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1.  Effects of 5-Fluorouracil on Morphology, Cell Cycle, Proliferation, Apoptosis, Autophagy and ROS Production in Endothelial Cells and Cardiomyocytes 
PLoS ONE  2015;10(2):e0115686.
Antimetabolites are a class of effective anticancer drugs interfering in essential biochemical processes. 5-Fluorouracil (5-FU) and its prodrug Capecitabine are widely used in the treatment of several solid tumors (gastro-intestinal, gynecological, head and neck, breast carcinomas). Therapy with fluoropyrimidines is associated with a wide range of adverse effects, including diarrhea, dehydration, abdominal pain, nausea, stomatitis, and hand-foot syndrome. Among the 5-FU side effects, increasing attention is given to cardiovascular toxicities induced at different levels and intensities. Since the mechanisms related to 5-FU-induced cardiotoxicity are still unclear, we examined the effects of 5-FU on primary cell cultures of human cardiomyocytes and endothelial cells, which represent two key components of the cardiovascular system. We analyzed at the cellular and molecular level 5-FU effects on cell proliferation, cell cycle, survival and induction of apoptosis, in an experimental cardioncology approach. We observed autophagic features at the ultrastructural and molecular levels, in particular in 5-FU exposed cardiomyocytes. Reactive oxygen species (ROS) elevation characterized the endothelial response. These responses were prevented by a ROS scavenger. We found induction of a senescent phenotype on both cell types treated with 5-FU. In vivo, in a xenograft model of colon cancer, we showed that 5-FU treatment induced ultrastructural changes in the endothelium of various organs. Taken together, our data suggest that 5-FU can affect, both at the cellular and molecular levels, two key cell types of the cardiovascular system, potentially explaining some manifestations of 5-FU-induced cardiovascular toxicity.
doi:10.1371/journal.pone.0115686
PMCID: PMC4324934  PMID: 25671635
2.  Islet Transplantation Stabilizes Hemostatic Abnormalities and Cerebral Metabolism in Individuals With Type 1 Diabetes 
Diabetes Care  2013;37(1):267-276.
OBJECTIVE
Islets after kidney transplantation have been shown to positively affect the quality of life of individuals with type 1 diabetes (T1D) by reducing the burden of diabetes complications, but fewer data are available for islet transplantation alone (ITA). The aim of this study was to assess whether ITA has a positive impact on hemostatic and cerebral abnormalities in individuals with T1D.
RESEARCH DESIGN AND METHODS
Prothrombotic factors, platelet function/ultrastructure, and cerebral morphology, metabolism, and function have been investigated over a 15-month follow-up period using ELISA/electron microscopy and magnetic resonance imaging, nuclear magnetic resonance spectroscopy, and neuropsychological evaluation (Profile of Mood States test and paced auditory serial addition test) in 22 individuals with T1D who underwent ITA (n = 12) or remained on the waiting list (n = 10). Patients were homogeneous with regard to metabolic criteria, hemostatic parameters, and cerebral morphology/metabolism/function at the time of enrollment on the waiting list.
RESULTS
At the 15-month follow-up, the group undergoing ITA, but not individuals with T1D who remained on the waiting list, showed 1) improved glucose metabolism; 2) near-normal platelet activation and prothrombotic factor levels; 3) near-normal cerebral metabolism and function; and 4) a near-normal neuropsychological test.
CONCLUSIONS
ITA, despite immunosuppressive therapy, is associated with a near-normalization of hemostatic and cerebral abnormalities.
doi:10.2337/dc13-1663
PMCID: PMC3867995  PMID: 24026546
3.  The Ontogeny of the Endocrine Pancreas in the Fetal/Newborn Baboon 
The Journal of endocrinology  2012;214(3):289-299.
Background
Erratic regulation of glucose metabolism including hyperglycemia is a common condition of premature infants and is associated with increased morbidity and mortality.
Objective
To examine histological and ultra-structural differences in the endocrine pancreas in fetal (throughout gestation) and neonatal baboons.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1530/JOE-12-0070
PMCID: PMC3686495  PMID: 22723715
Insulin; glucagon; fetus; islet cells; primates
4.  SEL1L, an UPR Response Protein, a Potential Marker of Colonic Cell Transformation 
Digestive Diseases and Sciences  2012;57(4):905-912.
Background
SEL1L gene product is implicated in the endoplasmic reticulum (ER)-associated protein degradation and Unfolded Protein Response pathways. This gene and associated miRNAs have been indicated as predictive and prognostic markers of pancreatic cancer.
Aim
Explore the role of SEL1L in colorectal cancer (CRC) progression.
Methods
SEL1L expression was analysed immunohistochemically in 153 adenomas and 71 CRCs from African American and North Italian patients. The distribution of stained cells was determined by computing median and inter quartile range. The receiver operating characteristics plot was used as discriminate power of SEL1L expression, CRC diagnosis and the effects on patient survival.
Results
SEL1L was low in normal mucosa and confined to few scattered cells at the base crypt of the villi and in the foveolar glandular compartment. The highest levels were in Paneth cells within the lysosomes. The enterocytic progenitor cells and mature enterocytes showed less cytoplasmic staining. In CRCs, SEL1L expression significantly correlated with the progression from adenoma to carcinoma (P = 0.0001) being stronger in well-to-moderately differentiated cancers. No correlation was found with other clinicopathological characteristics or ethnicity.
Conclusions
SEL1L expression is a potential CRC tissue biomarker since its expression is significantly higher in adenoma cells with respect to normal mucosa. The levels of expression decrease sensibly in undifferentiated CRC cancers. Interestingly, Paneth cells contain high levels of SEL1L protein that could indicate pre-neoplastic mucosa undergoing neoplastic transformation. Since SEL1L’s major function lies within ER stress and active ERAD response, it may identify CRCs with differentiated secretory phenotype and acute cellular stress.
doi:10.1007/s10620-011-2026-y
PMCID: PMC3345950  PMID: 22350780
SEL1L expression; Colorectal cancers; Paneth’s cells
5.  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.
Background
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.
Conclusions
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.
doi:10.1371/journal.pone.0009923
PMCID: PMC2848014  PMID: 20360867

Results 1-5 (5)