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- The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell-formation and acinar differentiation during pancreatic organogenesis. [JOURNAL ARTICLE]
- Development 2014 Jul 25.
The orphan nuclear receptor NR5A2 is necessary for the stem-like properties of the epiblast of the pre-gastrulation embryo and for cellular and physiological homeostasis of endoderm-derived organs postnatally. Using conditional gene inactivation, we show that Nr5a2 also plays crucial regulatory roles during organogenesis. During the formation of the pancreas, Nr5a2 is necessary for the expansion of the nascent pancreatic epithelium, for the subsequent formation of the multipotent progenitor cell (MPC) population that gives rise to pre-acinar cells and bipotent cells with ductal and islet endocrine potential, and for the formation and differentiation of acinar cells. At birth, the NR5A2-deficient pancreas has defects in all three epithelial tissues: a partial loss of endocrine cells, a disrupted ductal tree and a >90% deficit of acini. The acinar defects are due to a combination of fewer MPCs, deficient allocation of those MPCs to pre-acinar fate, disruption of acinar morphogenesis and incomplete acinar cell differentiation. NR5A2 controls these developmental processes directly as well as through regulatory interactions with other pancreatic transcriptional regulators, including PTF1A, MYC, GATA4, FOXA2, RBPJL and MIST1 (BHLHA15). In particular, Nr5a2 and Ptf1a establish mutually reinforcing regulatory interactions and collaborate to control developmentally regulated pancreatic genes by binding to shared transcriptional regulatory regions. At the final stage of acinar cell development, the absence of NR5A2 affects the expression of Ptf1a and its acinar specific partner Rbpjl, so that the few acinar cells that form do not complete differentiation. Nr5a2 controls several temporally distinct stages of pancreatic development that involve regulatory mechanisms relevant to pancreatic oncogenesis and the maintenance of the exocrine phenotype.
- Establishment of a novel, eco-friendly transgenic pig model using porcine pancreatic amylase promoter-driven fungal cellulase transgenes. [JOURNAL ARTICLE]
- Transgenic Res 2014 Jul 26.
Competition between humans and livestock for cereal and legume grains makes it challenging to provide economical feeds to livestock animals. Recent increases in corn and soybean prices have had a significant impact on the cost of feed for pig producers. The utilization of byproducts and alternative ingredients in pig diets has the potential to reduce feed costs. Moreover, unlike ruminants, pigs have limited ability to utilize diets with high fiber content because they lack endogenous enzymes capable of breaking down nonstarch polysaccharides into simple sugars. Here, we investigated the feasibility of a transgenic strategy in which expression of the fungal cellulase transgene was driven by the porcine pancreatic amylase promoter in pigs. A 2,488 bp 5'-flanking region of the porcine pancreatic amylase gene was cloned by the genomic walking technique, and its structural features were characterized. Using GFP as a reporter, we found that this region contained promoter activity and had the potential to control heterologous gene expression. Transgenic pigs were generated by pronuclear microinjection. Founders and offspring were identified by PCR and Southern blot analyses. Cellulase mRNA and protein showed tissue-specific expression in the pancreas of F1 generation pigs. Cellulolytic enzyme activity was also identified in the pancreas of transgenic pigs. These results demonstrated the establishment of a tissue-specific promoter of the porcine pancreatic amylase gene. Transgenic pigs expressing exogenous cellulase may represent a way to increase the intake of low-cost, fiber-rich feeds.
- Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases. [JOURNAL ARTICLE]
- Pancreatology 2014 July - August; 14(4):316-318.
Chronic pancreatitis lesions usually embrace both intraduct papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC). Patients at genetically-determined high risk of PDAC often harbor IPMN and/or chronic pancreatitis, suggesting IPMN, chronic pancreatitis and PDAC may share pathogenetic mechanisms. Chronic autoimmune pancreatitis (AIP) may also herald PDAC. Concurrent IPMN and AIP have been reported in few patients. Here we describe two patients with IPMN who developed type-1 AIP fulfilling the Honolulu and Boston diagnostic criteria. AIP diffusively affected the whole pancreas, as well as peripancreatic lymph nodes and the gallbladder. Previous pancreatic resection of focal IPMN did not show features of AIP. One of the patients carried a CFTR class-I mutation. Of notice, serum IgG4 levels gradually decreased to normal values after IPMN excision. Common risk factors to IPMN and AIP may facilitate its coincidental generation.
- Childhood cystic teratoma of the pancreas: Clinical presentation, evaluation and management. [JOURNAL ARTICLE]
- Pancreatology 2014 July - August; 14(4):312-315.
