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1.  Immunomodulatory Function of Bone Marrow-Derived Mesenchymal Stem Cells in Experimental Autoimmune Type 1 Diabetes1 
Human clinical trials in type 1 diabetes (T1D) patients using mesenchymal stem cells (MSC) are presently underway without prior validation in a mouse model for the disease. In response to this void, we characterized bone marrow-derived murine MSC for their ability to modulate immune responses in the context of T1D, as represented in NOD mice. In comparison to NOD mice, BALB/ c-MSC mice were found to express higher levels of the negative costimulatory molecule PD-L1 and to promote a shift toward Th2-like responses in treated NOD mice. In addition, transfer of MSC from resistant strains (i.e., nonobese resistant mice or BALB/c), but not from NOD mice, delayed the onset of diabetes when administered to prediabetic NOD mice. The number of BALB/c-MSC trafficking to the pancreatic lymph nodes of NOD mice was higher than in NOD mice provided autologous NOD-MSC. Administration of BALB/c-MSC temporarily resulted in reversal of hyperglycemia in 90% of NOD mice (p = 0.002). Transfer of autologous NOD-MSC imparted no such therapeutic benefit. We also noted soft tissue and visceral tumors in NOD-MSC-treated mice, which were uniquely observed in this setting (i.e., no tumors were present with BALB/c- or nonobese resistant mice-MSC transfer). The importance of this observation remains to be explored in humans, as inbred mice such as NOD may be more susceptible to tumor formation. These data provide important preclinical data supporting the basis for further development of allogeneic MSC-based therapies for T1D and, potentially, for other autoimmune disorders.
PMCID: PMC3895445  PMID: 19561093
2.  Mixed Exocrine-Neuroendocrine Carcinoma of the Nasal Cavity: Clinico-Pathologic and Molecular Study of a Case and Review of the Literature 
Head and Neck Pathology  2012;7(1):76-84.
Sinonasal intestinal-type adenocarcinomas (ITACs) are rare neoplasms histologically resembling intestinal adenocarcinomas. Although a neuroendocrine differentiation in ITACs has been described, true mixed exocrine-neuroendocrine carcinomas, neoplasms in which each component represents at least 30 % of the lesion, are extremely rare and their molecular alterations are largely unknown. We describe herein the clinico-pathologic features, the methylation profile, chromosomal gains and losses, and mutation analysis of KRAS, BRAF and p53 in a nasal mixed exocrine-neuroendocrine carcinoma resected in a 79-year-old man. The tumor was composed of an ITAC and a poorly differentiated neuroendocrine carcinoma. Both exocrine and neuroendocrine components were CK8, CK20, CDX2 and p53 positive, and CK7 and TTF1 negative. The neuroendocrine component also showed immunoreactivity for chromogranin A, synaptophysin, serotonin and glicentin. Gains and losses were found at following chromosome regions: 17p13 (TP53), 14q24 (MLH3), 19q13 (KLK3), 5q21 (APC), 7q21 (CDK6), 9q34 (DAPK1), 12p13 (TNFRSF 1A, CDKN1B), 13q12 (BRCA2), 17p13.3 (HIC1), 18q21 (BCL2), and 22q12 (TIMP3). Aberrant methylation was detected only in the neuroendocrine component and involved APC and DAPK1 genes. No mutation of KRAS (exons 2–4), BRAF (exon 15), and p53 (exons 4–10) was found in both components. The results suggest a monoclonal origin of the tumor from a pluripotent cell undergoing a biphenotypic differentiation and that the neuroendocrine differentiation may be from an exocrine to an endocrine pathway. We have also reviewed the literature on sinonasal mixed exocrine-neuroendocrine carcinomas to give to the reader a comprehensive overview of these very rare tumor types.
PMCID: PMC3597157  PMID: 22740238
Intestinal-type adenocarcinomas; Neuroendocrine carcinoma; Nasal cavity; Mixed adenoneuroendocrine carcinoma; Molecular profile
3.  The Ontogeny of the Endocrine Pancreas in the Fetal/Newborn Baboon 
The Journal of endocrinology  2012;214(3):289-299.
