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1.  Regional increases of cortical thickness in untreated, first-episode major depressive disorder 
Translational Psychiatry  2014;4(4):e378-.
The large majority of structural MRI studies of major depressive disorder (MDD) investigated volumetric changes in chronic medicated patients in whom course of illness and treatment effects may impact anatomic measurements. Further, in few studies, separate measurements of cortical thickness and surface area have been performed that reflect different neurobiological processes regulated by different genetic mechanisms. In the present study, we investigated both cortical thickness and surface area in first-episode, treatment-naïve, mid-life MDD to elucidate the core pathophysiology of this disease and its early impact on the brain. We observed increased cortical thickness in the right hemisphere, including medial orbitofrontal gyrus, pars opercularis, rostral middle frontal gyrus and supramarginal gyrus. Increased thickness of rostral middle frontal gyrus was negatively related with depression severity on the Hamilton Depression Rating Scale. Furthermore, MDD patients showed significantly increased associations in cortical thickness measurements among areas where increased cortical thickness was observed. Analysis of pial area revealed a trend toward increased surface area in the left parahippocampal gyrus in MDD. To permit comparison of our data with those of previous gray matter volume studies, voxel-based morphometry was performed. That analysis revealed significantly increased gray matter volume in left paracentral lobule, left superior frontal gyrus, bilateral cuneus and thalamus which form limbic-cortico–striato–pallido–thalamic loops. These changes in first-episode, treatment-naïve, mid-life MDD patients may reflect an active illness-related cortical change close to illness onset, and thus potentially provide important new insight into the early neurobiology of the disorder.
doi:10.1038/tp.2014.18
PMCID: PMC4012282  PMID: 24713859
3.  Rapid discovery and optimization of therapeutic antibodies against emerging infectious diseases 
Using a comprehensive set of discovery and optimization tools, antibodies were produced with the ability to neutralize SARS coronavirus (SARS-CoV) infection in Vero E6 cells and in animal models. These anti-SARS antibodies were discovered using a novel DNA display method, which can identify new antibodies within days. Once neutralizing antibodies were identified, a comprehensive and effective means of converting the mouse sequences to human frameworks was accomplished using HuFR™ (human framework reassembly) technology. The best variant (61G4) from this screen showed a 3.5–4-fold improvement in neutralization of SARS-CoV infection in vitro. Finally, using a complete site-saturation mutagenesis methodology focused on the CDR (complementarity determining regions), a single point mutation (51E7) was identified that improved the 80% plaque reduction neutralization of the virus by greater than 8-fold. These discovery and evolution strategies can be applied to any emerging pathogen or toxin where a causative agent is known.
doi:10.1093/protein/gzn027
PMCID: PMC2461042  PMID: 18480090
antibody discovery; humanized; optimized; SARS-CoV
4.  Multiple-trait genome-wide association study based on principal component analysis for residual covariance matrix 
Gao, H | Wu, Y | Zhang, T | Wu, Y | Jiang, L | Zhan, J | Li, J | Yang, R
Heredity  2015;114(4):428.
doi:10.1038/hdy.2015.11
PMCID: PMC4359982  PMID: 25757542
5.  Combinatorial Effects of Arginine and Fluoride on Oral Bacteria 
Journal of Dental Research  2015;94(2):344-353.
Dental caries is closely associated with the microbial disequilibrium between acidogenic/aciduric pathogens and alkali-generating commensal residents within the dental plaque. Fluoride is a widely used anticaries agent, which promotes tooth hard-tissue remineralization and suppresses bacterial activities. Recent clinical trials have shown that oral hygiene products containing both fluoride and arginine possess a greater anticaries effect compared with those containing fluoride alone, indicating synergy between fluoride and arginine in caries management. Here, we hypothesize that arginine may augment the ecological benefit of fluoride by enriching alkali-generating bacteria in the plaque biofilm and thus synergizes with fluoride in controlling dental caries. Specifically, we assessed the combinatory effects of NaF/arginine on planktonic and biofilm cultures of Streptococcus mutans, Streptococcus sanguinis, and Porphyromonas gingivalis with checkerboard microdilution assays. The optimal NaF/arginine combinations were selected, and their combinatory effects on microbial composition were further examined in single-, dual-, and 3-species biofilm using bacterial species–specific fluorescence in situ hybridization and quantitative polymerase chain reaction. We found that arginine synergized with fluoride in suppressing acidogenic S. mutans in both planktonic and biofilm cultures. In addition, the NaF/arginine combination synergistically reduced S. mutans but enriched S. sanguinis within the multispecies biofilms. More importantly, the optimal combination of NaF/arginine maintained a “streptococcal pressure” against the potential growth of oral anaerobe P. gingivalis within the alkalized biofilm. Taken together, we conclude that the combinatory application of fluoride and arginine has a potential synergistic effect in maintaining a healthy oral microbial equilibrium and thus represents a promising ecological approach to caries management.
doi:10.1177/0022034514561259
PMCID: PMC4438734  PMID: 25477312
Streptococcus mutans; Streptococcus sanguis; Porphyromonas gingivalis; biofilms; dental caries; drug synergism
6.  Translation and validation of the simplified Chinese new Knee Society Scoring System 
Background
The NKSS has recently been translated into Dutch version. The reliability and validity were also assessed. However, there is no Simplified Chinese version of New Society Knee Scoring System (SC-NKSS) for Chinese population.
