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1.  Associations of Educational Attainment, Occupation, Social Class and Major Depressive Disorder among Han Chinese Women 
PLoS ONE  2014;9(1):e86674.
Background
The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years.
Principal findings
We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25–0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77–0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86–0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders.
Conclusions
In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype.
doi:10.1371/journal.pone.0086674
PMCID: PMC3909008  PMID: 24497966
2.  Childhood Sexual Abuse and the Development of Recurrent Major Depression in Chinese Women 
PLoS ONE  2014;9(1):e87569.
Background
Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set?
Method
Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
Results
We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19–5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58–3.15), genital (OR 5.24, 95% CI 3.52–8.15) and intercourse (OR 10.65, 95% CI 5.56–23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11–2.27) and phobia (OR 1.41, 95%CI 1.09–1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20–1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02–2.02). Intercourse (OR 3.47, 95%CI 1.66–8.22), use of force and threats (OR 1.95, 95%CI 1.05–3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20–1.64) were significantly associated with recurrent MD.
Conclusions
In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD.
doi:10.1371/journal.pone.0087569
PMCID: PMC3906190  PMID: 24489940
3.  Clinical Features of Patients with Dysthymia in a Large Cohort of Han Chinese Women with Recurrent Major Depression 
PLoS ONE  2013;8(12):e83490.
Background
Dysthymia is a form of chronic mild depression that has a complex relationship with major depressive disorder (MDD). Here we investigate the role of environmental risk factors, including stressful life events and parenting style, in patients with both MDD and dysthymia. We ask whether these risk factors act in the same way in MDD with and without dysthymia.
Results
We examined the clinical features in 5,950 Han Chinese women with MDD between 30–60 years of age across China. We confirmed earlier results by replicating prior analyses in 3,950 new MDD cases. There were no significant differences between the two data sets. We identified sixteen stressful life events that significantly increase the risk of dysthymia, given the presence of MDD. Low parental warmth, from either mother or father, increases the risk of dysthymia. Highly threatening but short-lived threats (such as rape) are more specific for MDD than dysthymia. While for MDD more severe life events show the largest odds ratio versus controls, this was not seen for cases of MDD with or without dysthymia.
Conclusions
There are increased rates of stressful life events in MDD with dysthymia, but the impact of life events on susceptibility to dysthymia with MDD differs from that seen for MDD alone. The pattern does not fit a simple dose-response relationship, suggesting that there are moderating factors involved in the relationship between environmental precipitants and the onset of dysthymia. It is possible that severe life events in childhood events index a general susceptibility to chronic depression, rather than acting specifically as risk factors for dysthymia.
doi:10.1371/journal.pone.0083490
PMCID: PMC3873934  PMID: 24386213
4.  Suicidal Risk Factors of Recurrent Major Depression in Han Chinese Women 
PLoS ONE  2013;8(11):e80030.
The relationship between suicidality and major depression is complex. Socio- demography, clinical features, comorbidity, clinical symptoms, and stressful life events are important factors influencing suicide in major depression, but these are not well defined. Thus, the aim of the present study was to assess the associations between the above-mentioned factors and suicide ideation, suicide plan, and suicide attempt in 6008 Han Chinese women with recurrent major depression (MD). Patients with any suicidality had significantly more MD symptoms, a significantly greater number of stressful life events, a positive family history of MD, a greater number of episodes, a significant experience of melancholia, and earlier age of onset. Comorbidity with dysthymia, generalized anxiety disorder (GAD), social phobia, and animal phobia was seen in suicidal patients. The present findings indicate that specific factors act to increase the likelihood of suicide in MD. Our results may help improve the clinical assessment of suicide risk in depressed patients, especially for women.
doi:10.1371/journal.pone.0080030
PMCID: PMC3842272  PMID: 24312196
5.  Clinical features and risk factors for post-partum depression in a large cohort of Chinese women with recurrent major depressive disorder 
Journal of Affective Disorders  2012;136(3):983-987.
Background
Post partum depression (PPD) is relatively common in China but its clinical characteristics and risk factors have not been studied. We set out to investigate whether known risk factors for PPD could be found in Chinese women.
Methods
A case control design was used to determine the impact of known risk factors for PPD in a cohort of 1970 Chinese women with recurrent DSM-IV major depressive disorder (MDD). In a within-case design we examined the risk factors for PPD in patients with recurrent MDD. We compared the clinical features of MDD in cases with PPD to those without MDD. Odds ratios were calculated using logistic and ordinal regression.