Pancreatic cystic teratoma in children is extremely rare. Here we present a female infant with a mature cystic teratoma of the pancreatic body. The patient was admitted for a palpable abdominal mass and anorexia. Computed tomography (CT) indicated a huge cystic mass in the abdominal cavity. Exploratory laparotomy was performed, and the tumor was excised completely. Pathology confirmed the tumor was a mature cystic teratoma of pancreatic origin. Two months after the initial surgery, a pseudocyst was detected and then cystojejunostomy was performed. Fourteen months after the second surgery, tumor relapse occurred and distal pancreatectomy was performed. The patient remained well without tumor recurrence during the next 24 months of follow-up. Our experience suggests that clinical manifestations of children with pancreatic cystic teratomas might be nonspecific and preoperative diagnosis is difficult. Radical tumor resection and maximized preservation of healthy pancreatic tissue should always be balanced in surgical treatment.
- Pancreas volume measurement in patients with Type 2 diabetes using magnetic resonance imaging-based planimetry. [JOURNAL ARTICLE]
- Pancreatology 2014 July - August; 14(4):268-274.
To compare pancreas volume (PV) measurement using MRI-based planimetry in patients with Type 2 diabetes mellitus (DM) to PV in normoglycemic individuals.Our institutional review board granted approval of this retrospective study with waiver of informed consent. We searched 2296 consecutive abdominal MRI studies performed at our hospital on patients with no pancreas pathology between September 1, 2010 and February 28, 2013, for those who also had a fasting plasma glucose and/or hemoglobin A1C within six months of the MRI examination. For those patients who met biochemical criteria for DM, we used medication and clinical records to confirm that 32 of these patients had Type 2 DM. The pancreas contours of 32 Type 2 diabetics and 50 normoglycemic individuals were then traced on non-gadolinium T1-weighted 3D fat suppressed gradient echo images by a radiologist trained in abdominal MRI to calculate PV. PV index (PVI) was calculated as PV/weight to adjust PV for each patient's weight. PVs and PVIs in both cohorts were compared using t-tests and regression models correcting for weight, age and gender.Patients with Type 2 DM had significantly lower PVs than normoglycemic individuals (72.7 ± 20.7 cm(3) versus 89.6 ± 22.7 cm(3), p < 0.001), and significantly lower PVIs (1.0 ± 0.3 cm(3)/kg versus 1.3 ± 0.3 cm(3)/kg, p < 0.001). Using regression models, we found that given the same age, weight and gender, the PV in a patient with Type 2 DM was 17.9 mL (20%) lower compared to a normoglycemic individual (p < 0.001).PV is reduced in Type 2 DM compared to normoglycemic individuals and can be measured using MRI without contrast injection.
- Endotherapy in symptomatic pancreas divisum: A systematic review. [REVIEW]
- Pancreatology 2014 July - August; 14(4):244-250.
Pancreas divisum (PD) is the most common congenital variant of the pancreas and has been implicated as a cause of pancreatitis; however, endoscopic treatment is controversial. Our objective was to examine patient response to endotherapy for treatment of symptomatic PD in adult patients in a systematic review of the literature. A systematic review of all case series and case-control studies with ten or more patients undergoing endotherapy for treatment of symptomatic PD indicated by acute recurrent pancreatitis (ARP), chronic pancreatitis (CP), or chronic abdominal pain (CAP) was performed. PubMed, Embase, and Web of Science databases were searched from inception through February 2013 using [pancreas divisum] AND [endoscopic retrograde cholangiopancreatography (ERCP)] OR [endotherapy] OR [endoscopy] as search terms. Importantly, the majority of studies were retrospective in nature, significantly limiting analysis capacity. Main outcomes measures included endotherapy response rate in patients with PD and ARP, CP, or CAP. Twenty-two studies were included in the review, with a total of 838 patients. Response to endoscopy was seen in 528 patients, but response rate varied by clinical presentation. Patients with ARP had a response rate ranging from 43% to 100% (median 76%). Reported response rates were lower in the other two groups, ranging from 21% to 80% (median 42%) for patients with CP and 11%-55% (median 33%) for patients with CAP. Complications reported included perforation, post-endoscopic retrograde cholangiopancreatography pancreatitis, bleeding, and clogged stents. Endotherapy appears to offer an effective treatment option for patients with symptomatic PD, with the best results in patients presenting with ARP.
- McCune-Albright Syndrome: A Detailed Pathological And Genetic Analysis of Disease Effects in an Adult Patient. [JOURNAL ARTICLE]
- J Clin Endocrinol Metab 2014 Jul 25.:jc20141291.
