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1.  Type, Rather than Number, of Mental and Physical Comorbidities Increases the Severity of Symptoms in Patients with Irritable Bowel Syndrome 
BACKGROUND
Irritable bowel syndrome (IBS) has significant mental and physical comorbidities. However, little is known about the day-to-day burden these comorbidities place on quality of life (QOL), physical and mental function, distress, and symptoms of patients.
METHODS
We collected cross sectional data from 175 patients with IBS, diagnosed based on Rome III criteria (median age, 41 y; 78% women), referred to 2 specialty care clinics. Patients completed psychiatric interviews, a physical comorbidity checklist, the IBS symptom severity scale, the IBS quality of life instrument, the brief symptom inventory, the abdominal pain intensity scale, and the SF-12 health survey.
RESULTS
Patients with IBS reported an average of 5 comorbidities (1 mental, 4 physical). Subjects with more comorbidities reported worse QOL after adjusting for confounding variables. Multiple linear regression analyses indicated that comorbidity type was more consistently and strongly associated with illness burden indicators than disease counts. Of 10, 296 possible physical–mental comorbidity pairs, 6 of the 10 most frequent dyads involved specific conditions (generalized anxiety, depression, back pain, agoraphobia, tension headache, insomnia). These combinations were consistently associated with greater illness and symptom burdens (QOL, mental and physical function, distress, more severe symptoms of IBS, pain).
CONCLUSIONS
Comorbidities are common among patients with IBS. They are associated with distress and reduced QOL. Specific comorbidities are associated with more severe symptoms of IBS.
doi:10.1016/j.cgh.2013.03.011
PMCID: PMC3779619  PMID: 23524278
Chronic disease; health related quality of life; comorbidity; transdiagnostic; stress; IBSQOL
2.  Expression Profiles of Circulating Cytokines, Chemokines and Immune Cells in Patients With Hepatitis B Virus Infection 
Hepatitis Monthly  2014;14(6):e18892.
Background:
Immune cells and molecules play a vital role in initiating, maintaining, regulating immunological homeostasis and inflammation in many pathological and physiological processes; however, the changes on expressions and functions of these cells and molecules in hepatitis B virus (HBV) infection have not been elucidated well.
Objectives:
The current study aimed to determine the expression pattern of different cytokines, chemokines, immune cells in HBV infection and their association with disease progression.
Patients and Methods:
Sixty-nine patients with chronic HBV infection were enrolled. Five immune cell subsets and 46 cytokines and chemokines were analyzed by flow cytometry and Luminex 200.
Results:
In comparison to healthy individuals and asymptomatic HBV carriers, expression of CXCL9, CXCL10, CXCL11, and IL-10 were elevated in patients with chronic active HBV and had positive correlation with ALT levels. In contrast, G-CSF, MCP-3, and IFN-γ levels were significantly decreased in patients with chronic active HBV infection in contrast to carriers and healthy individuals; however, these down regulations did not show any correlation with either virological findings or liver inflammation. Although the proportion of CD4+ CD25 high regulatory T cells (Tregs) was higher in patients with HBV infection than in healthy controls, no correlations were found between Tregs and other cytokines or chemokines.
Conclusions:
CXCR3-associated chemokines might contribute to liver inflammation in chronic hepatitis B, while MCP-3 and G-CSF were inhibited by HBV infection. Host immune response was suppressed as manifested by an increase in CD4+ CD25high Tregs and IL-10 as well as a decrease in IFN-γ. Exploiting the expression pattern of cytokine and chemokine may help to develop a better understanding of chronic HBV infection pathogenesis.