Methods
The SC-NKSS was translated from the original English version following international guidelines. All patients undergoing total knee arthroplasty (TKA) between September 2012 and September 2013 were invited to participate in this study. Finally, a total of 105 did so. Patients (preoperative and postoperative) completed the Chinese version of NKSS, Oxford Knee Score (OKS), the Medical Outcomes General Health Survey (SF-36) and Visual analog scale (VAS). Psychometric testing of reliability, construct validity, content validity were conducted.
Results
All the 105 participants completed the questionnaires and no floor or ceiling effects were checked. Internal consistency was excellent with Cronbach’s alpha coefficient ranging from 0.71 to 0.85. Test-retest reliability was satisfactory with an intraclass correlation coefficient of 0.92 (95%confidence interval, 0.86–0.95). Construct validity was demonstrated to correlate well with the Chinese version of OKS (r =−0.78; p < 0.01), VAS (r =−0.70; p < 0.01), Physical Function (PF) (r = 0.74; p < 0.01), Body Pain (BP) (r = 0.63; p < 0.01) and General Health (GH) (r = 0.51; p < 0.01) of SF-36 domains.
Conclusion
The SC-NKSS was well accepted and demonstrated acceptable psychometric properties in mainland China.
Electronic supplementary material
The online version of this article (doi:10.1186/s12891-015-0854-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12891-015-0854-1
PMCID: PMC4687130  PMID: 26691170
Simplified Chinese version; New society knee scoring system; Questionnaire; Validity; Reliability
7.  Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations 
British Journal of Cancer  2014;111(12):2351-2360.
Background:
Male breast cancer (MBC) is still poorly understood with a large proportion arising in families with a history of breast cancer. Genomic studies have focused on germline determinants of MBC risk, with minimal knowledge of somatic changes in these cancers.
Methods:
Using a TruSeq amplicon cancer panel, this study evaluated 48 familial MBCs (3 BRCA1 germline mutant, 17 BRCA2 germline mutant and 28 BRCAX) for hotspot somatic mutations and copy number changes in 48 common cancer genes.
Results:
Twelve missense mutations included nine PIK3CA mutations (seven in BRCAX patients), two TP53 mutations (both in BRCA2 patients) and one PTEN mutation. Common gains were seen in GNAS (34.1%) and losses were seen in GNAQ (36.4%), ABL1 (47.7%) and ATM (34.1%). Gains of HRAS (37.5% vs 3%, P=0.006), STK11 (25.0% vs 0%, P=0.01) and SMARCB1 (18.8% vs 0%, P=0.04) and the loss of RB1 (43.8% vs 13%, P=0.03) were specific to BRCA2 tumours.
Conclusions:
This study is the first to perform high-throughput somatic sequencing on familial MBCs. Overall, PIK3CA mutations are most commonly seen, with fewer TP53 and PTEN mutations, similar to the profile seen in luminal A female breast cancers. Differences in mutation profiles and patterns of gene gains/losses are seen between BRCA2 (associated with TP53/PTEN mutations, loss of RB1 and gain of HRAS, STK11 and SMARCB1) and BRCAX (associated with PIK3CA mutations) tumours, suggesting that BRCA2 and BRCAX MBCs may be distinct and arise from different tumour pathways. This has implications on potential therapies, depending on the BRCA status of MBC patients.
doi:10.1038/bjc.2014.511
PMCID: PMC4264438  PMID: 25490678
male breast cancer; BRCA1; BRCA2; BRCAX; TP53; PIK3CA; MiSeq
8.  Meta-analysis of diagnostic value of 18F-FDG PET or PET/CT for detecting lymph node and distant metastases in patients with nasopharyngeal carcinoma 
Shen, G | Zhang, W | Jia, Z | Li, J | Wang, Q | Deng, H
The British Journal of Radiology  2014;87(1044):20140296.
Objective:
We performed this meta-analysis to comprehensively assess the diagnostic performance of positron emission tomography (PET) or PET/CT for detecting lymph node and distant metastases in patients with nasopharyngeal carcinoma (NPC).
Methods:
Through a search of four English and three Chinese databases (January 1990 to June 2013), pooled estimated sensitivity, specificity and diagnostic odds ratio (DOR) were calculated based on the data extracted from the included studies. We also constructed summary receiver operating characteristic curves, with the area under the curve (AUC) and obtained the Q* index. Heterogeneity and subgroup analysis were also performed.
Results:
In total, 18 articles consisting 20 studies were included in this meta-analysis. On a per-patient basis, the overall pooled estimates for sensitivity and specificity of PET or PET/CT in N and M staging of NPC were 0.89 [95% confidence interval (CI), 0.86–0.91] and 0.96 (95% CI, 0.95–0.96), respectively. The overall DOR, AUC and Q* index were 162.07 (95% CI, 90.72–289.55), 0.9689 and 0.9181, respectively. Subgroup analysis showed that AUC and Q* index were 0.9734 and 0.9255 for N staging and 0.9715 and 0.9223 for M staging, respectively.
Conclusion:
The present meta-analysis showed that PET or PET/CT has excellent diagnostic performance for detecting lymph node and distant metastases in patients with NPC.