Results
Lower occupational and educational statuses increased the risk of PPD, as did a history of pre-menstrual symptoms, stressful life events and elevated levels of the personality trait of neuroticism. Patients with PPD and MDD were more likely to experience a comorbid anxiety disorder, had a younger age of onset of MDD, have higher levels of neuroticism and dysthymia.
Limitations
Results obtained in this clinical sample may not be applicable to PPD within the community. Data were obtained retrospectively and we do not know whether the correlations we observe have the same causes as those operating in other populations.
Conclusions
Our results are consistent with the hypothesis that the despite cultural differences between Chinese and Western women, the phenomenology and risk factors for PPD are very similar.
doi:10.1016/j.jad.2011.06.047
PMCID: PMC3315022  PMID: 21824665
Postpartum depression; Major depressive disorder; Neuroticism; Anxiety disorder
6.  Selective Syntheses of Δα,β and Δβ,γ Butenolides from Allylic Cyclopropenecarboxylates via Tandem Ring Expansion/[3,3]-Sigmatropic Rearrangements 
Organic letters  2013;15(7):1500-1503.
Allylic cyclopropenecarboxylates undergo ring expansion reactions to give 2-allyloxyfuran intermediates, which subsequently rearrange to Δβ,γ butenolides via Claisen rearrangement or to the corresponding Δα,β butenolides via further Cope rearrangement. Also described are methods for chirality transfer in the rearrangement of non-racemic allylic esters.
doi:10.1021/ol400264a
PMCID: PMC3908874  PMID: 23514430
7.  Role of regulator of G protein signaling proteins in bone 
Regulators of G protein signaling (RGS) proteins are a family with more than 30 proteins that all contain an RGS domain. In the past decade, increasing evidence has indicated that RGS proteins play crucial roles in the regulation of G protein coupling receptors (GPCR), G proteins, and calcium signaling during cell proliferation, migration, and differentiation in a variety of tissues. In bone, those proteins modulate bone development and remodeling by influencing various signaling pathways such as GPCR-G protein signaling, Wnt, calcium oscillations and PTH. This review summarizes the recent advances in the understanding of the regulation of RGS genes expression, as well as the functions and mechanisms of RGS proteins, especially in regulating GPCR-G protein signaling, Wnt signaling, calcium oscillations signaling and PTH signaling during bone development and remodeling. This review also highlights the regulation of different RGS proteins in osteoblasts, chondrocytes and osteoclasts. The knowledge from the recent advances of RGS study summarized in the review would provide the insights into new therapies for bone diseases.
PMCID: PMC3966557  PMID: 24389209
Osteoblasts; Osteoclasts; Bone; Heterotrimeric G protein; G protein coupled receptor; PTH; PTHrP; Calcium Sensing Receptor; Regulator of G Protein Signaling; RGS2; RGS5; RGS10; RGS12; RGS18; Wnt; bone remodeling; bone development
8.  High-Sensitivity C-Reactive Protein Predicts Mortality and Technique Failure in Peritoneal Dialysis Patients 
PLoS ONE  2014;9(3):e93063.
Introduction
An elevated level of serum C-reactive protein (CRP) is widely considered an indicator of an underlying inflammatory disease and a long-term prognostic predictor for dialysis patients. This cross-sectional cohort study was designed to assess the correlation between the level of high-sensitivity CRP (HS-CRP) and the outcome of peritoneal dialysis (PD) patients.
Methods
A total of 402 patients were stratified into 3 tertiles (lower, middle, upper) according to serum HS-CRP level and and followed up from October 2009 to September 2011. During follow-up, cardiovascular events, infection episodes, technique failure, and mortality rate were recorded.
Results
During the 24-month follow-up, 119 of 402 patients (29.6%) dropped out from PD, including 28 patients (7.0%) who died, 81 patients (20.1%) who switched to hemodialysis, and 10 patients (2.5%) who underwent kidney transplantation. The results of Kaplan–Meier analysis and log-rank test demonstrated a significant difference in the cumulative patient survival rate across the 3 tertiles (the lowest rate in upper tertile). On multivariate Cox regression analysis, only higher HS-CRP level, older age, the presence of diabetes mellitus (DM), lower serum albumin level, and the occurrence of cardiovascular events during follow-up were identified as independent predictors of mortality. Every 1 mg/L increase in HS-CRP level was independently predictive of a 1.4% increase in mortality. Multivariate Cox regression analysis also showed that higher HS-CRP level, the presence of DM, lower hemoglobin level, lower serum albumin level, higher dialysate/plasma creatinine ratio, and the occurrence of infective episodes and cardiovascular events during follow-up were independent predictors of technique failure.