doi:10.5812/hepatmon.18892
PMCID: PMC4071355  PMID: 24976843
Hepatitis B Virus; Cytokines; Chemokines; Immunomodulation
3.  Effect of the timing of surgery on the fracture healing process and the expression levels of vascular endothelial growth factor and bone morphogenetic protein-2 
The aim of the present study was to observe the effect of varying the timing of surgery on the fracture healing process and the expression levels of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-2 in rats. A total of 192 rats underwent closed femur fracture modelling. The rats underwent open reduction and internal fixation surgery 1, 3, 5, 7, 11 and 14 days subsequent to the fracture occurring. Immunohistochemical staining and analysis of the VEGF and BMP-2 expression levels were simultaneously conducted on bone from the fracture site of the rats on various days. The VEGF and BMP-2 expression levels at the fracture sites were higher and were maintained for a longer period of time in the 7- and 11-day surgery groups than in the other surgery groups and the rats that did not undergo surgery. The 5-day surgery group demonstrated a greater intensity in BMP-2 expression compared with the remaining surgery groups; however, no significant differences were identified between 1-day surgery and non surgery groups. In the 3-day surgery group, the expression levels VEGF and BMP-2 were low at each stage of the fracture-healing process and were lower compared with those observed in the non-surgery group. The timing of the surgical procedures affected the VEGF and BMP-2 expression levels at the fracture sites of the experimental rats and, the optimal time for performing surgery was identified to be within the first two weeks. However, surgery may not be conducive to fracture healing if it is performed within the first few days following fracture.
doi:10.3892/etm.2014.1735
PMCID: PMC4079447  PMID: 25009626
fracture healing; vascular endothelial growth factor; bone morphogenetic protein-2; surgery timing
4.  Cytopenia and Autoimmune Diseases: a Vicious Cycle fueled by mTOR Dysregulation in Hematopoietic Stem Cells 
Journal of autoimmunity  2013;41:182-187.
A long-standing but poorly understood defect in autoimmune diseases is dysfunction of the hematopoietic cells. Leukopenia is often associated with systemic lupus erythematous (SLE) and other autoimmune diseases. In addition, homeostatic proliferation of T cells, which is a host response to T cell lymphopenia, has been implicated as potential cause of rheumatoid arthritis (RA) in human and experimental models of autoimmune diabetes in the NOD mice and the BB rats. Conversely, successful treatments of aplastic anemia by immune suppression suggest that the hematologic abnormality may have a root in autoimmune diseases. Traditionally, the link between autoimmune diseases and defects in hematopoietic cells has been viewed from the prism of antibody-mediated hemolytic cytopenia. While autoimmune destruction may well be part of pathogenesis of defects in hematopoietic system, it is worth considering the hypothesis that either leukopenia or pancytopenia may also result directly from defective hematopoietic stem cells (HSC). We have recently tested this hypothesis in the autoimmune Scurfy mice which has mutation Foxp3, the master regulator of regulatory T cells. Our data demonstrated that due to hyperactivation of mTOR, the HSC in the Scurfy mice are extremely poor in hematopoiesis. Moreover, rapamycin, an mTOR inhibitor rescued HSC defects and prolonged survival of the Scurfy mice. Our data raised the intriguing possibility that targeting mTOR dysregulation in the HSC may help to break the vicious cycle between cytopenia and autoimmune diseases.
doi:10.1016/j.jaut.2012.12.011
PMCID: PMC3622805  PMID: 23375848
Cytopenia; homeostatic proliferation; CD24; mTOR; hematopoietic stem cells; autoimmune diseases; inflammatory cytokines; rapamycin
5.  Sin1 regulates Treg development but is not required for T cell growth and proliferation 
European journal of immunology  2012;42(6):1639-1647.
Summary
Mammalian Sin1 plays key roles in the regulation of mitogen activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling. Sin1 is an essential component of mTOR complex (mTORC) 2. The function of Sin1 and mTORC2 remains largely unknown in T cells. Here we investigate Sin1 function in T cells using mice which lack Sin1 in the hematopoietic system. Sin1 deficiency blocks the mTORC2 dependent Akt phosphorylation in T cells during development and activation. Sin1 deficient T cells exhibit normal thymic cellularity and percentages of double negative, double positive and single positive CD4 and CD8 thymocytes. Sin1 deficiency does not impair T cell receptor (TCR) induced growth and proliferation, and normal CD4+ helper cell differentiation. However Sin1 deficiency results in an increased proportion of Foxp3+ natural T regulatory (nTreg) cells in the thymus. We show that the TGF-β dependent differentiation of CD4+ T cells in vitro is enhanced by the inhibition of mTOR but not loss of Sin1 function. Our results reveal that Sin1 and mTORC2 are dispensable for the development and activation of T cells but play a role in natural Treg cell differentiation.
doi:10.1002/eji.201142066
PMCID: PMC3663871  PMID: 22678916
6.  Integration of 1H NMR and UPLC-Q-TOF/MS for a Comprehensive Urinary Metabonomics Study on a Rat Model of Depression Induced by Chronic Unpredictable Mild Stress 
PLoS ONE  2013;8(5):e63624.