Context: McCune Albright syndrome (MAS) is a clinical association of endocrine and non-endocrine anomalies caused by post-zygotic mutation of the GNAS1 gene, leading to somatic activation of the stimulatory α subunit of G protein (Gsα). Important advances have been made recently in describing pathological characteristics of many MAS-affected tissues, particularly pituitary, testicular and adrenal disease. Other rarer disease related features are emerging. Objective: To study pathological and genetic findings of MAS on a tissue-by-tissue basis in classically and non classically affected tissues. Design: A comprehensive autopsy and genetic analysis Setting: Tertiary referral University Hospital Patients: Adult male patient with MAS and severe disease burden including gigantism Intervention(s): Clinical, hormonal and radiographic studies; gross and microscopic pathology analyses, conventional PCR and droplet digital PCR analyses of affected and non affected tissues Main Outcome Measure: Pathological findings, presence of GNAS1 mutations Results: The patient was diagnosed with MAS syndrome at six years of age based on the association of café-au-lait spots and radiological signs of polyostotic fibrous dysplasia. Gigantism developed and hyperprolactinemia, hypogonadotropic hypogonadism and hyperparathyroidism were diagnosed throughout adult period. The patient died at the age of 39 from pulmonary embolism. A detailed study revealed mosaiscism for the p.R201C GNAS mutation distributed across many endocrine and non-endocrine tissues. These genetically implicated tissues included rare or previously undescribed disease associations including primary hyperparathyroidism, and hyperplasia of the thymus and endocrine pancreas. Conclusions: This comprehensive pathological study of a single patient highlights the complex clinical profile of MAS and illustrates important advances in understanding the characteristics of somatic GNAS1 related pathology across a wide range of affected organs.
- Middle segment-preserving pancreatectomy for recurrent metastasis of renal cell carcinoma after pancreatoduodenectomy: a case report. [Journal Article]
- Case Rep Surg 2014.:648678.
Many cases of surgical resection of metastatic pancreatic tumors originating from renal cell carcinoma have been reported; however, cases of reresection of recurrent pancreatic metastasis of renal cell carcinoma in the remnant pancreas are rare. We performed a second resection for recurrent pancreatic metastasis of renal cell carcinoma six years after pancreatoduodenectomy with pancreaticogastrostomy reconstruction. By performing middle segment-preserving pancreatectomy, we were able to successfully spare the exocrine and endocrine pancreatic function compared to that observed after total pancreatectomy, with no signs of recurrence for two years after the surgery.
- Intraoperative radiation therapy opportunities for clinical practice normalization: Data recording and innovative development. [Journal Article]
- Rep Pract Oncol Radiother 2014 Jul; 19(4):246-52.
Intraoperative radiotherapy (IORT) refers to the delivery of a high dose of radiation at the time of surgery.To analyze clinical and research-oriented innovative activities developed in a 17-year period using intraoperative electron-radiation therapy (IOeRT) as a component of treatment in a multidisciplinary approach for cancer management.From 01/1995 to 03/2012 IOeRT procedures were registered in a specific Hospital-based database. Research and developments in imaging and recording for treatment planning implementation are active since 2006.1004 patients were treated and 1036 IORT procedures completed. Median age of patients was 61 (range 5 months to 94 years). Gender distribution was male in 54% of cases and female in 46%. Disease status at the time of IORT was 796 (77%) primary and 240 (23%) recurrent. Cancer type distribution included: 62% gastrointestinal, 18% sarcoma, 5% pancreas, 2% paediatric, 3% breast, 77 7% oligotopic recurrences, 2% other. IORT technical characteristics were: Applicator size 5 cm 22%, 6 cm 21%, 7 cm 21%, 8 cm 15%, 9 cm 6%, 10 cm 7% 12 cm 5% 15 cm 3%. Electron energies: 6 MeV 19%, 8 MeV 15%, 10 MeV 15%, 12 MeV 23%, 15 MeV 19%, 18 MeV 6%, other 3%. Multiple fields: 108 (11%). Dose: 7.5 Gy 3%, 10 Gy 35%, 12 Gy 3%, 12.5 Gy 49%, 15 Gy 5%, other 5%.An IORT programme developed in an Academic Hospital based on practice-oriented medical decisions is an attractive interdisciplinary oncology initiative proven to be able to generate an intensive clinical activity for cancer patient quality care and a competitive source of scientific patient-oriented research, development and innovation.
- Amelioration of cardiac morphology and function in type 1 diabetic patients with sustained success of pancreas transplant alone. [Letter]
- Diabetes Care 2014 Aug; 37(8):e171-2.