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1.  Atomically thin resonant tunnel diodes built from synthetic van der Waals heterostructures 
Nature Communications  2015;6:7311.
Vertical integration of two-dimensional van der Waals materials is predicted to lead to novel electronic and optical properties not found in the constituent layers. Here, we present the direct synthesis of two unique, atomically thin, multi-junction heterostructures by combining graphene with the monolayer transition-metal dichalcogenides: molybdenum disulfide (MoS2), molybdenum diselenide (MoSe2) and tungsten diselenide (WSe2). The realization of MoS2–WSe2–graphene and WSe2–MoS2–graphene heterostructures leads to resonant tunnelling in an atomically thin stack with spectrally narrow, room temperature negative differential resistance characteristics.
The family of two-dimensional materials is ever growing, but greater functionality can be realized by combining them together. Here, the authors report the direct synthesis of multijunction heterostructures made from graphene, tungsten diselenide and either molybdenum disulphide or molybdenum diselenide.
PMCID: PMC4557306  PMID: 26088295
2.  DEAH (Asp-Glu-Ala-His) box helicase 15 senses double-stranded RNA in myeloid dendritic cells 
Many members of the DEXD/H-box helicase family play important roles in the innate immune system against viral infection. We, therefore, isolated double-stranded RNA (dsRNA) complex in myeloid dendritic cells (mDCs). We found that DHX15, a DEXDc helicase family member, is one of the components of this complex. Knockdown of DHX15 expression by short hairpin RNA efficiently reduced the ability of mDCs to produce interferon beta (IFN-β), IL-6 and TNF-α in response to dsRNA and RNA virus. DHX15 specifically bound poly I:C via its HELICc domain. DHX15 interacted with MAVS and formed a complex following stimulation with poly I:C. The N-terminal domain containing a DEXDc motif in DHX15 bound the C-terminus of MAVS. DHX15 is required to activate IRF3 phosphorylation, as well as NF-κB and MAPK signaling during RNA virus infection. We, therefore, identified DHX15 as a new RNA virus sensor mediated by MAVS to activate the immune responses to RNA.
PMCID: PMC4108507  PMID: 24990078
Dendritic cells; Cytokine Receptors; Signal transduction; Innate immunity; RNA virus
3.  Immobilization of collagen peptide on dialdehyde bacterial cellulose nanofibers via covalent bonds for tissue engineering and regeneration 
Bacterial cellulose (BC) is an alternative nanostructured biomaterial to be utilized for a wide range of biomedical applications. Because of its low bioactivity, which restricted its practical application, collagen and collagen hydrolysate were usually composited into BC. It is necessary to develop a new method to generate covalent bonds between collagen and cellulose to improve the immobilization of collagen on BC. This study describes a facile dialdehyde BC/collagen peptide nanocomposite. BC was oxidized into dialdehyde bacterial cellulose (DBC) by regioselective oxidation, and then composited with collagen peptide (Col-p) via covalent bonds to form Schiff’s base type compounds, which was demonstrated by the results of microstructures, contact angle, Col-p content, and peptide-binding ratio. The peptide-binding ratio was further affected by the degree of oxidation, pH value, and zeta potential. In vitro desorption measurement of Col-p suggested a controlled release mechanism of the nanocomposite. Cell tests indicated that the prepared DBC/Col-p composite was bioactive and suitable for cell adhesion and attachment. This work demonstrates that the DBC/Col-p composite is a promising material for tissue engineering and regeneration.
PMCID: PMC4516256
bacterial cellulose; dialdehyde cellulose; collagen peptide; composite materials; cytoactivity
4.  Lack of Association between the TSPAN18 Gene and Schizophrenia Based on New Data from Han Chinese and a Meta-Analysis 
Tetraspanin-18 (TSPAN18) potentially plays a role in the calcium signaling that is associated with dopamine-induced cortical neuron apoptosis and is considered to be an important mechanism in the pathogenesis of schizophrenia (SCZ). Furthermore, a genome-wide association study (GWAS) identified TSPAN18 as a possible susceptibility gene for SCZ. To validate these findings and reveal the effects of different inheritance models, seven single nucleotide polymorphisms (SNPs) of the TSPAN18 gene were analyzed in 443 patients with SCZ and 628 controls of Han Chinese descent via the SNPscan method. Single SNP, genotype, and association analyses with different models (i.e., additive, dominant, and recessive models) were performed, and the published datasets (2062 cases and 2053 controls) were combined with our results to determine the inheritance effects of the SNPs on SCZ. We observed genotypes and allele distributions of TSPAN18 gene did not show any significant associations in the Han Chinese population based on our experimental and meta-analytical results. Our findings indicate that the TSPAN18 gene is unlikely to be a major susceptibility gene for schizophrenia in Han Chinese.