Depression is a type of complex psychiatric disorder with long-term, recurrent bouts, and its etiology remains largely unknown. Here, an integrated approach utilizing 1H NMR and UPLC-Q-TOF/MS together was firstly used for a comprehensive urinary metabonomics study on chronic unpredictable mild stress (CUMS) treated rats. More than twenty-nine metabolic pathways were disturbed after CUMS treatment and thirty-six potential biomarkers were identified by using two complementary analytical technologies. Among the identified biomarkers, nineteen (10, 11, 16, 17, 21–25, and 27–36) were firstly reported as potential biomarkers of CUMS-induced depression. Obviously, this paper presented a comprehensive map of the metabolic pathways perturbed by CUMS and expanded on the multitude of potential biomarkers that have been previously reported in the CUMS model. Four metabolic pathways, including valine, leucine and isoleucine biosynthesis; phenylalanine, tyrosine and tryptophan biosynthesis; tryptophan metabolism; synthesis and degradation of ketone bodies had the deepest influence in the pathophysiologic process of depression. Fifteen potential biomarkers (1–2, 4–6, 15, 18, 20–23, 27, 32, 35–36) involved in the above four metabolic pathways might become the screening criteria in clinical diagnosis and predict the development of depression. Moreover, the results of Western blot analysis of aromatic L-amino acid decarboxylase (DDC) and indoleamine 2, 3-dioxygenase (IDO) in the hippocampus of CUMS-treated rats indicated that depletion of 5-HT and tryptophan, production of 5-MT and altered expression of DDC and IDO together played a key role in the initiation and progression of depression. In addition, none of the potential biomarkers were detected by NMR and LC-MS simultaneously which indicated the complementary of the two kinds of detection technologies. Therefore, the integration of 1H NMR and UPLC-Q-TOF/MS in metabonomics study provided an approach to identify the comprehensive potential depression-related biomarkers and helpful in further understanding the underlying molecular mechanisms of depression through the disturbance of metabolic pathways.
doi:10.1371/journal.pone.0063624
PMCID: PMC3656962  PMID: 23696839
7.  Metabonomics Combined with UPLC-MS Chemical Profile for Discovery of Antidepressant Ingredients of a Traditional Chinese Medicines Formula, Chaihu-Shu-Gan-San 
This study proposed a new strategy for uncovering the active chemical constituents of a traditional Chinese medicines (TCMs) formula, Chaihu-Shu-Gan-San (CSGS). Metabonomics and chemical profile were integrated in combination with the multivariate statistical analysis (MVA) to discover the chemical constituents which contribute to the antidepressant effect of CSGS. Based upon the difference between CSGS and QZ (CSGS without Zhi-Qiao) extracts in the chemical profiles and the regulations of metabolic disturbances induced by CUMS, synephrine, naringin, hesperidin, and neohesperidin were recognized as the active constituents of CSGS from Zhi-qiao responsible for those missing regulations of CSGS when Zhi-Qiao was subtracted from the whole formula. They participated in the regulations of the deviated metabolites 2–4, 10–14, and 22–25, involved in metabolic pathways of ketone bodies synthesis, phenylalanine, tyrosine and tryptophan biosynthesis, valine, aspartate, glutamate metabolism, and glycolysis/gluconeogenesis. Furthermore, the assay of MAO-A activity confirmed the potential antidepressant effect of naringin and its active sites on the MAO-A was inferred by molecular docking study. The integration of metabonomics and chemical profile was proved to be a useful strategy for uncovering what the active chemical constituents in TCM formula are and how they make contributions for the efficacy of the formula.
doi:10.1155/2013/487158
PMCID: PMC3638638  PMID: 23662139
8.  A Proinflammatory Role for Interleukin-22 in the Immune Response to Hepatitis B Virus 
Gastroenterology  2011;141(5):1897-1906.
BACKGROUND & AIMS
T-helper (Th)17 cells that secrete interleukin (IL)-22 have immunomodulatory and protective properties in the liver and other tissues. IL-22 induces expression of proinflammatory genes, but is also mitogenic and anti-apoptotic in hepatocytes.
Therefore, it could have multiple functions in the immune response to hepatitis B virus (HBV).
