Bombesin administered subcutaneously to rats, three times daily for four days, induces pancreatic growth at a dose of 10 micrograms/kg. Growth was characterised by an increased pancreatic weight and content in protein and RNA, accompanied by cellular hypertrophy. Chronic bombesin also enhanced the pancreatic content in chymotrypsin and to a lesser degree its contents in amylase and lipase. The volume of the secretion and the output of enzymes in response to CCK under an infusion of secretin, however, remained unchanged although the functional capacity of individual cells to secret amylase and lipase was reduced. It is concluded that chronic bombesin exerts a trophic action on the rat pancreas but decreases the sensitivity of each cell to hormonal stimulation.
<div>Abstract<p>Pancreatic carcinoma is a gastrointestinal malignancy with poor prognosis. Treatment with gemcitabine, the most potent chemotherapeutic against this cancer up to date, is not curative, and resistance may appear. Complementary treatment with an oncolytic virus, such as the rat parvovirus H-1PV, which is infectious but nonpathogenic in humans, emerges as an innovative option.</p><p><b>Purpose:</b> To prove that combining gemcitabine and H-1PV in a model of pancreatic carcinoma may reduce the dosage of the toxic drug and/or improve the overall anticancer effect.</p><p><b>Experimental Design:</b> Pancreatic tumors were implanted orthotopically in Lewis rats or subcutaneously in nude mice and treated with gemcitabine, H-1PV, or both according to different regimens. Tumor size was monitored by micro-computed tomography, whereas bone marrow, liver, and kidney functions were monitored by measuring clinically relevant markers. Human pancreatic cell lines and gemcitabine-resistant derivatives were tested <i>in vitro</i> for sensitivity to H-1PV infection with or without gemcitabine.</p><p><b>Results:</b><i>In vitro</i> studies proved that combining gemcitabine with H-1PV resulted in synergistic cytotoxic effects and achieved an up to 15-fold reduction in the 50% effective concentration of the drug, with drug-resistant cells remaining sensitive to virus killing. Toxicologic screening showed that H-1PV had an excellent safety profile when applied alone or in combination with gemcitabine. The benefits of applying H-1PV as a second-line treatment after gemcitabine included reduction of tumor growth, prolonged survival of the animals, and absence of metastases on CT-scans.</p><p><b>Conclusion:</b> In addition to their potential use as monotherapy for pancreatic cancer, parvoviruses can be best combined with gemcitabine in a two-step protocol.</p></div>
A 90% jejunoileal bypass induces in the rat a protein malnutrition state which is characterized (1) by the decreased level of plasma proteins and albumins and (2) by the reduced level of most essential and non-essential plasma amino acids. In the exocrine pancreas there was a decreased content of digestive enzymes, especially of amylase, while the secretion of enzymes studied in vitro was reduced. In the ileum left in one piece, the specific activities of maltase and sucrase increased significantly while aminopeptidase was unaffected. It is suggested that exocrine pancreatic insufficiency observed after small bowel bypass in the rat might contribute to protein malnutrition (1) by producing maldigestion and (2) by inducing an imbalance in intestinal enzymes favouring a preferential absorption of carbohydrates compared to proteins, thus emphasizing the protein malnutrition state.
Our aim was to establish and characterize a novel pancreatic ductal adenocarcinoma cell line from a patient in whom the origin of the invasive carcinoma could be traced back to the intraductal papillary mucinous neoplasm (IPMN) precursor lesion.The primary patient-derived tumor was propagated in immunocompromised mice for 2 generations and used to establish a continuous in vitro culture termed ASAN-PaCa. Transplantation to fertilized chicken eggs confirmed the tumorigenic potential in vivo. Molecular analyses included karyotyping, next-generation genomic sequencing, expression analysis of marker proteins, and mucin-profiling.The analysis of marker proteins confirmed the epithelial nature of the established cell line, and revealed that the expression of the mucin MUC1 was higher than that of MUC2 and MUC5AC. ASAN-PaCa cells showed rapid in vitro and in vivo growth and multiple chromosomal aberrations. They harbored mutations in KRAS (Q61H), TP53 (Y220C), and RNF43 (I47V and L418M) but lacked either IPMN-specific GNAS or presumed pancreatic ductal adenocarcinoma-driving mutations in KRAS (codons 12/13), SMAD, and CDKN2A genes.ASAN-PaCa cell line represents a novel preclinical model of pancreatic adenocarcinoma arising in the background of IPMN, and offers an opportunity to study how further introduction of known driver mutations might contribute to pancreatic carcinogenesis.