PMCID: PMC4490419  PMID: 26016498
TSPAN18 gene; single nucleotide polymorphisms; schizophrenia; association; meta
5.  Hepatoid adenocarcinoma of the stomach is a special and easily misdiagnosed or missed diagnosed subtype of gastric cancer with poor prognosis but curative for patients of pN0/1: the experience of a single center 
Aim: To document the clinicopathological characteristics and analyze the possible reasons for misdiagnosis or missed diagnosis of hepatoid adenocarcinoma of the stomach (HAS), using data from a single center. Methods: We retrospectively analyzed 19 patients initially diagnosed as HAS and 7 patients initially diagnosed as common gastric cancer with high levels of serum α-fetoprotein (AFP). All had undergone surgical treatment, except 3 patients only had biopsies at our hospital. Immunohistochemistry for AFP and Hepatocyte antigen was performed. Final diagnosis for these 26 patients were made after HE and immunohistochemistry slides reviewed by 2 experienced pathologists. Prognostic factors were determined by univariate analysis. Results: Nineteen cases were confirmed to be HAS. A total of 4 out of 19 cases initially diagnosed as HAS and 4 out of 7 cases initially diagnosed as common gastric adenocarcinoma were misdiagnosed/missed diagnosed, thus, the misdiagnosis/missed diagnosis rate was 30.8% (8/26). The incidence of HAS among gastric cancer in our center was 0.19% (19/9915). Sixteen (84.2%) patients showed T stages greater than T2, 12 (70.6%) patients had positive lymph nodes in 17 available patients and 3 (15.8%) of the patients with tumors presented liver metastasis at the time of diagnosis. Histologically, cytoplasmic staining types included 10 cases of eosinophilic, 1 case of clear, 5 cases of clear mixed with eosinophilic and 3 cases of basophilic. Fourteen (73.7%) patients expressed AFP, whereas only 6 (31.6%) were hepatocyte-positive. Univariate analysis showed that N stage (HR 2.429, P=0.007) and tumor AFP expression (HR 0.428, P=0.036) were significantly associated with disease-free survival. The median overall survival time was 12.0 months, and the median disease-free survival time was 7.0 months. Four (80%) of 5 N0 patients and 2 (50%) of 4 N1 patients survived without progression, but no N2-3 patients survived. Conclusion: HAS remains easily being misdiagnosed/missed diagnosed based on a pathological examination, probably because the condition is rare and has various cytoplasmic types. Although the survival rate for HAS is poor, a curative effect may be achieved for N0 or N1 cases.
PMCID: PMC4509159  PMID: 26221214
Stomach; hepatoid adenocarcinoma; α-fetoprotein (AFP); diagnosis; survival
6.  Superoxide Mediates Depressive Effects Induced by Hydrogen Sulfide in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats 
Hydrogen sulfide (H2S) plays a crucial role in the regulation of blood pressure and oxidative stress. In the present study, we tested the hypothesis that H2S exerts its cardiovascular effects by reducing oxidative stress via inhibition of NADPH oxidase activity in the rostral ventrolateral medulla (RVLM). We examined cell distributions of cystathionine-β-synthase (CBS) and effects of H2S on reactive oxygen species (ROS) and mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHRs). We found that CBS was expressed in neurons of the RVLM, and the expression was lower in SHRs than in Wistar-Kyoto rats. Microinjection of NaHS (H2S donor), S-adenosyl-l-methionine (SAM, a CBS agonist), or Apocynin (NADPH oxidase inhibitor) into the RVLM reduced the ROS level, NADPH oxidase activity, and MAP, whereas microinjection of hydroxylamine hydrochloride (HA, a CBS inhibitor) increased MAP. Furthermore, intracerebroventricular infusion of NaHS inhibited phosphorylation of p47phox, a key step of NADPH oxidase activation. Since decreasing ROS level in the RVLM reduces MAP and heart rate and increasing H2S reduces ROS production, we conclude that H2S exerts an antihypertensive effect via suppressing ROS production. H2S, as an antioxidant, may be a potential target for cardiovascular diseases.
PMCID: PMC4442288  PMID: 26078823
7.  Colorectal carcinomas with KRAS codon 12 mutation are associated with more advanced tumor stages 
BMC Cancer  2015;15:340.
KRAS mutation occurs in 35%-40% of colorectal cancer (CRC). The aim of our study was to evaluate the pathological and molecular features of specific KRAS mutated colorectal carcinomas. KRAS and BRAFV600E mutation tests were performed in 762 primary tumors from a consecutive cohort study of Chinese CRC patients.
DNA mismatch repair (MMR) status was determined by immunohistochemistry (IHC) staining. Assessment of KRAS and BRAF V600E mutational status was performed using a multiplex allele-specific PCR-based assay.
