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1.  Validation of a criteria-specific long-term survival prediction model for hepatocellular carcinoma patients after liver transplantation 
Scientific Reports  2015;5:11733.
The aim of this study was to validate a criteria-specific long-term survival prediction model (MHCAT) in a large cohort of hepatocellular carcinoma (HCC) patients after liver transplantation (LT) in China. Independent risk factors in MHCAT were retrospectively analysed for HCC patients recorded in the China Liver Transplant Registry. Survival predictions for each patient were calculated using MHCAT scores and the Metroticket formula separately, and the prediction efficacy of MHCAT and Metroticket was compared using the area under ROC curve (c-statistic). A total of 1371 LTs for HCC were analysed in the study, with a median follow-up of 22.2 months (IQR 6.1–72.4 months). The proportions meeting the Milan, UCSF, Fudan and Hangzhou criteria were 34.4%, 39.7%, 44.2% and 51.9%, respectively. The c-statistics for MHCAT predictions of 3- and 5-year survival rates of HCC recipients were 0.712–0.727 and 0.726–0.741, respectively. Among these patients, 1298 LTs for HCC were ultimately selected for the comparison analysis for prediction efficacy. The c-statistic of MHCAT for predictions of 3-year survival with reference to the Milan, UCSF and Fudan criteria was significantly increased compared with that for Metroticket (p < 0.05). In conclusion, MHCAT can effectively predict long-term survival for HCC recipients after LT.
PMCID: PMC4476095  PMID: 26096817
2.  Sparse Representation for Infrared Dim Target Detection via a Discriminative Over-Complete Dictionary Learned Online 
Sensors (Basel, Switzerland)  2014;14(6):9451-9470.
It is difficult for structural over-complete dictionaries such as the Gabor function and discriminative over-complete dictionary, which are learned offline and classified manually, to represent natural images with the goal of ideal sparseness and to enhance the difference between background clutter and target signals. This paper proposes an infrared dim target detection approach based on sparse representation on a discriminative over-complete dictionary. An adaptive morphological over-complete dictionary is trained and constructed online according to the content of infrared image by K-singular value decomposition (K-SVD) algorithm. Then the adaptive morphological over-complete dictionary is divided automatically into a target over-complete dictionary describing target signals, and a background over-complete dictionary embedding background by the criteria that the atoms in the target over-complete dictionary could be decomposed more sparsely based on a Gaussian over-complete dictionary than the one in the background over-complete dictionary. This discriminative over-complete dictionary can not only capture significant features of background clutter and dim targets better than a structural over-complete dictionary, but also strengthens the sparse feature difference between background and target more efficiently than a discriminative over-complete dictionary learned offline and classified manually. The target and background clutter can be sparsely decomposed over their corresponding over-complete dictionaries, yet couldn't be sparsely decomposed based on their opposite over-complete dictionary, so their residuals after reconstruction by the prescribed number of target and background atoms differ very visibly. Some experiments are included and the results show that this proposed approach could not only improve the sparsity more efficiently, but also enhance the performance of small target detection more effectively.
PMCID: PMC4118372  PMID: 24871988
dim target detection; adaptive morphological over-compete dictionary; discriminative over-complete dictionary; Gaussian over-complete dictionary; sparsity
3.  The therapeutic effect of monocyte chemoattractant protein-1 delivered by an electrospun scaffold for hyperglycemia and nephrotic disorders 
Here, we investigated in diabetic mice the therapeutic effect of monocyte chemoattractant protein-1 (MCP-1), locally delivered by an electrospun scaffold, on transplanted islets. This therapeutic scheme is expected to exert a synergistic effect to ameliorate hyperglycemia and its associated nephrotic disorders. The cumulative amount of MCP-1 released from the scaffold in vitro within a 3-week window was 267.77±32.18 ng, without a compromise in bioactivity. After 8 weeks following the transplantation, the islet population stimulated by MCP-1 was 35.14%±7.23% larger than the non-stimulated islet population. Moreover, MCP-1 increased concentrations of blood insulin and C-peptide 2 by 49.83%±5.29% and 43.49%±9.21%, respectively. Consequently, the blood glucose concentration in the MCP-1 group was significantly lower than that in the control group at week 2 post-surgery. MCP-1 also enhanced the tolerance of sudden oral glucose challenge. The rapid decrease of blood creatinine, urine creatinine, and blood urea nitrogen suggested that the recovery of renal functions compromised by hyperglycemia could also be attributed to MCP-1. Our study shed new light on a synergistic strategy to alleviate hyperglycemia and nephrotic disorders in diabetic patients.