Erratic regulation of glucose metabolism including hyperglycemia is a common condition of premature infants and is associated with increased morbidity and mortality.
To examine histological and ultra-structural differences in the endocrine pancreas in fetal (throughout gestation) and neonatal baboons.
Twelve fetal baboons were delivered at 125 days (d) gestational age (GA), 140dGA, or 175dGA. Eight animals were delivered at term (185dGA); half were fed for 5d. Seventy-three non-diabetic adult baboons were used for comparison. Pancreatic tissue was studied utilizing light microscopy, confocal imaging and electron microscopy.
The fetal and neonatal endocrine pancreas islet architecture became more organized as GA advanced. The percent areas of α-β-δ-cell type were similar within each fetal and newborn GA (NS), but were higher than the adults (P<0.05) regardless of GA. The ratio of β-cells within the islet (whole and core) increased with gestation (P<0.01). Neonatal baboons who survived for 5 days (feeding), had a 2.5-fold increase in pancreas weight compared to their counterparts euthanized at birth (P=0.01). Endocrine cells were found amongst exocrine ductal and acinar cells in 125,140 and 175dGA fetuses. Subpopulation of cells that co-expressed trypsin and glucagon/insulin show the presence of cells with mixed endo-exocrine lineage in fetuses.
The fetal endocrine pancreas has no prevalence of a of α-β-δ-cell type with larger endocrine cell percent areas than adults. Cells with mixed endocrine/exocrine phenotype occur during fetal development. Developmental differences may play a role in glucose homeostasis during the neonatal period and may have long term implications.
PMCID: PMC3686495  PMID: 22723715
Insulin; glucagon; fetus; islet cells; primates
4.  The Proangiogenic Phenotype of Natural Killer Cells in Patients with Non-Small Cell Lung Cancer12 
Neoplasia (New York, N.Y.)  2013;15(2):133-142.
The tumor microenvironment can polarize innate immune cells to a proangiogenic phenotype. Decidual natural killer (dNK) cells show an angiogenic phenotype, yet the role for NK innate lymphoid cells in tumor angiogenesis remains to be defined. We investigated NK cells from patients with surgically resected non-small cell lung cancer (NSCLC) and controls using flow cytometric and functional analyses. The CD56+CD16- NK subset in NSCLC patients, which represents the predominant NK subset in tumors and a minor subset in adjacent lung and peripheral blood, was associated with vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and interleukin-8 (IL-8)/CXCL8 production. Peripheral blood CD56+CD16- NK cells from patients with the squamous cell carcinoma (SCC) subtype showed higher VEGF and PlGF production compared to those from patients with adenocarcinoma (AdC) and controls. Higher IL-8 production was found for both SCC and AdC compared to controls. Supernatants derived from NSCLC CD56+CD16- NK cells induced endothelial cell chemotaxis and formation of capillary-like structures in vitro, particularly evident in SCC patients and absent from controls. Finally, exposure to transforming growth factor-β1 (TGFβ1), a cytokine associated with dNK polarization, upregulated VEGF and PlGF in peripheral blood CD56+CD16- NK cells from healthy subjects. Our data suggest that NK cells in NSCLC act as proangiogenic cells, particularly evident for SCC and in part mediated by TGFβ1.
