Publications by authors named "Sharad Purohit"

46 Publications

Emerging urinary alpha-synuclein and miRNA biomarkers in Parkinson's disease.

Metab Brain Dis 2021 Apr 21. Epub 2021 Apr 21.

Department of Physical Therapy, College of Allied Health Sciences, Augusta University, 987 St. Sebastian Way, Augusta, GA, 30912, USA.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases after Alzheimer's disease (AD), afflicting adults above the age of sixty irrespective of gender, race, ethnicity, and social status. PD is characterized by motor dysfunctions, displaying resting tremor, rigidity, bradykinesia, and postural imbalance. Non-motor symptoms, including rapid eye movement (REM) behavior disorder, constipation, and loss of sense of smell, typically occur many years before the appearance of the PD motor symptoms that lead to a diagnosis. The loss of dopaminergic neurons in the substantia nigra, which leads to the motor symptoms seen in PD, is associated with the deposition of aggregated, misfolded α-Synuclein (α-Syn, SNCA) proteins forming Lewy Bodies. Additionally, dysregulation of miRNA (a short form of mRNA) may contribute to the developing pathophysiology in PD and other diseases such as cancer. Overexpression of α-Syn and miRNA in human samples has been found in PD, AD, and dementia. Therefore, evaluating these molecules in urine, present either in the free form or in association with extracellular vesicles of biological fluids, may lead to early biomarkers for clinical diagnosis. Collection of urine is non-invasive and thus beneficial, particularly in geriatric populations, for biomarker analysis. Considering the expression and function of α-Syn and miRNA, we predict that they can be used as early biomarkers in the diagnosis and prognosis of neurodegenerative diseases.
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http://dx.doi.org/10.1007/s11011-021-00735-2DOI Listing
April 2021

Serum Levels of Inflammatory Proteins Are Associated With Peripheral Neuropathy in a Cross-Sectional Type-1 Diabetes Cohort.

Front Immunol 2021 31;12:654233. Epub 2021 Mar 31.

Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States.

Chronic low-grade inflammation is involved in the pathogenesis of type-1 diabetes (T1D) and its complications. In this cross-section study design, we investigated association between serum levels of soluble cytokine receptors with presence of peripheral neuropathy in 694 type-1 diabetes patients. Sex, age, blood pressure, smoking, alcohol intake, HbA1c and lipid profile, presence of DPN (peripheral and autonomic), retinopathy and nephropathy was obtained from patient's chart. Measurement of soluble cytokine receptors, markers of systemic and vascular inflammation was done using multiplex immunoassays. Serum levels were elevated in in DPN patients, independent of gender, age and duration of diabetes. Crude odds ratios were significantly associated with presence of DPN for 15/22 proteins. The Odds ratio (OR) remained unchanged for sTNFRI (1.72, p=0.00001), sTNFRII (1.45, p=0.0027), sIL2Rα (1.40, p=0.0023), IGFBP6 (1.51, p=0.0032) and CRP (1.47, p=0.0046) after adjusting for confounding variables, HbA1C, hypertension and dyslipidemia. Further we showed risk of DPN is associated with increase in serum levels of sTNFRI (OR=11.2, p<10), sIL2Rα (8.69, p<10), sNTFRII (4.8, p<10) and MMP2 (4.5, p<10). We combined the serum concentration using ridge regression, into a composite score, which can stratify the DPN patients into low, medium and high-risk groups. Our results here show activation of inflammatory pathway in DPN patients, and could be a potential clinical tool to identify T1D patients for therapeutic intervention of anti-inflammatory therapies.
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http://dx.doi.org/10.3389/fimmu.2021.654233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044415PMC
March 2021

Retrospective Validation of a 168-Gene Expression Signature for Glioma Classification on a Single Molecule Counting Platform.

Cancers (Basel) 2021 Jan 25;13(3). Epub 2021 Jan 25.

Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, 1120, 15th St, Augusta, GA 30912, USA.

Gene expression profiling has been shown to be comparable to other molecular methods for glioma classification. We sought to validate a gene-expression based glioma classification method. Formalin-fixed paraffin embedded tissue and flash frozen tissue collected at the Augusta University (AU) Pathology Department between 2000-2019 were identified and 2 mm cores were taken. The RNA was extracted from these cores after deparaffinization and bead homogenization. One hundred sixty-eight genes were evaluated in the RNA samples on the nCounter instrument. Forty-eight gliomas were classified using a supervised learning algorithm trained by using data from The Cancer Genome Atlas. An ensemble of 1000 linear support vector models classified 30 glioma samples into TP1 with classification confidence of 0.99. Glioma patients in TP1 group have a poorer survival (HR (95% CI) = 4.5 (1.3-15.4), = 0.005) with median survival time of 12.1 months, compared to non-TP1 groups. Network analysis revealed that cell cycle genes play an important role in distinguishing TP1 from non-TP1 cases and that these genes may play an important role in glioma survival. This could be a good clinical pipeline for molecular classification of gliomas.
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http://dx.doi.org/10.3390/cancers13030439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865579PMC
January 2021

Niacin and Butyrate: Nutraceuticals Targeting Dysbiosis and Intestinal Permeability in Parkinson's Disease.

Nutrients 2020 Dec 23;13(1). Epub 2020 Dec 23.

Digestive Health Clinical Research Center, Division of Gastroenterology/Hepatology, Medical College of Georgia, Augusta University, 1120, 15th St, Augusta, GA 30912, USA.

