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Sample records for autoimmune pancreatitis expression

  1. Autoimmune pancreatitis

    DEFF Research Database (Denmark)

    Detlefsen, Sönke; Drewes, Asbjørn M

    2009-01-01

    bile duct. Obstructive jaundice is a common symptom at presentation, and pancreatic cancer represents an important clinical differential diagnosis. In late stages of the disease, the normal pancreatic parenchyma is often replaced by large amounts of fibrosis. Histologically, there seem to be two...... AIP responds to steroid treatment, also a trial with steroids, can help to differentiate AIP from pancreatic cancer. OUTLOOK AND DISCUSSION: This review presents the pathological, radiologic and laboratory findings of AIP. Moreover, the treatment and pathogenesis are discussed.......BACKGROUND: Autoimmune pancreatitis (AIP) is a relatively newly recognized type of pancreatitis that is characterized by diffuse or focal swelling of the pancreas due to lymphoplasmacytic infiltration and fibrosis of the pancreatic parenchyma. MATERIAL AND METHODS: A PubMed literature search was...

  2. Pancreatic Tuberculosis or Autoimmune Pancreatitis

    OpenAIRE

    Ayesha Salahuddin; Muhammad Wasif Saif

    2014-01-01

    Introduction. Isolated pancreatic and peripancreatic tuberculosis is a challenging diagnosis due to its rarity and variable presentation. Pancreatic tuberculosis can mimic pancreatic carcinoma. Similarly, autoimmune pancreatitis can appear as a focal lesion resembling pancreatic malignancy. Endoscopic ultrasound-guided fine needle aspiration provides an effective tool for differentiating between benign and malignant pancreatic lesions. The immune processes involved in immunoglobulin G4 relate...

  3. Autoimmune pancreatitis: A review

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Autoimmune pancreatitis has emerged over the last 40 years from a proposed concept to a well established and recognized entity. As an efficient mimicker of pancreatic carcinoma, its early and appropriate recognition are crucial. With mounting understanding of its pathogenesis and natural history, significant advances have been made in the diagnosis of autoimmune pancreatitis. The characteristic laboratory features and imaging seen in autoimmune pancreatitis are reviewed along with some of the proposed diagnostic criteria and treatment algorithms.

  4. Autoimmune Pancreatitis: A Succinct Overview

    OpenAIRE

    Juan Putra; Xiaoying Liu

    2015-01-01

    Autoimmune pancreatitis is a rare type of chronic pancreatitis with characteristic clinical, radiologic, and histopathologic findings. Diagnosis of autoimmune pancreatitis is often challenging due to its low incidence and nonspecific clinical and radiologic findings. Patients with autoimmune pancreatitis and pancreatic cancer share similar clinical presentations, including obstructive jaundice, abdominal pain and weight loss. Due to these overlapping features, autoimmune pancreatitis patients...

  5. Pancreatic Tuberculosis or Autoimmune Pancreatitis

    Directory of Open Access Journals (Sweden)

    Ayesha Salahuddin

    2014-01-01

    Full Text Available Introduction. Isolated pancreatic and peripancreatic tuberculosis is a challenging diagnosis due to its rarity and variable presentation. Pancreatic tuberculosis can mimic pancreatic carcinoma. Similarly, autoimmune pancreatitis can appear as a focal lesion resembling pancreatic malignancy. Endoscopic ultrasound-guided fine needle aspiration provides an effective tool for differentiating between benign and malignant pancreatic lesions. The immune processes involved in immunoglobulin G4 related systemic diseases and tuberculosis appear to have some similarities. Case Report. We report a case of a 59-year-old Southeast Asian male who presented with fever, weight loss, and obstructive jaundice. CT scan revealed pancreatic mass and enlarged peripancreatic lymph nodes. Endoscopic ultrasound-guided fine needle aspiration confirmed the presence of mycobacterium tuberculosis. Patient also had high immunoglobulin G4 levels suggestive of autoimmune pancreatitis. He was started on antituberculosis medications and steroids. Clinically, he responded to treatment. Follow-up imaging showed findings suggestive of chronic pancreatitis. Discussion. Pancreatic tuberculosis and autoimmune pancreatitis can mimic pancreatic malignancy. Accurate diagnosis is imperative as unnecessary surgical intervention can be avoided. Endoscopic ultrasound-guided fine needle aspiration seems to be the diagnostic test of choice for pancreatic masses. Long-term follow-up is warranted in cases of chronic pancreatitis.