PMCID: PMC3579316  PMID: 23441128
5.  Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via PD-L1 
Antagonism of CXCR4 disrupts the interaction between the CXCR4 receptor on HSCs and the CXCL12 expressed by stromal cells in the bone marrow, which subsequently results in the shedding of hematopoietic stem cells (HSCs) to the periphery. Due to their profound immunomodulatory effects, HSCs have emerged as a promising therapeutic strategy for autoimmune disorders. We sought to investigate the immunomodulatory role of mobilized autologous HSCs, via target of the CXCR4-CXL12 axis, to promote engraftment of islet cell transplantation. Islets from BALB/c mice were transplanted beneath the kidney capsule of hyperglycemic C57BL/6 mice, and treatment of recipients with CXCR4 antagonist resulted in mobilization of HSCs and in prolongation of islet graft survival. Addition of Rapamycin to anti-CXCR4 therapy further promoted HSC mobilization and islet allograft survival, inducing a robust and transferable host hyporesponsiveness, while administration of an ACK2 (anti-CD117) mAb halted CXCR4 antagonist-mediated HSC release and restored allograft rejection. Mobilized HSCs were shown to express high levels of the negative co-stimulatory molecule PD-L1, and HSCs extracted from WT mice, but not from PD-L1 KO, suppressed the in vitro alloimmune response. Moreover, HSC mobilization in PD-L1 KO mice failed to prolong islet allograft survival. Targeting the CXCR4-CXCL12 axis thus mobilizes autologous HSCs and promotes long-term survival of islet allografts via a PD-L1-mediated mechanism.
PMCID: PMC3404615  PMID: 21131428
Diabetes; CXCR4-CXCL12 axis; islet transplantation; stem cells
6.  Histotype-based prognostic classification of gastric cancer 
AIM: To test the efficiency of a recently proposed histotype-based grading system in a consecutive series of gastric cancers.
METHODS: Two hundred advanced gastric cancers operated upon in 1980-1987 and followed for a median 159 mo were investigated on hematoxylin-eosin-stained sections to identify low-grade [muconodular, well differentiated tubular, diffuse desmoplastic and high lymphoid response (HLR)], high-grade (anaplastic and mucinous invasive) and intermediate-grade (ordinary cohesive, diffuse and mucinous) cancers, in parallel with a previously investigated series of 292 cases. In addition, immunohistochemical analyses for CD8, CD11 and HLA-DR antigens, pancytokeratin and podoplanin, as well as immunohistochemical and molecular tests for microsatellite DNA instability and in situ hybridization for the Epstein-Barr virus (EBV) EBER1 gene were performed. Patient survival was assessed with death rates per 100 person-years and with Kaplan-Meier or Cox model estimates.
RESULTS: Collectively, the four low-grade histotypes accounted for 22% and the two high-grade histotypes for 7% of the consecutive cancers investigated, while the remaining 71% of cases were intermediate-grade cancers, with highly significant, stage-independent, survival differences among the three tumor grades (P = 0.004 for grade 1 vs 2 and P = 0.0019 for grade 2 vs grade 3), thus confirming the results in the original series. A combined analysis of 492 cases showed an improved prognostic value of histotype-based grading compared with the Lauren classification. In addition, it allowed better characterization of rare histotypes, particularly the three subsets of prognostically different mucinous neoplasms, of which 10 ordinary mucinous cancers showed stage-inclusive survival worse than that of 20 muconodular (P = 0.037) and better than that of 21 high-grade (P < 0.001) cases. Tumors with high-level microsatellite DNA instability (MSI-H) or EBV infection, together with a third subset negative for both conditions, formed the T8 cell-rich HLR group, the largest group among low-grade histotypes. Coexisting HLR proved to be a factor in improved prognosis in tumors with microsatellite instability (P = 0.0015 vs HLR-/MSI-H tumors) or DR type human leukocyte antigen expression (P = 0.033 vs HLR-/HLA-DR+ tumors).
CONCLUSION: Identification of low- and high-grade histotypes can improve the prognostic assessment of a substantial proportion of gastric cancers in routine diagnostic practice.
PMCID: PMC3297048  PMID: 22408348
Gastric cancer; High-grade histotype; Low-grade histotype; Lymphoid response; Epstein-Barr virus; Microsatellite instability
7.  Mixed Adenoneuroendocrine Carcinomas (MANECs) of the Gastrointestinal Tract: An Update 
Cancers  2012;4(1):11-30.
