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1.  Genome-Wide Association Studies of HIV-1 Host Control in Ethnically Diverse Chinese Populations 
Scientific Reports  2015;5:10879.
Genome-wide association studies (GWASs) have revealed several genetic loci associated with HIV-1 outcome following infection (e.g., HLA-C at 6p21.33) in multi-ethnic populations with genetic heterogeneity and racial/ethnic differences among Caucasians, African-Americans, and Hispanics. To systematically investigate the inherited predisposition to modulate HIV-1 infection in Chinese populations, we performed GWASs in three ethnically diverse HIV-infected patients groups (i.e., HAN, YUN, and XIN, N = 538). The reported loci at 6p21.33 was validated in HAN (e.g., rs9264942, P = 0.0018). An independent association signal (rs2442719, P = 7.85 × 10−7, HAN group) in the same region was observed. Imputation results suggest that haplotype HLA-B*13:02/C*06:02, which can partially account for the GWAS signal, is associated with lower viral load in Han Chinese. Moreover, several novel loci were identified using GWAS approach including the top association signals at 6q13 (KCNQ5, rs947612, P = 2.15 × 10−6), 6p24.1 (PHACTR1, rs202072, P = 3.8 × 10−6), and 11q12.3 (SCGB1D4, rs11231017, P = 7.39 × 10−7) in HAN, YUN, and XIN groups, respectively. Our findings imply shared or specific mechanisms for host control of HIV-1 in ethnically diverse Chinese populations, which may shed new light on individualized HIV/AIDS therapy in China.
doi:10.1038/srep10879
PMCID: PMC4454153  PMID: 26039976
2.  A panel of eight-miRNA signature as a potential biomarker for predicting survival in bladder cancer 
Background
There is increasing evidence to suggest that miRNAs play an important role in predicting cancer survival. To identify a panel of miRNA signature that can divided tumor from normal bladder using miRNA expression levels, and to assess the prognostic value of this specific miRNA markers in bladder cancer (BCa).
Methods
A comprehensive meta-review of published miRNA expression profiles that compared BCa and adjacent normal tissues was performed to determine candidate miRNAs as prognostic biomarkers for BCa. Vote-counting strategy and Robust Rank Aggregation method were used to identify significant meta-signature miRNAs.
Results
We identified an eight-miRNA signature including three upregulated (miR-141, miR-200c, miR-21) and five downregulated (miR-145, miR-125, miR-199a, let-7c and miR-99a) miRNAs for the prediction of overall survival (OS) using TCGA dataset, and validated in our 48 BCa patients. X-tile plot was used to generate the optimum cut-off point and Kaplan-Meier method was used to calculate OS. A linear prognostic model of eight miRNAs was constructed and weighted by the importance scores from the supervised principal component method to divide patients into high- and low-risk groups. Patients assigned to the high-risk group were associated with poor OS compared with patients in the low-risk group (HR = 5.21, p < 0.001). Our validation cohort of 48 patients confirmed the panel of 8-miRNAs as a reliable prognostic tool for OS in patients with BCa (HR = 5.04, p < 0.001).
Conclusion
The present meta-analysis identified eight highly significant and consistently dysregulated miRNAs from 19 datasets. We also constructed an eight-miRNA signature which provided predictive and prognostic value that complements traditional clinicopathological risk factors.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-015-0167-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-015-0167-0
PMCID: PMC4508815  PMID: 25991007
Bladder cancer; miRNA profiles; miRNA signature; Prognosis; Integrated analysis
3.  Prognostic value of meta-signature miRNAs in renal cell carcinoma: an integrated miRNA expression profiling analysis 
Scientific Reports  2015;5:10272.
To identify a robust panel of microRNA (miRNA) signatures that can distinguish renal cell carcinoma (RCC) from normal kidney using miRNA expression levels. We performed a comprehensive meta-analysis of 29 published studies that compared the miRNA expression profiles of RCC tissues and adjacent normal tissues (NT) to determine candidate miRNAs as prognostic biomarkers for RCC. Using vote-counting strategy and robust rank aggregation method, we identified a statistically significant miRNA meta-signature of two upregulated (miR-21, miR-210) and three downregulated (miR-141, miR-200c and miR-429) miRNAs. X-tile plot was used to generate the optimum cut-off point for the 15 different deregulated miRNAs and Kaplan-Meier method was used to calculate CSS. In a cohort of 45 patients, the high expression of miR-21 (HR: 5.46, 95%CI: 2.02-53.39) and miR-210 (HR: 6.85, 95%CI: 2.13-43.36), the low expression of miR-141 (HR: 0.16, 95%CI: 0.004-0.18), miR-200c (HR: 0.08, 95%CI: 0.01-0.43) and miR-429 (HR: 0.18, 95%CI: 0.02-0.50) were associated with poor cancer-specific survival (CSS) following RCC resection. We also constructed a five-miRNAs-based classifier as a reliable prognostic and predictive tool for CSS in patients with RCC, especially in clear cell RCC (ccRCC) (HR: 5.46, 95% CI: 1.51-19.66). This method might facilitate patient counselling and individualise management of RCC.