Advances in knowledge:
To provide evidence to assess the role of PET or PET/CT in staging of NPC.
doi:10.1259/bjr.20140296
PMCID: PMC4243207  PMID: 25348201
9.  Multiple-trait genome-wide association study based on principal component analysis for residual covariance matrix 
Gao, H | Zhang, T | Wu, Y | Wu, Y | Jiang, L | Zhan, J | Li, J | Yang, R
Heredity  2014;113(6):526-532.
Given the drawbacks of implementing multivariate analysis for mapping multiple traits in genome-wide association study (GWAS), principal component analysis (PCA) has been widely used to generate independent ‘super traits' from the original multivariate phenotypic traits for the univariate analysis. However, parameter estimates in this framework may not be the same as those from the joint analysis of all traits, leading to spurious linkage results. In this paper, we propose to perform the PCA for residual covariance matrix instead of the phenotypical covariance matrix, based on which multiple traits are transformed to a group of pseudo principal components. The PCA for residual covariance matrix allows analyzing each pseudo principal component separately. In addition, all parameter estimates are equivalent to those obtained from the joint multivariate analysis under a linear transformation. However, a fast least absolute shrinkage and selection operator (LASSO) for estimating the sparse oversaturated genetic model greatly reduces the computational costs of this procedure. Extensive simulations show statistical and computational efficiencies of the proposed method. We illustrate this method in a GWAS for 20 slaughtering traits and meat quality traits in beef cattle.
doi:10.1038/hdy.2014.57
PMCID: PMC4274615  PMID: 24984606
10.  A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1α in pancreatic ductal adenocarcinoma 
British Journal of Cancer  2014;111(11):2131-2141.
Background:
Invasion and metastasis are the distinct biologic characteristics of cancer, resulting in an exceptionally low 5-year survival rate in pancreatic ductal adenocarcinoma (PDAC). Understanding in detail the mechanisms underlying PDAC metastasis is critical for prevention and effective interventions. Long non-coding RNAs (lncRNAs) have been documented as having a critical role in cancer development and progression.
Methods:
We examined the expression levels of lncRNA ENST00000480739 and osteosarcoma amplified-9 (OS-9) mRNA in a cohort of 35 PDAC patients. Cell proliferation, invasion and migration were examined with and without ENST00000480739 overexpression in PDAC cells.
Results:
We determined that the ENST00000480739 expression level was remarkably decreased in tumorous tissues compared with their corresponding non-tumorous tissues. The expression of ENST00000480739 was negatively associated with tumour node metastasis stage and lymph node metastasis. In addition, ENST0000048073 was an independent prognostic factor of survival time in PDAC patients following surgery. Besides, enforced expression of ENST00000480739 suppressed PDAC cells' invasion in vitro. Overexpression of ENST00000480739 significantly increased both mRNA and protein levels of OS-9, and the luciferase assays confirmed that ENST00000480739 positively regulates OS-9 by activating the transcription level of the OS-9 promoter. We further found that ENST00000480739 may target hypoxia-inducible factor-1α (HIF-1α) expression by upregulating OS-9.
Conclusions:
These findings suggest that the frequently downregulated ENST00000480739 in PDAC contributes to tumour metastasis and progression by regulating HIF-1α. Long non-coding RNA ENST00000480739 may provide not only a therapeutic potential to suppress metastasis but it may also be a novel biomarker for risk prognostication and personal therapy screening of PDAC patients.
doi:10.1038/bjc.2014.520
PMCID: PMC4260035  PMID: 25314054
pancreatic ductal adenocarcinoma; long non-coding RNA; invasion OS-9; HIF-1α
11.  Spaceflight and hind limb unloading induce similar changes in electrical impedance characteristics of mouse gastrocnemius muscle 
Objective
To assess the potential of electrical impedance myography (EIM) to serve as a marker of muscle fiber atrophy and secondarily as an indicator of bone deterioration by assessing the effects of spaceflight or hind limb unloading.
Methods
In the first experiment, 6 mice were flown aboard the space shuttle (STS-135) for 13 days and 8 earthbound mice served as controls. In the second experiment, 14 mice underwent hind limb unloading (HLU) for 13 days; 13 additional mice served as controls. EIM measurements were made on ex vivo gastrocnemius muscle. Quantitative microscopy and areal bone mineral density (aBMD) measurements of the hindlimb were also performed.
Results
Reductions in the multifrequency phase-slope parameter were observed for both the space flight and HLU cohorts compared to their respective controls. For ground control and spaceflight groups, the values were 24.7±1.3°/MHz and 14.1±1.6°/MHz, respectively (p=0.0013); for control and HLU groups, the values were 23.9±1.6°/MHz and 19.0±1.0°/MHz, respectively (p=0.014). This parameter also correlated with muscle fiber size (ρ=0.65, p=0.011) for spaceflight and hind limb aBMD (ρ=0.65, p=0.0063) for both groups.
Conclusions
These data support the concept that EIM may serve as a useful tool for assessment of muscle disuse secondary to immobilization or microgravity.