The systematic application of immunohistochemical techniques to the study of tumors has led to the recognition that neuroendocrine cells occur rather frequently in exocrine neoplasms of the gut. It is now well known that there is a wide spectrum of combinations of exocrine and neuroendocrine components, ranging from adenomas or carcinomas with interspersed neuroendocrine cells at one extreme to classical neuroendocrine tumors with a focal exocrine component at the other. In addition, both exocrine and neuroendocrine components can have different morphological features ranging, for the former, from adenomas to adenocarcinomas with different degrees of differentiation and, for the latter, from well differentiated to poorly differentiated neuroendocrine tumors. However, although this range of combinations of neuroendocrine and exocrine components is frequently observed in routine practice, mixed exocrine-neuroendocrine carcinomas, now renamed as mixed adenoneuroendocrine carcinomas (MANECs), are rare; these are, by definition, neoplasms in which each component represents at least 30% of the lesion. Gastrointestinal MANECs can be stratified in different prognostic categories according to the grade of malignancy of each component. The present paper is an overview of the main clinicopathological, morphological, immunohistochemical and molecular features of this specific rare tumor type.
PMCID: PMC3712682  PMID: 24213223
adenoneuroendocrine carcinoma; mixed exocrine-neuroendocrine carcinoma; gut
8.  Inhibition of Sp1 dependent transcription and antitumor activity of the new aureolic acid analogues Mithramycin SDK and SK in human ovarian cancer xenografts 
Gynecologic oncology  2010;118(2):182-188.
Increased activity of Sp family of transcription factors is a frequent and critical event in cancer development and progression. Genes governing tumor growth, invasion and angiogenesis are regulated by Sp factors, like Sp1, Sp3 or Sp4, and are frequently over-expressed in tumors. Targeting Sp factors has been explored as a therapeutic approach. Mithramycin (MTM) is a natural antibiotic that binds DNA and inhibit Sp1-dependent transcription. New analogues, named MTM-SDK and MTM-SK, were recently obtained by genetic engineering of the MTM biosynthetic pathway and have demonstrated improved transcriptional and antiproliferative activity in ovarian cancer cell lines in vitro. In present study we evaluated the activity of the new compounds in human ovarian cancer xenografts.
Expression of Sp1 and target proteins in ovarian cancer specimens and tumor xenografts was assessed by immunohistochemistry. Drug –induced silencing of Sp1-regulated genes in cells and tumor xenograft samples was assessed by quantitative RT-PCR. Toxicity and antitumor activity of the compounds were investigated in healthy and tumor-bearing immunocompromised mice, respectively.
Expression of Sp1 was frequently increased in human epithelial ovarian cancers. MTM-SDK and MTM-SK acted as potent inhibitors of Sp1-dependent transcription both in vitro and in tumor xenografts. Both compounds were well tolerated even after prolonged administration and delayed growth of ovarian tumor xenografts. MTM-SDK was particularly effective against orthotopic tumors leading to a significant increase of survival and delay of tumor progression.
MTM-SDK and MTM-SK show relevant activity in vivo and represent interesting candidates for treatment of ovarian cancers.
PMCID: PMC2900446  PMID: 20452660
9.  Proteomics Reveals Novel Oxidative and Glycolytic Mechanisms in Type 1 Diabetic Patients' Skin Which Are Normalized by Kidney-Pancreas Transplantation 
PLoS ONE  2010;5(3):e9923.
In type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold.
Methods and Findings
We evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase δ chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3-3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients, confirming increased oxidative stress which was normalized after KP transplant.
Our data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+ESRD patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications. Restoration of normoglycemia and removal of uremia with KP transplant can correct these abnormalities. Some of these identified pathways may become potential therapeutic targets for a new generation of drugs.
PMCID: PMC2848014  PMID: 20360867
10.  Chlorambucil versus observation after anti-Helicobacter therapy in gastric MALT lymphomas: results of the international randomised LY03 trial 
British Journal of Haematology  2009;144(3):367-375.