Conclusions
The present study shows the importance of HS-CRP in the prediction of 2-year mortality and technique survival in PD patients independent of age, diabetes, hypoalbuminemia, and the occurrence of cardiovascular events.
doi:10.1371/journal.pone.0093063
PMCID: PMC3965534  PMID: 24667814
9.  Who’s in Favor of Translational Cell Therapy for Stroke: STEPS Forward Please? 
Cell transplantation  2009;18(7):691-693.
A consortium of translational stem cell and stroke experts from multiple academic institutes and biotechnology companies, under the guidance of the government (FDA/NIH), is missing. Here, we build a case for the establishment of this consortium if cell therapy for stroke is to advance from the laboratory to the clinic.
doi:10.3727/096368909X470883
PMCID: PMC3962837  PMID: 19796499
Stem cell transplantation; Tissue regeneration; Cellular therapy; Clinical translation
10.  Baculovirus Vector-Mediated Transfer of Sodium Iodide Symporter and Plasminogen Kringle 5 Genes for Tumor Radioiodide Therapy 
PLoS ONE  2014;9(3):e92326.
Background
Both tumor cells and their supporting endothelial cells should be considered for targeted cell killing when designing cancer treatments. Here we investigated the feasibility of combining radioiodide and antiangiogenic therapies after baculovirus-mediated transfer of genes encoding the sodium iodide symporter (NIS) and plasminogen kringle 5 (K5).
Methods
A recombinant baculovirus containing the NIS gene under control of the human telomerase reverse transcriptase (hTERT) promoter and the K5 gene driven by the early growth response 1 (Egr1) promoter was developed. Dual-luciferase reporter assay was performed to confirm the activation of hTERT transcription. NIS and K5 gene expression were identified by Western blot and Real-Time PCR. Functional NIS activity in baculovirus-infected Hela cells was confirmed by the uptake of 125I and cytotoxicity of 131I. The apoptotic effect of 131I-induced K5 on baculovirus-infected human umbilical vein endothelial cells (HUVECs) was analyzed by a flow cytometry-based assay. In vivo, NIS reporter gene imaging and therapeutic experiments with 131I were performed. Finally, the microvessel density (MVD) in tumors after treatment was determined by CD31 immunostaining.
Results
The activation of hTERT transcription was specifically up-regulated in tumor cells. NIS gene expression markedly increased in baculovirus-infected HeLa cells, but not in MRC5 cells. The Hela cells showed a significant increase of 125I uptake, which was inhibited by NaClO4, and a notably decreased cell survival rate by 131I treatment. Expression of the K5 gene induced by 131I was elevated in a dose- and time-dependent manner and resulted in the apoptosis of HUVECs. Furthermore, 131I SPECT imaging clearly showed cervical tumor xenografts infected with recombinant baculovirus. Following therapy, tumor growth was significantly retarded. CD31 immunostaining confirmed a significant decrease of MVD.
Conclusion
The recombinant baculovirus supports a promising strategy of NIS-based raidoiodide therapy combined with K5-based antiangiogenic therapy by targeting both the tumor and its supporting vessels.
doi:10.1371/journal.pone.0092326
PMCID: PMC3960225  PMID: 24647588
11.  V-ATPase subunit ATP6AP1 (Ac45) regulates osteoclast differentiation, extracellular acidification, lysosomal trafficking, and protease exocytosis in osteoclast-mediated bone resorption 
Lysosomal trafficking and protease exocytosis in osteoclasts are essential for ruffled border formation and bone resorption. Yet, the mechanism underlying lysosomal trafficking and the related process of exocytosis remains largely unknown. We found ATP6ap1 (Ac45), an accessory subunit of vacuolar-type H+-ATPases (V-ATPases), to be highly induced by receptor activator for nuclear factor kappa B ligand (RANKL) in osteoclast differentiation. Ac45 knockdown osteoclasts formed normal actin rings, but had severely impaired extracellular acidification and bone resorption. Ac45 knockdown significantly reduced osteoclast formation. The decrease in the number of osteoclasts does not result from abnormal apoptosis; rather, it results from decreased osteoclast precursor cell proliferation and fusion, which may be partially due to the downregulation of ERK phosphorylation and FBJ osteosarcoma oncogene (c-fos), nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and Tm7sf4 expression. Notably, Ac45 knockdown osteoclasts exhibited impaired lysosomal trafficking and exocytosis, as indicated by the absence of lysosomal trafficking to the ruffled border and a lack of cathepsin K exocytosis into the resorption lacuna. Our data revealed that the impaired exocytosis is specifically due to Ac45 deficiency, and not the general consequence of a defective V-ATPase. Together, our results demonstrate the essential role of Ac45 in osteoclast-mediated extracellular acidification and protease exocytosis, as well as the ability of Ac45 to guide lysosomal intracellular trafficking to the ruffled border, potentially through its interaction with the small GTPase Rab7. Our work indicates that Ac45 may be a novel therapeutic target for osteolytic disease.