PMCID: PMC4653813  PMID: 24292610
Muscle; Spaceflight; Hind Limb Unloading; Disuse; Electrical Impedance
12.  Treatment Outcomes of Patients With Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis According to Drug Susceptibility Testing to First- and Second-line Drugs: An Individual Patient Data Meta-analysis 
Bastos, Mayara L. | Hussain, Hamidah | Weyer, Karin | Garcia-Garcia, Lourdes | Leimane, Vaira | Leung, Chi Chiu | Narita, Masahiro | Penã, Jose M. | Ponce-de-Leon, Alfredo | Seung, Kwonjune J. | Shean, Karen | Sifuentes-Osornio, José | Van der Walt, Martie | Van der Werf, Tjip S. | Yew, Wing Wai | Menzies, Dick | Ahuja, S. | Ashkin, D. | Avendaño, M. | Banerjee, R. | Bauer, M. | Becerra, M. | Benedetti, A. | Burgos, M. | Centis, R. | Chan, E.D. | Chiang, C.Y. | Cobelens, F. | Cox, H. | D'Ambrosio, L. | de Lange, W.C.M. | DeRiemer, K. | Enarson, D. | Falzon, D. | Flanagan, K. | Flood, J. | Gandhi, N. | Garcia-Garcia, L. | Granich, R.M. | Hollm-Delgado, M.G. | Holtz, T.H. | Hopewell, P. | Iseman, M. | Jarlsberg, L.G. | Keshavjee, S. | Kim, H.R. | Koh, W.J. | Lancaster, J. | Lange, C. | Leimane, V. | Leung, C.C. | Li, J. | Menzies, D. | Migliori, G.B. | Mitnick, C.M. | Narita, M. | Nathanson, E. | Odendaal, R. | O'Riordan, P. | Pai, M. | Palmero, D. | Park, S.K. | Pasvol, G. | Pena, J. | Pérez-Guzmán, C. | Ponce-de-Leon, A. | Quelapio, M.I.D. | Quy, H.T. | Riekstina, V. | Robert, J. | Royce, S. | Salim, M. | Schaaf, H.S. | Seung, K.J. | Shah, L. | Shean, K. | Shim, T.S. | Shin, S.S. | Shiraishi, Y. | Sifuentes-Osornio, J. | Sotgiu, G. | Strand, M.J. | Sung, S.W. | Tabarsi, P. | Tupasi, T.E. | Vargas, M.H. | van Altena, R. | van der Walt, M. | van der Werf, T.S. | Viiklepp, P. | Westenhouse, J. | Yew, W.W. | Yim, J.J.
The clinical validity of drug susceptibility testing (DST) for pyrazinamide, ethambutol, and second-line antituberculosis drugs is uncertain. In an individual patient data meta-analysis of 8955 patients with confirmed multidrug-resistant tuberculosis, DST results for these drugs were associated with treatment outcomes.
Background. Individualized treatment for multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis depends upon reliable and valid drug susceptibility testing (DST) for pyrazinamide, ethambutol, and second-line tuberculosis drugs. However, the reliability of these tests is uncertain, due to unresolved methodological issues. We estimated the association of DST results for pyrazinamide, ethambutol, and second-line drugs with treatment outcomes in patients with MDR tuberculosis and XDR tuberculosis.
Methods. We conducted an analysis of individual patient data assembled from 31 previously published cohort studies of patients with MDR and XDR tuberculosis. We used data on patients' clinical characteristics including DST results, treatment received, outcomes, and laboratory methods in each center.
Results. DST methods and treatment regimens used in different centers varied considerably. Among 8955 analyzed patients, in vitro susceptibility to individual drugs was consistently and significantly associated with higher odds of treatment success (compared with resistance to the drug), if that drug was used in the treatment regimen. Various adjusted and sensitivity analyses suggest that this was not explained by confounding. The adjusted odds of treatment success for ethambutol, pyrazinamide, and the group 4 drugs ranged from 1.7 to 2.3, whereas for second-line injectables and fluoroquinolones, odds ranged from 2.4 to 4.6.
Conclusions. DST for ethambutol, pyrazinamide, and second-line tuberculosis drugs appears to provide clinically useful information to guide selection of treatment regimens for MDR and XDR tuberculosis.
doi:10.1093/cid/ciu619
PMCID: PMC4296130  PMID: 25097082
tuberculosis; drug susceptibility test; treatment outcomes; multidrug resistant; meta-analysis
13.  Serum microRNA panel as biomarkers for early diagnosis of colorectal adenocarcinoma 
Zheng, G | Du, L | Yang, X | Zhang, X | Wang, L | Yang, Y | Li, J | Wang, C
British Journal of Cancer  2014;111(10):1985-1992.
Background:
Currently, none of the available colorectal adenocarcinoma (CAC) testing has been established as a well-accepted diagnosis tool, particularly for the early stage of CAC. The recent discovery of serum microRNA (miRNA) profile has provided a new auxiliary approach for tumour diagnosis. Our study is involved in the global analysis of serum miRNAs during the normal–colorectal adenoma (CA)–CAC sequence.
Methods:
Serum samples were collected from 307 CAC patients, 164 CA patients and 226 healthy controls. Differentially expressed serum miRNAs were screened with Miseq sequencing followed by the reverse transcription PCR (RT–qPCR) validation. The miRNA panel was developed with a logistic regression model and validated using an independent cohort. The miRNA levels in CAC patients of different clinical stages and CA patients of different grades were compared. Receiver operating characteristic curves were constructed to evaluate the diagnostic accuracy of the panel.
