Extracellular HMGB1 exacerbates autoimmune progression and recurrence of type 1 diabetes by impairing regulatory T cell stability.

Aims/hypothesis: High-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, was rediscovered to be a 'danger signal' (alarmin) that alerts the immune system once released extracellularly. Therefore, it has been recognised contributing to the pathogenesis of autoimmune diabetes, but its exact impact on the initiation and progression of type 1 diabetes, as well as the related molecular mechanisms, are yet to be fully characterised.

Methods: In the current report, we employed NOD mice as a model to dissect the impact of blocking HMGB1 on the prevention, treatment and reversal of type 1 diabetes.

Ubc9 deficiency selectively impairs the functionality of common lymphoid progenitors (CLPs) during bone marrow hematopoiesis.

Hematopoietic development occurs in the bone marrow, and this process begins with hematopoietic stem cells (HSCs). Ubc9 is a unique E2-conjugating enzyme required for SUMOylation, an evolutionarily conserved post-translational modification system. We herein show that a conditional Ubc9 deletion in the hematopoietic system caused decreased thymus weight and reduced lymphocyte to myeloid cell ratio.

Loss of Jak2 protects cardiac allografts from chronic rejection by attenuating Th1 response along with increased regulatory T cells.

Chronic rejection acts as the most formidable obstacle for organ transplantation in clinical settings. Herein we demonstrated in a cardiac transplantation model that blockade of Janus kinase 2 (Jak2) provides protection for cardiac allografts against chronic rejection. Specifically, loss of almost completely abolished the production of IFN-γ Th1 cells, while the percentage of Foxp3 regulatory T cells (Tregs) was significantly increased.

Feasibility and Benefit of Incorporating a Multimedia Cadaver Laboratory Training Program into a Didactics Curriculum for Junior and Senior Surgical Residents.

Objective: As operative experience in general surgery decreases and work hour limitations increase there is less exposure of surgical residents to advanced vascular and trauma exposures. Many institutions have demonstrated benefits of cadaver laboratory courses. We have incorporated a multimedia cadaver laboratory course into our general surgery residency didactics curriculum with the objective to demonstrate a benefit of the program as well as the feasibility of incorporation.

Descriptive Analysis of Venous Thromboembolism in Georgia Trauma Centers Compared with National Trauma Centers Participating in the Trauma Quality Improvement Program.

This study was designed to compare the incidence of venous thromboembolism (VTE) in Georgia trauma centers with other national trauma centers participating in the Trauma Quality Improvement Program (TQIP). The use of chemoprophylaxis and characteristics of patients who developed VTE were also examined. We conducted a retrospective observational study of 325,703 trauma admissions to 245 trauma centers from 2013 to 2014.

Racial disparities in the use of laparoscopic surgery to treat colonic diverticulitis Are not fully explained by socioeconomics or disease complexity.

Background: Several studies have demonstrated favorable outcomes for laparoscopic surgery over open surgery for the treatment of diverticular disease. This study was designed to analyze the relationship between race, socioeconomic status and the use of laparoscopy to address diverticulitis.

Methods: A retrospective analysis of 53,054 diverticulitis admissions was performed using data from the 2009-2013 National Inpatient Sample (NIS).

Repeated exposure to chlorpyrifos leads to prolonged impairments of axonal transport in the living rodent brain.

The toxicity of the class of chemicals known as the organophosphates (OP) is most commonly attributed to the inhibition of the enzyme acetylcholinesterase. However, there is significant evidence that this mechanism may not account for all of the deleterious neurologic and neurobehavioral symptoms of OP exposure, especially those associated with levels that produce no overt signs of acute toxicity. In the study described here we evaluated the effects of the commonly used OP-pesticide, chlorpyrifos (CPF) on axonal transport in the brains of living rats using manganese (Mn(2+))-enhanced magnetic resonance imaging (MEMRI) of the optic nerve (ON) projections from the retina to the superior colliculus (SC).

Evaluation of nicotine and cotinine analogs as potential neuroprotective agents for Alzheimer's disease.

The currently available therapies for Alzheimer's disease (AD) and related forms of dementia are limited by modest efficacy, adverse side effects, and the fact that they do not prevent the relentless progression of the illness. The purpose of the studies described here was to investigate the neuroprotective effects of the nicotine metabolite cotinine as well as a small series of cotinine and nicotine analogs (including stereoisomers) and to compare their effects to the four clinically prescribed AD therapies.