PMCID: PMC3933709  PMID: 24600221
MCP-1; electrospinning; islet transplantation; diabetes
5.  RNA interference-mediated USP22 gene silencing promotes human brain glioma apoptosis and induces cell cycle arrest 
Oncology Letters  2013;5(4):1290-1294.
Ubiquitin-specific protease 22 (USP22) is a novel tumor stem cell marker that plays a key role in tumorigenesis and cell cycle progression. However, the effect of silencing the USP22 gene on human brain glioma cell growth is not well understood. In the present study, high gene expression of USP22 was identified in human brain glioma cells. In addition, RNA interference technology was used to silence USP22 gene expression in human brain glioma cells. Silencing the USP22 gene was found to effectively inhibit proliferation of human brain glioma cells, resulting in cell apoptosis and cell cycle arrest at the G2/M phase. USP22 silencing was also found to lead to reduced expression of cell cycle proteins, including CDK1, CDK2 and CyclinB1. In summary, in this study the USP22 gene was demonstrated to play a key regulatory role in the growth of human brain glioma cells by affecting progression of apoptosis and the cell cycle.
PMCID: PMC3629196  PMID: 23599781
RNA interference; USP22 gene; human brain glioma; cell apoptosis; cell cycle
6.  Ectopic adrenal cortical adenoma in the gastric wall: Case report 
Ectopic adrenal cortical neoplasms are extremely rare. Ectopic adrenocortical tissue can be found in locations such as the celiac axis, the broad ligament, the adnexa of the testes, and the spermatic cord; however, they rarely involve the stomach. We report an unusual case of a patient with an ectopic adrenal cortical adenoma in the gastric wall. The patient was a 72-year old female admitted to our hospital with upper abdominal discomfort. Physical examination revealed tenderness below the xiphoid process. Both computed tomography and fibergastroscopy revealed a mass on the lesser curvature side of the gastric antrum; it was initially diagnosed as a gastric stromal tumor. After adequate preparation, the patient underwent surgery. During the procedure, we found a 30 mm × 30 mm mass with medium density in the lesser curvature near the gastric antrum within the serosa. Following immunohistochemistry examination, we corrected the diagnosis to an ectopic adrenal cortical adenoma; the tumor was nonfunctional.
PMCID: PMC3574608  PMID: 23429246
Ectopic adrenal cortical neoplasms; Adrenal adenoma; Stomach; Adult; Nonfunctional adenoma
7.  Netrin-1 Protects against L-Arginine-Induced Acute Pancreatitis in Mice 
PLoS ONE  2012;7(9):e46201.
Acute pancreatitis (AP) is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with infiltration of leukocytes. The neuronal guidance protein, netrin-1, has been shown to control leukocyte trafficking and modulate inflammatory responses in several inflammation-based diseases. The present study was aimed toward investigating the effects of netrin-1 in an in vivo model of AP in mice. AP was induced in C57BL/6 mice by administration of two intraperitoneal injections of L-Arginine (4 g/kg). Mice were treated with recombinant mouse netrin-1 at a dose of 1 µg/mouse or vehicle (0.1% BSA) intravenously through the tail vein immediately after the second injection of L-Arginine, and every 24 h thereafter. Mice were sacrificed at several time intervals from 0 to 96 h after the induction of pancreatitis. Blood and tissue samples of pancreas and lung were collected and processed to determine the severity of pancreatitis biochemically and histologically. Immunohistochemical staining demonstrated that netrin-1 was mainly expressed in the islet cells of the normal pancreas and the AP model pancreas, and the pancreatic expression of netrin-1 was down-regulated at both the mRNA and protein levels during the course of AP. Exogenous netrin-1 administration significantly reduced plasma amylase levels, myeloperoxidase activity, pro-inflammatory cytokine production, and pancreas and lung tissue damages. Furthermore, netrin-1 administration did not cause significant inhibition of nuclear factor-kappa B activation in the pancreas of L-Arginine-induced AP. In conclusion, our novel data suggest that netrin-1 is capable of improving damage of pancreas and lung, and exerting anti-inflammatory effects in mice with severe acute pancreatitis. Thus, our results indicate that netrin-1 may constitute a novel target in the management of AP.