METHODS
We examined the role of IL-22 in regulating liver inflammation in HBV transgenic mice and measured levels of IL-22 in HBV-infected patients.
RESULTS
In HBV transgenic mice, injection of a single dose of IL-22 increased hepatic expression of proinflammatory genes, but did not directly inhibit virus replication. When splenocytes from HBV-immunized mice were transferred into HBV transgenic mice, the severity of the subsequent liver damage was ameliorated by neutralization of IL-22. In this model, IL-22 depletion did not affect interferon-γ–mediated noncytopathic inhibition of virus replication initiated by HBV-specific cytotoxic T cells, but it significantly inhibited recruitment of antigen–non-specific inflammatory cells into the liver. In patients with acute HBV infections, the percentage of Th17 cells in peripheral blood and concentration of IL-22 in serum were significantly increased.
CONCLUSION
IL-22 appears to be an important mediator of the inflammatory response following recognition of HBV by T cells in the liver. These findings might be relevant to the development of cytokine-based therapies for patients with HBV infection.
doi:10.1053/j.gastro.2011.06.051
PMCID: PMC3199295  PMID: 21708106
liver disease; immune response; mouse model; anti-viral
9.  The kinases MEKK2 and MEKK3 regulate Transforming Growth Factor-β-mediated helper T cell differentiation 
Immunity  2011;34(2):201-212.
Summary
Mitogen-activated protein kinases (MAPKs) are key mediators of the T cell receptor (TCR) signals but their roles in T helper (Th) cell differentiation are unclear. Here we showed that the MAPK kinase kinases MEKK2 (encoded by Map3k2) and MEKK3 (encoded by Map3k3), negatively regulated transforming growth factor-β (TGF-β)-mediated Th cell differentiation. Map3k2-/-Map3k3Lck-Cre/- mice showed an abnormal accumulation of regulatory T (Treg) and Th17 cells in the periphery, consistent with Map3k2-/-Map3k3Lck-Cre/- naïve CD4+ T cells' differentiation into Treg and Th17 cells with a higher frequency than wild-type (WT) cells after TGF-β stimulation in vitro. In addition, Map3k2-/-Map3k3Lck-Cre/- mice developed more severe experimental autoimmune encephalomyelitis. Map3k2-/-Map3k3Lck-Cre/- T cells exhibited impaired phosphorylation of the SMAD2 and SMAD3 proteins at their linker regions, which negatively regulated the TGF-β responses in T cells. Thus, the crosstalk between TCR-induced MAPK and the TGF-β signaling pathways is important in regulating Th cell differentiation.
doi:10.1016/j.immuni.2011.01.017
PMCID: PMC3073014  PMID: 21333552
10.  Oxygen Concentration and Pulmonary Hemodynamics in Newborn Lambs with Pulmonary Hypertension 
Pediatric research  2009;66(5):539-544.
The effect of oxygen concentration on lowering pulmonary vascular resistance (PVR) during resuscitation in a model of persistent pulmonary hypertension of the newborn (PPHN) is not known. PPHN was induced in fetal lambs by ductal ligation 9 d prior to delivery. Following delivery by cesarean section, resuscitation of PPHN lambs with 21%, 50%, or 100% O2 (n=6 each) for 30min produced similar decreases in PVR. Lambs were then ventilated with 50% O2 for 60min and exposed to inhaled NO (iNO-20ppm). Initial resuscitation with 100% O2 significantly impaired the subsequent response to iNO compared to 21% O2 (42±9 vs. 22±4% decrease from baseline PVR). Finally, each lamb was randomly and sequentially ventilated with 10%, 21%, 50%, or 100% O2. PVR decreased with increased concentrations of inhaled O2 up to 50%, there being no additional decrease in PVR with 100% O2. When PVR was correlated with PaO2, the maximal change in PVR was achieved at PaO2 values < 60 mmHg. We conclude that resuscitation with 100% O2 does not enhance pulmonary vasodilation compared to 21% and 50% O2, but impairs the subsequent response to iNO in PPHN lambs. Hypoxia increases PVR but hyperoxia does not confer significant additional pulmonary vasodilation in lambs with PPHN.