Dysbiosis is implicated by many studies in the pathogenesis of Parkinson's disease (PD). Advances in sequencing technology and computing have resulted in confounding data regarding pathogenic bacterial profiles in conditions such as PD. Changes in the microbiome with reductions in short-chain fatty acid (SCFA)-producing bacteria and increases in endotoxin-producing bacteria likely contribute to the pathogenesis of PD. GPR109A, a G-protein coupled receptor found on the surface of the intestinal epithelium and immune cells, plays a key role in controlling intestinal permeability and the inflammatory cascade. The absence of GPR109A receptors is associated with decreased concentration of tight junction proteins, leading to increased intestinal permeability and susceptibility to inflammation. In inflammatory states, butyrate acts via GPR109A to increase concentrations of tight junction proteins and improve intestinal permeability. Niacin deficiency is exacerbated in PD by dopaminergic medications. Niacin supplementation has been shown to shift macrophage polarization from pro-inflammatory to an anti-inflammatory profile. Niacin and butyrate, promising nutrients and unique ligands for the G protein-coupled receptor GPR109A, are reviewed in this paper in detail.
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http://dx.doi.org/10.3390/nu13010028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824468PMC
December 2020

Comparative analysis of transcriptomic profile, histology, and IDH mutation for classification of gliomas.

Sci Rep 2020 11 26;10(1):20651. Epub 2020 Nov 26.

Center for Biotechnology and Genomic Medicine, Augusta, USA.

Gliomas are currently classified through integration of histology and mutation information, with new developments in DNA methylation classification. However, discrepancies exist amongst the major classification methods. This study sought to compare transcriptome-based classification to the established methods. RNAseq and microarray data were obtained for 1032 gliomas from the TCGA and 395 gliomas from REMBRANDT. Data were analyzed using unsupervised and supervised learning and other statistical methods. Global transcriptomic profiles defined four transcriptomic glioma subgroups with 91.4% concordance with the WHO-defined mutation subtypes. Using these subgroups, 168 genes were selected for the development of 1000 linear support vector classifiers (LSVC). Based on plurality voting of 1000 LSVC, the final ensemble classifier confidently classified all but 17 TCGA gliomas to one of the four transcriptomic profile (TP) groups. The classifier was validated using a gene expression microarray dataset. TP1 cases include IDHwt, glioblastoma high immune infiltration and cellular proliferation and poor survival prognosis. TP2a is characterized as IDHmut-codel, oligodendrogliomas with high tumor purity. TP2b tissue is mostly composed of neurons and few infiltrating malignant cells. TP3 exhibit increased NOTCH signaling, are astrocytoma and IDHmut-non-codel. TP groups are highly concordant with both WHO integrated histology and mutation classification as well as methylation-based classification of gliomas. Transcriptomic profiling provides a robust and objective method to classify gliomas with high agreement to the current WHO guidelines and may provide additional survival prediction to the current methods.
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http://dx.doi.org/10.1038/s41598-020-77777-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692499PMC
November 2020

Senescence-Associated Secretory Phenotype Determines Survival and Therapeutic Response in Cervical Cancer.

Cancers (Basel) 2020 Oct 9;12(10). Epub 2020 Oct 9.

Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, 1120, 15th St, Augusta, GA 30912, USA.

Molecular biomarkers that can predict survival and therapeutic outcome are still lacking for cervical cancer. Here we measured a panel of 19 serum proteins in sera from 565 patients with stage II or III cervical cancer and identified 10 proteins that have an impact on disease specific survival (DSS) (Hazzard's ratio; HR = 1.51-2.1). Surprisingly, all ten proteins are implicated in senescence-associated secreted phenotype (SASP), a hallmark of cellular senescence. Machine learning using Ridge regression of these SASP proteins can robustly stratify patients with high SASP, which is associated with poor survival, and patients with low SASP associated with good survival (HR = 3.09-4.52). Furthermore, brachytherapy, an effective therapy for cervical cancer, greatly improves survival in SASP-high patients (HR = 3.3, < 5 × 10) but has little impact on survival of SASP-low patients (HR = 1.5, = 0.31). These results demonstrate that cellular senescence is a major determining factor for survival and therapeutic response in cervical cancer and suggest that senescence reduction therapy may be an efficacious strategy to improve the therapeutic outcome of cervical cancer.
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http://dx.doi.org/10.3390/cancers12102899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601905PMC
October 2020

A 73-gene proliferative transcriptomic signature predicts uterine serous carcinoma patient survival and response to primary therapy.

Gynecol Oncol 2020 05 14;157(2):340-347. Epub 2020 Feb 14.

Center for Biotechnology and Genomic Medicine, 1120 15(th) Street, Augusta, GA 30912, USA; Department of Obstetrics and Gynecology, Medical College of Georgia, 1120 15(th) Street, Augusta, GA 30912, USA. Electronic address:

Objectives: To develop a transcriptomic signature capable of predicting overall survival (OS) for uterine serous carcinoma (USC).

Methods: RNAseq data for 58 USC patients were obtained from TCGA. Expression of 73 candidate genes was measured for 67 Augusta University (AU) samples using NanoString technology.

Results: Analysis of the TCGA RNAseq data identified 73 genes that individually predict prognosis for USC patients and an elastic net model with all 73 genes (USC73) distinguishes a good OS group with low USC73 score from a poor OS group with high USC73 score (5-year OS = 83.3% and 13.3% respectively, HR = 40.1; p = 3 × 10). This finding was validated in the independent AU cohort (HR = 4.3; p = 0.0004). The poor prognosis group with high USC73 score consists of 37.9% and 32.8% of patients in the TCGA and AU cohort respectively. USC73 score and pathologic stage independently contribute to OS and together provide the best prognostic value. Early stage, low USC73 patients have the best prognosis (5-year OS = 85.1% in the combined dataset), while advanced stage, high USC73 patients have the worst prognosis (5-year OS = 6.4%, HR = 30.5, p = 1.2 × 10). Consistent with the observed poor survival, primary cell cultures from high USC73 patients had higher proliferation rate and cell cycle progression; and high USC73 patients had lower rates of complete response to standard therapy.