PMCID: PMC3459888  PMID: 23029434
8.  Emergence and Continuous Evolution of Genotype 1E Rubella Viruses in China 
Journal of Clinical Microbiology  2012;50(2):353-363.
In China, rubella vaccination was introduced into the national immunization program in 2008, and a rubella epidemic occurred in the same year. In order to know whether changes in the genotypic distribution of rubella viruses have occurred in the postvaccination era, we investigate in detail the epidemiological profile of rubella in China and estimate the evolutionary rate, molecular clock phylogeny, and demographic history of the predominant rubella virus genotypes circulating in China using Bayesian Markov chain Monte Carlo phylodynamic analyses. 1E was found to be the predominant rubella virus genotype since its initial isolation in China in 2001, and no genotypic shift has occurred since then. The results suggest that the global 1E genotype may have diverged in 1995 and that it has evolved at a mutation rate of 1.65 × 10−3 per site per year. The Chinese 1E rubella virus isolates were grouped into either cluster 1 or cluster 2, which likely originated in 1997 and 2006, respectively. Cluster 1 viruses were found in all provinces examined in this study and had a mutation rate of 1.90 × 10−3 per site per year. The effective number of infections remained constant until 2007, and along with the introduction of rubella vaccine into the national immunization program, although the circulation of cluster 1 viruses has not been interrupted, some viral lineages have disappeared, and the epidemic started a decline that led to a decrease in the effective population size. Cluster 2 viruses were found only in Hainan Province, likely because of importation.
PMCID: PMC3264136  PMID: 22162559
9.  Impact of lymphatic and/or blood vessel invasion in stage II gastric cancer 
AIM: To determine the prognostic value of lymphatic and/or blood vessel invasion (LBVI) in patients with stage II gastric cancer.
METHODS: From January 2001 to December 2006, 487 patients with histologically confirmed primary gastric adenocarcinoma were diagnosed with stage II gastric cancer according to the new 7th edition American Joint Committee on Cancer stage classification at the Department of Gastric Cancer and Soft Tissue Surgery, Fudan University Shanghai Cancer Center. All patients underwent curative gastrectomy with standard lymph node (LN) dissection. Fifty-one patients who died in the postoperative period, due to various complications or other conditions, were excluded. Clinicopathological findings and clinical outcomes were analyzed. Patients were subdivided into four groups according to the status of LBVI and LN metastases. These four patient groups were characterized with regard to age, sex, tumor site, pT category, tumor grading and surgical procedure (subtotal resection vs total resection), and compared for 5-year overall survival by univariate and multivariate analysis.
RESULTS: The study was composed of 320 men and 116 women aged 58.9 ± 11.5 years (range: 23-88 years). The 5-year overall survival rates were 50.7% and the median survival time was 62 mo. Stage IIa cancer was observed in 334 patients, including 268 T3N0, 63 T2N1, and three T1N2, and stage IIb was observed in 102 patients, including 49 patients T3N1, 51 T2N2, one T1N3, and one T4aN0. The incidence of LBVI was 28.0% in stage II gastric cancer with 19.0% (51/269) and 42.5% (71/167) in LN-negative and LN-positive patients, respectively. In 218 patients (50.0%), there was neither a histopathologically detectable LBVI nor LN metastases (LBVI−/LN−, group I); in 51 patients (11.7%), LBVI with no evidence of LN metastases was detected (LBVI+/LN−, group II). In 167 patients (38.3%), LN metastases were found. Among those patients, LBVI was not determined in 96 patients (22.0%) (LBVI−/LN+, group III), and was determined in 71 patients (16.3%) (LBVI+/LN+, group IV). Correlation analysis showed that N category and the number of positive LNs were significantly associated with the presence of LBVI (P < 0.001). The overall 5-year survival was significantly longer in LN-negative patients compared with LN-positive patients (56.1% vs 42.3%, P = 0.015). There was a significant difference in the overall 5-year survival between LBVI-positive and LBVI-negative tumors (39.6% vs 54.8%, P = 0.006). Overall 5-year survival rates in each group were 58.8% (I), 45.8% (II), 45.7% (III) and 36.9% (IV), and there was a significant difference in overall survival between the four groups (P = 0.009). Multivariate analysis in stage II gastric cancer patients revealed that LBVI independently affected patient prognosis in LN-negative patients (P = 0.018) but not in LN-positive patients (P = 0.508).
