Disulfide bond rearrangement during formation of the chorionic gonadotropin beta-subunit cystine knot in vivo.

The intracellular kinetic folding pathway of the human chorionic gonadotropin beta-subunit (hCG-beta) reveals the presence of a disulfide between Cys residues 38-57 that is not detected by X-ray analysis of secreted hCG-beta. This led us to propose that disulfide rearrangement is an essential feature of cystine knot formation during CG-beta folding. To test this, we used disulfide bond formation to monitor progression of intracellular folding intermediates of a previously uncharacterized protein, the CG-beta subunit of cynomolgous macaque (Macaca fascicularis).

Diabetes mellitus: a risk factor for pancreatic cancer?

The relationship between pancreatic cancer (PC) and diabetes is controversial. While some investigators assume that type II diabetes is a predisposition to PC, recent data argue that diabetes and altered glucose metabolism are a consequence of PC, and yet, the clinical presentation of the altered glucose metabolism in these patients varies considerably. Around 70% of patients with PC have impaired glucose tolerance (IGT) or frank diabetes.

Full-length dominant-negative survivin for cancer immunotherapy.

Purpose: The goal of this study is to investigate the possible utility of dendritic cells (DCs) transduced with the human full-length dominant-negative survivin for cancer immunotherapy.

Experimental Design: Mononuclear cells were collected from HLA-A2-positive healthy volunteers and patients with prostate cancer. DCs were transduced with an adenoviral vector containing a full-length, dominant-negative survivin gene.

Differences in immunohistochemical expression of xenobiotic-metabolizing enzymes between normal pancreas, chronic pancreatitis and pancreatic cancer.

Metabolic activation of many toxins, carcinogens, drugs, and anti-cancer agents is governed by the cytochrome P450 (CYP) drug-metabolizing enzyme system. To help elucidate the role of this enzyme system in the pathogenesis of chronic inflammatory and malignant pancreatic diseases, we compared the immunohistochemical expression pattern of 8 CYP-enzymes in 24 normal, 20 chronic pancreatitis, and 21 pancreatic cancer specimens using antibodies to CYP 1A1, 1A2, 2B6, 2C8/9/19, 2D6, 2E1, and 3A4, and the NADPH cytochrome P450 oxido-reductase (NA-OR). Compared to the normal pancreas, a higher frequency of immunopositivity for CYP 1A2, 2B6, 2C8/9/19, 2D6, and NA-OR was found in chronic pancreatitis, and of all CYPs but 1A2 in pancreatic cancer.

Cadherins as modulators of cellular phenotype.

Cadherins are transmembrane glycoproteins that mediate calcium-dependent cell-cell adhesion. The cadherin family is large and diverse, and proteins are considered to be members of this family if they have one or more cadherin repeats in their extracellular domain. Cadherin family members are the transmembrane components of a number of cellular junctions, including adherens junctions, desmosomes, cardiac junctions, endothelial junctions, and synaptic junctions.

Characterization of cadherin-24, a novel alternatively spliced type II cadherin.

Cadherins comprise a superfamily of calcium-dependent cell-cell adhesion molecules. Within the superfamily are six subfamilies including type I and type II cadherins. Both type I and type II cadherins are composed of five extracellular repeat domains with conserved calcium-binding motifs, a single pass transmembrane domain, and a highly conserved cytoplasmic domain that interacts with beta-catenin and p120 catenin.

Diabetes and its relationship to pancreatic carcinoma.

Introduction: The mechanism of impaired glucose metabolism that develops in most patients with pancreatic cancer (PC) is obscure and the association between PC and diabetes is controversial. According to the published data, about 70% of patients with PC have an impaired glucose tolerance (IGT) or frank diabetes, whereas 30% do not. Up to 60% of the patients with IGT or diabetes show improvement in glucose metabolism after surgery, whereas other patients show only mild or no improvement.

Neural invasion in the staging of pancreatic cancer.

The natural history of pancreatic ductal adenocarcinoma makes it one of the most malignant human diseases. Unknown etiology, lack of early symptoms, explosive outcome, short survival, and resistance to therapy are hallmarks of this cancer. Although surgery has been shown to be an effective therapeutic approach, the inevitable tendency for recurrence, even after apparently curative operation, has remained a mystery.

N-cadherin-catenin complexes form prior to cleavage of the proregion and transport to the plasma membrane.