Mutations of KRAS (34.8%) and BRAFV600E (3.1%) were nearly mutually exclusive. Both KRAS- and BRAF- mutated tumors were more likely to be located at proximal colon than wild-type (WT) carcinomas. KRAS-mutated carcinomas were more frequently observed in female patients (47.5% vs 37.1%, p = 0.005) and mucinous differentiation (34.7% vs 24.8%, p = 0.004), but have no difference between lymph node (LN) metastases and among pTNM stages. Whereas, BRAF-mutated carcinomas more frequently demonstrated histologic features such as proximal location (60.9% vs 20.9%, p = 0.001), low-grade histology (43.5% vs 18.0%, p = 0.005), mucinous differentiation (69.6% vs 25.9%, p = 0.001) and deficient MMR (dMMR) (21.7% vs 7.6%, p = 0.03). In particular, KRAS codon 12 mutated carcinomas had increased lymph node metastasis (odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.04 to 1.65; P = 0.02) and were more likely in higher disease stage (III-IV) than that of WT carcinomas (OR = 1.30; 95% CI = 1.03 to 1.64; P = 0.03). However, there were no significant differences in lymph node metastasis and disease stage between KRAS codon 13 mutated carcinoma and WT carcinoma patients.
In summary, KRAS codon 12 mutation, but not codon 13 mutation, is associated with lymph node metastasis and higher tumor stages.
PMCID: PMC4423107  PMID: 25929517
KRAS mutation; BRAF mutation; Colorectal cancer; Codon 12 and 13; DNA mismatch repair
8.  Postoperative Capecitabine with Concurrent Intensity-Modulated Radiotherapy or Three-Dimensional Conformal Radiotherapy for Patients with Stage II and III Rectal Cancer 
PLoS ONE  2015;10(4):e0124601.
The aim of this study was to evaluate the survival outcomes and toxicity of postoperative chemoradiotherapy with capecitabine and concurrent intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) in patients with stage II and III rectal cancer.
We recruited 184 patients with pathologically proven, stage II or III rectal cancer. Following total mesorectal excision (TME), the patients were treated with capecitabine and concurrent IMRT/3D-CRT. The treatment regimen consisted of two cycles of oral capecitabine (1600 mg/m2/day), administered twice daily from day 1–14 of radiotherapy, followed by a 7-day rest. The median pelvic dose was 50 Gy in 25 fractions. Oxaliplatin-based adjuvant chemotherapy was administered after the chemoradiotherapy.
The 5-year overall survival, disease-free survival and locoregional control (LRC) rates were 85.1%, 80% and 95.4%, respectively. Grade 3 and 4 toxicities were observed in 28.3% of patients during treatment. Grade 3 or 4 late toxicity, including neurotoxicity or gastrointestinal toxicity, was only observed in nine patients (4.9%).
This study demonstrated that capecitabine chemotherapy with concurrent IMRT/3D-CRT following TME is safe, is well tolerated and achieves superior LRC and favorable survival rates, with acceptable toxicity.
PMCID: PMC4411062  PMID: 25915948
9.  Physical activity as a protective factor against depressive symptoms in older Chinese veterans in the community: result from a national cross-sectional study 
Physical activity is generally considered to be effective in reducing the prevalence of depression and promoting remission of its symptoms. However, large-scale epidemiological research on this issue is lacking in older Chinese adults. We performed a nationwide epidemiological survey to determine the relationship between physical activity and depressive symptoms in older Chinese veterans in the community, with adjustment for potential confounders.
A cross-sectional study was conducted in a representative sample of 9,676 community-dwelling older Chinese veterans. Depressive symptoms were identified using the Center for Epidemiological Studies Depression Scale. Physical activity was self-reported using a one-year physical activity questionnaire. Information about covariates was obtained by questionnaire-based interview. Relationships between study variables and symptoms of depression were estimated using unadjusted and adjusted analyses.
The median age was 82.29 (interquartile range 80.25–84.60) years. In total, 81.84% of the study participants engaged in physical activity that was predominantly light in intensity. In unadjusted analyses, physical activity was associated with a significantly decreased likelihood of depressive symptoms (5.43% versus 18.83%, P<0.0001). Multivariate logistic regression with adjustment and controlling for confounders, physical activity was still inversely associated with depressive symptoms and was the only independent protective factor (odds ratio 0.57, 95% confidence interval 0.44–0.72, P<0.0001) among the associated factors in this study. In a univariate general linear model, there was a significant difference in Center for Epidemiological Studies Depression Scale score between subjects participating in active physical activity and those who did not (F=59.07, P<0.0001).
This study found an inverse relationship between physical activity and symptoms of depression in older Chinese veterans in the community. It was also indicated that the antidepressant effect of physical activity probably extended to the oldest-old, and the light-intensity physical activity was probably available for the same protective effect. This information could be used to devise further interventions to prevent or ameliorate symptoms of depression.
PMCID: PMC4376303  PMID: 25848278
physical activity; depression; protective factor; older adults; Chinese veteran
10.  Cattle encephalon glycoside and ignotin injection improves cognitive impairment in APPswe/PS1dE9 mice used as multitarget anti-Alzheimer’s drug candidates 
Cattle encephalon glycoside and ignotin injection (CEGI), a multitargeted neurotrophic drug, has been widely used in the treatment of central and peripheral nerve injuries, such as stroke, hypoxic ischemic encephalopathy, and diabetic neuropathy in the People’s Republic of China. However, data regarding the effect of CEGI on Alzheimer’s disease (AD) remain scarce. The present study aimed to investigate the effect of CEGI on learning and memory in an APPswe/PS1dE9 double-transgenic mouse model, a suitable animal model of AD, and elucidate its possible mechanisms.