doi:10.1038/srep10272
PMCID: PMC4431463  PMID: 25974855
4.  A Novel Candidate Region for Genetic Adaptation to High Altitude in Andean Populations 
PLoS ONE  2015;10(5):e0125444.
Humans living at high altitude (≥2,500 meters above sea level) have acquired unique abilities to survive the associated extreme environmental conditions, including hypoxia, cold temperature, limited food availability and high levels of free radicals and oxidants. Long-term inhabitants of the most elevated regions of the world have undergone extensive physiological and/or genetic changes, particularly in the regulation of respiration and circulation, when compared to lowland populations. Genome scans have identified candidate genes involved in altitude adaption in the Tibetan Plateau and the Ethiopian highlands, in contrast to populations from the Andes, which have not been as intensively investigated. In the present study, we focused on three indigenous populations from Bolivia: two groups of Andean natives, Aymara and Quechua, and the low-altitude control group of Guarani from the Gran Chaco lowlands. Using pooled samples, we identified a number of SNPs exhibiting large allele frequency differences over 900,000 genotyped SNPs. A region in chromosome 10 (within the cytogenetic bands q22.3 and q23.1) was significantly differentiated between highland and lowland groups. We resequenced ~1.5 Mb surrounding the candidate region and identified strong signals of positive selection in the highland populations. A composite of multiple signals like test localized the signal to FAM213A and a related enhancer; the product of this gene acts as an antioxidant to lower oxidative stress and may help to maintain bone mass. The results suggest that positive selection on the enhancer might increase the expression of this antioxidant, and thereby prevent oxidative damage. In addition, the most significant signal in a relative extended haplotype homozygosity analysis was localized to the SFTPD gene, which encodes a surfactant pulmonary-associated protein involved in normal respiration and innate host defense. Our study thus identifies two novel candidate genes and associated pathways that may be involved in high-altitude adaptation in Andean populations.
doi:10.1371/journal.pone.0125444
PMCID: PMC4427407  PMID: 25961286
5.  Clinicopathologic and prognostic significance of p21 (Cip1/Waf1) expression in bladder cancer 
Recent studies have shown that altered expression p21 is shown to associate with tumorigenesis and tumor progression. To investigate the clinicopathological significance and prognostic value of p21 in bladder cancer (BCa). A total of 48 patients with BCa were included in this study. The correlation between p21 expression and clinicopathologic features and survival was studied. Also, a meta-analysis was performed to investigate the relationship between the p21 and BCa survival. Low p21 expression was detected both in tumor tissues compared with adjacent normal tissues. The expression of p21 was closely associated with advanced pathologic TNM stage (P = 0.001) and tumor grade (P = 0.013). Moreover, patients with low p21 expression had shorter recurrence-free survival (P = 0.016) and overall survival rates (P = 0.039). Multivariate Cox regression analysis revealed that p21 low expression was an independent prognostic factor for recurrence free survival (P = 0.03). Additionally, our meta-analysis. The available outcome data from six articles were examined. A meta-analysis of the HR indicated a significantly poor overall survival (OS, HR: 1.75, 95% CI: 1.38-2.21), recurrence free survival (RFS, HR: 1.83, 95% CI: 1.57-2.15), progression free survival (PFS, HR: 2.02, 95% CI: 1.48-2.75), and cancer specific survival (CSS, HR: 1.89, 95% CI: 1.53-2.33) in patients with low expression levels of p21. Our present results indicated that low p21 expression predicated tumor recurrence and poor prognosis in bladder cancer.
