluid inclusions 
Scientific Reports  2014;4:5776.
Climate changes within Cenozoic extreme climate events such as the Paleocene–Eocene Thermal Maximum and the First Oligocene Glacial provide good opportunities to estimate the global climate trends in our present and future life. However, quantitative paleotemperatures data for Cenozoic climatic reconstruction are still lacking, hindering a better understanding of the past and future climate conditions. In this contribution, quantitative paleotemperatures were determined by fluid inclusion homogenization temperature (Th) data from continental halite of the first member of the Shahejie Formation (SF1; probably late Eocene to early Oligocene) in Bohai Bay Basin, North China. The primary textures of the SF1 halite typified by cumulate and chevron halite suggest halite deposited in a shallow saline water and halite Th can serve as an temperature proxy. In total, one-hundred-twenty-one Th data from primary and single-phase aqueous fluid inclusions with different depths were acquired by the cooling nucleation method. The results show that all Th range from 17.7°C to 50.7°C,with the maximum homogenization temperatures (ThMAX) of 50.5°C at the depth of 3028.04 m and 50.7°C at 3188.61 m, respectively. Both the ThMAX presented here are significantly higher than the highest temperature recorded in this region since 1954and agree with global temperature models for the year 2100 predicted by the Intergovernmental Panel on Climate Change.
PMCID: PMC4105707  PMID: 25047483
25.  Increased Risk of Cerebrovascular Events in Patients with Cancer Treated with Bevacizumab: A Meta-Analysis 
PLoS ONE  2014;9(7):e102484.
Arterial ischemia and hemorrhage are associated with bevacizumab, an inhibitor of vascular endothelial growth factor that is widely used to treat many types of cancers. As specific types of arterial ischemia and hemorrhage, cerebrovascular events such as central nervous system (CNS) ischemic events and CNS hemorrhage are serious adverse events. However, increased cerebrovascular events have not been uniformly reported by previous studies. New randomized controlled trials (RCTs) have been reported in recent years and we therefore conducted an up-to-date meta-analysis of RCTs to fully characterize the risk of cerebrovascular events with bevacizumab. We searched the databases of PubMed, Web of Science, and the American Society of Clinical Oncology conferences to identify relevant clinical trials up to February 2014. Eligible studies included prospective RCTs that directly compared patients with cancer treated with and without bevacizumab. A total of 12,917 patients from 17 RCTs were included in our analysis. Patients treated with bevacizumab had a significantly increased risk of cerebrovascular events compared with patients treated with control medication, with a relative risk of 3.28 (95% CI, 1.97–5.48). The risks of CNS ischemic events and CNS hemorrhage were increased compared with control, with RRs of 3.22 (95% CI, 1.71–6.07) and 3.09 (95% CI, 1.36–6.99), respectively. Risk varied with the bevacizumab dose, with RRs of 3.97 (95% CI, 2.15–7.36) and 1.96 (95% CI, 0.76–5.06) at 5 and 2.5 mg/kg/week, respectively. Higher risks were observed in patients with metastatic colorectal cancer (RR, 6.42; 95% CI, 1.76–35.57), and no significant risk was observed in other types of tumors. In conclusion, the addition of bevacizumab significantly increased the risk of cerebrovascular events compared with controls, including CNS ischemic events and CNS hemorrhage. The risk may vary with bevacizumab dose and tumor type.
PMCID: PMC4099178  PMID: 25025282

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