Effects of chlorpyrifos and chlorpyrifos-oxon on the dynamics and movement of mitochondria in rat cortical neurons.

Organophosphate (OP)-based pesticides have been used extensively for decades, and as a result, they have become almost ubiquitous in our environment. There is clinical and animal evidence to suggest that chronic exposures to OPs can lead to cognitive dysfunction and other neurological abnormalities, although the mechanism for these effects is unknown. We previously reported that repeated, subthreshold exposures (defined as doses not associated with signs of acute toxicity) to the commonly used OP chlorpyrifos (CPF) resulted in protracted impairments in the performance of attention and memory-related tasks in rodents as well as deficits in axonal transport ex vivo (in the sciatic nerve).

Neuroprotective effects and mechanism of cognitive-enhancing choline analogs JWB 1-84-1 and JAY 2-22-33 in neuronal culture and Caenorhabditis elegans.

Background: Our previous work indicated that novel analogs of choline have cytoprotective effects in vitro that might be useful in neurodegenerative conditions such as Alzheimer's disease (AD). Furthermore, two lead compounds (JWB1-84-1 and JAY2-22-33) from a library of more than 50 improved cognitive performances in a transgenic mouse model of AD. The purpose of these experiments was to more specifically investigate the neuroprotective capabilities of these lead compounds both in vitro and in vivo.

Use of combination proteomic analysis to demonstrate molecular similarity of head and neck squamous cell carcinoma arising from different subsites.

Objective: To evaluate head and neck squamous cell carcinomas (HNSCCs) for differences in protein expression between oral cavity, oropharynx, larynx, and hypopharynx subsites.

Design: Retrospective proteomic analysis using tissue microarray (TMA) and 2-dimensional difference gel electrophoresis (2D-DIGE). For the TMA, automated quantitative protein expression analysis was used to interrogate levels of 4 cell-cycle regulatory proteins chosen for their known roles in cancer (cyclin D1, p53, Rb, and p14).

Stable reversal of multidrug resistance in colon cancer cells by RNA interference targeting the MDR1 gene.

Colon cancer is one of the most common cancers in the world. Overexpression of MDR1 mRNA and P-gp is associated with the classic multidrug resistance of colon cancer cells. In our previous study, we reported on the transient specific reversal of MDR1/P-gp-dependent multi-drug resistance by RNA interference (RNAi) in colon cancer cells.

Proteomic identification of serum biomarkers for head and neck cancer surveillance.

Objectives/hypothesis: Serum protein profiling by SELDI-TOF-MS distinguishes pretreatment and post-treatment samples from patients with head and neck squamous cell cancer (HNSCC) by disease status (disease-free or recurrence) with a high degree of sensitivity and specificity. We sought to identify biomarkers for recurrence with potential utility for surveillance and incorporated 2-D DIGE and MALDI-TOF-MS techniques to overcome the limitations of SELDI-TOF-MS in determining biomarker identity.

Methods: Serum samples were collected prospectively from 143 HNSCC patients and analyzed based on disease status following treatment.

Comparative analysis of the islet proteome between NOD/Lt and ALR/Lt mice.

Although alloxan-resistant (ALR) mice share 70% of the NOD genome, ALR islets are remarkably resistant to oxidative stress and autoimmunity. Using 2D PAGE comparative analysis, we have characterized 55 proteins that are differentially expressed between the NOD and ALR islet proteome. Ten proteins were found to be highly expressed in the NOD islets.

Specific reversal of MDR1/P-gp-dependent multidrug resistance by RNA interference in colon cancer cells.

No control cell line was available for previous RNA interference studies on reversal of multidrug resistance (MDR) in colon cancer cells. Here, human COLO 320DM, with HT-29 as the control, colon cancer cell lines were used to investigate the reversal of MDR1/P-gp-dependent MDR by siRNA (#4123 and #4029 MDR1 siRNAs) targeting to MDR1 mRNA. Both siRNAs inhibited expression of MDR1 and P-gp in COLO 320DM.

Proteomics blood testing to distinguish chronic rhinosinusitis subtypes.

Objectives: To evaluate the potential of surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) proteomic profiling of serum samples to distinguish chronic rhinosinusitis subtypes.

Study Design: Translational study of serum samples from prospectively enrolled patients undergoing sinus surgery.

Methods: Patients undergoing endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis were prospectively enrolled in an ongoing, institutional review board approved proteomics study.

Serum inflammatory protein profiles in patients with chronic rhinosinusitis undergoing sinus surgery: a preliminary analysis.