PMCID: PMC4503065  PMID: 26191193
p21 (Cip1/Waf1); recurrence; prognosis; bladder cancer
6.  Haplotypes of RHO polymorphisms and susceptibility to age-related macular degeneration 
Objective: To investigate whether haplotypes of rhodopsin (RHO) polymorphisms including rs7984, rs2855552, rs2855557 and rs2410 were associated with age-related macular degeneration (AMD) risk in Chinese Han population. Methods: Genotypes of rs7984, rs2855552, rs2855557 and rs2410 were detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 186 cases and 196 healthy controls. Then, the haplotypes were established with Haploview 4.2 software. And the effects of clinical charactersitics on the frequency of GTTG haplotype were also analyzed. Odds ratios (ORs) with 95% confidence interval (95% CI) were utilized to assess the relationship of haplotypes and genotypes of RHO polymorphisms with susceptibility to AMD. Results: Genotype distribution of all polymorphisms in control group were all in agreement with Hardy-Weinberg equilibrium (HWE) (P>0.05). In the analysis, we found that mutant alleles of rs7984 and rs2855557 were both associated with increased risk of AMD. For genotype analysis, rs7984 AA and rs2855557AA, rs2410GG genotypes all could increase the risk for AMD (OR=1.905, 95% CI=1.143-3.174; OR=2.226, 95% CI=1.261-3.932; OR=2.073, 95% CI=1.105-3.888). However, rs2855552 showed no effects on the onset of AMD. Compared with GTTA, the haplotypes of GGTG, ATAA and GTTG were all related with AMD susceptibility. Further analysis suggested that age, hypertension and hyperlipidemia history play important roles in the frequency alteration of GTTG haplotype. Conclusion: RHO polymorphisms (rs7984, rs2855557 and rs2410) and haplotypes may confer remarkable susceptibility to AMD. Further investigation showed that gene and environmental factors may work together in the pathogenesis of AMD.
PMCID: PMC4440145  PMID: 26045836
Rhodopsin; age-related macular degeneration; haplotype; polymorphism
7.  Huachansu suppresses human bladder cancer cell growth through the Fas/Fasl and TNF- alpha/TNFR1 pathway in vitro and in vivo 
Background
Huachansu (HCS), a class of toxic steroids extracted from toad venom, which has been shown to be a valuable anticancer drug in many kinds of cancers. However, the effect of HCS on bladder cancer has not been elucidated. In this study, we focused on the antitumor activities and related mechanisms of HCS on bladder cancer in vitro and in vivo.
Methods
Cell viability of T24, EJ, RT-4, SV-HUC-1 cells after HCS treatment was measured by MTS, whereas the changes of cell morphology were observed by transmission electron microscopy. The early apoptosis induced by HCS was evaluated by flow cytometry, and the expression level of apoptosis-related molecules (Bax, Bcl-2, XIAP, PARP, cleaved-Caspases 3, 8, 9) was detected using Western blot. We then evaluated the impact of HCS on the expression of Fas/Fasl, TNF- alpha/TNFR1, and the activation of NF-Kappa B pathway, and furthermore the effect of these pathways in HCS induced-apoptosis were also detected. At last, xenograft tumor in nude mice was used to further investigate the antitumor effect of HCS in vivo.
Results
Our results showed that HCS could efficiently inhibit proliferation and induce apoptosis in human bladder cancer cell lines. The expression of Fas, Fasl, TNF- alpha were all elevated at both mRNA and protein level after HCS treatment. Furthermore, down regulation of TNF- alpha, TNFR1, Fas or inhibition of Fas/Fasl interaction decreased the relative number of death cells induced by HCS. In vivo, HCS treatment significantly suppressed tumor growth and induced apoptosis in xenografts tumor in nude mice.
Conclusions
HCS could efficiently inhibit proliferation and induce apoptosis in human bladder cancer cells in vitro and in vivo, which is largely mediated by Fas/Fasl and TNF- alpha/TNFR1 pathway.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-015-0134-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-015-0134-9
PMCID: PMC4354737  PMID: 25887782
Huachansu; Bladder cancer; Apoptosis; TNF- alpha/TNFR1; Fas/Fasl
8.  The Value of Cerebral CT Angiography with Low Tube Voltage in Detection of Intracranial Aneurysms 
BioMed Research International  2015;2015:876796.
Objective. The aim of this study is to investigate the value of cerebral CT angiography (CTA) with low tube voltage in detection of intracranial aneurysms. Materials and Methods. A total of 294 consecutive patients with spontaneous subarachnoid hemorrhage (SAH) were enrolled in this study and randomly assigned into conventional voltage CTA (C-CTA) group and low voltage CTA (L-CTA) group. The objective and subjective image qualities were analyzed and compared between C-CTA and L-CTA groups. With the results of 3D-DSA as “gold standard,” the sensitivity, specificity, and accuracy of C-CTA and L-CTA in diagnosis of aneurysms were calculated and compared with each other. Results. Compared with group C-CTA, the CT dose index volume (CTDIvol) of group L-CTA reduced by 35.65%. There were no significant differences between C-CTA and L-CTA groups regarding objective and subjective image qualities. The sensitivity, specificity, and accuracy of L-CTA in diagnosis of aneurysms were 95.16%, 99.72%, and 99.42%, respectively. There were no significant differences in sensitivity, specificity, and accuracy between the C-CTA and L-CTA groups. Conclusion. The value of cerebral CTA with 100 kV low tube voltage in detection of intracranial aneurysms is significant, and it should be recommended as a routine scan method.
doi:10.1155/2015/876796
PMCID: PMC4331409  PMID: 25710034
9.  Recent Coselection in Human Populations Revealed by Protein–Protein Interaction Network 
Genome Biology and Evolution  2014;7(1):136-153.