Conclusions: The USC73 transcriptomic signature and stage independently predict OS of USC patients and the best prediction is achieved using USC73 and stage. USC73 may also serve as a therapeutic biomarker to guide patient care.
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http://dx.doi.org/10.1016/j.ygyno.2020.02.015DOI Listing
May 2020

Better survival is observed in cervical cancer patients positive for specific anti-glycan antibodies and receiving brachytherapy.

Gynecol Oncol 2020 04 17;157(1):181-187. Epub 2020 Jan 17.

Center for Biotechnology and Genomic Medicine, USA; Department of Obstetrics and Gynecology, Medical College of, Georgia. Electronic address:

Objective: To measure anti-glycan antibodies (AGA) in cervical cancer (CC) patient sera and assess their effect on therapeutic outcome.

Patients And Methods: Serum AGA was measured in 276 stage II and 292 stage III Peruvian CC patients using a high content and throughput Luminex multiplex glycan array (LMGA) containing 177 glycans. Association with disease-specific survival (DSS) and progression free survival (PFS) were analyzed using Cox regression.

Results: AGAs were detected against 50 (28.3%) of the 177 glycans assayed. Of the 568 patients, 84.5% received external beam radiation therapy (EBRT) plus brachytherapy (BT), while 15.5% only received EBRT. For stage-matched patients (Stage III), receiving EBRT alone was significantly associated with worse survival (HR 6.4, p < 0.001). Stage III patients have significantly worse survival than Stage II patients after matching for treatment (HR = 2.8 in EBRT+BT treatment group). Furthermore, better PFS and DSS were observed in patients positive for AGA against multiple glycans belonging to the blood group H, Lewis, Ganglio, Isoglobo, lacto and sialylated tetrarose antigens (best HR = 0.49, best p = 0.0008).

Conclusions: Better PFS and DSS are observed in cervical cancer patients that are positive for specific antiglycan antibodies and received brachytherapy.
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http://dx.doi.org/10.1016/j.ygyno.2020.01.014DOI Listing
April 2020

A complex case of brown tumors as initial manifestation of primary hyperparathyroidism in a young female.

J Oral Maxillofac Pathol 2019 Sep-Dec;23(3):477

Department of Oral Pathology and Microbiology, Navodaya Dental College and Hospital, Raichur, Karnataka, India.

Brown tumor is one of the lesions that develop in patients with hyperparathyroidism (HPT) and represents the terminal stages of bone remodeling process. Any of the skeletal bones can be affected including the craniomaxillofacial ones. Many a times, brown tumor was detected after a final diagnosis of HPT is made. However, on occasions, brown tumor can be the first clinical sign of the disease. Primary HPT is an uncommon systemic disease usually caused by hyperplasia or adenoma of the parathyroid glands. It causes overproduction of parathormone, which may affect the entire skeleton, causing bone resorption appear as cyst-like lesions called osteitis fibrosa cystica or brown tumors. Here, we report such a rare case in which multiple radiolucent lesions were noticed in the ramus part of the mandible and premolar region bilaterally, as the initial signs of primary HPT are presented in this report.
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http://dx.doi.org/10.4103/jomfp.JOMFP_166_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948047PMC
January 2020

Niacin Ameliorates Neuro-Inflammation in Parkinson's Disease via GPR109A.

Int J Mol Sci 2019 Sep 14;20(18). Epub 2019 Sep 14.

Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.

In this study, we used macrophage RAW264.7 cells to elucidate the molecular mechanism underlying the anti-inflammatory actions of niacin. Anti-inflammatory actions of niacin and a possible role of its receptor GPR109A have been studied previously. However, the precise molecular mechanism of niacin's action in reducing inflammation through GPR109A is unknown. Here we observed that niacin reduced the translocation of phosphorylated nuclear kappa B (p-NF-κB) induced by lipopolysaccharide (LPS) in the nucleus of RAW264.7 cells. The reduction in the nuclear translocation in turn decreased the expression of pro-inflammatory cytokines IL-1β, IL-6 in RAW264.7 cells. We observed a decrease in the nuclear translocation of p-NF-κB and the expression of inflammatory cytokines after knockdown of GPR109A in RAW264.7 cells. Our results suggest that these molecular actions of niacin are mediated via its receptor GPR109A (also known as HCAR2) by controlling the translocation of p-NF-κB to the nucleus. Overall, our findings suggest that niacin treatment may have potential in reducing inflammation by targeting GPR109A.
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http://dx.doi.org/10.3390/ijms20184559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770365PMC
September 2019

Cell-based high throughput screening identified a novel compound that promotes regulatory T cells and prevents autoimmune colitis.

Biochem Pharmacol 2019 11 23;169:113618. Epub 2019 Aug 23.

Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, United States; Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States. Electronic address:

Regulatory T cells (T) show great promise for treating autoimmune diseases, allergies and preventing transplant rejection; however, their clinical application has been hampered by the lack of efficient ex vivo or in vivo expansion strategies. Here we report screening data on 130,000 low molecular weight (LMW) compounds for their T promoting potential using a self-developed high-throughput cell-based assay. One of the lead compounds, an isoxazolecarboxamide designated as TRP38, efficiently converts naïve CD4 T cells to T cells in vitro and protects mice from autoimmune colitis in vivo. In addition, TRP38 can synergize with other compounds and/or cytokines such as rapamycin and TGFβ for T conversion, probably via directly inhibiting P70s6 phosphorylation without affecting mTOR expression, underscoring the importance of complementary and coordinated activity of multiple signaling pathways for the increased level of stable T cell production.
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http://dx.doi.org/10.1016/j.bcp.2019.08.020DOI Listing
November 2019

A combined score of clinical factors and serum proteins can predict time to recurrence in high grade serous ovarian cancer.

Gynecol Oncol 2019 03 18;152(3):574-580. Epub 2018 Dec 18.

Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, United States of America; Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, United States of America. Electronic address:

Objective: To investigate the utility of a combined panel of protein biomarkers and clinical factors to predict recurrence in serous ovarian cancer patients.

Methods: Women at Augusta University diagnosed with ovarian cancer were enrolled between 2005 and 2015 (n = 71). Blood was drawn at enrollment and follow-up visits. Patient serum collected at remission was analyzed using the SOMAscan array (n = 35) to measure levels of 1129 proteins. The best 26 proteins were confirmed using Luminex assays in the same 35 patients and in an additional 36 patients (n = 71) as orthogonal validation. The data from these 26 proteins was combined with clinical factors using an elastic net multivariate model to find an optimized combination predictive of progression-free survival (PFS).

Results: Of the 26 proteins, Brain Derived Neurotrophic Factor and Platelet Derived Growth Factor molecules were significant for predicting PFS on both univariate and multivariate analyses. All 26 proteins were combined with clinical factors using the elastic net algorithm. Ten components were determined to predict PFS (HR of 6.55, p-value 1.12 × 10, CI 2.57-16.71). This model was named the serous high grade ovarian cancer (SHOC) score.

Conclusion: The SHOC score can predict patient prognosis in remission. This tool will hopefully lead to early intervention and consolidation therapy strategies in remission patients destined to recur.
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http://dx.doi.org/10.1016/j.ygyno.2018.12.015DOI Listing
March 2019

Proteins of TNF-α and IL6 Pathways Are Elevated in Serum of Type-1 Diabetes Patients with Microalbuminuria.

Front Immunol 2018 31;9:154. Epub 2018 Jan 31.

Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, United States.

Soluble cytokine receptors may play an important role in development of microalbuminuria (MA) in type-1 diabetes (T1D). In this study, we measured 12 soluble receptors and ligands from TNF-α/IL6/IL2 pathways in T1D patients with MA ( = 89) and T1D patients without MA ( = 483) participating in the PAGODA study. Twelve proteins in the sera from T1D patients with and without MA were measured using multiplex Luminex assays. Ten serum proteins (sTNFR1, sTNFR2, sIL2Rα, MMP2, sgp130, sVCAM1, sIL6R, SAA, CRP, and sICAM1) were significantly elevated in T1D patients with MA. After adjusting for age, duration of diabetes, and sex in logistic regression, association remained significant for seven proteins. MA is associated with increasing concentrations of all 10 proteins, with the strongest associations observed for sTNFR1 (OR = 108.3,  < 10) and sTNFR2 (OR = 65.5,  < 10), followed by sIL2Rα (OR = 12.9,  < 10), MMP2 (OR = 5.5,  < 10), sgp130 (OR = 5.2,  < 10), sIL6R (OR = 4.6,  < 10), and sVCAM1 (OR = 3.3,  < 10). We developed a risk score system based on the combined odds ratios associated with each quintile for each protein. The risk scores cluster MA patients into three subsets, each associated with distinct risk for MA attributable to proteins in the TNF-α/IL6 pathway (mean OR = 1, 13.5, and 126.3 for the three subsets, respectively). Our results suggest that the TNF-α/IL6 pathway is overactive in approximately 40% of the MA patients and moderately elevated in the middle 40% of the MA patients. Our results suggest the existence of distinct subsets of MA patients identifiable by their serum protein profiles.
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http://dx.doi.org/10.3389/fimmu.2018.00154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797770PMC
April 2019

Multiplex glycan bead array for high throughput and high content analyses of glycan binding proteins.

Nat Commun 2018 01 17;9(1):258. Epub 2018 Jan 17.

Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.

Glycan-binding proteins (GBPs) play critical roles in diverse cellular functions such as cell adhesion, signal transduction and immune response. Studies of the interaction between GBPs and glycans have been hampered by the availability of high throughput and high-content technologies. Here we report multiplex glycan bead array (MGBA) that allows simultaneous analyses of 384 samples and up to 500 glycans in a single assay. The specificity, sensitivity and reproducibility of MGBA are evaluated using 39 plant lectins, 13 recombinant anti-glycan antibodies, and mammalian GBPs. We demonstrate the utility of this platform by the analyses of natural anti-glycan IgM and IgG antibodies in 961 human serum samples and the discovery of anti-glycan antibody biomarkers for ovarian cancer. Our data indicate that the MGBA platform is particularly suited for large population-based studies that require the analyses of large numbers of samples and glycans.
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http://dx.doi.org/10.1038/s41467-017-02747-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772357PMC
January 2018

Sphingosine Toxicity in EAE and MS: Evidence for Ceramide Generation via Serine-Palmitoyltransferase Activation.

Neurochem Res 2017 Oct 5;42(10):2755-2768. Epub 2017 May 5.

Institute of Molecular Medicine and Genetics, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.