Materials and methods
Five-month-old APP/PS1 mice were intraperitoneally administered 6.6 mL/kg or 13.2 mL/kg of CEGI for 1 month. After 1 month of administration, all mice received Morris water maze training and a probe test. Mouse brain sections were detected by standard biochemical and immunohistochemical measures.
CEGI treatment significantly improved the spatial learning and memory deficits and decreased cerebral amyloid-β42 levels in brain homogenates of APP/PS1 mice. CEGI treatment elevated the activities of superoxide dismutase, and reduced the levels of malondialdehyde. CEGI attenuated neuronal damage in the hippocampus of APP/PS1 mice and upregulated protein and gene expression of Bcl-2 and the ratio of Bcl-2/Bax. CEGI treatment decreased the number of Iba1+ activated microglia in the cortex of the APP/PS1 mice.
Our results showed that CEGI prevents memory impairment, possibly by decreasing the amyloid-β42 levels in APP/PS1 mice and inhibiting oxidative stress, apoptosis, and inflammation, making CEGI a promising therapeutic agent for AD.
PMCID: PMC4356454  PMID: 25784809
Alzheimer’s disease; cognitive impairment; amyloid-β; oxidative stress; apoptosis; inflammation
11.  The interaction between the helicase DHX33 and IPS-1 as a novel pathway to sense double-stranded RNA and RNA viruses in myeloid dendritic cells 
In eukaryotes, there are at least 60 members of the DExD/H helicase family, many of which are able to sense viral nucleic acids. By screening all known family members, we identified the helicase DHX33 as a novel double-stranded RNA (dsRNA) sensor in myeloid dendritic cells (mDCs). The knockdown of DHX33 using small heteroduplex RNA (shRNA) blocked the ability of mDCs to produce type I interferon (IFN) in response to poly I:C and reovirus. The HELICc domain of DHX33 was shown to bind poly I:C. The interaction between DHX33 and IPS-1 is mediated by the HELICc region of DHX33 and the C-terminal domain of IPS-1 (also referred to MAVS and VISA). The inhibition of DHX33 expression by RNA interference blocked the poly I:C-induced activation of MAP kinases, NF-κB and IRF3. The interaction between the helicase DHX33 and IPS-1 was independent of RIG-I/MDA5 and may be a novel pathway for sensing poly I:C and RNA viruses in mDCs.
PMCID: PMC4002151  PMID: 24037184
DHX33; helicase; innate immunity; IPS-1; myeloid dendritic cell; viral nucleic acid
12.  Typical or atypical progressive supranuclear palsy: a comparative clinicopathologic study of three Chinese cases 
Progressive supranuclear palsy (PSP) is an atypical parkinsonism, which is the third most common geriatric neurodegenerative disease. We reported three pathology-confirmed Chinese PSP cases with special focus on the pathological accumulations of tau, a-synuclein and A-beta in the three PSP brains. Cases 1 and 2 initiated with extrapyramidal signs and gait disorders, while case 3 suffered behavioral abnormalities with cognitive decline at the beginning. In neuropathology, PSP-changes such as tau-positive tufed astrocytes, oligdendrocytes with the tau-positive coiled-body and threads and globose NFTs were widely seen in the basal ganglia, isocortex and allocortex, as well as in brainstem, cerebellum and spinal cord. In addition, numerous AGs were found in the hippocampus of cases 1 & 2, while Aβ amyloid depositions were found in hippocampus and leptomeningeal vessels of case 1 and in neocortex, entorhinal cortex, hippocampus, cingulate gyrus and amygdale of case 3. Vessel infarcts were observed in cases 1. Cortical laminar III necrosis in case 1 suggested the ischemic damage. Cervical spinal cords in cases 2 & 3 were obtained with tau-positive globose NFTs, tufted astrocytes and neuropil threads were respectively found in the neurons of anterior horn and surrounding white matters. In summary, pathological examination is crucial for the ambiguous cases to exclude other neurodegenerative diseases. Furthermore, cervical spinal cord should be routinely examined in the PSP autopsy.
PMCID: PMC4348809  PMID: 25755788
Progressive supranuclear palsy; autopsy; pathology; Alzheimer’s disease
13.  A Low Lymphocyte-to-Monocyte Ratio Predicts Unfavorable Prognosis in Pathological T3N0 Rectal Cancer Patients Following Total Mesorectal Excision 
Journal of Cancer  2015;6(7):616-622.