Cadherins are calcium-dependent glycoproteins that function as cell-cell adhesion molecules and are linked to the actin cytoskeleton via catenins. Newly synthesized cadherins contain a prosequence that must be proteolytically removed to generate a functional adhesion molecule. The goal of this study was to examine the proteolytic processing of N-cadherin and the assembly of the cadherin-catenin complex in cells that express endogenous N-cadherin.

Expression of drug-metabolizing enzymes in the pancreas of hamster, mouse, and rat, responding differently to the pancreatic carcinogenicity of BOP.

Background/methods: N-nitroso-bis(2-oxopropyl)amine (BOP) induces pancreatic ductal adenocarcinoma in Syrian golden hamsters, but not in rats or mice. To examine whether this difference is due to the diversity in the presence and distribution of enzymes involved in the metabolism of BOP, the cellular expression of nine cytochrome P-450 isozymes (CYP1A1, CYP1A2, CYP2B6, CYP2C8,9,19, CYP2D1, CYP2E1, CYP3A1, CYP3A2, and CYP3A4) and of three glutathione S-transferase isozymes (GST-pi, GST-alpha, and GST-mu) was investigated in the pancreas of hamsters, rats, and mice by immunohistochemistry.

Results: We found a wide species variation in the presence and cellular localization of the enzymes and a lack of several enzymes, including GST-alpha in islets, CYP2B6, CYP2C8,9,19, CYP3A1 in acinar cells, and CYP3A4 in ductal cells, in the rat as compared with hamster and mouse.

Transferrin-facilitated lipofection gene delivery strategy: characterization of the transfection complexes and intracellular trafficking.

We previously showed that mixing transferrin with a cationic liposome prior to the addition of DNA, greatly enhanced the lipofection efficiency. Here, we report characterization of the transfection complexes in formulations prepared with transferrin, lipofectin, and DNA (pCMVlacZ) in various formulations. DNA in all the formulations that contain lipofectin was resistant to DNase I treatment.

Are islet cells the gatekeepers of the pancreas?

The pancreas is one of the body's most complex tissues composed of a mixture of endocrine and exocrine cell components. Although, islets comprise 1-2% of the pancreatic volume, there is some evidence that they control the function and the integrity of the pancreas and play the role of a gatekeeper. This review intends to highlight the importance of islet cells, not only for glucose metabolism, but also for their significant role in drug metabolism and diseases, especially in pancreatic cancer.

5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy.

5-Azacytidine was first synthesized almost 40 years ago. It was demonstrated to have a wide range of anti-metabolic activities when tested against cultured cancer cells and to be an effective chemotherapeutic agent for acute myelogenous leukemia. However, because of 5-azacytidine's general toxicity, other nucleoside analogs were favored as therapeutics.

Abnormal differentiation of islet cells in pancreatic cancer.

Pancreatic cancer in many patients is associated with altered glucose metabolism and abnormalities in pancreatic islet hormones at serum and tissue levels. Our previous studies have indicated a tendency of islet cells to differentiate toward ductal cell lineage, but the specificity of these findings for pancreatic cancer was not investigated. In the present study, we examined the immunoreactivity of pancreatic islets to antibodies against tumor-associated antigens DU-PAN-2, TAG-72 and CA19-9 in tissues from the normal pancreas, chronic pancreatitis and pancreatic cancer.

Generation of monoclonal antibodies specific for desmoglein family members.

Desmosomes are the most prominent cell-cell junctions in most epithelial cells and serve to link the intermediate filament cytoskeletons of adjacent cells. Desmogleins and desmocollins are the transmembrane core of the desmosome and both are members of the cadherin family of cell-cell adhesion molecules. In the skin, the three desmoglein gene products (Dsg 1, 2, and 3) are expressed in a stratification dependent manner, and therefore contribute to compositionally different desmosomes throughout the differentiating layers.

Species differences in the distribution of drug-metabolizing enzymes in the pancreas.

We investigated the cellular expression of 9 cytochrome P450-isozymes (CYP1A1, CYPIA2, CYP2B6, CYP2C8,9,19, CYP2D1, CYP2E1, CYP3A1, CYP3A2, CYP3A4) and 3 glutathione S-transferase-isozymes (GST-pi, GST-alpha. GST-mu) in the pancreas of hamsters, mice, rats, rabbits, pigs, dogs and monkeys, and in comparison with the human pancreas. A wide variation was found in the cellular localization of these enzymes between the 8 species.

Differences in the expression of glutathione S-transferases in normal pancreas, chronic pancreatitis, secondary chronic pancreatitis, and pancreatic cancer.