doi:10.1002/jbmr.1623
PMCID: PMC3951719  PMID: 22467241
V-ATPase subunit ATP6AP1 (Ac45); osteoclast; lysosomal trafficking; protease exocytosis; bone resorption
12.  Synthesis, Spectroscopic Characterization, X-Ray Structure, and DFT Calculations of Some New 1,4-Dihydro-2,6-Dimethyl-3,5 -Pyridinedicarboxamides 
PLoS ONE  2014;9(3):e91361.
A series of novel 1,4-dihydro-2,6- dimethyl-3,5-pyridinedicarboxamides were synthesized and characterized by infrared absorption spectrum (IR), proton nuclear magnetic resonance (1H NMR), elemental analysis, ultraviolet spectrum (UV), and fluorescence techniques, together with X-ray single crystal diffraction. The results of density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations provided a reasonable explanation on the molecular structures, the molecular frontier orbital, and the spectra of electronic absorption and emission. The present work will be helpful to systematically understanding of the structures and the optical properties of 1,4-dihydropyridines for studying the structure-activity relationship and to develop new drugs and their analytical methods.
doi:10.1371/journal.pone.0091361
PMCID: PMC3953339  PMID: 24625887
13.  A Novel Algicide: Evidence of the Effect of a Fatty Acid Compound from the Marine Bacterium, Vibrio sp. BS02 on the Harmful Dinoflagellate, Alexandrium tamarense 
PLoS ONE  2014;9(3):e91201.
Alexandrium tamarense is a notorious bloom-forming dinoflagellate, which adversely impacts water quality and human health. In this study we present a new algicide against A. tamarense, which was isolated from the marine bacterium Vibrio sp. BS02. MALDI-TOF-MS, NMR and algicidal activity analysis reveal that this compound corresponds to palmitoleic acid, which shows algicidal activity against A. tamarense with an EC50 of 40 μg/mL. The effects of palmitoleic acid on the growth of other algal species were also studied. The results indicate that palmitoleic acid has potential for selective control of the Harmful algal blooms (HABs). Over extended periods of contact, transmission electron microscopy shows severe ultrastructural damage to the algae at 40 μg/mL concentrations of palmitoleic acid. All of these results indicate potential for controlling HABs by using the special algicidal bacterium and its active agent.
doi:10.1371/journal.pone.0091201
PMCID: PMC3953379  PMID: 24626054
14.  The Role of Astrocytes in Mediating Exogenous Cell-Based Restorative Therapy for Stroke 
Glia  2013;62(1):1-16.
Astrocytes have not been a major therapeutic target for the treatment of stroke, with most research emphasis on the neuron. Given the essential role that astrocytes play in maintaining physiological function of the central nervous system and the very rapid and sensitive reaction astrocytes have in response to cerebral injury or ischemic insult, we propose to replace the neurocentric view for treatment with a more nuanced astrocytic centered approach. In addition, after decades of effort in attempting to develop neuroprotective therapies, which target reduction of the ischemic lesion, there are no effective clinical treatments for stroke, aside from thrombolysis with tissue plasminogen activator, which is used in a small minority of patients. A more promising therapeutic approach, which may affect nearly all stroke patients, may be in promoting endogenous restorative mechanisms, which enhance neurological recovery. A focus of efforts in stimulating recovery post stroke is the use of exogenously administered cells. The present review focuses on the role of the astrocyte in mediating the brain network, brain plasticity, and neurological recovery post stroke. As a model to describe the interaction of a restorative cell-based therapy with astrocytes, which drives recovery from stroke, we specifically highlight the subacute treatment of stroke with multipotent mesenchymal stromal cell therapy.
doi:10.1002/glia.22585
PMCID: PMC3947888  PMID: 24272702
stroke; marrow stromal cells; microRNA; exosomes; Shh; tPA; restoration; plasticity
15.  First Report of Pseudobodo sp, a New Pathogen for a Potential Energy-Producing Algae: Chlorella vulgaris Cultures 
PLoS ONE  2014;9(3):e89571.