Genome-wide scans for signals of natural selection in human populations have identified a large number of candidate loci that underlie local adaptations. This is surprising given the relatively short evolutionary time since the divergence of the human population. One hypothesis that has not been formally examined is whether and how the recent human evolution may have been shaped by coselection in the context of complex molecular interactome. In this study, genome-wide signals of selection were scanned in East Asians, Europeans, and Africans using 1000 Genome data, and subsequently mapped onto the protein–protein interaction (PPI) network. We found that the candidate genes of recent positive selection localized significantly closer to each other on the PPI network than expected, revealing substantial clustering of selected genes. Furthermore, gene pairs of shorter PPI network distances showed higher similarities of their recent evolutionary paths than those further apart. Last, subnetworks enriched with recent coselection signals were identified, which are substantially overrepresented in biological pathways related to signal transduction, neurogenesis, and immune function. These results provide the first genome-wide evidence for association of recent selection signals with the PPI network, shedding light on the potential mechanisms of recent coselection in the human genome.
doi:10.1093/gbe/evu270
PMCID: PMC4316623  PMID: 25532814
recent positive selection; PPI network; network topology; coselection; coevolution; pathway selection
10.  Ultrasound-Guided Miniscalpel-Needle Release versus Dry Needling for Chronic Neck Pain: A Randomized Controlled Trial 
Objective. To compare ultrasound-guided miniscalpel-needle (UG-MSN) release versus ultrasound-guided dry needling (UG-DN) for chronic neck pain. Methods. A total of 169 patients with chronic neck pain were randomized to receive either UG-MSN release or UG-DN. Before treatment and at 3 and 6 months posttreatment, pain was measured using a 10-point visual analogue scale (VAS). Neck function was examined using the neck disability index. Health-related quality of life was examined using the physical component score (PCS) and mental component score (MCS) of the SF-36 health status scale. Results. Patients in the UG-MSN release had greater improvement on the VAS (by 2 points at 3 months and 0.9 points at 6 months) versus in the UG-DN arm; (both P < 0.0001). Patients receiving UG-MSN release also showed significantly lower scores on the adjusted neck disability index, as well as significantly lower PCS. No severe complications were observed. Conclusion. UG-MSN release was superior to UG-DN in reducing pain intensity and neck disability in patients with chronic neck pain and was not associated with severe complications. The procedural aspects in the two arms were identical; however, we did not verify the blinding success. As such, the results need to be interpreted with caution.
doi:10.1155/2014/235817
PMCID: PMC4214050  PMID: 25386218
11.  Cholesterol and Triglycerides in Antipsychotic-Naive Patients with Nonaffective Psychosis 
Psychiatry research  2010;178(3):559-561.
Patients with psychosis have an increased prevalence of hyperlipidemia. We compared fasting concentrations of lipids in newly diagnosed, antipsychotic-naïve patients with nonaffective psychosis (N-87) and control subjects (N=92). After accounting for gender, age, smoking, socioeconomic status, and body mass index, there was no significant difference between the two groups in total cholesterol, high-density lipoproteins, low-density lipoproteins, or triglycerides.
doi:10.1016/j.psychres.2010.06.001
PMCID: PMC4185193  PMID: 20576293
lipids; cholesterol; triglycerides; schizophrenia; metabolism
12.  Anomalous refraction of airborne sound through ultrathin metasurfaces 
Scientific Reports  2014;4:6517.
Similar to their optic counterparts, acoustic components are anticipated to flexibly tailor the propagation of sound. However, the practical applications, e.g. for audible sound with large wavelengths, are frequently hampered by the issue of device thickness. Here we present an effective design of metasurface structures that can deflect the transmitted airborne sound in an anomalous way. This flat lens, made of spatially varied coiling-slit subunits, has a thickness of deep subwavelength. By elaborately optimizing its microstructures, the proposed lens exhibits high performance in steering sound wavefronts. Good agreement has been demonstrated experimentally by a sample around the frequency 2.55 kHz, incident with a Gaussian beam at normal or oblique incidence. This study may open new avenues for numerous daily life applications, such as controlling indoor sound effects by decorating rooms with light metasurface walls.
doi:10.1038/srep06517
PMCID: PMC4180806  PMID: 25269757
13.  Laparoscopic versus Open Radical Cystectomy in Bladder Cancer: A Systematic Review and Meta-Analysis of Comparative Studies 
PLoS ONE  2014;9(5):e95667.