  6. Autoimmune pancreatitis and cholangitis

    Institute of Scientific and Technical Information of China (English)

    Niraj; Jani; James; Buxbaum

    2015-01-01

    Autoimmune pancreatitis(AIP) is part of a systemic fibrosclerotic process characterized by lymphoplasmacytic infiltrate with immunoglobulin G subtype-4(Ig G4) positive cells. It characteristically presents with biliary obstruction due to mass-like swelling of the pancreas. Frequently AIP is accompanied by extra-pancreaticmanifestations including retroperitoneal fibrosis, thyroid disease, and salivary gland involvement. Auto-antibodies, hypergammaglobulemia, and prompt resolution of pancreatic and extrapancreatic findings with steroids signify its autoimmune nature. Refractory cases are responsive to immunomodulators and rituximab. Involvement of the biliary tree, termed IgG 4 associated cholangiopathy, mimics primary sclerosing cholangitis and is challenging to manage. High IgG 4 levels and swelling of the pancreas with a diminutive pancreatic duct are suggestive of autoimmune pancreatitis. Given similarities in presentation but radical differences in management and outcome, differentiation from pancreatic malignancy is of paramount importance. There is controversy regarding the optimal diagnostic criterion and steroid trials to make the diagnosis. Additionally, the retroperitoneal location of the pancreas and requirement for histologic sampling, makes tissue acquisition challenging. Recently, a second type of autoimmune pancreatitis has been recognized with similar clinical presentation and steroid response though different histology, serologic, and extrapancreatic findings.

  7. Pancreatic Ductal Adenocarcinoma Associated with Autoimmune Pancreatitis

    OpenAIRE

    Pezzilli, Raffaele; Vecchiarelli, Silvia; Di Marco, Maria Cristina; SERRA, CARLA; Santini, Donatella; Calculli, Lucia; Fabbri, Dario; Rojas Mena, Betzabè; Imbrogno, Andrea

    2011-01-01

    Autoimmune pancreatitis (AIP), in contrast to other benign chronic pancreatic diseases, can be cured with immunosuppressant drugs, thus the differentiation of AIP from pancreatic cancer is of particular interest in clinical practice. There is the possibility that some patients with AIP may develop pancreatic cancer, and this possibility contributes to increasing our difficulties in differentiating AIP from pancreatic cancer. We herein report the case of a 70-year-old man in whom pancreatic ad...

  8. Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota.

    Science.gov (United States)

    Sun, Jia; Furio, Laetitia; Mecheri, Ramine; van der Does, Anne M; Lundeberg, Erik; Saveanu, Loredana; Chen, Yongquan; van Endert, Peter; Agerberth, Birgitta; Diana, Julien

    2015-08-18

    Antimicrobial peptides (AMPs) expressed by epithelial and immune cells are largely described for the defense against invading microorganisms. Recently, their immunomodulatory functions have been highlighted in various contexts. However how AMPs expressed by non-immune cells might influence autoimmune responses in peripheral tissues, such as the pancreas, is unknown. Here, we found that insulin-secreting β-cells produced the cathelicidin related antimicrobial peptide (CRAMP) and that this production was defective in non-obese diabetic (NOD) mice. CRAMP administrated to prediabetic NOD mice induced regulatory immune cells in the pancreatic islets, dampening the incidence of autoimmune diabetes. Additional investigation revealed that the production of CRAMP by β-cells was controlled by short-chain fatty acids produced by the gut microbiota. Accordingly, gut microbiota manipulations in NOD mice modulated CRAMP production and inflammation in the pancreatic islets, revealing that the gut microbiota directly shape the pancreatic immune environment and autoimmune diabetes development. PMID:26253786