Neoadjuvant radio-chemotherapy followed by total mesorectal excision (TME) is the standard treatment option for stage II and III rectal cancer. However, for pT3N0 rectal cancer patients who receive upfront TME, the lack of an efficient method to predict their prognosis hampers postoperative treatment. A low lymphocyte-to-monocyte ratio (LMR) is associated with an unfavorable prognosis for certain malignancies; however, this association has not been investigated in rectal cancer. The purpose of this study was to evaluate whether LMR can predict the prognosis of pT3N0 rectal cancer patients following TME. Rectal cancer patients who received radical TME without preoperative treatment between June 2004 and Nov. 2011 at the Sun Yat-sen University Cancer Center were retrospectively reviewed. Counts for pre-surgery peripheral absolute lymphocytes and monocytes were obtained and used to calculate the LMR. A retrospective cohort of 280 pT3N0 rectal cancer patients who received TME was recruited. Significantly worse disease-free survival can be observed in patients with lower LMR levels (<3.78) using univariate and multivariate analyses (P=0.01 and P=0.015, respectively). Subgroup analysis in patients with elevated carcinoembryonic antigen (CEA) and LMR <3.78 exhibited an accumulated 5-year disease failure rate of approximately 40%, whereas patients with normal CEA regardless of LMR and patients with LMR ≥3.78 exhibited accumulated 5-year disease failure rates of only approximately 15%. Low pre-surgery peripheral LMR was significantly unfavorable for pT3N0 rectal cancer patient prognosis, especially in patients with elevated CEA. This easily obtained variable might serve as a valuable marker to predict the outcomes of pT3N0 rectal cancer and indicate appropriate postoperative management.
PMCID: PMC4466410  PMID: 26078791
Rectal cancer; Pathological T3N0; Lymphocyte-to-monocyte ratio; Total mesorectal excision
14.  Elevated LRP6 levels correlate with vascular endothelial growth factor in the vitreous of proliferative diabetic retinopathy 
Molecular Vision  2015;21:665-672.
To measure intravitreal low-density lipoprotein receptor-related protein 6 (LRP6) and vascular endothelial growth factor (VEGF) levels in the eyes of patients with proliferative diabetic retinopathy (PDR) and to observe their correlation with PDR activity.
Fifty-five eyes of 55 patients were enrolled consecutively. Vitreous samples from 30 eyes with PDR and 25 eyes with nondiabetic macular disease were collected. Active PDR was present in 16 patients and quiescent PDR in 14 patients according to retinal neovascularization. LRP6 and VEGF concentrations in samples were determined using enzyme-linked immunosorbent assay (ELISA).
ELISA revealed significant increases in the vitreous levels of VEGF in eyes affected with PDR compared to the controls (p<0.001). The mean concentrations of LRP6 were also higher in the vitreous samples from patients with PDR compared to the nondiabetic controls: 39.85 ng/ml and 15.48 ng/ml, respectively (p=0.002). In addition, the vitreous levels of LRP6 and VEGF were significantly higher in active PDR than in quiescent PDR (p=0.022 and p=0.015, respectively). Furthermore, a significant positive correlation was found between intravitreal levels of LRP6 and VEGF in patients with PDR (r=0.567, p=0.001). However, comparison of patients with PDR with controls revealed that the plasma levels of LRP6 were not significantly different between the two groups (p=0.636).
LRP6 and VEGF levels in the vitreous body from patients with PDR were increased and correlated mutually. LRP6 may be a good diagnostic biomarker and a new therapeutic target for PDR.
PMCID: PMC4462953  PMID: 26120271
15.  A CLDN1-Negative Phenotype Predicts Poor Prognosis in Triple-Negative Breast Cancer 
PLoS ONE  2014;9(11):e112765.
Triple-negative breast cancer (TNBC) is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs) presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs.
Materials and Methods
The surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed.
Positive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014). The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003). Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS) in both lymph node positive (LN+) and negative (LN−) cases (both P<0.001). Similarly it was also associated with shorter overall survival (OS)(P = 0.003 in LN+ cases; P = 0.018 in LN− cases). In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008). Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664–11.475, P<0.001; HR 3.459, 95% CI 1.555–7.696, P = 0.002). However, neither CLDN4 nor CLDN7 expression was associated with survival.
In TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor in this heterogeneous subtype of breast cancer.
PMCID: PMC4231092  PMID: 25393310
16.  Diagnosis and staging of superficial esophageal precursor based on pre-endoscopic resection system comparable to endoscopic resection 
BMC Cancer  2014;14:774.
Endoscopic treatments for early esophageal squamous cell carcinoma and the esophageal neoplasm are two types: endoscopic resection (ER) and ablation. Resection enables evaluation of the lesion in the ER specimens, while ablation cannot. We sought to establish a pre-ER evaluated system with a diagnostic and staging accuracy similar to ER for the development of ablation therapy.
In our study, we collected data pertaining to early esophageal cancer and esophageal neoplasm treated with ER, analyzed the pre- and post-ER data of the lesions and evaluated the diagnostic accuracy of pre-ER system compared with the gold standard.
The diagnostic accuracy rate was 91% based on the pre-ER system compared with the gold standard, and 93% based on the ER diagnosis. The AUC of the pre-ER system was 0.964, while the ER examination was 0.971.
These results suggest that the accuracy of pre-ER system was comparable to ER. The pre-ER system enables prediction of histological diagnosis and stage of the lesions, and the choice of treatment for superficial esophageal neoplasm.