Results:
The Miseq sequencing results revealed 15 differentially expressed miRNAs in the intersection of CAC vs CA and CA vs healthy controls according to our criteria. After the selection and validation process via RT–qPCR, we identified a four-miRNA panel (miR-19a-3p, miR-223-3p, miR-92a-3p and miR-422a) with a high diagnostic accuracy of CAC. Even in the low-carcinoembryonic antigen level group, the diagnostic accuracy of this miRNA panel was still acceptable (AUC=0.810). Surprisingly, our results indicated that the miRNA panel could differentiate stage I/II CAC from controls. In addition, this panel could also differentiate CA from CAC (AUC=0.886) and healthy controls (AUC=0.765).
Conclusions:
We established a serum four-miRNA panel with considerable clinical value in the early-stage diagnosis of CAC.
doi:10.1038/bjc.2014.489
PMCID: PMC4229633  PMID: 25233400
microRNA; colorectal adenocarcinoma; colorectal adenoma; miseq sequencing; RT–qPCR
14.  Dietary Protein Sources Affect Internal Quality of Raw and Cooked Shell Eggs under Refrigerated Conditions 
This study was conducted to evaluate the effects of various protein sources (soybean meal, SBM; cottonseed protein, CSP; double-zero rapeseed meal, DRM) on the internal quality of refrigerated eggs. A total of 360 laying hens (32 wk of age) were randomly allotted to six treatment groups (five replicates per treatment) and fed diets containing SBM, CSP, or DRM individually or in combination with equal crude protein content (SBM-CSP, SBM-DRM, and CSP-DRM) as the protein ingredient(s). A 6×3 factorial arrangement was employed with dietary types and storage time (0 d, 2 wk, and 4 wk) as the main effects. After 12 wk of diet feeding, a total of 270 eggs were collected for egg quality determination. The egg Haugh unit (HU) in the CSP, SBM-DRM, and DRM groups were significantly lower than those in the SBM and SBM-CSP groups. The hardness and springiness of the cooked yolk in the CSP group were significantly higher than those in the other treatment groups. A lower HU, lower yolk index and higher albumen pH were observed in the DRM group compared to the SBM and SBM-CSP groups when the eggs were stored to 4 wk, and the HU was improved in the CSP-DRM group compared to the DRM group (p<0.05). Higher yolk hardness was observed in the CSP group compared to the other groups during storage (p<0.05), but the hardness of the cooked yolk in the SBM-CSP and CSP-DRM groups showed no difference in comparison to the SBM group. In conclusion, CSP may ameliorate the negative effects of DRM on the HU of refrigerated eggs, and SBM or DRM may alleviate the adverse effects of CSP on yolk hardness.
doi:10.5713/ajas.15.0181
PMCID: PMC4647105  PMID: 26580286
Plant Protein Ingredient; Internal Quality; Refrigeration; Chicken Egg
15.  Catabolic cytokines disrupt the circadian clock and the expression of clock-controlled genes in cartilage via an NFкB-dependent pathway 
Osteoarthritis and Cartilage  2015;23(11):1981-1988.
Summary
Objective
To define how the catabolic cytokines (Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFα)) affect the circadian clock mechanism and the expression of clock-controlled catabolic genes within cartilage, and to identify the downstream pathways linking the cytokines to the molecular clock within chondrocytes.
Methods
Ex vivo cartilage explants were isolated from the Cry1-luc or PER2::LUC clock reporter mice. Clock gene dynamics were monitored in real-time by bioluminescence photon counting. Gene expression changes were studied by qRT-PCR. Functional luc assays were used to study the function of the core Clock/BMAL1 complex in SW-1353 cells. NFкB pathway inhibitor and fluorescence live-imaging of cartilage were performed to study the underlying mechanisms.
Results
Exposure to IL-1β severely disrupted circadian gene expression rhythms in cartilage. This effect was reversed by an anti-inflammatory drug dexamethasone, but not by other clock synchronizing agents. Circadian disruption mediated by IL-1β was accompanied by disregulated expression of endogenous clock genes and clock-controlled catabolic pathways. Mechanistically, NFкB signalling was involved in the effect of IL-1β on the cartilage clock in part through functional interference with the core Clock/BMAL1 complex. In contrast, TNFα had little impact on the circadian rhythm and clock gene expression in cartilage.
Conclusion
In our experimental system (young healthy mouse cartilage), we demonstrate that IL-1β (but not TNFα) abolishes circadian rhythms in Cry1-luc and PER2::LUC gene expression. These data implicate disruption of the chondrocyte clock as a novel aspect of the catabolic responses of cartilage to pro-inflammatory cytokines, and provide an additional mechanism for how chronic joint inflammation may contribute to osteoarthritis (OA).
doi:10.1016/j.joca.2015.02.020
PMCID: PMC4638193  PMID: 26521744
Circadian clock; Cartilage; Cytokine; Inflammation; Osteoarthritis
16.  The effects of comorbidity in defining major depression subtypes associated with long-term course and severity 
Psychological medicine  2014;44(15):3289-3302.
Background
Although variation in long-term course of major depressive disorder (MDD) is not strongly predicted by existing symptom subtype distinctions, recent research suggests that prediction can be improved by using machine learning methods. However, it is not known whether these distinctions can be refined by added information about comorbid conditions. The current report presents results on this question.