  9. Autoimmune pancreatitis can develop into chronic pancreatitis

    OpenAIRE

    Maruyama, Masahiro; Watanabe, Takayuki; Kanai, Keita; Oguchi, Takaya; Asano, Jumpei; Ito, Tetsuya; Ozaki, Yayoi; Muraki, Takashi; Hamano, Hideaki; ARAKURA, Norikazu; Kawa, Shigeyuki

    2014-01-01

    Autoimmune pancreatitis (AIP) has been recognized as a distinct type of pancreatitis that is possibly caused by autoimmune mechanisms. AIP is characterized by high serum IgG4 and IgG4-positive plasma cell infiltration in affected pancreatic tissue. Acute phase AIP responds favorably to corticosteroid therapy and results in the amelioration of clinical findings. However, the long-term prognosis and outcome of AIP remain unclear. We have proposed a working hypothesis that AIP can develop into o...

  10. Type 1 autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Zen Yoh

    2011-12-01

    Full Text Available Abstract Before the concept of autoimmune pancreatitis (AIP was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of

  11. Autoimmune pancreatitis. An update

    International Nuclear Information System (INIS)

    Autoimmune pancreatitis (AIP) is a rare disease, the pathophysiological understanding of which has been greatly improved over the last years. The most common form, type 1 AIP belongs to the IgG4-related diseases and must be distinguished from type 2 AIP, which is a much rarer entity associated with chronic inflammatory bowel disease. Clinically, there is an overlap with pancreatic cancer. Imaging and further criteria, such as serological and histological parameters are utilized for a differentiation between both entities in order to select the appropriate therapy and to avoid the small but ultimately unnecessary number of pancreatectomies. The diagnostics of AIP are complex, whereby the consensus criteria of the International Association of Pancreatology have become accepted as the parameters for discrimination. These encompass five cardinal criteria and one therapeutic criterion. By applying these criteria AIP can be diagnosed with a sensitivity of 84.9 %, a specificity of 100 % and an accuracy of 93.8 %. The diagnosis of AIP is accomplished by applying several parameters of which two relate to imaging. As for the routine diagnostics of the pancreas these are ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). Important for the differential diagnosis is the exclusion of signs of local and remote tumor spread for which CT and MRI are established. The essential diagnostic parameter of histology necessitates sufficient sample material, which cannot usually be acquired by a fine needle biopsy. CT or MRI are the reference standard methods for identification of the optimal puncture site and imaging-assisted (TruCut) biopsy. In patients presenting with unspecific upper abdominal pain, painless jaundice combined with the suspicion of a pancreatic malignancy in imaging but a mismatch of secondary signs of malignancy, AIP should also be considered as a differential diagnosis. As the diagnosis of AIP only partially relies on imaging radiologists also

  12. Cystic Lesions in Autoimmune Pancreatitis

    OpenAIRE

    Gompertz, Macarena; Morales, Claudia; Aldana, Hernán; Castillo, Jaime; Berger, Zoltán

    2015-01-01

    Autoimmune pancreatitis (AIP) can be chronic or recurrent, but frequently completely reversible after steroid treatment. A cystic lesion in AIP is a rare finding, and it can mimic a pancreatic cystic neoplasm. Difficulties in an exact diagnosis interfere with treatment, and surgery cannot be avoided in some cases. We report the history of a 63-year-old male presenting with jaundice and pruritus. AIP was confirmed by imaging and elevated IgG4 blood levels, and the patient completely recovered ...