CONCLUSION: In LN-negative stage II gastric cancer patients, LBVI is an additional independent prognostic marker, and may provide useful information to identify patients with poorer prognosis.
PMCID: PMC3400865  PMID: 22826628
Stage II cancer; Gastric cancer; Lymphatic invasion; Blood vessel invasion; Prognosis
10.  XRCC1 Arg399Gln was associated with repair capacity for DNA damage induced by occupational chromium exposure 
BMC Research Notes  2012;5:263.
Occupational chromium exposure may induce DNA damage and lead to lung cancer and other work-related diseases. DNA repair gene polymorphisms, which may alter the efficiency of DNA repair, thus may contribute to genetic susceptibility of DNA damage. The aim of this study was to test the hypothesis that the genetic variations of 9 major DNA repair genes could modulate the hexavalent chromium (Cr (VI))-induced DNA damage.
The median (P25-P75) of Olive tail moment was 0.93 (0.58–1.79) for individuals carrying GG genotype of XRCC1 Arg399Gln (G/A), 0.73 (0.46–1.35) for GA heterozygote and 0.50 (0.43–0.93) for AA genotype. Significant difference was found among the subjects with three different genotypes (P = 0.048) after adjusting the confounding factors. The median of Olive tail moment of the subjects carrying A allele (the genotypes of AA and GA) was 0.66 (0.44–1.31), which was significantly lower than that of subjects with GG genotype (P = 0.043). The A allele conferred a significantly reduced risk of DNA damage with the OR of 0.39 (95% CI: 0.15–0.99, P = 0.048). No significant association was found between the XRCC1Arg194Trp, ERCC1 C8092A, ERCC5 His1104Asp, ERCC6 Gly399Asp, GSTP1 Ile105Val, OGG1 Ser326Cys, XPC Lys939Gln, XPD Lys751Gln and DNA damage.
The polymorphism of Arg399Gln in XRCC1 was associated with the Cr (VI)- induced DNA damage. XRCC1 Arg399Gln may serve as a genetic biomarker of susceptibility for Cr (VI)- induced DNA damage.
PMCID: PMC3500259  PMID: 22642904
DNA damage; Genetic susceptibility; XRCC1; Occupational chromium exposure
11.  Chemistry and Biology of Macrolide Antiparasitic Agents 
Journal of medicinal chemistry  2011;54(8):2792-2804.
Macrolide antibacterial agents inhibit parasite proliferation by targeting the apicoplast ribosome. Motivated by the long-term goal of identifying antiparasitic macrolides that lack antibacterial activity, we have systematically analyzed the structure-activity relationships among erythromycin analogues and have also investigated the mechanism of action of selected compounds. Two lead compounds, N-benzyl-azithromycin (11) and N-phenylpropyl-azithromycin (30), were identified with significantly higher antiparasitic activity and lower antibacterial activity than erythromycin or azithromycin. Molecular modeling based on the co-crystal structure of azithromycin bound to the bacterial ribosome suggested that a substituent at the N-9 position of desmethyl-azithromycin could improve selectivity due to species-specific interactions with the ribosomal L22 protein. Like other macrolides, these lead compounds display a strong “delayed death phenotype”; however, their early effects on T. gondii replication are more pronounced.
PMCID: PMC3085955  PMID: 21428405
12.  5,6-Dimethyl­pyrazine-2,3-dicarb­oxy­lic acid 
The asymmetric unit of the title compound, C8H8N2O4, consists of one complete mol­ecule and a second mol­ecule generated by the application of twofold axis. The mean planes of the two carboxyl groups attached to the pyrazine ring at neighboring positions are twisted by 10.8 (1) and 87.9 (1)° in the complete molecule and 43.0 (1)° in the symmetry-generated molecule. The crystal packing features O—H⋯N hydrogen bonds, which link the mol­ecules into layers along [101].