Background: The specific aim of this study was to evaluate surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy (SELDI-TOF-MS) as a clinical screening tool in differentiating patients with chronic rhinosinusitis (CRS) from healthy control patients.

Methods: Serum samples were prospectively collected at a tertiary care academic medical center from 96 CRS patients who underwent functional endoscopic sinus surgery (FESS) and 38 control volunteers who were negatively screened according to the Rhinosinusitis Task Force guidelines on CRS. SELDI-TOF-MS was performed on serum samples to detect protein profiles in the range of 1-100 kDa.

Detection of papillary thyroid carcinoma with serum protein profile analysis.

Objective: To determine the sensitivity and specificity of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) for papillary thyroid carcinoma (PTC) detection.

Design: The SELDI-TOF-MS protein profiles of patients with PTC, patients with benign nodular disease (BND), and healthy controls were analyzed to determine the sensitivity and specificity of SELDI-TOF-MS assay for PTC detection. Data analysis was performed to process the spectral data and classify the disease status of the patients.

Serum protein profile analysis following definitive treatment in patients with head and neck squamous cell carcinoma.

Objective: To determine the sensitivity and specificity of surface-enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF-MS) assay for head and neck squamous cell carcinoma (HNSCC) disease surveillance.

Design: The SELDI-TOF-MS serum protein profiles of patients with HNSCC were analyzed to determine the sensitivity and specificity of the SELDI assay for HNSCC detection following definitive treatment.

Setting: Academic research.

Association of nuclear, cytoplasmic expression of galectin-3 with beta-catenin/Wnt-pathway activation in thyroid carcinoma.

Objectives: To characterize the localization of galectin-3 in benign and malignant thyroid neoplasms and to correlate this with alterations in beta-catenin and cyclin D1 expression.

Design: Immunohistochemical study of 116 paraffin-embedded archival specimens from 113 patients who had undergone thyroidectomy and tissue placed into a commercially available tissue microarray.

Setting: Tertiary care hospital.

A mixture model approach to the tests of concordance and discordance between two large-scale experiments with two-sample groups.

Motivation: Due to advances in experimental technologies, such as microarray, mass spectrometry and nuclear magnetic resonance, it is feasible to obtain large-scale data sets, in which measurements for a large number of features can be simultaneously collected. However, the sample sizes of these data sets are usually small due to their relatively high costs, which leads to the issue of concordance among different data sets collected for the same study: features should have consistent behavior in different data sets. There is a lack of rigorous statistical methods for evaluating this concordance or discordance.

Serum protein profile analysis in patients with head and neck squamous cell carcinoma.

Objectives: To analyze surface-enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF-MS) protein profiles of patients with head and neck squamous cell carcinoma (HNSCC) and healthy controls and to determine the sensitivity and specificity of SELDI assay for HNSCC detection before and after treatment.

Design: Proteomic analysis and comparison of serum samples.

Setting: Tertiary care academic medical center.

Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress.

The substrates of SUMO4, a novel member for the SUMO gene family, were characterized in HEK293 cells cultured under serum starvation by proteomic analysis. We identified 90 SUMO4 substrates including anti-stress proteins such as antioxidant enzymes and molecular chaperones or co-chaperones. The substrates also include proteins involved in the regulation of DNA repair and synthesis, RNA processing, protein degradation, and glucose metabolism.

Analysis of Human Proteome Organization Plasma Proteome Project (HUPO PPP) reference specimens using surface enhanced laser desorption/ionization-time of flight (SELDI-TOF) mass spectrometry: multi-institution correlation of spectra and identification of biomarkers.

We report on a multicenter analysis of HUPO reference specimens using SELDI-TOF MS. Eight sites submitted data obtained from serum and plasma reference specimen analysis. Spectra from five sites passed preliminary quality assurance tests and were subjected to further analysis.

SELDI-TOF MS profiling of serum for detection of the progression of chronic hepatitis C to hepatocellular carcinoma.

Proteomic profiling of serum is an emerging technique to identify new biomarkers indicative of disease severity and progression. The objective of our study was to assess the use of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to identify multiple serum protein biomarkers for detection of liver disease progression to hepatocellular carcinoma (HCC). A cohort of 170 serum samples obtained from subjects in the United States with no liver disease (n = 39), liver diseases not associated with cirrhosis (n = 36), cirrhosis (n = 38), or HCC (n = 57) were applied to metal affinity protein chips for protein profiling by SELDI-TOF MS.