PMCID: PMC4213488  PMID: 25330811
Endoscopic resection (ER); Endoscopic treatment; Superficial esophageal neoplasm; Histological diagnosis
17.  miR-10b is overexpressed in hepatocellular carcinoma and promotes cell proliferation, migration and invasion through RhoC, uPAR and MMPs 
Recently, miR-10b is identified as a miRNA highly expressed in many human cancers, promoting cell migration and invasion. However, the specific function of miR-10b in hepatocellular carcinoma (HCC) is unclear at this point.
The miR-10b expression levels in 60 paired different TNM Stage HCC tumor tissues compared with adjacent non-tumor (ANT) tissues, normal tissue control (8 benign tumor and 7 normal liver tissues), 3 normal liver and 7 HCC cell lines were measured by real-time quantitative RT-PCR and to evaluate their association with HCC clinicopathologic features. Invasion assay, MTT proliferation assay and wound-healing assay were performed to test the invasion and proliferation of HCC cell after transfection. The effect of miR-10b on HCC in vivo was validated by murine xenograft model.
We found that miR-10b expression was increased in human HCC tissues and cell lines compared with normal control, respectively. The expression of miR-10b was correlated with HCC metastatic ability. Overexpression of miR-10b in MHCC-97L cells increased cell motility and invasiveness, whereas inhibition of miR-10b in MHCC-97H cells reduced cell motility and invasiveness in vitro and in vivo. We also showed that HOXD10 was negatively regulated by miR-10b at the posttranscriptional level, via a specific target site within the 3′UTR by luciferase reporter assay. Furthermore, we found that miR-10b induced HCC cell invasion and migration by modulating the HOXD10 target gene RhoC, uPAR, MMP-2 and MMP-9 expression.
Our results suggested that miR-10b was overexpressed in HCC and promoted HCC cell migration and invasion through the HOXD10/ RhoC/ uPAR/ MMPs pathway which may provide a novel bio-target for HCC therapy.
PMCID: PMC4192292  PMID: 25236186
miR-10b; HCC; invasion; migration; RhoC; uPAR; MMPs
18.  Nanotubular surface modification of metallic implants via electrochemical anodization technique 
Due to increased awareness and interest in the biomedical implant field as a result of an aging population, research in the field of implantable devices has grown rapidly in the last few decades. Among the biomedical implants, metallic implant materials have been widely used to replace disordered bony tissues in orthopedic and orthodontic surgeries. The clinical success of implants is closely related to their early osseointegration (ie, the direct structural and functional connection between living bone and the surface of a load-bearing artificial implant), which relies heavily on the surface condition of the implant. Electrochemical techniques for modifying biomedical implants are relatively simple, cost-effective, and appropriate for implants with complex shapes. Recently, metal oxide nanotubular arrays via electrochemical anodization have become an attractive technique to build up on metallic implants to enhance the biocompatibility and bioactivity. This article will thoroughly review the relevance of electrochemical anodization techniques for the modification of metallic implant surfaces in nanoscale, and cover the electrochemical anodization techniques used in the development of the types of nanotubular/nanoporous modification achievable via electrochemical approaches, which hold tremendous potential for bio-implant applications. In vitro and in vivo studies using metallic oxide nanotubes are also presented, revealing the potential of nanotubes in biomedical applications. Finally, an outlook of future growth of research in metallic oxide nanotubular arrays is provided. This article will therefore provide researchers with an in-depth understanding of electrochemical anodization modification and provide guidance regarding the design and tuning of new materials to achieve a desired performance and reliable biocompatibility.
PMCID: PMC4172084  PMID: 25258532
nanotubular arrays; anodization; implant; bioactivity; in vitro; in vivo
19.  Fibroblast α11β1 Integrin Regulates Tensional Homeostasis in Fibroblast/A549 Carcinoma Heterospheroids 
PLoS ONE  2014;9(7):e103173.
We have previously shown that fibroblast expression of α11β1 integrin stimulates A549 carcinoma cell growth in a xenograft tumor model. To understand the molecular mechanisms whereby a collagen receptor on fibroblast can regulate tumor growth we have used a 3D heterospheroid system composed of A549 tumor cells and fibroblasts without (α11+/+) or with a deletion (α11-/-) in integrin α11 gene. Our data show that α11-/-/A549 spheroids are larger than α11+/+/A549 spheroids, and that A549 cell number, cell migration and cell invasion in a collagen I gel are decreased in α11-/-/A549 spheroids. Gene expression profiling of differentially expressed genes in fibroblast/A549 spheroids identified CXCL5 as one molecule down-regulated in A549 cells in the absence of α11 on the fibroblasts. Blocking CXCL5 function with the CXCR2 inhibitor SB225002 reduced cell proliferation and cell migration of A549 cells within spheroids, demonstrating that the fibroblast integrin α11β1 in a 3D heterospheroid context affects carcinoma cell growth and invasion by stimulating autocrine secretion of CXCL5. We furthermore suggest that fibroblast α11β1 in fibroblast/A549 spheroids regulates interstitial fluid pressure by compacting the collagen matrix, in turn implying a role for stromal collagen receptors in regulating tensional hemostasis in tumors. In summary, blocking stromal α11β1 integrin function might thus be a stroma-targeted therapeutic strategy to increase the efficacy of chemotherapy.