Background and Objective
More recently laparoscopic radical cystectomy (LRC) has increasingly been an attractive alternative to open radical cystectomy (ORC) and many centers have reported their early experiences in the treatment of bladder cancer. Evaluate the safety and efficacy of LRC compared with ORC in the treatment of bladder cancer.
Methods
A systematic search of Medline, Scopus, and the Cochrane Library was performed up to Mar 1, 2013. Outcomes of interest assessing the two techniques included demographic and clinical baseline characteristics, perioperative, pathologic and oncological variables, and post-op neobladder function and complications.
Results
Sixteen eligible trials evaluating LRC vs ORC were identified including seven prospective and nine retrospective studies. Although LRC was associated with longer operative time (p<0.001), patients might benefit from significantly fewer overall complications (p<0.001), less blood loss (p<0.001), shorter length of hospital stay (p<0.001), less need of blood transfusion (p<0.001), less narcotic analgesic requirement (p<0.001), shorter time to ambulation (p = 0.03), shorter time to regular diet (p<0.001), fewer positive surgical margins (p = 0.006), fewer positive lymph node (p = 0.05), lower distant metastasis rate (p = 0.05) and fewer death (p = 0.004). There was no significant difference in other demographic parameters except for a lower ASA score (p = 0.01) in LRC while post-op neobladder function were similar between the two groups.
Conclusions
Our data suggest that LRC appears to be a safe, feasible and minimally invasive alternative to ORC with reliable perioperative safety, pathologic & oncologic efficacy, comparable post-op neobladder function and fewer complications. Because of the inherent limitations of the included studies, further large sample prospective, multi-centric, long-term follow-up studies and randomized control trials should be undertaken to confirm our findings.
doi:10.1371/journal.pone.0095667
PMCID: PMC4023936  PMID: 24835573
14.  Scaling of Geometric Quantum Discord Close to a Topological Phase Transition 
Scientific Reports  2014;4:4473.
Quantum phase transition is one of the most interesting aspects in quantum many-body systems. Recently, geometric quantum discord has been introduced to signature the critical behavior of various quantum systems. However, it is well-known that topological quantum phase transition can not be described by the conventional Landau's symmetry breaking theory, and thus it is unknown that whether previous study can be applicable in this case. Here, we study the topological quantum phase transition in Kitaev's 1D p-wave spinless quantum wire model in terms of its ground state geometric quantum discord. The derivative of geometric quantum discord is nonanalytic at the critical point, in both zero temperature and finite temperature cases. The scaling behavior and the universality are verified numerically. Therefore, our results clearly show that all the key ingredients of the topological phase transition can be captured by the nearest neighbor and long-range geometric quantum discord.
doi:10.1038/srep04473
PMCID: PMC3966051  PMID: 24667280
15.  Pharmacological characteristics and efficacy of a novel anti-angiogenic antibody FD006 in corneal neovascularization 
BMC Biotechnology  2014;14:17.
Background
Vascular endothelial growth factor (VEGF) is a key angiogenic factors. It plays an important role in both physiologic and pathologic angiogenesis and increases permeability across the vessels. Using antibody phage display technology, we obtained a novel anti-VEGFA IgG, named as FD006. In this study, the pharmacological characteristics and efficacy of FD006 in corneal neovascularization (CoNV) were evaluated.
Results
FD006 was predicted to have similar binding mode to bevacizumab. Experimental analysis showed that the binding ability of FD006 seemed a little stronger than bevacizumab, for the EC50 of FD006 to bind VEGF analyzed by ELISA was about 0.037 μg/mL while that of bevacizumab was 0.18 μg/mL. Binding kinetics assays showed similar results that FD006 possessed 2-fold higher affinity to bind VEGF than bevacizumab due to slower dissociation rate of FD006; meanwhile, FD006 inhibited the VEGF-induced proliferation of HUVEC with an IC50 value of 0.031 ± 0.0064 μg/ml, which seemed similar or a litter better than bevacizumab (0.047 ± 0.0081 μg/ml). The subconjunctival administration of FD006, bevacizumab or dexamethasone could significantly inhibit the growth of CoNV contrasting to N.S (p < 0.01). At the early stage, FD006 showed better inhibitory effect on the growth of CoNV compared with bevacizumab (p < 0.05). Western blot analysis showed that FD006 could inhibit the expression of VEGF, VEGFR-1, VEGFR-2, MMP-9 and ICAM-1, which could explain its favorable anti-angiogenic activity.