Chlorella vulgaris, is a kind of single-celled green algae, which could serve as a potential source of food and energy because of its photosynthetic efficiency. In our study, a pathogenic organism targeting C. vulgaris was discovered. The algae-lytic activity relates to a fraction from lysates of infected C. vulgaris that was blocked upon filtration through a 3 µm filter. 18S rRNA gene sequence analysis revealed that it shared 99.0% homology with the protist Pseudobodo tremulans. Scanning electron microscope analysis showed that Pseudobodo sp. KD51 cells were approximately 4–5 µm long, biflagellate with an anterior collar around the anterior part of the cell in unstressed feeding cells. Besides the initial host, Pseudobodo sp. KD51 could also kill other algae, indicating its relatively wide predatory spectrum. Heat stability, pH and salinity tolerance experiments were conducted to understand their effects on its predatory activities, and the results showed that Pseudobodo sp. KD51 was heat-sensitive, and pH and salinity tolerant.
doi:10.1371/journal.pone.0089571
PMCID: PMC3943784  PMID: 24599263
16.  Expression of the Murine Norovirus (MNV) ORF1 Polyprotein Is Sufficient to Induce Apoptosis in a Virus-Free Cell Model 
PLoS ONE  2014;9(3):e90679.
Investigations into human norovirus infection, replication and pathogenesis, as well as the development of potential antiviral agents, have been restricted by the lack of a cell culture system for human norovirus. To date, the optimal cell culture surrogate virus model for studying human norovirus biology is the murine norovirus (MNV). In this report we generate a tetracycline-regulated, inducible eukaryotic cell system expressing the entire MNV ORF1 polyprotein. Once induced, the MNV ORF1 polyprotein was faithfully processed to the six mature non-structural proteins that predominately located to a discrete perinuclear region, as has been observed in active MNV infection. Furthermore, we found that expression of the ORF1 polyprotein alone was sufficient to induce apoptosis, characterised by caspase-9 activation and survivin down-regulation. This cell line provides a valuable new tool for studying MNV ORF1 non-structural protein function, screening for potential antiviral agents and acts as a proof-of-principle for such systems to be developed for human noroviruses.
doi:10.1371/journal.pone.0090679
PMCID: PMC3944349  PMID: 24599381
17.  Cancer Incidence in Patients With Schizophrenia or Bipolar Disorder: A Nationwide Population-Based Study in Taiwan, 1997–2009 
Schizophrenia Bulletin  2011;39(2):407-416.
Background: Both genetic and environmental factors have been reasoned for cancer development in schizophrenia patients. However, the influence of age of onset and duration of schizophrenia on cancer incidence has rarely been emphasized. Besides, bipolar disorder tends to resemble schizophrenia from the perspective of multiple rare mutations. Comparing pattern and risk of cancers between schizophrenia and bipolar patients is illuminating. Methods: This study used the Taiwan National Health Insurance Database. A total of 71 317 schizophrenia and 20 567 bipolar disorder patients from 1997 to 2009 were enrolled. Both cohorts were followed up for cancer during the same period by record linkage with the cancer certification in Taiwan. Age and gender standardized incidence ratios (SIRs) of overall and site-specific cancers were calculated. Results: The SIR for all cancers was 1.17 for the schizophrenia cohort. Increased cancer risk (SIR: 1.31, 95% CI: 1.17–1.48) was observed in females but not males. For the bipolar disorder cohort, the SIR for all cancers was 1.29, but the excess risk was found in males (SIR: 1.42, 95% CI: 1.14–1.77) and not females. Cancer risk decreases as the duration and age of onset of schizophrenia increases. If schizophrenia is diagnosed before 50, the SIRs for colorectal, breast, cervical, and uterine cancers increase but if diagnosed after 50, the SIRs for all cancers decrease except for breast cancer. In bipolar disorder, the SIRs for all site-specific cancers were insignificant. Conclusions: Among schizophrenia patients, overall cancer risk varies inversely with age at diagnosis and disease duration. Besides, gender-specific cancer risks differ between schizophrenia and bipolar disorder.
doi:10.1093/schbul/sbr162
PMCID: PMC3576164  PMID: 22045828
schizophrenia; bipolar disorder; cancer; standardized incidence ratio
18.  A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells 
Cell Research  2012;23(3):394-408.