Gastric mucosa-associated lymphoid tissue (MALT) lymphomas are uncommon tumours characterised by a tendency to remain localised for long periods. The aetiological association between MALT lymphomas and Helicobacter pylori is well established. The role of additional chemotherapy after H. pylori eradication in localised MALT lymphomas is unclear. The LY03 trial was designed to establish whether chlorambucil after treatment for H. pylori would help prevent recurrence. Patients were treated with antibiotics for H. pylori infection. Those with successful eradication of H. pylori and no evidence of progression of lymphoma were eligible for randomisation to chlorambucil or observation. Two hundred and thirty-one patients were registered. Ninety-seven percent patients had H. pylori eradicated after antibiotics and 59% achieved macroscopically normal gastric mucosa. One hundred and ten patients were randomised. With a median follow-up of 58 months, six patients were dead and 17 had recurrent/progressive disease. The recurrence/progression rates at 5 years were 11% for chlorambucil, and 21% for observation with a difference of 10%, 95% confidence interval (CI) = −9% to 29%, P = 0·15. No difference was detected in recurrence/progression-free survival [Hazard Ratio (HR) = 0·96, 95% CI = 0·41–2·2, P = 0·91] or overall survival (HR = 1·93, 95% CI = 0·39–9·58, P = 0·42). This is the first randomised trial to show there is no good evidence to support that additional single agent chemotherapy to anti-H. pylori treatment contributes to prevent recurrence in localised gastric MALT lymphomas.
PMCID: PMC2659366  PMID: 19036078
gastric MALT lymphomas; chemotherapy; randomised controlled trial; chlorambucil; observation
11.  Simultaneous medullary and papillary thyroid cancer: two case reports 
Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) have always been considered different from each other; in their incidence, their cell origin and their histopathological features.
Case presentation
This paper describes two rare cases of the simultaneous occurrence of MTC and PTC in the thyroid gland. Case 1 is unique for different reasons: (a) the patient was affected by both multicentric MTC and PTC; (b) a "composite thyroid carcinoma" with mixed feautures of MTC and PTC carcinomas was found in the istmus of the gland; and (c) these tumors were associated with diffuse lymphocytic-type thyroiditis (LT). Case 2 is notable for the long follow up: 16 years disease free.
There are only 16 reports in the English medical literature describing a total of 20 cases of concurrent occurrence of both PTC and MTC in the same thyroid gland. We discuss whether the finding of another cancer in these patients was coincidental or from possible activation of a common tumorigenic pathway for both follicular and parafollicular thyroid cells.
PMCID: PMC2194707  PMID: 17997826
12.  Cellular and Molecular Consequences of Peroxisome Proliferator-Activated Receptor-γ Activation in Ovarian Cancer Cells1* 
Neoplasia (New York, N.Y.)  2006;8(10):851-861.
Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-activated transcription factor. In addition to its canonical role in lipid and glucose metabolism, PPAR-γ controls cell proliferation, death, and differentiation in several tissues. Here we have examined the expression of PPAR-γ in ovarian tumors and the cellular and molecular consequences of its activation in ovarian cancer cells. PPAR-γ was expressed in a large number of epithelial ovarian tumors and cell lines. The PPAR-γ ligand ciglitazone inhibited the growth and clonogenic survival of ovarian cancer cells, inducing cell cycle arrest and cell death. Growth inhibition by ciglitazone was reversed by the PPAR-γ antagonist GW9662, indicating the involvement of PPAR-γ-dependent mechanisms. Microarray-based gene profiling revealed complex changes in the transcriptional program of ovarian cancer cells on treatment with ciglitazone and identified multiple pathways that may contribute to PPAR-γ ligands' antitumor activity. Genes upregulated by ciglitazone were predominantly associated with metabolic, differentiation, and tumor-suppressor pathways, whereas downregulated genes were involved in cell proliferation, cell cycle, cell organization, and steroid biosynthesis. Collectively, our data indicate that PPAR-γ activation by selective agonists is a valid strategy for ovarian cancer therapy and prevention, and should be tested alone and in combination with other anticancer drugs.
PMCID: PMC1715924  PMID: 17032502
Peroxisome proliferator-activated receptor γ; ovarian cancer; nuclear receptor; gene expression profiling; thiazolidinediones

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