  13. Cystic Lesions in Autoimmune Pancreatitis

    Directory of Open Access Journals (Sweden)

    Macarena Gompertz

    2015-11-01

    Full Text Available Autoimmune pancreatitis (AIP can be chronic or recurrent, but frequently completely reversible after steroid treatment. A cystic lesion in AIP is a rare finding, and it can mimic a pancreatic cystic neoplasm. Difficulties in an exact diagnosis interfere with treatment, and surgery cannot be avoided in some cases. We report the history of a 63-year-old male presenting with jaundice and pruritus. AIP was confirmed by imaging and elevated IgG4 blood levels, and the patient completely recovered after corticosteroid therapy. One year later, he presented with a recurrent episode of AIP with elevated IgG4 levels, accompanied by the appearance of multiple intrapancreatic cystic lesions. All but 1 of these cysts disappeared after steroid treatment, but the remaining cyst in the pancreatic head was even somewhat larger 1 year later. Pancreatoduodenectomy was finally performed. Histology showed the wall of the cystic lesion to be fibrotic; the surrounding pancreatic tissue presented fibrosis, atrophy and lymphoplasmacytic infiltration by IgG4-positive cells, without malignant elements. Our case illustrates the rare possibility that cystic lesions can be part of AIP. These pseudocysts appear in the pancreatic segments involved in the autoimmune disease and can be a consequence of the local inflammation or related to ductal strictures. Steroid treatment should be initiated, after which these cysts can completely disappear with recovery from AIP. Surgical intervention may be necessary in some exceptional cases.

  14. Autoimmune Pancreatitis Exhibiting Multiple Mass Lesions

    OpenAIRE

    Shiokawa, Masahiro; Kodama, Yuzo; Hiramatsu, Yukiko; Kurita, Akira; Sawai, Yugo; Uza, Norimitsu; Watanabe, Tomohiro; Chiba, Tsutomu

    2011-01-01

    Our case is a first report of autoimmune pancreatitis with multiple masses within the pancreas which was pathologically diagnosed by endoscopic ultrasound-guided fine needle aspiration and treated by steroid. The masses disappeared by steroid therapy. Our case is informative to know that autoimmune pancreatitis sometimes exhibits multiple masses within the pancreas and to diagnose it without unnecessary surgery.

  15. Autoimmune pancreatitis exhibiting multiple mass lesions.

    OpenAIRE

    Shiokawa, Masahiro; Kodama, Yuzo; Hiramatsu, Yukiko; Kurita, Akira; Sawai, Yugo; Uza, Norimitsu; Watanabe, Tomohiro; Chiba, Tsutomu

    2011-01-01

    Our case is a first report of autoimmune pancreatitis with multiple masses within the pancreas which was pathologically diagnosed by endoscopic ultrasound-guided fine needle aspiration and treated by steroid. The masses disappeared by steroid therapy. Our case is informative to know that autoimmune pancreatitis sometimes exhibits multiple masses within the pancreas and to diagnose it without unnecessary surgery.

  16. [Autoimmune pancreatitis as an element of autoimmune polyglandular syndrome].

    Science.gov (United States)

    Dyrla, Przemysław; Nowak, Tomasz; Gil, Jerzy; Adamiec, Cezary; Bobula, Mariusz; Saracyn, Marek

    2016-05-01

    Autoimmune pancreatitis constantly belongs to diseases which often causes significant diagnostic problem and often runs out with surgical intervention as considered to be a pancreatic cancer. Important although usually underestimated problems are polyglandular syndromes, which may consist of autoimmune pancreatitis (AIP) problem as well. This case report is an example of autoimmune polyglandular syndrome (APS), which was connected with the surgical treatment with biliary bypass anastomosis because of the unresectable lesion in the head of pancreas. The definite remission of the pancreatic lesion finally came after a steroid therapy. Differentiation between neoplastic and inflammatory pancreatic tumors very often remains a serious clinical problem. On grounds of imaging and cytopathology exams it is often difficult to decide about the nature of a lesion. The negative result of cytopathological biopsy examination does not finally settle straightforward diagnosis. Diagnostic problems affect also autoimmune pancreatitis. It is worth to undertake attempts to differentiate pancreatic lesions especially in cases of concomitance with other autoimmune polyglandular syndromes. That is because it is connected with completely different treatment and outcome. We should remember about diagnostic criteria of autoimmune pancreatitis. Appropriate diagnosis for patients with AIP gives them a chance to avoid serious surgical resection and possible complications.