The ileal uptake of polyalkylcyanoacrylate nanocapsules (less than 300 nm in diameter) has been investigated in the rat. Iodised oil (Lipiodol) was used as the tracer for X-ray microprobe analysis in scanning electron microscopy. Lipiodol nanocapsules, or an emulsion of Lipiodol, were administered in the lumen of an isolated ileal loop of rat. Lipiodol nanocapsules improved the absorption of the tracer as indicated by increased concentrations of iodine in the mesenteric blood (+27%, P < 0-01, compared with Lipiodol emulsion). Intestinal biopsies were taken at different time points and the samples underwent cryofixation and freeze-drying. The nanocapsules were characterized by their strong iodine emission, and electron microscopy of the biopsy samples revealed nanocapsules in the intraluminal mucus of the non-follicular epithelium, then in the intercellular spaces between enterocytes, and finally the nanocapsules were found within intravillus capillaries. However, nanocapsules were most abundant in the Peyer's patches, where the intestinal epithelium had been crossed by way of the specialized epithelial cells, designated membranous cells, or M cells, and their adjacent absorptive cells. These observations were confirmed quantitatively by measuring iodine concentrations in the various tissue compartments. Ten minutes after the intraluminal administration of Lipiodol nanocapsules, the emission of iodine peaked in the mucus (+77%, P < 0.01), in M cells (+366%, P <0.001), in enterocytes adjacent to M cells (+70%, P < 0.05) and in lymph vessels (+59%, P < 0.05). Polyalkylcyanoacrylate nanocapsules were able to pass through the ileal mucosa of the rat via a paracellular pathway in the non-follicular epithelium, and most predominantly, via M cells and adjacent enterocytes in Peyer's patches.
Whole-body imaging of green fluorescent protein (GFP) can be used to test the efficiency of gene carriers for in vivo transduction. The aim of the current study was to determine the sensitivity and the accuracy of a GFP imaging procedure by in vivo investigation of GFP-expressing tumor cells. An improved method of whole-body GFP imaging made use of a laser excitation source and band-pass filters matched specifically to GFP and constitutive tissue fluorescence emission bands. Processing of the primary GFP fluorescence images acquired by the CCD camera subtracted background tissue autofluorescence. Our approach achieved 100% sensitivity and specificity for in vivo detection of 10%-transfected BxPc3 pancreatic tumor after subcutaneous grafting or orthotopical implantation in the pancreas of nude mice. It also detected less transfected tumors (i.e., 1 to 5%) but with a loss in sensitivity (50% of cases). The system was employed over a 5-week period to monitor the persistence of GFP expression in 10%-transfected BxPc3 tumors orthotopically implanted in the pancreas of two nude mice, allowing the direct visualization of tumor progression and spread. In facilitating the temporal-spatial follow-up of GFP expression in vivo, the optimized laser-induced fluorescence imaging device can support preclinical investigations of vectors for therapeutic gene transduction through regular, harmless, real-time monitoring of theirin vivo transductional efficacy and persistence.
Abstract A new artificial connective matrix which results from two reactions of fibrinogen and fibronectin on elastin was used to obturate a slit made in the abdominal aorta of rabbit. The so‐called Elastin—Fibrin biomaterial behaved as a scaffold through which all the different structures were restored to their former condition. At 3 months, the material had disappeared and no thrombus, no inflammation or reject had been detected.