CCL5 is a member of the CC chemokine family expressed in a wide array of immune and non-immune cells in response to stress signals. CCL5 expression correlates with advanced human breast cancer. However, its functional significance and mode of action have not been established. Here, we show that CCL5-deficient mice are resistant to highly aggressive, triple-negative mammary tumor growth. Hematopoietic CCL5 is dominant in this phenotype. The absence of hematopoietic CCL5 causes aberrant generation of CD11b+/Gr-1+, myeloid-derived suppressor cells (MDSCs) in the bone marrow in response to tumor growth by accumulating Ly6Chi and Ly6G+ MDSCs with impaired capacity to suppress cytotoxicity of CD8+ T cells. These properties of CCL5 are observed in both orthotopic and spontaneous mammary tumors. Antibody-mediated systemic blockade of CCL5 inhibits tumor progression and enhances the efficacy of therapeutic vaccination against non-immunogenic tumors. CCL5 also helps maintain the immunosuppressive capacity of human MDSCs. Our study uncovers a novel, chemokine-independent activity of the hematopoietically derived CCL5 that promotes mammary tumor progression via generating MDSCs in the bone marrow in cooperation with tumor-derived colony-stimulating factors. The study sheds considerable light on the interplay between the hematopoietic compartment and tumor niche. Because of the apparent dispensable nature of this molecule in normal physiology, CCL5 may represent an excellent therapeutic target in immunotherapy for breast cancer as well as a broad range of solid tumors that have significant amounts of MDSC infiltration.
doi:10.1038/cr.2012.178
PMCID: PMC3587709  PMID: 23266888
CCL5; myeloid-derived suppressor cell; triple-negative breast cancer; immune response; mammary tumor; bone marrow; cytotoxic T lymphocyte
19.  Comparing strategies to assess multiple behavior change in behavioral intervention studies 
Background
Alternatives to individual behavior change methods have been proposed, however, little has been done to investigate how these methods compare.
Purpose
To explore four methods that quantify change in multiple risk behaviors targeting four common behaviors.
Methods
We utilized data from two cluster-randomized, multiple behavior change trials conducted in two settings: small businesses and health centers. Methods used were: (1) summative; (2) z-score; (3) optimal linear combination; and (4) impact score.
Results
In the Small Business study, methods 2 and 3 revealed similar outcomes. However, physical activity did not contribute to method 3. In the Health Centers study, similar results were found with each of the methods. Multivitamin intake contributed significantly more to each of the summary measures than other behaviors.
Conclusions
Selection of methods to assess multiple behavior change in intervention trials must consider study design, and the targeted population when determining the appropriate method/s to use.
doi:10.1007/s13142-013-0195-2
PMCID: PMC3597762  PMID: 23504621
multiple behavior change; intervention; methods; multiple risk factors
20.  Mx1-Cre mediated Rgs12 conditional knockout mice exhibit increased bone mass phenotype 
Genesis (New York, N.Y. : 2000)  2013;51(3):201-209.
Regulators of G-protein Signaling (Rgs) proteins are the members of a multigene family of GTPase-accelerating proteins (GAP) for the Galpha subunit of heterotrimeric G-proteins. Rgs proteins play critical roles in the regulation of G protein couple receptor (GPCR) signaling in normal physiology and human diseases such as cancer, heart diseases and inflammation. Rgs12 is the largest protein of the Rgs protein family. Some in vitro studies have demonstrated that Rgs12 plays a critical role in regulating cell differentiation and migration; however its function and mechanism in vivo is largely unknown. Here, we generated a floxed Rgs12 allele (Rgs12flox/flox) in which the exon 2, containing both PDZ and PTB_PID domains of Rgs12, was flanked with two loxp sites. By using the inducible Mx1-cre and Poly I:C system to specifically delete Rgs12 at postnatal 10 days in interferon-responsive cells including monocyte and macrophage cells, we found that Rgs12 mutant mice had growth retardation with the phenotype of increased bone mass. We further found that deletion of Rgs12 reduced osteoclast numbers and had no significant effect on osteoblast formation. Thus, Rgs12flox/flox conditional mice provide a valuable tool for in vivo analysis of Rgs12 function and mechanism through time- and cell-specific deletion of Rgs12.