doi:10.1203/PDR.0b013e3181bab0c7
PMCID: PMC2782958  PMID: 19680165
11.  MEKK3 Is Essential for Lymphopenia-Induced T Cell Proliferation and Survival1 
T cell homeostasis is crucial for maintaining an efficient and balanced T cell immunity. The interaction between TCR and self peptide (sp) MHC ligands is known to be the key driving force in this process, and it is believed to be functionally and mechanistically different from that initiated by the antigenic TCR stimulation. Yet, very little is known about the downstream signaling events triggered by this TCR-spMHC interaction and how they differ from those triggered by antigenic TCR stimulation. In this study, we show that T cell conditional ablation of MEKK3, a Ser/Thr kinase in the MAPK cascade, causes a significant reduction in peripheral T cell numbers in the conditional knockout mice, but does not perturb thymic T cell development and maturation. Using an adoptive mixed transfer method, we show that MEKK3-deficient T cells are severely impaired in lymphopenia-induced cell proliferation and survival. Interestingly, the Ag-induced T cell proliferation proceeds normally in the absence of MEKK3. Finally, we found that the activity of ERK1/2, but not p38 MAPK, was attenuated during the lymphopenia-driven response in MEKK3-deficient T cells. Together, these data suggest that MEKK3 may play a crucial selective role for spMHC-mediated T cell homeostasis.
doi:10.4049/jimmunol.0803738
PMCID: PMC2923428  PMID: 19265138
12.  Fluctuation AnaLysis CalculatOR: a web tool for the determination of mutation rate using Luria–Delbrück fluctuation analysis 
Bioinformatics  2009;25(12):1564-1565.
Summary:The program Fluctuation AnaLysis CalculatOR (FALCOR) is a web tool designed for use with Luria–Delbrück fluctuation analysis to calculate the frequency and rate from various mutation assays in bacteria and yeast. Three calculation methods are available through this program: (i) Ma-Sandri-Sarkar Maximum Likelihood Estimator (MSS-MLE) method, (ii) Lea-Coulson method of the median (LC) and (iii) frequency.
Availability: The FALCOR rate calculator is currently accessible at http://www.mitochondria.org/protocols/FALCOR.html. This program is written as a Java™ Applet, requiring a web browser enabled with Sun MicroSystems' Java Virtual Machine.
Contact: brandon.hall@roswellpark.org
doi:10.1093/bioinformatics/btp253
PMCID: PMC2687991  PMID: 19369502
13.  Acitretin systemic and retinoic acid 0.1% cream supression of basal cell carcinoma 
Dermatology Reports  2010;2(1):e4.
Retinoids have been used for years as monotherapy and/or in combination for treatment and suppression of cutaneous malignancies in patients with basal cell nevus syndrome, xeroderma pigmentosum, or cutaneous T-cell lymphoma (CTCL) basal cell carcinoma (BCC). We report 4 cases with BCC confirmed by histopathology who were treated by short-term systemic acitretin combined with retinoic acid 0.1% cream. The 4 cases with BCC showed good response to the treatment without severe adverse effects during treatment and follow-up. The finding suggests that acitretin may be an appropriate treatment option for elderly patients who require less invasive treatment for BCC.
doi:10.4081/dr.2010.e4
PMCID: PMC4211482  PMID: 25386240
acitretin; basal cell carcinoma.
14.  Proteus syndrome: a case report and a case study review in China 
Dermatology Reports  2010;2(1):e3.
Proteus syndrome (PS) is a rare and sporadic disorder characterized by overgrowth of multiple tissues and a propensity to develop particular neoplasms. The clinical manifestations of PS include macrodactyly, vertebral abnormalities, asymmetric limb overgrowth and length discrepancy, hyperostosis, abnormal and asymmetric fat distribution, asymmetric muscle development, connective tissue nevi, and vascular malformations. We report a 16-year old female patient who manifested a number of these complications and review the Chinese literature about the diagnosis, natural history, and management of PS.
doi:10.4081/dr.2010.e3
PMCID: PMC4211478  PMID: 25386239
Proteus syndrome; clinical manifestation; diagnosis
15.  Selective Elimination of Autoreactive T cells in vivo by the Regulatory T Cells 
Summary
How regulatory T cells (Treg) control autoreactive T cells has not been analyzed in animals with a normal T cell repertoire. Using endogenous viral superantigens (VSAg) as the primary self antigens and mice with the Scurfy mutation of FoxP3, we show here that the Treg defect causes preferential accumulation of autoreactive T cells. Interestingly, in the Scurfy mice, the proliferation of VSAg-reactive T cells was no more vigorous than that of non-VSAg-reactive T cells, which indicated that the preferential accumulation is not due to preferential proliferation. In contrast, VSAg-reactive T cells disappears in WT host despite their preferential proliferation. Importantly, when adoptively transferred into the newborn Scurfy mice, the Treg selectively kill autoreactive T cells without affecting their proliferation. The selective elimination is due to increased susceptibility of autoreactive T cells to Treg-mediated killing.