Multiple sclerosis (MS) is a demyelinating disorder characterized by massive neurodegeneration and profound axonal loss. Since myelin is enriched with sphingolipids and some of them display toxicity, biological function of sphingolipids in demyelination has been investigated in MS brain tissues. An elevation of sphingosine with a decrease in monoglycosylceramide and psychosine (myelin markers) was observed in MS white matter and plaque compared to normal brain tissue. This indicated that sphingosine toxicity might mediate oligodendrocyte degeneration. To explain the source of sphingosine accumulation, total sphingolipid profile was investigated in Lewis rats after inducing experimental autoimmune encephalomyelitis (EAE) and also in human oligodendrocytes in culture. An intermittent increase in ceramide followed by sphingosine accumulation in EAE spinal cord along with a stimulation of serine-palmitoyltransferase (SPT) activity was observed. Apoptosis was identified in the lumbar spinal cord, the most prominent demyelinating area, in the EAE rats. TNFα and IFNγ stimulation of oligodendrocytes in culture also led to an accumulation of ceramide with an elevation of sphingosine. Ceramide elevation was drastically blocked by myriocin, an inhibitor of SPT, and also by FTY720. Myriocin treatment also protected oligodendrocytes from cytokine mediated apoptosis or programmed cell death. Hence, we propose that sphingosine toxicity may contribute to demyelination in both EAE and MS, and the intermittent ceramide accumulation in EAE may, at least partly, be mediated via SPT activation, which is a novel observation that has not been previously reported.
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http://dx.doi.org/10.1007/s11064-017-2280-2DOI Listing
October 2017

Intraosseous mucoepidermoid carcinoma of maxilla: a rare entity.

J Exp Ther Oncol 2016 Jul;11(3):207-211

Ashutosh Harsh, Department of Dentistry, Dr Sampurnanand Medical College and Hospital, Jodhpur, Rajasthan, India.

Mucoepidermoid carcinoma (MEC) is the malignant salivary gland neoplasm chiefly occurred in minor salivary gland. One of the rare variant of MEC is intra-osseous variant found in the jaws known as central mucoepidermoid carcinoma. Presently in this case report, we described a 28-year-old male diagnosed with central low grade mucoepidermoid carcinoma subsequently with the presence of asymptomatic swelling with a history of trauma. Clinically mimicking a cystic lesion and radiographically gives an idea of mixed radio-opaque radiolucent lesion which creates a confusion to render a final diagnosis. The site, duration and history of the case are uncommon for the occurrence of intra-osseous malignant lesion of salivary glands. Present case adds new dimensions to the present knowledge about the clinical and radiographical picture that a central mucoepidermoid carcinoma can mimic.
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July 2016

Psammomatoid juvenile ossifying fibroma of mandible in a 6-year-old child.

Indian J Dent 2016 Jan-Mar;7(1):44-7

Department of Oral Pathology and Microbiology, Navodaya Dental College and Hospital, Mantralayam Road, Navodaya Nagar, Raichur, Karnataka, India.

Juvenile ossifying fibroma (JOF) is a rare fibro-osseous lesion of the jaw occurs at the early age of onset frequently under 15 years with a propensity to recur. It appears as a unilobulated/multilobulated lesion at an early stage followed by radiopaque appearance surrounded by radiolucent rimming at advanced stages. The psammomatous type of JOF (PsJOF) principally involves the bones of the orbit and paranasal sinuses. However in some cases, maxilla or rarely the mandible may be pretentious. Here, we report a challenging case of PsJOF in a 6-year-old child with a complaint of swelling imitating a cystic lesion in left back region of the lower jaw for 2 months. The authors propose that a careful examination and correlations of clinical, radiological, and histopathological features are essential to arrive at correct diagnosis and play a vital role in management of such patients.
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http://dx.doi.org/10.4103/0975-962X.179370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836097PMC
May 2016

Dentigerous cyst arising from a complex odontoma: an unusual presentation.

BMJ Case Rep 2016 Apr 18;2016:10.1136/bcr-2016-214936. Epub 2016 Apr 18.

Department of Dental Anatomy & Oral Biology, Basic Dental Sciences, Faculty of Dentistry Al-Hawiyah, Al Taif-21944, University of Taif, Kingdom of Saudi Arabia.

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http://dx.doi.org/10.1136/bcr-2016-214936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840631PMC
April 2016

IGF-Binding Proteins in Type-1 Diabetes Are More Severely Altered in the Presence of Complications.

Front Endocrinol (Lausanne) 2016 29;7. Epub 2016 Jan 29.

Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, USA; Department of Pathology, Augusta University, Augusta, GA, USA.

Aims: Reduced levels of free and total insulin-like growth factor 1 (IGF-I) have been observed in type-1 diabetes (T1D) patients. The bioavailability of IGF-I from the circulation to the target cells is controlled by multifunctional IGF-binding proteins (IGFBPs). The aim of this study was to profile serum IGFBPs in T1D and its complications.

Design: We measured the IGFBP levels in 3662 patient serum samples from our ongoing Phenome and Genome of Diabetes Autoimmunity (PAGODA) study. IGFBP levels of four different groups of T1D patients (with 0, 1, 2, and ≥3 complications) were compared with healthy controls.

Results: Three serum IGFBPs (IGFBP-1, -2, and -6) are significantly higher in T1D patients, and these alterations are greater in the presence of diabetic complications. IGFBP-3 is lower in patients with diabetic complications. Analyses using quintiles revealed that risk of T1D complications increases with increasing concentrations of IGFBP-2 (fifth quintile ORs: 18-60, p < 10(-26)), IGFBP-1 (fifth quintile ORs: 8-20, p < 10(-15)), and IGFBP-6 (fifth quintile ORs: 3-148, p < 10(-3)). IGFBP-3 has a negative association with T1D complications (fifth quintile ORs: 0.12-0.25, p < 10(-5)).