Methods
Data come from 8,261 respondents with lifetime DSM-IV MDD in the WHO World Mental Health (WMH) Surveys. Outcomes include four retrospectively-reported measures of persistence-severity of course (years in episode; years in chronic episodes, hospitalization for MDD; disability due to MDD). Machine learning methods (regression tree analysis; lasso, ridge, and elastic net penalized regression) followed by k-means cluster analysis were used to augment previously-detected subtypes with information about prior comorbidity to predict these outcomes.
Results
Predicted values were strongly correlated across outcomes. Cluster analysis of predicted values found 3 clusters with consistently high, intermediate, or low values. The high-risk cluster (32.4% of cases) accounted for 56.6–72.9% of high persistence, high chronicity, hospitalization, and disability. This high-risk cluster had both higher sensitivity and likelihood-ratio positive (relative proportions of cases in the high-risk cluster versus other clusters having the adverse outcomes) than in a parallel analysis that excluded measures of comorbidity as predictors.
Conclusions
Although results using the retrospective data reported here suggest that useful MDD subtyping distinctions can be made with machine learning and clustering across multiple indicators of illness persistence-severity, replication is need with prospective data to confirm this preliminary conclusion.
doi:10.1017/S0033291714000993
PMCID: PMC4180779  PMID: 25066141
Comorbidity; data mining; depression subtypes; depression symptom profiles; elastic net; machine learning; predictive modeling; risk assessment
17.  TIFA, an inflammatory signaling adaptor, is tumor suppressive for liver cancer 
Shen, W | Chang, A | Wang, J | Zhou, W | Gao, R | Li, J | Xu, Y | Luo, X | Xiang, R | Luo, N | Stupack, D G
Oncogenesis  2015;4(10):e173-.
TIFA (TNF receptor associated factor (TRAF)-interacting protein with a Forkhead-associated (FHA) domain), also called T2BP, was first identified using a yeast two-hybrid screening. TIFA contains a FHA domain, which directly binds phosphothreonine and phosphoserine, and a consensus TRAF6-binding motif. TIFA-mediated oligomerization and poly-ubiquitinylation of TRAF6 mediates signaling downstream of the Tumor necrosis factor alpha receptor 1 (TNFaR-I) and interleukin-1/Toll-like receptor 4 (TLR4) pathways. Examining TIFA expression in hepatocellular carcinoma (HCC) tissues microarrays, we noted marked decreases TIFA reactivity in tumor versus control samples. In agreement, we found that HCC cell lines show reduced TIFA expression levels versus normal liver controls. Reconstituting TIFA expression in HCC cell lines promoted two independent apoptosis signaling pathways: the induction of p53 and cell cycle arrest, and the activation of caspase-8 and caspase-3. In contrast, the expression of a non-oligomerizing mutant of TIFA impacted cells minimally, and suppression of TIFA expression protected cells from apoptosis. Mice bearing TIFA overexpression hepatocellular xenografts develop smaller tumors versus TIFA mutant tumors; terminal deoxynucleotidyl transferase dUTP nick end labeling staining demonstrates increased cell apoptosis, and decreased proliferation, reflecting cell cycle arrest. Interestingly, p53 has a greater role in decreased proliferation than cell death, as it appeared dispensable for TIFA-induced cell killing. The findings demonstrate a novel suppressive role of TIFA in HCC progression via promotion of cell death independent of p53.
doi:10.1038/oncsis.2015.30
PMCID: PMC4632091  PMID: 26501855
18.  Transformation and Removal Pathways of Four Common PPCP/EDCs in Soil 
Dodgen, LK | Li, J | Wu, X | Lu, Z | Gan, JJ
Pharmaceutical and personal care products (PPCPs) and endocrine disrupting chemicals (EDCs) enter the soil environment via irrigation with treated wastewater, groundwater recharge, and land application of biosolids. The transformation and fate of PPCP/EDCs in soil affects their potential for plant uptake and groundwater pollution. This study examined four PPCP/EDCs (bisphenol A, diclofenac, naproxen, and 4-nonylphenol) in soil by using 14C-labeling and analyzing mineralization, extractable residue, bound residue, and formation of transformation products. At the end of 112 d of incubation, the majority of 14C-naproxen and 14C-diclofenac was mineralized to 14CO2, while a majority of 14C-bisphenol A and 14C-nonylphenol was converted to bound residue. After 112 d, the estimated half-lives of the parent compounds were only 1.4 – 5.4 d. However a variety of transformation products were found and several for bisphenol A and diclofenac were identified, suggesting the need to consider degradation intermediates in soils impacted by PPCP/EDCs.
doi:10.1016/j.envpol.2014.06.002
PMCID: PMC4134382  PMID: 24997388
19.  PD-1+ CD8+ T cells are exhausted in tumours and functional in draining lymph nodes of colorectal cancer patients 
Wu, X | Zhang, H | Xing, Q | Cui, J | Li, J | Li, Y | Tan, Y | Wang, S
British Journal of Cancer  2014;111(7):1391-1399.
Background:
The blockade of PD-1–PD-L1 pathway is emerging as an effective therapeutic strategy for several advanced cancers. But the immune regulatory role of PD-1–PD-L1 pathway is not clear in colorectal cancer (CRC) patients. This study aims to evaluate the role of PD-1–PD-L1 pathway in CD8+ T-cell functions in tumour-draining lymph nodes (TDLNs) and tumours of CRC patients.