doi:10.1016/j.clim.2008.08.014
PMCID: PMC2643025  PMID: 18838339
autoimmune diseases; clonal deletion; FoxP3; viral super-antigen; regulatory T cells
16.  Broad expression of the FoxP3 locus in epithelial cells: A caution against an early interpretation of fatal inflammatory diseases following in vivo depletion of FoxP3-expressing cells1 
Dogma that the Treg prevents catastrophic autoimmunity throughout the lifespan relies on the assumption that the FoxP3 locus is transcribed exclusively in Treg. To test the assumption, we used the Rag2−/− and the Rag2−/− mice with the Scurfy mutation (FoxP3sf/y or FoxP3sf/sf) to evaluate FoxP3 expression outside of lymphoid system. Immunohistochemistry and real-time PCR revealed FoxP3 expression in breast epithelial cells, lung respiratory epithelial cells and in prostate secretory epithelial cells, although not in liver, heart and intestine. The specificity of the assays is confirmed as the signals were ablated by the Scurfy mutation of the FoxP3 gene. Using mice with green fluorescence protein (GFP) open-reading frame knocked into the 3′ untranslated region of the FoxP3 locus, we showed that the locus is transcribed broadly in epithelial cells of multiple organs. These results refute an essential underlying assumption of the dogma and question the specificity of FoxP3-based Treg depletion.
PMCID: PMC2527697  PMID: 18390696
17.  Modeling the Genetic Control of HIV-1 Dynamics After Highly Active Antiretroviral Therapy 
Current Genomics  2008;9(3):208-211.
The progression of HIV disease has been markedly slowed by the use of highly active antiretroviral therapy (HAART). However, substantial genetic variation was observed to occur among different people in the decay rate of viral loads caused by HAART. The characterization of specific genes involved in HIV dynamics is central to design personalized drugs for the prevention of this disease, but usually cannot be addressed by experimental methods alone rather than require the help of mathematical and statistical methods. A novel statistical model has been recently developed to detect genetic variants that are responsible for the shape of HAART-induced viral decay curves. This model was employed to an HIV/AIDS trial, which led to the identification of a major genetic determinant that triggers an effect on HIV dynamics. This detected major genetic determinant also affects several clinically important parameters, such as half-lives of infected cells and HIV eradication times.
doi:10.2174/138920208784340777
PMCID: PMC2679648  PMID: 19440518
Hardy-weinberg equilibrium; bi-exponential function; quantitative trait loci; HIV dynamics; functional mapping.
18.  FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene 
Cell  2007;129(7):1275-1286.
The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germ-line mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that Foxp3sf/+ heterozygous mice developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and ErbB2 was over-expressed. Foxp3 bound and repressed the ErbB2 promoter. Deletion, functionally significant somatic mutations and down-regulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2 over-expression, regardless of the status of HER-2 amplification. In toto, the data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.
doi:10.1016/j.cell.2007.04.034
PMCID: PMC1974845  PMID: 17570480
19.  FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2  
The Journal of Clinical Investigation  2007;117(12):3765-3773.
S-phase kinase-associated protein 2 (SKP2) is a component of the E3 ubiquitin ligase SKP1-Cul1-Fbox complex. Overexpression of SKP2 results in cell cycle dysregulation and carcinogenesis; however, the genetic lesions that cause this upregulation are poorly understood. We recently demonstrated that forkhead box P3 (FOXP3) is an X-linked breast cancer suppressor and an important repressor of the oncogene ERBB2/HER2. Since FOXP3 suppresses tumor growth regardless of whether the tumors overexpress ERBB2/HER2, additional FOXP3 targets may be involved in its tumor suppressor activity. Here, we show that mammary carcinomas from mice heterozygous for a Foxp3 mutation exhibited increased Skp2 expression. Ectopic expression of FOXP3 in mouse mammary cancer cells repressed SKP2 expression with a corresponding increase in p27 and polyploidy. Conversely, siRNA silencing of the FOXP3 gene in human mammary epithelial cells increased SKP2 expression. We also show that Foxp3 directly interacted with and repressed the Skp2 promoter. Moreover, the analysis of over 200 primary breast cancer samples revealed an inverse correlation between FOXP3 and SKP2 levels. Finally, we demonstrated that downregulation of SKP2 was critical for FOXP3-mediated growth inhibition in breast cancer cells that do not overexpress ERBB2/HER2. Our data provide genetic, biochemical, and functional evidence that FOXP3 is a novel transcriptional repressor for the oncogene SKP2.