Conclusion: We found that elevated serum levels of IGFBP-1, -2, and -6 were associated with T1D, and its complications and IGFBP-3 level was found to be decreased in T1D with complications. Given the known role of these IGFBPs, the overall impact of these alterations suggests a negative effect on IGF signaling.
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http://dx.doi.org/10.3389/fendo.2016.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731488PMC
February 2016

Adenomatoid odontogenic tumor associated with a dentigerous cyst.

J Cancer Res Ther 2015 Jul-Sep;11(3):649

Department of Oral Pathology and Microbiology, K M Shah Dental College and Hospital, Vadodara, Gujrat, India.

Adenomatoid odontogenic tumor (AOT) is a relatively uncommon benign lesion of odontogenic origin mainly affecting females in second decade of life, having a predilection for the anterior region of the maxilla. Histologically, it is composed of odontogenic epithelium in a variety of histopathological patterns in a mature, fibrous connective tissue stroma and characterized by slow but progressive growth. Very few cases of AOT associated with a dentigerous cyst have been reported in the literature. PubMed and Medline data showed a total of 11 cases of AOT associated with a dentigerous cyst in the literature. We present an additional case of an AOT arising from a dentigerous cyst around the crown of an unerupted upper canine in a 20-year-old female, which was clinically diagnosed as a dentigerous cyst. Histologically, the case showed proliferation of odontogenic epithelium in the form of whorls and islands typical of AOT associated with dentigerous cyst appearing thin reduced enamel like epithelium lining the cystic cavity, described previously. However, it is unclear whether this entity has a more aggressive potential.
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http://dx.doi.org/10.4103/0973-1482.138120DOI Listing
August 2016

Elevated Serum Levels of Soluble TNF Receptors and Adhesion Molecules Are Associated with Diabetic Retinopathy in Patients with Type-1 Diabetes.

Mediators Inflamm 2015 3;2015:279393. Epub 2015 Aug 3.

Center for Biotechnology and Genomic Medicine, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.

Aims: To examine the association of the serum levels of TNF receptors, adhesion molecules, and inflammatory mediators with diabetic retinopathy (DR) in T1D patients.

Methods: Using the multiplex immunoassay, we measured serum levels of eight proteins in 678 T1D subjects aged 20-75 years. Comparisons were made between 482 T1D patients with no complications and 196 T1D patients with DR.

Results: The levels of sTNFR-I, sTNFR-II, CRP, SAA, sgp130, sIL6R, sVCAM1, and sICAM1 were significantly higher in the T1D patients with DR as compared to T1D patients with no complications. Multivariate logistic regression analysis revealed significant association for five proteins after adjustment for age, sex, and disease duration (sTNFR-I: OR = 1.57, sgp130: OR = 1.43, sVCAM1: OR = 1.27, sICAM1: OR = 1.42, and CRP: OR = 1.15). Conditional logistic regression on matched paired data revealed that subjects in the top quartile for sTNFR-I (OR = 2.13), sTNFR-II (OR = 1.66), sgp130 (OR = 1.82), sIL6R (OR = 1.75), sVCAM1 (OR = 1.98), sICAM1 (OR = 2.23), CRP (OR = 2.40) and SAA (OR = 2.03), had the highest odds of having DR.

Conclusions: The circulating markers of inflammation, endothelial injury, and TNF signaling are significantly associated with DR in patients with T1D. TNFR-I and TNFR-II receptors are highly correlated, but DR associated more strongly with TNFR-I in these patients.
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http://dx.doi.org/10.1155/2015/279393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539119PMC
May 2016

Large-Scale Discovery and Validation Studies Demonstrate Significant Reductions in Circulating Levels of IL8, IL-1Ra, MCP-1, and MIP-1β in Patients With Type 1 Diabetes.

J Clin Endocrinol Metab 2015 Sep 9;100(9):E1179-87. Epub 2015 Jul 9.

Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.

Context: Previous studies have attempted to elucidate the potential role of various cytokines and chemokines in human type 1 diabetes (T1D); however, the precise role of these serum proteins in T1D is still controversial and undetermined primarily due to the small sample sizes of the previous studies. We profiled a panel of serum cytokines and chemokines using a large-scale, two-stage study design for the discovery and validation of the serum proteins associated with T1D.

Participants: The participants were patients with T1D and islet autoantibody-negative control subjects from the Phenome and Genome of Diabetes Autoimmunity study.

Main Outcome Measures: Thirteen cytokines and chemokines were measured in serum of 4424 subjects using multiplex immunoassays.

Results: Using 1378 samples in Stage 1, we found that four of the 13 proteins are significantly lower in patients with T1D than controls (IL8: odds ratio [OR] = 0.40; P = 5.7 × 10(-19); IL-1Ra: OR = 0.42; P = 1.1 × 10(-13); MCP-1: OR = 0.60; P = 6.7 × 10(-9); and MIP-1β: OR = 0.63; P = 4.2 × 10(-7)). Our confirmation data with 3046 samples in Stage 2 further confirmed the significant negative associations of these four proteins with T1D (IL8: OR = 0.43; P = 8.9 × 10(-32); IL-1Ra: OR = 0.56, P = 3.7 × 10(-27); MCP-1: OR = 0.61, P = 4.3 × 10(-17); and MIP-1β: OR = 0.69, P = 2.4 × 10(-13)). Quartile analyses also suggested that significantly more T1D cases have protein levels in the bottom quartile than in the top quartile for all four proteins: IL8 (OR = 0.09), IL-1Ra (OR = 0.18), MCP-1 (OR = 0.38), and MIP-1β (OR = 0.44). Furthermore, the negative associations between T1D and serum levels of all four proteins are stronger in genetically high-risk groups compared with the moderate and low-risk groups.