PMCID: PMC3254478  PMID: 22259420
13.  Poly[[μ7-l-cysteato(2−)]disodium] 
The title compound {systematic name: poly[[μ7-(2R)-2-amino-3-sulfonato­propano­ato]disodium]}, [Na2(C3H5NO5S)]n, was obtained through solvent-thermal reaction of l-cysteic acid and aqueous sodium hydroxide. The monomer consists of two Na+ cations that are coordinated to the deprotonated amino acid. The latter acts as donor utilizing all available coordination sites, viz. the amino, the carboxyl­ate and the sulfonate residues, so producing a monomeric framework in which the two coordinated Na+ ions have different coordination spheres and geometries. One of the Na+ ions has an O5 coordination sphere with a typical geometric arrangement, inter­mediate between trigonal–bipyramidal and square–pyramidal; all the O atoms from the amino acid (three from the sulfonate and two from the caboxylate residues) act as donors. The second Na+ ion is tetracoordinated within an NO3 coordination sphere. The Na+ ion binds to the amino N atom, to one of the O atom of the carb­oxy­lic residue and to two O atoms of the sulfonate group in a distorted tetra­hedral arrangement. As the sulfonate O atoms bind to both Na+ ions, a three-dimensional polymeric framework is obtained.
PMCID: PMC3201222  PMID: 22058689
14.  Suppression of Allograft Rejection by Tim-1-Fc through Cross-Linking with a Novel Tim-1 Binding Partner on T Cells 
PLoS ONE  2011;6(7):e21697.
Engagement of T-cell immunoglobulin mucin (Tim)-1 on T cells with its ligand, Tim-4, on antigen presenting cells delivers positive costimulatory signals to T cells. However, the molecular mechanisms for Tim-1-mediated regulation of T-cell activation and differentiation are relatively poorly understood. Here we investigated the role of Tim-1 in T-cell responses and allograft rejection using recombinant human Tim-1 extracellular domain and IgG1-Fc fusion proteins (Tim-1-Fc). In vitro assays confirmed that Tim-1-Fc selectively binds to CD4+ effector T cells, but not dendritic cells or natural regulatory T cells (nTregs). Tim-1-Fc was able to inhibit the responses of purified CD4+ T cells that do not express Tim-4 to stimulation by anti-CD3/CD28 mAbs, and this inhibition was associated with reduced AKT and ERK1/2 phosphorylation, but it had no influence on nTregs. Moreover, Tim-1-Fc inhibited the proliferation of CD4+ T cells stimulated by allogeneic dendritic cells. Treatment of recipient mice with Tim-1-Fc significantly prolonged cardiac allograft survival in a fully MHC-mismatched strain combination, which was associated with impaired Th1 response and preserved Th2 and nTregs function. Importantly, the frequency of Foxp3+ cells in splenic CD4+ T cells was increased, thus shifting the balance toward regulators, even though Tim-1-Fc did not induce Foxp3 expression in CD4+CD25− T cells directly. These results indicate that Tim-1-Fc can inhibit T-cell responses through an unknown Tim-1 binding partner on T cells, and it is a promising immunosuppressive agent for preventing allograft rejection.
PMCID: PMC3130052  PMID: 21750723
15.  Urocortin induced expression of COX-2 and ICAM-1 via corticotrophin-releasing factor type 2 receptor in rat aortic endothelial cells 
British Journal of Pharmacology  2009;158(3):819-829.
Background and purpose:
Our previous study showed that urocortin (Ucn1) exacerbates the hypercoagulable state and vasculitis in a rat model of sodium laurate-induced thromboangiitis obliterans. Furthermore, the inflammatory molecules COX-2 and ICAM-1 may participate in this effect. In the present study, the effects of Ucn1 on COX-2 and ICAM-1 expression in lipopolysaccharide (LPS)-induced rat aortic endothelial cells (RAECs) were investigated and the mechanisms involved explored.
Experimental approach:
RAECs were isolated from adult male Wistar rats, and identified at the first passage. Experiments were performed on cells, from primary culture, at passages 5–8. The expression of COX-2 and ICAM-1 at both mRNA and protein levels was determined by semi-quantitative RT-PCR and Western blot analysis. Levels of PGE2 and soluble ICAM-1 (sICAM-1) in culture medium were measured by enzyme-linked immunosorbent assay. Furthermore, the phosphorylation status of p38MAPK, ERK1/2, JNK, Akt and NF-κB was analysed by Western blot; nuclear translocation of NF-κB was observed by immunofluorescence.
Key results:
Ucn1 augmented LPS-induced expression of COX-2 and ICAM-1 in RAECs in a time- and concentration-dependent manner. Ucn1 increased PGE2 and sICAM-1 levels. These effects were abolished by the CRF2 receptor antagonist, antisauvagine-30, but not by the CRF1 receptor antagonist, NBI-27914. Moreover, Ucn2 activated p38MAPK and augmented NF-κB nuclear translocation and phosphorylation, whereas ERK1/2, JNK and Akt pathways were not involved in this process.
