Tracing cell lineages in health and disease: experimental and human studies

PhDThis study aimed to investigate stem cell biology in the normal and diseased pancreas and liver employing robust methods for tracking stem cells and their progeny in both pre-clinical and human scenario. Bone marrow (BM) plasticity had been demonstrated in diseased organ remodelling. By detection of the Y chromosome in female mice receiving a sexmismatch BM transplantation, BM-derived cells were present in murine pancreas with cerulein-induced pancreatitis. BM-derived myofibroblasts functionally contributed to around 8% of the total population of myofibroblasts, the cells with a key fibrogenic role. Fibrocytes are circulating pro-fibrogenic cells; a decrease of BM-derived fibrocytes in blood and detection of these cells in areas of collagen deposition indicated they migrated to inflamed pancreas and played a role in extracellular matrix formation. IL-10 is an anti-inflammatory cytokine mainly secreted by BM; a lack of IL-10 increased the fibrosis, the inflammation and the numbers of BM-derived myofibroblasts suggesting a potential role of IL-10 in chronic pancreatitis. Mitochondrial DNA (mtDNA) mutations permit lineage tracing within human tissues. Cells having identical mtDNA mutations within a cytochrome c oxidase (CCO)- deficient area must be related having originated from a common founder cell, presumably a stem cell. I have demonstrated that regenerative nodules in cirrhotic liver are invariably clonal populations, and that these nodules often originate from progenitor cells from the abutting ductular reactions. An attempt to build a phylogenetic tree based on the accumulation of mutations in normal liver reinforced the belief that hepatic stem cells are located within the portal tract area and that their cell progeny migrate centrifugally from the portal tract region. The same techniques were applied to the pancreas, but many areas of CCO deficiency could be ascribed to autolysis, while the 3 discovery of identical mtDNA base changes within and outwith CCO-deficient patches suggested these were genetic polymorphisms, previously unreported

Outcomes of patients with acetaminophen-associated toxic hepatitis at a far east poison center

Abstract Background There is an overall paucity of data regarding the outcomes of patients with acetaminophen-associated toxic hepatitis in Taiwan. Therefore, the purpose of this study was to recruit a larger number of patients and to examine the clinical features, the degrees of toxic hepatitis, the physiological markers, and the clinical outcomes after intentional acetaminophen poisoning, and to determine what association, if any, might exist between these findings. Methods We examined the medical records of 187 patients with intentional acetaminophen poisoning who were examined at Chang Gung Memorial Hospital between 2000 and 2011. Patients were categorized into 2 groups according to hepatic complications, i.e. with (n = 15) or without (n = 172) toxic hepatitis. Demographic, clinical, and laboratory data were collected, and the mortality rate was analyzed. Results It was found that patients with toxic hepatitis had higher serum acetaminophen level (P = 0.007), but they also arrived to the hospital later (P &lt; 0.001) than patients without toxic hepatitis. Furthermore, patients with toxic hepatitis showed higher incidences of acute respiratory failure (P = 0.012) than those shown by patients who did not have hepatitis. The laboratory examinations also revealed greater degrees of granulocytosis (P &lt; 0.001) and poorer liver function tests (P &lt; 0.001) in patients with hepatitis than in patients without hepatitis. Nevertheless, a univariate logistic regression model failed to identify any significant risk factors for toxic hepatitis complication after ingestion (P &gt; 0.05). At the end of the analysis, 1 patient with toxic hepatitis died of liver failure. Finally, there was no significant difference in mortality between patients with and without hepatitis (P = 0.080). Conclusion The analytical data revealed that toxic hepatitis was not uncommon (15/187 or 8.0%) after acetaminophen overdose. Further studies are warranted. </jats:sec

Risk factors for fatal candidemia caused by Candida albicans and non-albicans Candida species

BACKGROUND: Invasive fungal infections, such as candidemia, caused by Candida species have been increasing. Candidemia is not only associated with a high mortality (30% to 40%) but also extends the length of hospital stay and increases the costs of medical care. Sepsis caused by Candida species is clinically indistinguishable from bacterial infections. Although, the clinical presentations of the patients with candidemia caused by Candida albicans and non-albicans Candida species (NAC) are indistinguishable, the susceptibilities to antifungal agents of these species are different. In this study, we attempted to identify the risk factors for candidemia caused by C. albicans and NAC in the hope that this may guide initial empiric therapy. METHODS: A retrospective chart review was conducted during 1996 to 1999 at the Veterans General Hospital-Taipei. RESULTS: There were 130 fatal cases of candidemia, including 68 patients with C. albicans and 62 with NAC. Candidemia was the most likely cause of death in 55 of the 130 patients (42.3 %). There was no significant difference in the distribution of Candida species between those died of candidemia and those died of underlying conditions. Patients who had one of the following conditions were more likely to have C. albicans, age ≧ 65 years, immunosuppression accounted to prior use of steroids, leukocytosis, in the intensive care unit (ICU), and intravascular and urinary catheters. Patients who had undergone cancer chemotherapy often appeared less critically ill and were more likely to have NAC. CONCLUSION: Clinical and epidemiological differences in the risk factors between candidemia caused by C. albicans and NAC may provide helpful clues to initiate empiric therapy for patients infected with C. albicans versus NAC

Regenerating the liver: not so simple after all? [version 1; referees: 3 approved]

Under normal homeostatic conditions, hepatocyte renewal is a slow process and complete turnover likely takes at least a year. Studies of hepatocyte regeneration after a two-thirds partial hepatectomy (2/3 PH) have strongly suggested that periportal hepatocytes are the driving force behind regenerative re-population, but recent murine studies have brought greater complexity to the issue. Although periportal hepatocytes are still considered pre-eminent in the response to 2/3 PH, new studies suggest that normal homeostatic renewal is driven by pericentral hepatocytes under the control of Wnts, while pericentral injury provokes the clonal expansion of a subpopulation of periportal hepatocytes expressing low levels of biliary duct genes such as Sox9 and osteopontin. Furthermore, some clarity has been given to the debate on the ability of biliary-derived hepatic progenitor cells to generate physiologically meaningful numbers of hepatocytes in injury models, demonstrating that under appropriate circumstances these cells can re-populate the whole liver

GALNT14: An Emerging Marker Capable of Predicting Therapeutic Outcomes in Multiple Cancers

Members of the polypeptide N-acetylgalactosaminyltransferase (GALNT) family function as the initiating enzymes that catalyze mucin-type O-glycosylation of proteins, and their dysregulated expression can alter cancer cell behaviors such as de novo occurrence, proliferation, migration, metastasis, and drug resistance. Recent studies have demonstrated that one of the family’s members, GALNT14, is aberrantly expressed in multiple cancers and involved in a variety of biological functions. Moreover, the single nucleotide polymorphisms (SNPs) of GALNT14-rs9679162 have been shown to predict therapeutic outcomes in patients with hepatocellular carcinoma as well as several other different types of gastrointestinal cancer. This review summarizes the structural features of GANLT14, its functional roles, and the predictive values of GALNT14 genotypes and enzyme levels in multiple cancers receiving distinct anticancer therapies.</jats:p