doi:10.1172/JCI32538
PMCID: PMC2075479  PMID: 18008005
20.  Massive and destructive T cell response to homeostatic cue in CD24-deficient lymphopenic hosts 
The Journal of Experimental Medicine  2006;203(7):1713-1720.
In response to a lymphopenic cue, T lymphocytes undergo a slow-paced homeostatic proliferation in an attempt to restore T cell cellularity. The molecular interaction that maintains the pace of homeostatic proliferation is unknown. In this study, we report that in lymphopenic CD24-deficient mice, T cells launch a massive proliferation that results in the rapid death of the recipient mice. The dividing T cells have phenotypes similar to those activated by cognate antigens. The rapid homeostatic proliferation is caused by a lack of CD24 on dendritic cells (DCs). Interestingly, although CD24 expression in T cells is required for optimal homeostatic proliferation in the wild-type (WT) host, mice lacking CD24 on all cell types still mount higher homeostatic proliferation than the WT mice. Thus, a lack of CD24 in the non–T host cells bypassed the requirement for T cell expression of CD24 in homeostatic proliferation in the WT host. Our data demonstrate that CD24 expressed on the DCs limits T cell response to homeostatic cue and prevents fatal damage associated with uncontrolled homeostatic proliferation.
doi:10.1084/jem.20052293
PMCID: PMC2118348  PMID: 16769998
21.  The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis 
The Journal of Experimental Medicine  2005;202(8):1141-1151.
The Scurfy mutation of the FoxP3 gene (FoxP3sf) in the mouse and analogous mutations in human result in lethal autoimmunity. The mutation of FoxP3 in the hematopoietic cells impairs the development of regulatory T cells. In addition, development of the Scurfy disease also may require mutation of the gene in nonhematopoietic cells. The T cell–extrinsic function of FoxP3 has not been characterized. Here we show that the FoxP3sf mutation leads to defective thymopoiesis, which is caused by inactivation of FoxP3 in the thymic stromal cells. FoxP3 mutation also results in overexpression of ErbB2 in the thymic stroma, which may be involved in defective thymopoiesis. Our data reveal a novel T cell–extrinsic function of FoxP3. In combination, the T cell–intrinsic and –extrinsic defects provide plausible explanation for the severity of the autoimmune diseases in the scurfy mice and in patients who have immunodysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome.
doi:10.1084/jem.20050157
PMCID: PMC2213221  PMID: 16230479
22.  A hierarchical statistical model for estimating population properties of quantitative genes 
BMC Genetics  2002;3:10.
Background
Earlier methods for detecting major genes responsible for a quantitative trait rely critically upon a well-structured pedigree in which the segregation pattern of genes exactly follow Mendelian inheritance laws. However, for many outcrossing species, such pedigrees are not available and genes also display population properties.
Results
In this paper, a hierarchical statistical model is proposed to monitor the existence of a major gene based on its segregation and transmission across two successive generations. The model is implemented with an EM algorithm to provide maximum likelihood estimates for genetic parameters of the major locus. This new method is successfully applied to identify an additive gene having a large effect on stem height growth of aspen trees. The estimates of population genetic parameters for this major gene can be generalized to the original breeding population from which the parents were sampled. A simulation study is presented to evaluate finite sample properties of the model.
Conclusions
A hierarchical model was derived for detecting major genes affecting a quantitative trait based on progeny tests of outcrossing species. The new model takes into account the population genetic properties of genes and is expected to enhance the accuracy, precision and power of gene detection.
doi:10.1186/1471-2156-3-10
PMCID: PMC117225  PMID: 12097145

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