Pancreatic endocrine tumours (PETs) occur sporadically or are inherited as part of the multiple endocrine neoplasia type-1 syndrome. Little is known about the molecular events leading to these ...tumours. Cyclin D1, a key regulator of the G1/S transition of the cell cycle, is overexpressed in a variety of human cancers as well as certain endocrine tumours. We hypothesized that similar to other endocrine tumours, cyclin D1 is overexpressed in human sporadic PETs. Cyclin D1 protein overexpression was found in 20 of 31 PETs (65%) when compared with normal pancreatic tIssue. Furthermore, Northern blot analysis suggests that cyclin D1 up-regulation occurs at the post-transcriptional level in some PETs. Because the key cell growth signalling pathways p42/p44/ERK (extracellular signal-regulated kinase), p38/MAPK (mitogen-activated protein kinase), and Akt/PKB (protein kinase B) can regulate cyclin D1 protein expression in other cell types, pancreatic endocrine tumours were analysed with phospho-specific antibodies against the active forms of these proteins to elucidate a tIssue-specific regulatory mechanism of cyclin D1 in PETs. We found frequent activation of the p38/MAPK and Akt pathways, but down-regulation of the ERK pathway, in cyclin D1 overexpressing PETs. This study demonstrates that cyclin D1 overexpression is associated with human sporadic PET tumorigenesis, and suggests that this up-regulation may occur at the post-transcriptional level. These findings will direct future studies of PETs towards cell cycle dysregulation and the identification of key growth factor pathways involved in the formation of these tumours.
Pancreatic endocrine tumors (PETs) arise from neuroendocrine cells in and around the pancreas. As loss of heterozygosity (LOH) of chromosome 3 has been reported in sporadic PETs, we examined 16 ...sporadic PETs for LOH of 10 polymorphic DNA markers spanning both arms of chromosome 3. LOH was demonstrated in 4 of 8 (50%) sporadic PETs with hepatic metastasis, but in none of 8 sporadic PETs without hepatic involvement. The smallest common-deleted region (SCDR) mapped to 3q27-qter. Analysis of this data with the status of markers on chromosomes 1, 11, and
MEN1 mutations in these 16 sporadic PETs revealed that chromosome 3q loss may be a late event in sporadic PET tumorigenesis. These data, combined with reports from other investigators, indicate that chromosome 3q27-qter may contain a tumor suppressor gene that's important in the tumorigenesis of sporadic PETs.
Background:
Oral mucositis (OM) is a painful and debilitating complication of allogeneic hematopoietic stem cell transplantation (HSCT). Conditioning regimen correlates development of OM, but no ...studies have analyzed incidence and severity of OM among various condition regimens.
Aims:
This study was designed to evaluate the incidence and severity of OM receiving various conditioning regimens in early period after HSCT.
Methods:
We included 120 adult patients with a median age of 54.5 years (range 18 ‐ 72) who received allogeneic HSCT at Kindai University Hospital. Four conditioning regimens were administered for patients before transplantation based on the underlying diseases. Twenty‐two patients were received cyclophosphamide (CY)/total body irradiation (TBI) regimen (CY/TBI), 27 were received busulfan (BU)/CY regimen (BU/CY), 54 were received fludarabine (FLU)/BU regimen (FLU/BU), and 17 were received FLU/ melphalan (MEL) regimen (FLU/MEL). National Cancer Institute Common Toxicity Criteria for Adverse Events scale was used to assess the severity of OM. Severe OM defined as grade 2 to 4.
Results:
OM of any grades occurred 77.3% of CY/TBI, 48.1% of BU/CY, 85.2% of FLU/BU, and 70.6% of FLU/MEL. There were significant differences between CY/TBI and BU/CY (p = 0.05), and BU/CY and FLU/BU (p = 0.001). There was no patient with grade 4 OM. The incidence of severe OM (grade 2 ‐ 3) was 54.5% of CY/TBI, 18.5% of BU/CY, 57.4% of FLU/BU, and 52.9% of FLU/MEL. There were significant differences between CY/TBI and BU/CY (p = 0.02), BU/CY and FLU/BU (p = 0.0009), and BU/CY and FLU/MEL (p = 0.02).
Summary/Conclusion:
Incidence and severity of OM in patients receiving BU/CY regimen was the lowest among 4 types conditioning regimens.
Little is known about the cellular defects and molecular mechanisms leading to pancreatic endocrine tumors (PETs). p27(Kip1) is a universal cyclin-dependent kinase inhibitor (CDKI), which acts as a ...tumor suppressor and a negative regulator of cell cycle. From previous reports, quiescent cells show high levels of p27(Kip1) expression while neoplastic and proliferating cells show no detectable p27(Kip1) expression. We hypothesize that in malignant sporadic PETs, p27(Kip1) expression would be decreased compared with benign PETs and normal pancreatic tissue.
Western analysis was performed on 28 PETs (7 malignant, 21 benign), 2 nonendocrine cell lines, and 5 endocrine cell lines. Signal intensities were quantitated using densitometry and standardized to normal pancreas.
Unexpectedly, increased p27(Kip1) expression as compared with control was seen in both benign and malignant tumors, as well as in all four pancreatic islet tumor cell lines, but not fibroblast or pituitary cell lines, evaluated. There was no difference in p27(Kip1) level between benign and malignant tumors.
This represents the first report of anomalous p27(Kip1) overexpression in sporadic PETs, and is part of a growing literature describing the paradoxical overexpression of p27(Kip1) in human tumors that includes other endocrine tumors. These studies suggest a unique molecular pathway leading to endocrine tumorigenesis.
Background. Little is known about the cellular defects and molecular mechanisms leading to pancreatic endocrine tumors (PETs). p27Kip1 is a universal cyclin-dependent kinase inhibitor (CDKI), which ...acts as a tumor suppressor and a negative regulator of cell cycle. From previous reports, quiescent cells show high levels of p27Kip1 expression while neoplastic and proliferating cells show no detectable p27Kip1 expression. We hypothesize that in malignant sporadic PETs, p27Kip1 expression would be decreased compared with benign PETs and normal pancreatic tissue.
Methods. Western analysis was performed on 28 PETs (7 malignant, 21 benign), 2 nonendocrine cell lines, and 5 endocrine cell lines. Signal intensities were quantitated using densitometry and standardized to normal pancreas.
Results. Unexpectedly, increased p27Kip1 expression as compared with control was seen in both benign and malignant tumors, as well as in all four pancreatic islet tumor cell lines, but not fibroblast or pituitary cell lines, evaluated. There was no difference in p27Kip1 level between benign and malignant tumors.
Conclusion. This represents the first report of anomalous p27Kip1 overexpression in sporadic PETs, and is part of a growing literature describing the paradoxical overexpression of p27Kip1 in human tumors that includes other endocrine tumors. These studies suggest a unique molecular pathway leading to endocrine tumorigenesis.
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