Conclusions
The pharmacological characteristics of FD006 were similar or even a little better than bevacizumab in inhibiting corneal neovascularization.
doi:10.1186/1472-6750-14-17
PMCID: PMC3942068  PMID: 24575750
Neovascularization; Cornea; Bevacizumab; Angiogenesis; Anti-angiogenic treatment
16.  Modeling recent human evolution in mice by expression of a selected EDAR variant 
Cell  2013;152(4):691-702.
Summary
An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in Central China approximately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knock-in mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify novel biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans.
doi:10.1016/j.cell.2013.01.016
PMCID: PMC3575602  PMID: 23415220
17.  Diagnosis and surgical treatment of multiple endocrine neoplasia type 2A 
Background
This study aims to introduce the diagnosis and surgical treatment of the rare disease multiple endocrine neoplasia type 2A (MEN 2A).
Methods
Thirteen cases of MEN 2A were diagnosed as medullary thyroid carcinoma (MTC) and pheochromocytoma by biochemical tests and imaging examination. They were treated by bilateral adrenal tumor excision or laparoscopic surgery.
Results
Nine patients were treated by bilateral adrenal tumor excision and the remaining four were treated by laparoscopic surgery for pheochromocytoma. Ten patients were treated by total thyroidectomy and bilateral lymph nodes dissection and the remaining three were treated by unilateral thyroidectomy for MTC. Up to now, three patients have died of MTC distant metastasis.
Conclusions
We confirmed that MEN 2A can be diagnosed by biochemical tests and imaging examination when genetic testing is not available. Surgical excision is the predominant way to treat MEN 2A; pheochromocytoma should be excised at first when pheochromocytoma and MTC occur simultaneously.
doi:10.1186/1477-7819-12-8
PMCID: PMC3895851  PMID: 24400812
Diagnosis; Multiple endocrine neoplasia type 2A; Surgical excision; Treatment
18.  Detecting Genetic Association of Common Human Facial Morphological Variation Using High Density 3D Image Registration 
PLoS Computational Biology  2013;9(12):e1003375.
Human facial morphology is a combination of many complex traits. Little is known about the genetic basis of common facial morphological variation. Existing association studies have largely used simple landmark-distances as surrogates for the complex morphological phenotypes of the face. However, this can result in decreased statistical power and unclear inference of shape changes. In this study, we applied a new image registration approach that automatically identified the salient landmarks and aligned the sample faces using high density pixel points. Based on this high density registration, three different phenotype data schemes were used to test the association between the common facial morphological variation and 10 candidate SNPs, and their performances were compared. The first scheme used traditional landmark-distances; the second relied on the geometric analysis of 15 landmarks and the third used geometric analysis of a dense registration of ∼30,000 3D points. We found that the two geometric approaches were highly consistent in their detection of morphological changes. The geometric method using dense registration further demonstrated superiority in the fine inference of shape changes and 3D face modeling. Several candidate SNPs showed potential associations with different facial features. In particular, one SNP, a known risk factor of non-syndromic cleft lips/palates, rs642961 in the IRF6 gene, was validated to strongly predict normal lip shape variation in female Han Chinese. This study further demonstrated that dense face registration may substantially improve the detection and characterization of genetic association in common facial variation.
Author Summary
Heritability of human facial appearance is an intriguing question to the general public and researchers. Although it is known that some facial features are highly heritable, the exact genetic basis is unknown. Previous studies used simple linear measurements such as landmark distances, to evaluate the facial shape variation. Such approaches, although easy to carry out, may lack statistical power and miss complex morphological changes. In this study, we utilized a new 3D face registration method that enables subtle differences to be detected at high resolution 3D images. Based on this, we tried to test and characterize the associations of 10 candidate genetic variants to common facial morphological variations. Different types of phenotype data were extracted and compared in the association tests. Our results show that geometry based data performed better than simple distance based data. Furthermore, high density geometric data outstood the others in capturing small shape changes and modeling the 3D face visualization. Interestingly, a genetic variant from IRF6 gene, which is also a well-known risk factor of non-syndrome cleft lip, was found to strongly predispose the mouth shape in Han Chinese females.
