Immunology and Laboratory Medicine

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Immunology and Laboratory Medicine

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Zuluaga Toro T.,Immunology and Laboratory Medicine | Feely M.M.,Immunology and Laboratory Medicine | Trevino J.G.,University of Florida
Gastrointestinal Cancer Research | Year: 2013

BACKGROUND: Adenosquamous carcinoma of the pancreas (ASCAP) is a rare histologic type of pancreatic carcinoma that constitutes 1% to 4% of all pancreatic exocrine malignancies. It has a clinical presentation similar to that of adenocarcinoma of the pancreas (ACP), but may have a worse overall prognosis, with most patients surviving for less than 2 years. METHODS: This was an institutional, retrospective, cohort analysis of 237 patients who underwent resection of pancreatic cancer with curative intent. RESULTS: Of the 237 cases examined, we identified 7 (2.9%) with histologically confirmed ASCAP. Demographics, comorbidities, risk factors, presenting symptoms, survival data, tumor characteristics, and types of treatment for each patient were included in the analysis. Risk factors for development of ASCAP were not conclusive. Although human papilloma virus (HPV) has been implicated in other squamous cell cancers, in our cohort, its involvement in ASCAP was 0%. Presurgical fineneedle aspiration failed to identify the invasive squamous cell component in all cases. In this cohort analysis, overall survival ranged from 3 to 25 months, with 2 patients surviving more than 20 months after surgical resection. With a median follow-up of 2.9 years, our data demonstrate a trend to worse median overall survival for ASCAP than for ACP (8.2 vs. 20.4 months; P=23), with a limited number of long-term survivors. CONCLUSIONS: Although recommended, adjuvant treatment was inconsistently provided for patients in this ASCAP cohort. Published data show variability in overall survival, but our findings support that surgical resection is one of the few options for control of this rare, poorly understood pancreatic malignancy. Further research is necessary to define risk factors and adjuvant and neoadjuvant treatments, to help improve patient outcomes. © 2013 by International Society of Gastrointestinal Oncology.

Muller V.,Semmelweis University | Muller V.,West Virginia University | Tain Y.-L.,Chang Gung University | Tain Y.-L.,Immunology and Laboratory Medicine | And 3 more authors.
American Journal of Nephrology | Year: 2010

Background/Aims: The C57Bl6 mouse is resistant to chronic kidney disease (CKD) induced by reduction of renal mass (RRM). Nitric oxide (NO) deficiency exacerbates CKD progression so this study investigated whether combination of RRM and NO deficiency would render the C57Bl6 mouse vulnerable to CKD. Methods: We used wild-type (WT) mice with RRM, chronic NO synthase (NOS) inhibition and a combination. Also, endothelial NOS (eNOS) knockout (KO) C57Bl6 mice were studied with and without RRM. Primary endpoints were albuminuria and structural damage. Results: Both nonselective (+L-NAME) and neuronal NOS 'selective' (+7NI) NOS inhibition greatly exacerbated the albuminuria and structural damage seen with RRM in the WT mice; NOS inhibition alone had little effect. The eNOS KO mice showed marked structural damage and significant albuminuria in the shams and RRM produced minimal exacerbation of structural damage although the albuminuria was massively amplified. Conclusion: These studies demonstrate that the C57Bl6 mouse is rendered vulnerable to RRM-induced CKD when concomitant NO deficiency is produced. This observation supports previous work in CKD-resistant rats and suggests that NO deficiency is required for progression of CKD. Copyright © 2010 S. Karger AG, Basel.

Jin Y.,Aurora University | Birlea S.A.,Aurora University | Fain P.R.,Aurora University | Fain P.R.,Barbara Davis Center for Childhood Diabetes | And 21 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. METHODS: To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. RESULTS: We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility- complex class I molecules (P = 9.05×10-23) and class II molecules (P = 4.50×10-34), PTPN22 (P = 1.31×10 -7), LPP (P = 1.01×10-11), IL2RA (P = 2.78×10-9), UBASH3A (P = 1.26×10-9), and C1QTNF6 (P = 2.21×10-16). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P = 7.07×10-15) and GZMB (P = 3.44×10-8), and in a locus containing TYR (P = 1.60×10-18), encoding tyrosinase. CONCLUSIONS: We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma. Copyright © 2010 Massachusetts Medical Society.