Introduction: In our previous study, glutathione S-transferase-pi (GST-pi), a phase II drug metabolizing enzyme, was found to be expressed in pancreatic ductal and ductular cells but not acinar cells of the normal pancreas, chronic pancreatitis, and secondary pancreatitis caused by pancreatic cancer. A greater percentage of the cells expressing GST-pi was shown in the islets of chronic pancreatitis specimens compared with the normal pancreas and secondary pancreatitis.

Aims And Methodology: To examine whether the increased number of islet cells expressing GST-pi and the absence in the acinar cells are compensated for by other GST isozymes, we investigated the expression of GST-alpha and GST-mu in the same specimens.

Pancreatic cell lines: a review.

Pancreatic cancer has an extremely poor prognosis and lacks early diagnostic and therapeutic possibilities, mainly because of its silent course and explosive fatal outcome. The histogenesis of the disease and early biochemical and genetic alterations surrounding carcinogenesis are still controversial. In vitro studies offer a useful tool to study physiologic, pathophysiologic, differentiation, and transformation processes of cells and to understand some of these shortcomings.

Transdifferentiation of human islet cells in a long-term culture.

It has been established that ductal cells or precursor cells within the ductal tree of the pancreas can differentiate into islet cells. Although islet cells can also form exocrine cells, it is unclear whether they arise from precursor (stem) cells or from mature endocrine cells by transdifferentiation. Using a defined culture medium and technique for islet purification, for the first time we were able to maintain human islets in culture for more than a year.

Pacinian corpuscle in the human pancreas.

During our systematic examination of the distribution of cytochrome P450 enzymes in the normal and diseased human pancreas, we observed a Pacinian corpuscle in a serial section of a tissue from a pancreatic cancer patient. We report the histologic and immunohistochemical patterns in this corpuscle and review the literature. The Pacinian corpuscle was situated within the pancreas of a 76-year-old woman with cancer in the head of the pancreas.

Effect of sulfosulfuron on the urine and urothelium of male rats.

Sulfosulfuron, developed as a herbicide, caused increased microcrystalluria and the formation of urinary tract calculi when fed to male and female rats in a chronic 2-year study at doses of 5,000 ppm and 20,000 ppm. Hyperplasia was also seen in urinary bladders at 5,000 ppm and 20,000 ppm, almost exclusively in the presence of observable calculi/microcalculi. Urinary bladder tumors were found in 2 females in the 5000 ppm group, both in the presence of calculi.

Experimental animal models in pancreatic carcinogenesis: lessons for human pancreatic cancer.

The silent course of pancreatic cancer and its explosive fatal outcome have hindered studies of tumor histogenesis and the identification of early biochemical and genetic alterations that could help to diagnose the disease at a curable stage and develop therapeutic strategies. Experimental animal models provide important tools to assess risk factors, as well as preventive and therapeutic possibilities. Although several pancreatic cancer models presently exist, only models that closely resemble human tumors in morphological, clinical, and biological aspects present useful media for preclinical studies.

Alteration of the Langerhans islets in pancreatic cancer patients.

An abnormal glucose metabolism occurs in up to 80% of pancreatic cancer patients shortly or a few months before the first clinical admission. Reasons for this abnormality are obscure. We investigated immunohistochemically the pattern of islets in 14 pancreatic cancer specimens and used 14 chronic pancreatitis samples and 10 normal pancreata as controls.

Increased expression of glutathione S-transferase-pi in the islets of patients with primary chronic pancreatitis but not secondary chronic pancreatitis.

The mechanism of tissue alteration in chronic pancreatitis (CP) is still unclear. Different hypotheses have been discussed, including increasing oxidant stress in the acinar cells, often as a result of exposure to xenobiotics. To evaluate the role of oxidative stress in CP, the authors investigated the expression of the drug-metabolizing phase II enzyme, glutathione S-transferase-pi (GST-pi), in the pancreatic tissue of patients with CP and compared it with the healthy pancreatic tissue from age-matched donors.

Combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and actinomycin D induces apoptosis even in TRAIL-resistant human pancreatic cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel member of the tumor necrosis factor superfamily of cytokines that induces cell death by apoptosis. TRAIL has been shown to be effective in almost two-thirds of solid tumors tested thus far, but its effect on pancreatic cancer cells is unknown. We tested the effect of TRAIL on seven human pancreatic cancer cell lines (HPAF, Panc1, Miapaca2, Bxpc3, Panc89, SW979, and Aspc1) in vitro.