doi:10.1371/journal.pcbi.1003375
PMCID: PMC3854494  PMID: 24339768
19.  Sexual function improvement in association with serum leptin level elevation in patients with premature ejaculation following sertraline treatment: a preliminary observation 
The objective of our work was to evaluate the effect of sertraline hydrochloride on serum levels of leptin and sexual function in patients with premature ejaculation (PE). A total of 124 patients with a history of PE at least 6 months, aged 20-50 years, were treated with sertraline hydrochloride. One hundred and four age-matched normal males without a history of PE were included control subjects and were untreated. Before and after the 8 week experiment, sexual performance parameters including the intravaginal ejaculation latency time (IELT) and the Chinese premature ejaculation index (CIPE) were collected from both PE patients and control subjects through a questionnaire survey and analyzed. Serum levels of leptin were measured. Correlations of serum leptin with Body Mass Index (BMI) were analyzed. Before sertraline treatment, serum levels of leptin were significantly higher (32.9 vs 8.8μg/L, p<0.001) but IELT and CIPE score were significantly lower (54 vs 590, p <0.001; 8.7 vs 22.3, p <0.0001) in PE patients than control subjects. After 8 weeks of treatment with sertraline, serum levels of leptinl in PE patients were decreased markedly to 8.0 μg/L, which was not significantly different from the levels in control subjects (p >0.05); and IELT and CIPE score in PE patients were increased to the values similar to those in control subjects. The sensitivity and specificity values were 87.5% and 96.3% for leptin as a diagnosis target. These observations suggest sertraline as a selective serotonin reuptake inhibitor may offer an effective option for treating premature ejaculation.
PMCID: PMC4334005  PMID: 24289761
premature ejaculation; therapeutic target; serum leptin; diagnosis; treatment
20.  Somatostatin Receptor-Based Molecular Imaging and Therapy for Neuroendocrine Tumors 
BioMed Research International  2013;2013:102819.
Neuroendocrine tumors (NETs) are tumors originated from neuroendocrine cells in the body. The localization and the detection of the extent of NETs are important for diagnosis and treatment, which should be individualized according to the tumor type, burden, and symptoms. Molecular imaging of NETs with high sensitivity and specificity is achieved by nuclear medicine method using single photon-emitting and positron-emitting radiopharmaceuticals. Somatostatin receptor imaging (SRI) using SPECT or PET as a whole-body imaging technique has become a crucial part of the management of NETs. The radiotherapy with somatostatin analogues labeled with therapeutic beta emitters, such as lutetium-177 or yttrium-90, has been proved to be an option of therapy for patients with unresectable and metastasized NETs. Molecular imaging can deliver an important message to improve the outcome for patients with NETs by earlier diagnosis, better choice of the therapeutic method, and evaluation of the therapeutic response.
doi:10.1155/2013/102819
PMCID: PMC3784148  PMID: 24106690
21.  Neurofibrosarcoma of the gallbladder: a case report 
Sarcoma of the gallbladder is a rare entity. This report presents an extremely rare clinical case of a neurofibrosarcoma of the gallbladder. On examination, a mass was felt in the right hypochondrium. An ultrasound of the abdomen showed a mass in the gallbladder. Computed tomography (CT) scan of the abdomen showed a grossly distended gallbladder with soft tissue mass in the gallbladder. The mass was diagnosed as carcinoma of the gallbladder and an extended cholecystectomy was performed. Histopathological examination revealed spindle-cell proliferation and the possibility of a malignant tumor of mesenchymal origin.
doi:10.1186/1477-7819-11-189
PMCID: PMC3765290  PMID: 23938157
Gallbladder; Neurofibrosarcoma
22.  Automatic landmark annotation and dense correspondence registration for 3D human facial images 
BMC Bioinformatics  2013;14:232.
Background
Traditional anthropometric studies of human face rely on manual measurements of simple features, which are labor intensive and lack of full comprehensive inference. Dense surface registration of three-dimensional (3D) human facial images holds great potential for high throughput quantitative analyses of complex facial traits. However there is a lack of automatic high density registration method for 3D faical images. Furthermore, current approaches of landmark recognition require further improvement in accuracy to support anthropometric applications.
Result
Here we describe a novel non-rigid registration method for fully automatic 3D facial image mapping. This method comprises two steps: first, seventeen facial landmarks are automatically annotated, mainly via PCA-based feature recognition following 3D-to-2D data transformation. Second, an efficient thin-plate spline (TPS) protocol is used to establish the dense anatomical correspondence between facial images, under the guidance of the predefined landmarks. We demonstrate that this method is highly accurate in landmark recognition, with an average RMS error of ~1.7 mm. The registration process is highly robust, even for different ethnicities.