PubMed | Immunology and Laboratory Medicine and Florida College
Type: Journal Article | Journal: American journal of clinical pathology | Year: 2015

Accurate grading of gastrointestinal stromal tumors (GISTs), based on mitotic index, can be problematic.In this study, we compared interobserver variability in detecting mitosis on H&E with PHH3 immunohistochemistry (IHC). In addition, we examined the correlation between H&E mitosis and Ki-67 and the association of PHH3 and Ki-67 with overall survival. Four pathologists independently reviewed 50 GIST cases.Intraclass correlation coefficients showed good interobserver variability for mitotic counts on both H&E (0.918; 95% confidence interval [CI], 0.874-0.950) and PHH3 IHC (0.923; 95% CI, 0.882-0.953). Nineteen (38%) cases were graded higher and five (10%) cases were downgraded by at least one observer using PHH3 compared with H&E. Using receiver operating characteristic curve analysis, a PHH3 cutoff of seven or more mitoses was associated with worse overall survival (P = .028). Ki-67 showed poor correlation with H&E mitotic counts and overall survival (P = .077).PHH3 may thus be a valuable adjunct for risk stratification in GISTs.

PubMed | Coswig Specialist Hospital, Immunology and Laboratory Medicine, Charité - Medical University of Berlin, Lungenklinik Heckeshorn and 7 more.
Type: Journal Article | Journal: Pneumologie (Stuttgart, Germany) | Year: 2016

Non-tuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis-complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide, a rising prevalence and significance of non-tuberculous mycobacterioses is recognized. The present recommendations summarise current aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of non-tuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

Donelan W.,Immunology and Laboratory Medicine | Li S.,Immunology and Laboratory Medicine | Wang H.,Immunology and Laboratory Medicine | Lu S.,Immunology and Laboratory Medicine | And 4 more authors.
American Journal of Translational Research | Year: 2015

Ectopic expression of Pdx1 triggers rapid hepatocyte dedifferentiation by down-regulating liver-enriched transcription factors and liver-specific functional genes such as hepatic nuclear factor-1α (HNF1α), albumin, and AAT. However, the links between Pdx1 over-expression and hepatic gene down-regulation are incompletely understood. HNF1α and HNF4α are important transcription factors that establish and maintain the hepatocyte phenotype. The human HNF4α gene contains two promoters (P1 and P2) that drive expression of P1-(HNF4α 1-6) or P2-(HNF4α 7-9)-derived isoforms, which are used in different tissues and at different times during development. We hypothesized that the relative expression of HNF1α and HNF4α following ectopic Pdx1 expression may promote hepatic cell dedifferentiation and transdifferentiation toward pancreatic beta-cells. We produced lentiviruses expressing Pdx1, Pdx1-VP16, and Ngn3, along with dual-color reporter genes to indicate hepatic and pancreatic betacell phenotype changes. Using these PTF alone or in combinations, we demonstrated that Pdx1 not only activates specific beta-cell genes but down-regulates HNF1α. Pdx1-mediated reduction of HNF1α is accompanied by altered expression of its major activator, HNF4α isoforms, down-regulating hepatic genes ALB and AAT. Pdx1 up-regulates HNF4α via the P2 promoter. These P2-driven isoforms compete with P1-driven isoforms to suppress target gene transcription. In Huh7 cells, the AF-1 activation domain is more important for transactivation, whereas in INS1 cells, the F inhibitory domain is more important. The loss and gain of functional activity strongly suggests that Pdx1 plays a central role in reprogramming hepatocytes into beta-cells by suppressing the hepatic phenotype. © 2015 E-Century Publishing Corporation. All rights reserved.

Winter W.E.,Immunology and Laboratory Medicine | Winter W.E.,University of Florida | Bazydlo L.A.L.,Immunology and Laboratory Medicine | Harris N.S.,Immunology and Laboratory Medicine
Laboratory Medicine | Year: 2014

Iron is one of the most important nonorganic substances that make life possible. Iron plays major roles in oxygen transport (eg, hemoglobin; ∼67% of total body iron [TBI]), short-term oxygen storage (eg, myoglobin; ∼3.5% of TBI), and energy generation (eg, cytochromes; ∼3% of TBI).1 Iron also serves vital roles in various nonheme-containing enzymes (∼2% of TBI). Figure 1 lists heme-containing and nonheme iron-containing proteins. TBI is controlled by the rate of iron absorption; there are no physiologic mechanisms to excrete excess iron. Iron deficiency has many adverse consequences, including anemia, and in children, behavioral and learning disorders.2-4 Iron excess is toxic to the body, harming the heart, liver, skin, pancreatic islet beta cells, bones, joints, and pituitary gland. Maintaining proper iron balance is essential for maintaining homeostasis and health. TBI in adults normally ranges between 3.5 and 5.0 g.5 A total of 75% of TBI is functional, and 25% is stored within cells as ferritin or hemosiderin. Ferritin contains 24 subunits of light chains (L chains; 19.7 kDa) and heavy chains (H chains; 21.1 kDa). The L chains are encoded on chromosome 19q13.33 and are 175 amino acids long. The H chains are encoded on chromosome 11q1 and are 183 amino acids long. Each ferritin molecule can contain as many as approximately 4500 ferric ions. Because the major role of iron is in hemoglobin synthesis, this review will focus on iron, iron transport, and hematopoiesis.