Methods:
PD-1 expression on CD8+ T cells was examined by flow cytometry, and PD-L1 expression in TDLNs and tumour tissues were examined by immunohistochemistry. Production of IFN-γ, IL-2 and expression of granzyme B, perforin in CD8+ T cells were detected by intracellular staining.
Results:
PD-1 expression is markedly upregulated on CD8+ T cells in TDLNs and tumours compared with that in peripheral blood. PD-1-expressing CD8+ T cells are competent for production of cytokine (IL-2 and IFN-γ) and perforin in the tumour-free lymph nodes (TFLNs), but exhibit exhausted phenotypes in tumours. In addition, PD-L1 is highly expressed in tumours rather than TFLNs, which is closely correlated with the impairment of IFN-γ production of tumour-infiltrating PD-1+ CD8+ T cells.
Conclusions:
Our findings suggest a suppressive effect of PD-1 on CD8+ T-cell function in tumours, but not in TFLNs.
doi:10.1038/bjc.2014.416
PMCID: PMC4183848  PMID: 25093496
PD-1; exhaustion; CD8+ T cell; draining lymph node; colorectal cancer
20.  MFG-E8, a clearance glycoprotein of apoptotic cells, as a new marker of disease severity in chronic obstructive pulmonary disease 
Milk fat globule epidermal growth factor 8 (MFG-E8) is an opsonin involved in the phagocytosis of apoptotic cells. In patients with chronic obstructive pulmonary disease (COPD), apoptotic cell clearance is defective. However, whether aberrant MFG-E8 expression is involved in this defect is unknown. In this study, we examined the expression of MFG-E8 in COPD patients. MFG-E8, interleukin (IL)-1β and transforming growth factor (TGF)-β levels were measured in the plasma of 96 COPD patients (93 males, 3 females; age range: 62.12±10.39) and 87 age-matched healthy controls (85 males, 2 females; age range: 64.81±10.11 years) using an enzyme-linked immunosorbent assay. Compared with controls, COPD patients had a significantly lower plasma MFG-E8 levels (P<0.01) and significantly higher plasma TGF-β levels (P=0.002), whereas there was no difference in plasma IL-1β levels between the two groups. Moreover, plasma MFG-E8 levels decreased progressively between Global Initiative for Chronic Obstructive Lung Disease (GOLD) I and GOLD IV stage COPD. Multiple regression analysis showed that the forced expiratory volume in 1 s (FEV1 % predicted) and smoking habit were powerful predictors of MFG-E8 in COPD (P<0.01 and P=0.026, respectively). MFG-E8 was positively associated with the FEV1 % predicted and negatively associated with smoking habit. The area under the receiver operating characteristic curve was 0.874 (95% confidence interval: 0.798-0.95; P<0.01). Our findings demonstrated the utility of MFG-E8 as a marker of disease severity in COPD and that cigarette smoke impaired MFG-E8 expression in these patients.
doi:10.1590/1414-431X20154730
PMCID: PMC4671530  PMID: 26375445
Apoptosis; COPD; MFG-E8; Phagocytosis; Smoking
21.  Fibroblasts Regulate Variable Aggressiveness of Syndromic Keratocystic and Non-syndromic Odontogenic Tumors 
Journal of Dental Research  2014;93(9):904-910.
Keratocystic odontogenic tumors (KCOTs) are jaw lesions that can be either sporadic or associated with nevoid basal cell carcinoma syndrome, which typically occurs as multiple, aggressive lesions that can lead to large areas of bone destruction and resorption and cause major impairment and even jaw fracture. To clarify the role of fibroblasts in the aggressivness of syndromic (S-) as compared with non-syndromic (NS-) KCOTs, we assessed fibroblasts derived from 16 S- and NS-KCOTs for differences in cell proliferation, multilineage differentiation potential, alkaline phosphatase activity, and osteoclastogenic potential. S-KCOT fibroblasts had proliferative and osteoclastogenic capacity higher than those from NS-KCOTs, as evidenced by higher numbers of tartrate-resistant acid-phosphatase-positive multinuclear cells, expression of cyclooxygenase 2, and ratio of receptor activator of nuclear factor–kappa B ligand to osteoprotegerin. The osteogenic potential was higher for S- than for NS-KCOT fibroblasts and was associated with lower mRNA expression of runt-related transcription factor 2, collagen type I α1, osteocalcin, and osteopontin as well as reduced alkaline phosphatase activity. These results suggest that the distinct characteristics of fibroblasts in KCOTs are responsible for the greater aggressiveness observed in the syndromic subtype.