Conclusions: IL8, IL-1Ra, MCP-1, and MIP-1β are significantly lower in patients with T1D than controls.
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http://dx.doi.org/10.1210/JC.2015-1388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570171PMC
September 2015

Luminex and other multiplex high throughput technologies for the identification of, and host response to, environmental triggers of type 1 diabetes.

Biomed Res Int 2015 25;2015:326918. Epub 2015 Mar 25.

Center for Biotechnology and Genomic Medicine (CBGM), Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA ; Department of Pathology, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.

Complex interactions between a series of environmental factors and genes result in progression to clinical type 1 diabetes in genetically susceptible individuals. Despite several decades of research in the area, these interactions remain poorly understood. Several studies have yielded associations of certain foods, infections, and immunizations with the onset and progression of diabetes autoimmunity, but most findings are still inconclusive. Environmental triggers are difficult to identify mainly due to (i) large number and complex nature of environmental exposures, including bacteria, viruses, dietary factors, and environmental pollutants, (ii) reliance on low throughput technology, (iii) less efforts in quantifying host response, (iv) long silent period between the exposure and clinical onset of T1D which may lead to loss of the exposure fingerprints, and (v) limited sample sets. Recent development in multiplex technologies has enabled systematic evaluation of different classes of molecules or macroparticles in a high throughput manner. However, the use of multiplex assays in type 1 diabetes research is limited to cytokine assays. In this review, we will discuss the potential use of multiplex high throughput technologies in identification of environmental triggers and host response in type 1 diabetes.
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http://dx.doi.org/10.1155/2015/326918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389818PMC
February 2016

Glandular odontogenic cyst in maxilla: A case report and literature review.

J Oral Maxillofac Pathol 2014 May;18(2):320-3

Department of Dentistry, Dr. Sampurnanand Medical College and Hospital, Jodhpur, Rajasthan, India.

Glandular odontogenic cyst (GOC) is an uncommon jaw bone cyst of odontogenic origin described in 1987 by Gardner et al. It is a cyst having an unpredictable and potentially aggressive behavior. The increased recurrence rate can be due to its multilocularity and incomplete removal of the lining following conservative treatment. Clinically, the most common site of occurrence is the anterior region of mandible. GOC has a slight male predilection and occurs primarily in middle-aged patients. This article presents a case of glandular odontogenic cyst in a 30-year-old female patient in the posterior region of the maxilla, which is quite rare.
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http://dx.doi.org/10.4103/0973-029X.140923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196310PMC
May 2014

Twelve serum proteins progressively increase with disease stage in squamous cell cervical cancer patients.

Int J Gynecol Cancer 2014 Jul;24(6):1085-92

*Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA; †Sino-American Cancer Research Center and Institute of Translational Medicine, School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing, Jiangsu Province, China; ‡Department of Obstetrics and Gynecology, Cancer Center, Georgia Regents University, Augusta, GA; and §Department of Gynecologic Oncology, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru.

Objective: This study aimed to reliably identify serum protein profile alterations that may be useful for elucidation of the disease mechanism and/or finding new targets for treatment and intervention.

Materials And Methods: A total of 1057 women at 4 different squamous cell cervical cancer stages (noninvasive, invasive International Federation of Gynecology and Obstetrics stages I, II, and III) were included in this cross-sectional study. Forty-seven serum proteins were profiled using multiplex Luminex immunoassays.

Results: Serum concentration of serum amyloid A (SAA), C-reactive protein (CRP), soluble tumor necrosis factor receptor I and II (sTNFRI and sTNFRII), soluble interleukin 2 receptor α (sIL2Rα), CXCL1, CXCL9, hepatocyte growth factor, squamous cell carcinoma antigen (SCCA), insulin-like growth factor binding protein 2, CA125, and carcinoembryonic antigen (CEA) were elevated significantly as disease progressed in cervical cancer patients. Serum levels are significantly different at early stage (I) for SAA, CRP, sIL2Rα, sTNFRII, SCCA, and CEA (P values ranged from 0.02 for CEA to 0.0001 for CRP and SCCA) and at late stages (II and III) for all 12 proteins (P values ranged from 8.78E-5 for CA125 to 3.49E-47 for SAA), as compared to the noninvasive stage. The areas under the curves of these proteins for disease state separation also improved with the advancement of the disease. The correlations between serum concentrations of these proteins also show different patterns at different clinical stages. These proteins are involved in multiple mechanisms including inflammation and immunity, angiogenesis, growth promotion, and metastasis.

Conclusions: A number of serum proteins are significantly different between patients at different stages of cervical cancer.
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http://dx.doi.org/10.1097/IGC.0000000000000153DOI Listing
July 2014

Labial and palatal talon cusp on the maxillary supernumerary tooth in a deciduous dentition.

BMJ Case Rep 2014 Mar 18;2014. Epub 2014 Mar 18.

Department of Pedodontics & Preventive Dentistry, K M Shah Dental College & Hospital, Vadodara, Gujarat, India.

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http://dx.doi.org/10.1136/bcr-2013-202300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962889PMC
March 2014

Mycophenolic acid inhibits migration and invasion of gastric cancer cells via multiple molecular pathways.