  17. Acute recurrent pancreatitis: An autoimmune disease?

    Institute of Scientific and Technical Information of China (English)

    Raffaele Pezzilli

    2008-01-01

    In this review article,we will briefly describe the main characteristics of autoimmune pancreatitis and then we will concentrate on our aim,namely,evaluating the clinical characteristics of patients having recurrence of pain from the disease.In fact,the open question is to evaluate the possible presence of autoimmune pancreatitis in patients with an undefined etiology of acute pancreatitis and for this reason we carried out a search in the literature in order to explore this issue.In cases of recurrent attacks of pain in patients with "idiopathic"pancreatitis,we need to keep in mind the possibility that our patients may have autoimmune pancreatitis.Even though the frequency of this disease seems to be quite low,we believe that in the future,by increasing our knowledge on the subject,we will be able to diagnose an ever-increasing number of patients having acute recurrence of pain from autoimmune pancreatitis.

  18. Dilemmas in autoimmune pancreatitis. Surgical resection or not?

    Science.gov (United States)

    Hoffmanova, I; Gurlich, R; Janik, V; Szabo, A; Vernerova, Z

    2016-01-01

    Surgical treatment is not commonly recommended in the management of autoimmune pancreatitis. The article describes a dilemma in diagnostics and treatment of a 68-year old man with the mass in the head of the pancreas that mimicked pancreatic cancer and that was diagnosed as a type 1 autoimmune pancreatitis (IgG4-related pancreatitis) after a surgical resection. Diagnosis of the autoimmune pancreatitis is a real clinical challenge, as in the current diagnostic criteria exists some degree of overlap in the findings between autoimmune pancreatitis and pancreatic cancer (indicated by the similarity in radiologic findings, elevation of IgG4, sampling errors in pancreatic biopsy, and the possibility of synchronous autoimmune pancreatitis and pancreatic cancer). Despite the generally accepted corticosteroids as the primary treatment modality in autoimmune pancreatitis, we believe that surgical resection remains necessary in a specific subgroup of patients with autoimmune pancreatitis (Fig. 4, Ref. 37). PMID:27546699

  19. Autoimmune Pancreatitis Associated with Retroperitoneal Fibrosis

    Directory of Open Access Journals (Sweden)

    Ohkawa M

    2005-05-01

    Full Text Available CONTEXT: Autoimmune pancreatitis is sometimes associated with other autoimmune diseases. We have presented two cases of autoimmune pancreatitis with retroperitoneal fibrosis and compared our findings with those found in the literature. CASE 1: A 71-year-old male developed anorexia and weight loss. Abdominal ultrasonography (US and computed tomography (CT showed diffuse swelling of the pancreas and the peritoneal soft tissue surrounding the aorta, associated with right hydronephrosis. Endoscopic retrograde pancreatography showed narrowing of the main pancreatic duct. He was diagnosed as having autoimmune pancreatitis associated with retroperitoneal fibrosis and underwent steroid therapy. After 3 weeks, a follow-up CT showed a marked reduction in the size of both the pancreas and retroperitoneal mass. CASE 2: A 62-year-old male was admitted to another hospital complaining of obstructive jaundice. Abdominal CT and US showed swelling of the pancreas. Endoscopic retrograde cholangiopancreatography demonstrated stenosis of the lower bile duct and narrowing of the main pancreatic duct. With the diagnosis of pancreatic head carcinoma, a choledochojejunostomy and a gastrojejunostomy were performed. Histological examination of the biopsy of the pancreatic mass revealed marked fibrosis with lymphoplasmacytic infiltration. One year later, a retroperitoneal mass was detected on follow-up CT. He was treated with prednisolone for two years. Recurrence of retroperitoneal mass with left hydronephrosis occurred 18 months later. There was no sign of recurrence of the autoimmune pancreatitis. He was again treated with prednisolone, and the retroperitoneal mass was gradually reduced. CONCLUSIONS: A total of 7 cases including the present cases have been reported. All were middle-aged males. Steroid therapy was effective for both the pancreatic and the retroperitoneal masses.