Stupp G.S.,University of Florida | Clendinen C.S.,University of Florida | Ajredini R.,University of Florida | Szewc M.A.,Thermo Fisher Scientific | And 6 more authors.
Analytical Chemistry | Year: 2013

We demonstrate the global metabolic analysis of Caenorhabditis elegans stress responses using a mass-spectrometry-based technique called isotopic ratio outlier analysis (IROA). In an IROA protocol, control and experimental samples are isotopically labeled with 95 and 5% 13C, and the two sample populations are mixed together for uniform extraction, sample preparation, and LC-MS analysis. This labeling strategy provides several advantages over conventional approaches: (1) compounds arising from biosynthesis are easily distinguished from artifacts, (2) errors from sample extraction and preparation are minimized because the control and experiment are combined into a single sample, (3) measurement of both the molecular weight and the exact number of carbon atoms in each molecule provides extremely accurate molecular formulas, and (4) relative concentrations of all metabolites are easily determined. A heat-shock perturbation was conducted on C. elegans to demonstrate this approach. We identified many compounds that significantly changed upon heat shock, including several from the purine metabolism pathway. The metabolomic response information by IROA may be interpreted in the context of a wealth of genetic and proteomic information available for C. elegans. Furthermore, the IROA protocol can be applied to any organism that can be isotopically labeled, making it a powerful new tool in a global metabolomics pipeline. © 2013 American Chemical Society.

Nahid M.A.,University of Florida | Satoh M.,Immunology and Laboratory Medicine | Satoh M.,University of Florida | Satoh M.,University of Occupational and Environmental Health Japan | Chan E.K.L.,University of Florida
Journal of Innate Immunity | Year: 2015

Unwarranted overproduction of cytokines, such as interleukin (IL)-1β, can cause moderate to severe pathological complications, and thus elaborate mechanisms are needed to regulate its onset and termination. One such, well-known, mechanism is endotoxin tolerance, generally described as controlling lipopolysaccharide Toll-like receptor 4 (LPS-TLR4) signaling. Similarly, cytokine-induced tolerance plays an important role in regulating an overactive cytokine response. In this report, the capability of IL-1β to induce tolerance and cross-tolerance to various inflammatory ligands was investigated. IL-1β-stimulated THP-1 monocytes showed a gradual increase of microRNA (miR)-146a, reaching 15-fold expression by 24 h. miR-146a upregulation induced tolerance toward subsequent challenges of IL-1β, LPS, peptidoglycan, Pam and flagellin in THP-1 cells. The induction of tolerance was dependent on the IL-1β priming dose and associated increase of miR-146a expression. Moreover, IL-1β-treated THP-1 cells showed sustained miR-146a upregulation that repressed IRAK1 and TRAF6 adaptor molecules. Transfection of miR-146a alone mimicked IL-1β-induced tolerance in monocytes, while cells transfected with miR-146a inhibitor increased chemokine production. A comparable cytokine response regulated by miR-146a was also detected in lung epithelial A549 cells, purified human monocytes and mouse peritoneal macrophages. Thus, our studies showed that miR-146a was crucial for monocytic cell-based IL-1β tolerance and cross-tolerance, and thus opens the way for future research in the development of therapeutics for inflammatory diseases. © 2015 S. Karger AG, Basel.

Polyak S.,University of Iowa | Polyak S.,Immunology and Laboratory Medicine | Mach A.,Immunology and Laboratory Medicine | Porvasnik S.,Immunology and Laboratory Medicine | And 12 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2012

Effective gene transfer with sustained gene expression is an important adjunct to the study of intestinal inflammation and future therapy in inflammatory bowel disease. Recombinant adeno-associated virus (AAV) vectors are ideal for gene transfer and long-term transgene expression. The purpose of our study was to identify optimal AAV pseudotypes for transduction of the epithelium in the small intestine and colon, which could be used for studies in experimental colitis. The tropism and transduction efficiencies of AAV pseudotypes 1-10 were examined in murine small intestine and colon 8 wk after administration by real-time PCR and immunohistochemistry. The clinical and histopathological effects of IL-10-mediated intestinal transduction delivered by AAVrh10 were examined in the murine IL-10 -/- enterocolitis model. Serum IL-10 levels and IL-10 expression were followed by ELISA and real-time PCR, respectively. AAV pseudotypes 4, 7, 8, 9, and 10 demonstrated optimal intestinal transduction. Transgene expression was sustained 8 wk after administration and was frequently observed in enteroendocrine cells. Long-term IL-10 gene expression and serum IL-10 levels were observed following AAV transduction in an IL-10 -/- model of enterocolitis. Animals treated with AAVrh10-IL-10 had lower disease activity index scores, higher colon weight-to-length ratios, and lower microscopic inflammation scores. This study identifies novel AAV pseudotypes with small intestine and colon tropism and sustained transgene expression capable of modulating mucosal inflammation in a murine model of enterocolitis. © 2012 the American Physiological Society.

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