doi:10.1002/dvg.22373
PMCID: PMC3908791  PMID: 23349096
Cre; loxP; FRT; conditional inactivation; Regulator of G protein signaling protein
21.  COL1A1 and COL2A1 Genes and Myopia Susceptibility: Evidence of Association and Suggestive Linkage to the COL2A1 Locus 
Purpose
Collagen involvement in myopia development via scleral remodeling is well-known. Recently, COL1A1 and COL2A1 gene polymorphisms were reported to be associated with high-grade and common myopia, respectively. This study was conducted to investigate whether these collagen genes are associated and/or genetically linked with myopia in large Caucasian family datasets.
Methods
High-grade myopia was defined as ≤–5.00 D. Two independent datasets comprising 146 (Duke) and 130 (Cardiff) families with high-grade myopia participated in the association study. Allelic discrimination assays were performed on tagging SNPs for COL1A1 and COL2A1. The pedigree disequilibrium test (PDT) and the association test in the presence of linkage (APL) were used for association analyses. Linkage analyses for COL2A1 locus markers were performed with the Fastlink and Merlin programs in conjunction with data obtained from our collaborative whole-genome linkage study (254 families).
Results
Significant association was identified between five SNPs (rs1034762, rs1635529, rs1793933, rs3803183, and rs17122571) of the COL2A1 locus and high-grade myopia (P < 0.045, minimum (min) P = 0.008) and with myopia status set at ≤–0.50 or –0.75 D (min P = 0.004) in the Duke dataset. The SNP rs1635529 also showed significant association in the Cardiff dataset (≤–5.00 D, min P = 0.004; ≤–0.50 D, min P = 0.007). Linkage analyses showed suggestive linkage to the COL2A1 locus on 12q. No association was found between COL1A1 SNPs and any degree of myopia.
Conclusions
The COL2A1 gene was associated with high-grade myopia in two independent Caucasian family datasets. COL1A1 gene polymorphisms were not associated with myopia in our dataset, indicating possible heterogeneity across different ethnicities.
doi:10.1167/iovs.08-3346
PMCID: PMC3936411  PMID: 19387081
22.  AKR1C3 overexpression may serve as a promising biomarker for prostate cancer progression 
Diagnostic Pathology  2014;9:42.
Background
Aldo-keto reductase family 1 member C3 (AKR1C3) is a key steroidogenic enzyme that is overexpressed in prostate cancer (PCa) and is associated with the development of castration-resistant prostate cancer (CRPC). The aim of this study was to investigate the correlation between the expression level of AKR1C3 and the progression of PCa.
Methods
Sixty human prostate needle biopsy tissue specimens and ten LNCaP xenografts from intact or castrated male mice were included in the study. The relationship between the level of AKR1C3 expression by immunohistochemistry and evaluation factors for PCa progression, including prostate-specific antigen (PSA), Gleason score (GS) and age, were analyzed.
Results
Low immunoreactivity of AKR1C3 was detected in normal prostate epithelium, benign prostatic hyperplasia (BPH) and prostatic intraepithelial neoplasia (PIN). Positive staining was gradually increased with an elevated GS in PCa epithelium and LNCaP xenografts in mice after castration. The Spearman’s r values (rs) of AKR1C3 to GS and PSA levels were 0.396 (P = 0.025) and -0.377 (P = 0.036), respectively, in PCa biopsies. The rs of AKR1C3 to age was 0.76 (P = 0.011). No statistically significant difference was found with other variables.
Conclusion
Our study suggests that the level of AKR.
1C3 expression is positively correlated with an elevated GS, indicating that AKR1C3 can serve as a promising biomarker for the progression of PCa.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7748245591110149.
doi:10.1186/1746-1596-9-42
PMCID: PMC3939640  PMID: 24571686
AKR1C3; Prostate cancer; Gleason score; PSA; Biomarker
23.  Evaluation of the X-Linked High-Grade Myopia Locus (MYP1) with Cone Dysfunction and Color Vision Deficiencies 
Purpose
X-linked high myopia with mild cone dysfunction and color vision defects has been mapped to chromosome Xq28 (MYP1 locus). CXorf2/TEX28 is a nested, intercalated gene within the red-green opsin cone pigment gene tandem array on Xq28. The authors investigated whether TEX28 gene alterations were associated with the Xq28-linked myopia phenotype. Genomic DNA from five pedigrees (with high myopia and either protanopia or deuteranopia) that mapped to Xq28 were screened for TEX28 copy number variations (CNVs) and sequence variants.