PMCID: PMC4116160  PMID: 25076207
20.  PIK3CA Gene Mutations and Overexpression: Implications for Prognostic Biomarker and Therapeutic Target in Chinese Esophageal Squamous Cell Carcinoma 
PLoS ONE  2014;9(7):e103021.
To evaluate PIK3CA gene mutations and PIK3CA expression status in Chinese esophageal squamous cell carcinoma (ESCC) patients, and their correlation with clinicopathological characteristics and clinical outcomes.
Direct sequencing was applied to investigate mutations in exons 9 and 20 of PIK3CA in 406 Chinese ESCC patients. PIK3CA expression was evaluated using immunohistochemistry analysis. The associations of PIK3CA gene mutations and PIK3CA expression with clinicopathological characteristics and clinical outcome were examined.
Thirty somatic point mutations (30/406, 7.4%) were identified in exon 9 whereas no mutations were detected in exon 20. PIK3CA mutations were not correlated with clinicopathological characteristics or clinical outcomes. However in the ESCC patients with family cancer history, PIK3CA mutations were independently correlated with worse overall survival (multivariate hazard ratio (HR) = 10.493, 95% CI: 2.432–45.267, P = 0.002). Compared to normal esophageal tissue, PIK3CA was significantly overexpressed in cancer tissue (P<0.001). PIK3CA overexpression was independently associated with higher risk of local recurrence (multivariate HR  = 1.435, 95% CI: 1.040–1.979, P = 0.028). In female ESCC patients, PIK3CA overexpression was independently correlated with worse overall survival (multivariate HR  = 2.341, 95% CI: 1.073–5.108, P = 0.033).
Our results suggest PIK3CA gene mutation and overexpression could act as biomarkers for individualized molecular targeted therapy for Chinese ESCC patients.
PMCID: PMC4108430  PMID: 25054828
21.  Effects of Biochar on Soil Microbial Biomass after Four Years of Consecutive Application in the North China Plain 
PLoS ONE  2014;9(7):e102062.
The long term effect of biochar application on soil microbial biomass is not well understood. We measured soil microbial biomass carbon (MBC) and nitrogen (MBN) in a field experiment during a winter wheat growing season after four consecutive years of no (CK), 4.5 (B4.5) and 9.0 t biochar ha−1 yr−1 (B9.0) applied. For comparison, a treatment with wheat straw residue incorporation (SR) was also included. Results showed that biochar application increased soil MBC significantly compared to the CK treatment, and that the effect size increased with biochar application rate. The B9.0 treatment showed the same effect on MBC as the SR treatment. Treatments effects on soil MBN were less strong than for MBC. The microbial biomass C∶N ratio was significantly increased by biochar. Biochar might decrease the fraction of biomass N mineralized (KN), which would make the soil MBN for biochar treatments underestimated, and microbial biomass C∶N ratios overestimated. Seasonal fluctuation in MBC was less for biochar amended soils than for CK and SR treatments, suggesting that biochar induced a less extreme environment for microorganisms throughout the season. There was a significant positive correlation between MBC and soil water content (SWC), but there was no significant correlation between MBC and soil temperature. Biochar amendments may therefore reduce temporal variability in environmental conditions for microbial growth in this system thereby reducing temporal fluctuations in C and N dynamics.
PMCID: PMC4098902  PMID: 25025330
22.  Particulate Matter Pollution and Population Exposure Assessment over Mainland China in 2010 with Remote Sensing 
The public is increasingly concerned about particulate matter pollution caused by respirable suspended particles (PM10) and fine particles (PM2.5). In this paper, PM10 and PM2.5 concentration are estimated with remote sensing and individual air quality indexes of PM10 and PM2.5 (IPM10 and IPM2.5) over mainland China in 2010 are calculated. We find that China suffered more serious PM2.5 than PM10 pollution in 2010, and they presented a spatial differentiation. Consequently, a particulate-based air quality index (PAQI) based on a weighting method is proposed to provide a more objective assessment of the particulate pollution. The study demonstrates that, in 2010, most of mainland China faced a lightly polluted situation in PAQI case; there were three areas obviously under moderate pollution (Hubei, Sichuan-Chongqing border region and Ningxia-Inner Mongolia border region). Simultaneously, two indicators are calculated with the combination of population density gridded data to reveal Chinese population exposure to PM2.5. Comparing per capita PM2.5 concentration with population-weighted PM2.5 concentration, the former shows that the high-level regions are distributed in Guangdong, Shanghai, and Tianjin, while the latter are in Hebei, Chongqing, and Shandong. By comparison, the results demonstrate that population-weighted PM2.5 concentration is more in line with the actual situation.