Conclusion
This method supports fully automatic registration of dense 3D facial images, with 17 landmarks annotated at greatly improved accuracy. A stand-alone software has been implemented to assist high-throughput high-content anthropometric analysis.
doi:10.1186/1471-2105-14-232
PMCID: PMC3724574  PMID: 23870191
3D face; Facial morphology; Registration; Landmark localization; Dense correspondence
23.  Human Infection with Candidatus Neoehrlichia mikurensis, China 
Emerging Infectious Diseases  2012;18(10):1636-1639.
To identify Candidatus Neoehrlichia mikurensis infection in northeastern China, we tested blood samples from 622 febrile patients. We identified in 7 infected patients and natural foci for this bacterium. Field surveys showed that 1.6% of ticks and 3.8% of rodents collected from residences of patients were also infected.
doi:10.3201/eid1810.120594
PMCID: PMC3471638  PMID: 23017728
Candidatus Neoehrlichia mikurensis; bacteria; human infection; ticks; rodents; vector-borne infections; China
24.  Genome Patterns of Selection and Introgression of Haplotypes in Natural Populations of the House Mouse (Mus musculus) 
PLoS Genetics  2012;8(8):e1002891.
General parameters of selection, such as the frequency and strength of positive selection in natural populations or the role of introgression, are still insufficiently understood. The house mouse (Mus musculus) is a particularly well-suited model system to approach such questions, since it has a defined history of splits into subspecies and populations and since extensive genome information is available. We have used high-density single-nucleotide polymorphism (SNP) typing arrays to assess genomic patterns of positive selection and introgression of alleles in two natural populations of each of the subspecies M. m. domesticus and M. m. musculus. Applying different statistical procedures, we find a large number of regions subject to apparent selective sweeps, indicating frequent positive selection on rare alleles or novel mutations. Genes in the regions include well-studied imprinted loci (e.g. Plagl1/Zac1), homologues of human genes involved in adaptations (e.g. alpha-amylase genes) or in genetic diseases (e.g. Huntingtin and Parkin). Haplotype matching between the two subspecies reveals a large number of haplotypes that show patterns of introgression from specific populations of the respective other subspecies, with at least 10% of the genome being affected by partial or full introgression. Using neutral simulations for comparison, we find that the size and the fraction of introgressed haplotypes are not compatible with a pure migration or incomplete lineage sorting model. Hence, it appears that introgressed haplotypes can rise in frequency due to positive selection and thus can contribute to the adaptive genomic landscape of natural populations. Our data support the notion that natural genomes are subject to complex adaptive processes, including the introgression of haplotypes from other differentiated populations or species at a larger scale than previously assumed for animals. This implies that some of the admixture found in inbred strains of mice may also have a natural origin.
Author Summary
Although there is abundant evidence for phenotypic adaptation in natural populations, it is still a challenge to understand the underlying genetic processes. House mice have colonized the world in several successive waves, the most recent ones in the wake of the spread of human agriculture and trans-oceanic shipping. They have adapted to many habitats and climates, and their populations provide a rich source of opportunities for studying the impact of adaptation and positive selection on the genome. By scanning the whole genome of four natural populations of mice, we detect abundant evidence for recent positive selection, including loci that are known to be involved in genetic diseases in humans. Unexpectedly, we also find a high proportion of gene exchange between populations that have long been separated. This finding supports the notion that hybridization and transfer of alleles can significantly contribute to new genetic material subject to positive selection.
doi:10.1371/journal.pgen.1002891
PMCID: PMC3431316  PMID: 22956910
25.  Effect of Low Tube Voltage on Image Quality, Radiation Dose, and Low-Contrast Detectability at Abdominal Multidetector CT: Phantom Study 
Purpose. To investigate the effect of low tube voltage (80 kV) on image quality, radiation dose, and low-contrast detectability (LCD) at abdominal computed tomography (CT). Materials and Methods. A phantom containing low-contrast objects was scanned with a CT scanner at 80 and 120 kV, with tube current-time product settings at 150–650 mAs. The differences between image noise, contrast-to-noise ratio (CNR), and scores of LCD obtained with 80 kV at 150–650 mAs and those obtained with 120 kV at 300 mAs were compared respectively. Results. The image noise substantially increased with low tube voltage. However, with identical dose, use of 80 kV resulted in higher CNR compared with CNR at 120 kV. There were no statistically significant difference in CNR and scores of LCD between 120 kV at 300 mAs and 80 kV at 550–650 mAs (P > 0.05). The relative dose delivered at 80 kV ranged from 58% at 550 mAs to 68% at 650 mAs. Conclusion. With a reduction of the tube voltage from 120 kV to 80 kV at abdominal CT, the radiation dose can be reduced by 32% to 42% without degradation of CNR and LCD.
doi:10.1155/2012/130169
PMCID: PMC3347747  PMID: 22619490

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