Conclusions and implications:
These findings suggest that Ucn1 exerts pro-inflammatory effects by augmenting LPS-induced expression of COX-2 and ICAM-1 in RAECs via CRF2 receptors and the activation of p38MAPK and NF-κB.
PMCID: PMC2765601  PMID: 19694731
urocortin; COX-2; ICAM-1; CRF2 receptor; rat aortic endothelial cells
16.  Urocortin promotes the development of vasculitis in a rat model of thromboangiitis obliterans via corticotrophin-releasing factor type 1 receptors 
British Journal of Pharmacology  2009;157(8):1368-1379.
Background and purpose:
Urocortin is a locally expressed pro-inflammatory peptide. Here we have examined the effects of urocortin on sodium laurate-induced peripheral arterial vasculitis in rats, modelling the mechanisms of thromboangiitis obliterans (TAO).
Experimental approach:
Peripheral vasculitis in rats was induced by sodium laurate and graded by gross appearance on the 12th day after injection. Histological changes in rat femoral arteries were assessed by histopathology and transmission electron microscopy. Blood cell counts, blood rheology, blood coagulation and plasma urocortin, thromboxane B2, prostaglandin E2 and soluble intercellular adhesion molecule-1 levels were measured. Expression of urocortin, corticotrophin-releasing factor (CRF1/2) receptors, cyclooxygenase (COX)-2 and intercellular adhesion molecule-1 (ICAM-1) at both mRNA and protein levels were determined by RT-PCR and Western blot.
Key results:
Rats showed grossly visible signs and symptoms of TAO on the 12th day after sodium laurate injection. In these rats, blood was in a hypercoagulable state; plasma urocortin, prostaglandin E2 and soluble intercellular adhesion molecule-1 levels were elevated; and the expression of urocortin, CRF1 and CRF1α-receptors, COX-2 and ICAM-1 in rat femoral arteries were markedly increased. Exogenous urocortin, given for 12 days after sodium laurate, exacerbated the hypercoagulable state and augmented expression of CRF1α-receptors, COX-2 and ICAM-1. These effects were abolished by a CRF1-receptor antagonist, NBI-27914, or a non-selective CRF-receptor antagonist, astressin, but not by the CRF2-receptor antagonist, antisauvagine-30, given with exogenous urocortin.
Conclusion and implications:
Urocortin exacerbated the hypercoagulable state and vasculitis in a model of TAO induced by sodium laurate in rats, via CRF1-receptors. COX-2 and ICAM-1 might also have contributed to this exacerbation.
PMCID: PMC2765315  PMID: 19572944
Urocortin; thromboangiitis obliterans; vasculitis; CRF1-receptor; CRF2- receptor
17.  Dendritic Cells Transduced with SOCS1 Gene Exhibit Regulatory DC Properties and Prolong Allograft Survival 
SOCS1 is a key regulator of cytokine signaling and is important for maintaining balance in the immune system. It is thought to participate in negative feedback loops in cytokine signaling and may be an important signal for the regulation of dendritic cell (DC) maturation. However, it remains unclear whether DCs transduced with SOCS1 exhibit characteristics of regulatory DCs and induce allogeneic T-cell hyporesponsiveness. In this study, we constructed adenoviral vector coding SOCS1 (Ad-SOCS1) that can efficiently increase SOCS1 gene expression in bone marrow-derived dendritic cells. DCs transduced with Ad-SOCS1 (DC-SOCS1) expressed low levels of costimulatory and MHC molecules, were resistant to maturation and activation stimulation, induced allogeneic T-cell hyporesponsiveness, and promoted the generation of regulatory-like T cells in vitro. DC-SOCS1 pretreatment significantly prolonged the survival of allografts and led to a substantial increase in the generation of regulatory T cells. Our data suggest that SOCS1 inhibits DC maturation and induces regulatory DC generation, therefore possessing therapeutic potential to prevent rejection in organ transplantation.
PMCID: PMC4002644  PMID: 19403057
dendritic cell; SOCS1; tolerance; regulatory dendritic cell; allograft survival
18.  Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle 
BMC Medical Genetics  2007;8:64.
Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype.
To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function.
Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens.
The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.
PMCID: PMC2140053  PMID: 17937813

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