PLoS One 2013 15;8(11):e81702. Epub 2013 Nov 15.

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China ; Institute of Translational Medicine, School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing, China ; Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.

Mycophenolic acid (MPA) is the metabolized product and active element of mycophenolate mofetil (MMF) that has been widely used for the prevention of acute graft rejection. MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and MPA is known to inhibit cancer cell proliferation as well as fibroblast and endothelial cell migration. In this study, we demonstrated for the first time MPA's antimigratory and anti-invasion abilities of MPA-sensitive AGS (gastric cancer) cells. Genome-wide expression analyses using Illumina whole genome microarrays identified 50 genes with ≥2 fold changes and 15 genes with > 4 fold alterations and multiple molecular pathways implicated in cell migration. Real-time RT-PCR analyses of selected genes also confirmed the expression differences. Furthermore, targeted proteomic analyses identified several proteins altered by MPA treatment. Our results indicate that MPA modulates gastric cancer cell migration through down-regulation of a large number of genes (PRKCA, DOCK1, INF2, HSPA5, LRP8 and PDGFRA) and proteins (PRKCA, AKT, SRC, CD147 and MMP1) with promigratory functions as well as up-regulation of a number of genes with antimigratory functions (ATF3, SMAD3, CITED2 and CEAMCAM1). However, a few genes that may promote migration (CYR61 and NOS3) were up-regulated. Therefore, MPA's overall antimigratory role on cancer cells reflects a balance between promigratory and antimigratory signals influenced by MPA treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081702PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829969PMC
June 2014

Embryonal rhabdomyosarcoma occurring on mandibular gingiva in an adult.

J Clin Diagn Res 2013 Sep 10;7(9):2088-9. Epub 2013 Sep 10.

Reader, Jodhpur Dental College General Hospital, Jodhpur National University , Jodhpur, Rajasthan, India .

An embryonal rhabdomyosarcoma (ERMS) is a primitive, malignant, soft tissue sarcoma that recapitulates the phenotypic and biological features of embryonic skeletal muscles. Occurrence of intraoral ERMS in adults is extremely rare. This unique case report highlights the clinical, radiographic, histopathological and immunohistochemical findings of an intraoral ERMS.
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http://dx.doi.org/10.7860/JCDR/2013/6008.3415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809692PMC
September 2013

Serum insulin-like growth factor binding protein 6 (IGFBP6) is increased in patients with type 1 diabetes and its complications.

Int J Clin Exp Med 2012 10;5(3):229-37. Epub 2012 Jun 10.

Insulin-like growth factor binding proteins (IGFBPs) are associated with insulin resistance and accelerated micro- and macro-vascular complications of diabetes. We investigated the relationship between serum levels of IGFBP6 in type-1 diabetes (T1D) patients and diabetic complications. In this study, IGFBP6 was measured in the sera from 697 T1D patients and 681 healthy controls using a Luminex assay. Mean serum levels of IGFBP6 were higher in T1D patients than controls matched for sex and age (119.7 vs 130.6 ng/ml, p < 10(-4)). Subject age, sex and duration of disease have a significant impact on serum IGFBP6 levels in both T1D patients and healthy controls. Patients with complications have significantly higher mean serum IGFBP6 than patients without any complication (p = 3.5x10(-6)). More importantly, conditional logistic regression analysis suggested that T1D patients are more likely to have very high levels of serum IGFBP6 (in the 4(th) quartile) (OR = 1.7) than healthy controls. Furthermore, T1D patients with various complications are more likely to have very high levels of serum IGFBP6 (in the 4(th) quartile) than patients without any complication (OR = 1.7 - 22.9). These results indicate the clinical importance of measuring IGFBP6 to the better management of T1D patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403553PMC
August 2012

Over-expression of Stat5b confers protection against diabetes in the non-obese diabetic (NOD) mice via up-regulation of CD4(+)CD25(+) regulatory T cells.

Biochem Biophys Res Commun 2012 Aug 10;424(4):669-74. Epub 2012 Jul 10.

Center for Biotechnology and Genomic Medicine, Georgia Health Sciences University, GA 30912, USA.

The signal transducers and activators of transcription (STAT) family of proteins play a critical role in cytokine signaling required for fine tuning of immune regulation. Previous reports showed that a mutation (L327M) in the Stat5b protein leads to aberrant cytokine signaling in the NOD mice. To further elaborate the role of Stat5b in diabetes, we established a NOD transgenic mouse that over-expresses the wild type Stat5b gene. The incidences of spontaneous diabetes as well as cyclophosphamide-induced diabetes were significantly reduced and delayed in the Stat5b transgenic NOD mice compared to their littermate controls. The total cell numbers of CD4(+) T cells and especially CD8(+) T cells in the spleen and pancreatic lymph node were increased in the Stat5b transgenic NOD mice. Consistent with these findings, CD4(+) and CD8(+) T cells from the Stat5b transgenic NOD mice showed a higher proliferation capacity and up-regulation of multiple cytokines including IL-2, IFN-γ, TNF-α and IL-10 as well as anti-apoptotic gene Bcl-xl. Furthermore, the number and proportion of CD4(+)CD25(+) regulatory T cells were significantly increased in transgenic mice although in vitro suppression ability of the regulatory T-cells was not affected by the transgene. Our results suggest that Stat5b confers protection against diabetes in the NOD mice by regulating the numbers and function of multiple immune cell types, especially by up-regulating CD4(+)CD25(+) regulatory T cells.
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http://dx.doi.org/10.1016/j.bbrc.2012.06.162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990414PMC
August 2012