Abbreviations: AP, alkaline phosphatase; CK, cytokeratin; COL1A1, collagen type I α1; COX-2, cyclooxygenase-2; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-1α, interleukin 1α; KCOT, keratocystic odontogenic tumor; NBCCS, nevoid basal cell carcinoma syndrome; NS-KCOT, non-syndrome-associated KCOT; OCN, osteocalcin; OPG, osteoprotegerin; OPN, osteopontin; RANKL, receptor activator of nuclear factor-kappa B ligand; Runx2, runt-related transcription factor 2; S-KCOT, syndrome-associated KCOT; TAF, tumor-associated fibroblast; and TRAP, tartrate-resistant acid phosphatase.
doi:10.1177/0022034514542108
PMCID: PMC4541102  PMID: 24972872
PTCH1; nevoid basal cell carcinoma syndrome; keratocystic odontogenic tumors; osteogenesis; osteoclastogenesis; stroma cell
22.  Ufmylation and FATylation Pathways are Down Regulated in Human Alcoholic and Non Alcoholic Steatohepatitis, and Mice Fed DDC, where Mallory-Denk Bodies (MDBs) Form 
We previously reported the mechanisms involved in the formation of Mallory-Denk bodies (MDBs) in mice fed DDC. To further provide clinical evidence as to how ubiquitin-like protein (Ubls) modification, gene transcript expression in Ufmylation and FATylation were investigated in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies and frozen liver sections from DDC re-fed mice were used. Real-time PCR analysis showed that all Ufmylation molecules (Ufm1, Uba5, Ufc1, Ufl1 and UfSPs) were significantly down regulated, both in DDC re-fed mice livers and patients’ livers where MDBs had formed, indicating that gene transcript changes were limited to MDB-forming livers where the protein quality control system was down regulated. FAT10 and subunits of the immunoproteasome (LMP2 and LMP7) were both up regulated as previously shown. An approximate 176- and 5-fold up regulation (respectively) of FAT10 were observed in the DDC re-fed mice liver and in the livers of human alcoholic hepatitis with MDBs present, implying that there was an important role played by this gene. The FAT10-specific E1 and E2 enzymes Uba6 and USE1, however, were found to be down regulated both in patients’ livers and in the liver of DDC re-fed mice. Interestedly, the down regulation of mRNA levels was proportionate to MDB abundance in the liver tissues. Our results show the first systematic demonstration of transcript regulation of Ufmylation and FATylation in the liver of patients who form MDBs, where protein quality control is down regulated. This was also shown in livers of DDC re-fed mice where MDBs had formed.
doi:10.1016/j.yexmp.2014.05.010
PMCID: PMC4127344  PMID: 24893112
Ubiquitin-like (Ubl) modifiers; Mallory-Denk bodies (MDBs); Ufm1; FAT10; transcript regulation
23.  CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis 
Background
The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them.
Methods
We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES).
Results
997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported.
Conclusions
Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT.
Clinical trial registration
ID number NCT01193075.
doi:10.1136/jnnp-2014-308826
PMCID: PMC4516002  PMID: 25430934
GENETICS; NEUROGENETICS; NEUROPATHY
24.  Water-Soluble Silicon Quantum Dots with Quasi-Blue Emission 
In this study, water-soluble silicon quantum dots have quasi-blue emission at 390 nm by being capped with 1-vinylimidazole in resese micelles. As-obtained silicon quantum dots have a diameter of 2~5 nm and high crystallinity. The quasi-blue emission of the silicon quantum dots is likely attributed to the polarity of the capping ligands. Moreover, the silicon quantum dots are water-soluble and have photoluminescence nanosecond decay time, suggesting their potential application in biological field.
doi:10.1186/s11671-015-1012-2
PMCID: PMC4512961  PMID: 26204998
Water-soluble; Quasi-blue emission; Silicon quantum dots
25.  Association of body mass index with disease severity and prognosis in patients with non-cystic fibrosis bronchiectasis 
The objective of this observational, multicenter study was to evaluate the association of body mass index (BMI) with disease severity and prognosis in patients with non-cystic fibrosis bronchiectasis. A total of 339 patients (197 females, 142 males) diagnosed with non-cystic fibrosis bronchiectasis by high-resolution computed tomography were classified into four groups: underweight (BMI<18.5 kg/m2), normal weight (18.5≤BMI<25.0 kg/m2), overweight (25.0≤BMI<30.0 kg/m2), and obese (BMI≥30.0 kg/m2). Clinical variables expressing disease severity were recorded, and acute exacerbations, hospitalizations, and survival rates were estimated during the follow-up period. The mean BMI was 21.90 kg/m2. The underweight group comprised 28.61% of all patients. BMI was negatively correlated with acute exacerbations, C-reactive protein, erythrocyte sedimentation rate, radiographic extent of bronchiectasis, and chronic colonization by P. aeruginosa and positively correlated with pulmonary function indices. BMI was a significant predictor of hospitalization risk independent of relevant covariates. The 1-, 2-, 3-, and 4-year cumulative survival rates were 94%, 86%, 81%, and 73%, respectively. Survival rates decreased with decreasing BMI (χ2=35.16, P<0.001). The arterial carbon dioxide partial pressure, inspiratory capacity, age, BMI, and predicted percentage of forced expiratory volume in 1 s independently predicted survival in the Cox proportional hazard model. In conclusion, an underweight status was highly prevalent among patients with non-cystic fibrosis bronchiectasis. Patients with a lower BMI were prone to developing more acute exacerbations, worse pulmonary function, amplified systemic inflammation, and chronic colonization by P. aeruginosa. BMI was a major determinant of hospitalization and death risks. BMI should be considered in the routine assessment of patients with non-cystic fibrosis bronchiectasis.
doi:10.1590/1414-431X20154135
PMCID: PMC4541691  PMID: 26176309
Bronchiectasis; Body mass index; Prognosis; Survival; Underweight

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