Methods
To examine for CNVs, ultra-high resolution array-comparative genomic hybridization (array-CGH) assays were performed comparing the subject genomic DNA with control samples (two pairs from two pedigrees). Opsin or TEX28 gene-targeted quantitative real-time gene expression assays (comparative CT method) were performed to validate the array-CGH findings. All exons of TEX28, including intron/exon boundaries, were amplified and sequenced using standard techniques.
Results
Array-CGH findings revealed predicted duplications in affected patient samples. Although only three copies of TEX28 were previously reported within the opsin array, quantitative real-time analysis of the TEX28 targeted assay of affected male or carrier female individuals in these pedigrees revealed either fewer (one) or more (four or five) copies than did related and control unaffected individuals. Sequence analysis of TEX28 did not reveal any variants associated with the disease status.
Conclusions
CNVs have been proposed to play a role in disease inheritance and susceptibility as they affect gene dosage. TEX28 gene CNVs appear to be associated with the MYP1 X-linked myopia phenotypes.
doi:10.1167/iovs.08-2455
PMCID: PMC3934550  PMID: 19098318
24.  Coccidiomycosis infection of the patella mimicking a neoplasm – two case reports 
BMC Medical Imaging  2014;14:8.
Background
Coccidioidomycosis is an endemic fungal infection in the southwestern of United States. Most infections are asymptomatic or manifest with mild respiratory complaints. Rare cases may cause extrapulmonary or disseminated disease. We report two cases of knee involvement that presented as isolated lytic lesions of the patella mimicking neoplasms.
Case Presentation
The first case, a 27 year-old immunocompetent male had progressive left anterior knee pain for four months. The second case was a 78 year-old male had left anterior knee pain for three months. Both of them had visited general physicians without conclusive diagnosis. A low attenuation lytic lesion in the patella was demonstrated on their image studies, and the initial radiologist’s interpretation was suggestive of a primary bony neoplasm. The patients were referred for orthopaedic oncology consultation. The first case had a past episode of pulmonary coccioidomycosis 2 years prior, while the second case had no previous coccioidal infection history but lived in an endemic area, the central valley of California. Surgical biopsy was performed in both cases due to diagnostic uncertainty. Final pathologic examination revealed large thick walled spherules filled with endospores establishing the final diagnosis of extrapulmonary coccidioidomycosis.
Conclusions
Though history and laboratory findings are supportive, definitive diagnosis still depends on growth in culture or endospores identified on histology. We suggest that orthopaedic surgeons and radiologists keep in mind that chronic fungal infections can mimic osseous neoplasm by imaging.
doi:10.1186/1471-2342-14-8
PMCID: PMC3939934  PMID: 24548622
Coccidioidomycosis; Patella; Infection; Lytic lesion; Computed tomography; MRI
25.  Detection and Genetic Analysis of Porcine Bocavirus in Different Swine Herds in North Central China 
The Scientific World Journal  2014;2014:947084.
Porcine Bocavirus (PBoV) has been reported to be associated with postweaning multisystemic wasting syndrome and pneumonia in pigs. In this study, a survey was conducted to evaluate the prevalence of PBoV in slaughter pigs, sick pigs, asymptomatic pigs and classical swine fever virus (CSFV) eradication plan herds in five provinces of China (Henan, Liaoning, Shandong, Hebei and Tianjin) by means of PCR targeting NS1 gene of PBoV. Among the total of 403 tissue samples, 11.41% were positive for PBoV. The positive rates of spleen (20.75%) and inguinal lymph node (27.18%) are higher than those of other organs. PCR products of twenty PBoV positive samples from slaughter pigs were sequenced for phylogenetic analysis. The result revealed that PBoV could be divided into 6 groups (PBoV-a~PBoV-f). All PBoV sequenced in this study belong to PBoV-a–PBoV-d with 90.1% to 99% nucleotide identities. Our results exhibited significant genetic diversity of PBoV and suggested a complex prevalence of PBoV in Chinese swine herds. Whether this diversity of PBoV has a significance to pig production or even public health remains to be further studied.
doi:10.1155/2014/947084
PMCID: PMC3950361

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