PMCID: PMC4053876  PMID: 24830453
particulate matter pollution; population exposure; air quality assessment; remote sensing
23.  A MicroRNA Signature Predicts Survival in Early Stage Small-Cell Lung Cancer Treated with Surgery and Adjuvant Chemotherapy 
PLoS ONE  2014;9(3):e91388.
Small-cell lung cancer (SCLC) is one of the most aggressive cancers, yet the molecular mechanisms underlying its devastating clinical outcome remain elusive. In this study, we investigated whether microRNA (miRNA) expression profiles can predict the clinical outcomes of SCLC patients. A total of 82 patients with limited SCLC, who were treated with surgical resection and adjuvant chemotherapy, were enrolled in this study. First, we surveyed the expression of 924 miRNAs from 42 SCLC patients to discover survival-relevant miRNAs and develop prognostic models, which were then validated in an independent cohort of 40 cases using quantitative real-time PCR. We found that the miR-150/miR-886-3p signature was significantly correlated with the overall survival (OS) of SCLC patients (p = 0.02) in the training set, and both miRNA expression levels were much lower in the SCLC samples than normal lung samples. The miRNA signature also proved to be a significant predictor of survival in the validation set. Patients with high-risk miRNA signatures had poor overall survival (p = 0.005) and progression-free survival (p = 0.017) compared with those with low-risk scores. These findings retained statistical significance after adjusting for age, gender and smoking status (HR: 0.26, 95%: CI 0.10–0.69, p = 0.007), which suggested it may be an independent predictor of survival. In summary, we developed a prognostic miR-150/miR-886-3p signature and validated expression in an independent dataset of resectable SCLC. These preliminary results indicated that miRNAs may serve as promising molecular prognostic markers and new therapeutic targets for SCLC.
PMCID: PMC3956664  PMID: 24637927
24.  Overexpression of OLC1 Promotes Tumorigenesis of Human Esophageal Squamous Cell Carcinoma 
PLoS ONE  2014;9(3):e90958.
OLC1 was recently identified to be a potential oncogene. However, the role of OLC1 in human esophageal cell carcinoma (ESCC) is unknown. The aim of this study was therefore to evaluate the expression of OLC1 in human ESCC from normal, premalignant, and malignant lesions, and to clarify the mechanisms by which OLC1 contributes to the progression of ESCC.
Experimental Design
Two hundred and fourteen paired ESCC specimens, and an independent set from 28 ESCC patients, were used to analyze the correlation between OLC1 expression and the pathological characteristics of tumors using immunohistochemistry. Stable OLC1-overexpressing and OLC1-interfering esophageal cancer cells were established and a series of experimental methods were used to investigate the biological functions and mechanisms of action of OLC1.
We showed that OLC1 was overexpressed in 145 of 214 (67.8%) of human ESCC specimens, compared with in only 59 of 214 (27.57%) paired adjacent normal tissues (P<0.001). OLC1 overexpression occurred at a rate of 35% (10/28) at the stage of mild/moderate dysplasia, but was significantly upregulated to 66% (22/33) at the stages of severe dysplasia and in situ carcinoma, while 71% positive staining (22/28) was observed in invasive carcinoma tissues compared with normal tissues (P<0.05). We also provided evidence that OLC1 abnormalities significantly altered the cell proliferation and apoptosis induced by cytotoxic agents. OLC1 overexpression suppressed apoptosis, and was associated with attenuated caspase-3 activation and increased Bcl-2 stability.
Our study provides strong evidence suggesting OLC1 abnormalities may contribute to the development of human ESCC and have some important clinical significance.
PMCID: PMC3946619  PMID: 24608342
25.  Severe sepsis: Low expression of the renin-angiotensin system is associated with poor prognosis 
Severe sepsis has a high fatality rate, but no clinical indices for prognosis have been established. In recent years, the renin-angiotensin system (RAS) has received considerable attention. However, clinical data on RAS are inconsistent. Therefore, the aim of the present study was to assess the significance of RAS in the prognosis of sepsis. Blood samples were collected from patients, who met the diagnostic criteria of severe sepsis, on day 1 (D1) and 3 (D3). For each sample, the levels of angiotensin II (AngII), angiotensin-converting enzyme (ACE) and additional indices were measured. Patients were monitored for 28 days. On the D1 of inclusion, the average Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 22.2 and the Sepsis-related Organ Failure Assessment (SOFA) score was 6.1. Logistic regression analysis revealed that mortality-associated variables included the APACHE II score on D1, the SOFA score on D1, high lactic acid levels on D3 and low AngII and ACE levels on D1 and D3. AngII levels (<86.1 ng/ml) on D1 had a sensitivity of 88.2% and specificity of 77.3% for predicting mortality. ACE levels (<39.2 ng/ml) on D1 had a sensitivity of 88.2% and specificity of 72.7% for predicting mortality. These two indices were better than the APACHE II and SOFA scores. Therefore, low expression levels of AngII and ACE are valuable in predicting the mortality of patients with severe sepsis.
PMCID: PMC3991516  PMID: 24940436
severe sepsis; angiotensin II; angiotensin-converting enzyme; mortality; prognosis

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