  20. A practical approach to the diagnosis of autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Luca Frulloni; Antonio Amodio; Anna Maria Katsotourchi; Italo Vantini

    2011-01-01

    Autoimmune pancreatitis is a disease characterized by specific pathological features, different from those of other forms of pancreatitis, that responds dramatically to steroid therapy. The pancreatic parenchyma may be diffusely or focally involved with the possibility of a low-density mass being present at imaging, mimicking pancreatic cancer. Clinically, the most relevant problems lie in the diagnosis of autoimmune pancreatitis and in distinguishing autoimmune pancreatitis from pancreatic cancer. Since in the presence of a pancreatic mass the probability of tumour is much higher than that of pancre-atitis, the physician should be aware that in focal autoimmune pancreatitis the first step before using steroids is to exclude pancreatic adenocarcinoma. In this review, we briefly analyse the strategies to be followed for a correct diagnosis of autoimmune pancreatitis.

  1. Diagnostic criteria for autoimmune pancreatitis in Japan

    Institute of Scientific and Technical Information of China (English)

    Terumi Kamisawa; Kazuichi Okazaki; Shigeyuki Kawa

    2008-01-01

    Autoimmune pancreatitis (AIP) is a particular type of pancreatitis of presumed autoimmune etiology.Currently, AIP should be diagnosed based on combination of clinical, serological, morphological,and hisLopathological features. When diagnosing AlP,it is most Jmportant to differentiate it from pancreatic cancer. DJagnostic criteria for AIP, proposed by the Japan Pancreas Society in 2002 first in the world,were revised in 2006. The criteria are based on the minimum consensus of AIP and aim to avoid misdiagnosing pancreatic cancer as far as possible,but not for screening AIP. The criteria consist of the following radiological, serological, and histopathological items: (1) radiological imaging showing narrowing of the main pancreatic duct and enlargement of the pancreas, which are characteristic of the disease; (2)laboratory data showing abnormally elevated levels of serum γ-globulin, IgG or IgG4, or the presence of autoantibodies; (3) histopathological examJnation of the pancreas demonstrating marked fibrosis and prominent infiltration of lymphocytes and plasma cells, which is called lymphoplasmacytic sclerosing pancreatitis (LPSP). For a diagnosis of AIP, criterion 1 must be present, together with criterion 2 and/or criterion 3. However, it is necessary to exclude malignant diseases such as pancreatic or biliary cancer.

  2. Autoimmune pancreatitis in an 11-year-old boy

    Energy Technology Data Exchange (ETDEWEB)

    Refaat, Rania [Johann-Wolfgang-Goethe University, Department of Diagnostic and Interventional Radiology, Frankfurt am Main (Germany); Ain Shams University, Department of Diagnostic and Interventional Radiology, Cairo (Egypt); Harth, Marc; Proschek, Petra; Lindemayr, Sebastian; Vogl, Thomas J. [Johann-Wolfgang-Goethe University, Department of Diagnostic and Interventional Radiology, Frankfurt am Main (Germany)

    2009-04-15

    We report a case of histopathologically proven autoimmune pancreatitis in an 11-year-old boy. Abdominal US and MRI showed a focal swelling of the pancreatic head, the latter also showing delayed contrast enhancement. There was diffuse irregular pancreatic duct narrowing, compression of the intrapancreatic common bile duct, and mild proximal biliary dilatation on MR cholangiopancreatography. Laboratory results revealed normal serum IgG and subclass 4 with negative autoimmune antibodies, and slightly elevated carbohydrate antigen 19-9. This highlights the differentiation of autoimmune pancreatitis from pancreatic head cancer and, to a lesser extent, other forms of pancreatitis in children. (orig.)

  3. Autoimmune pancreatitis: An illustrated guide to diagnosis

    International Nuclear Information System (INIS)

    Autoimmune pancreatitis (AIP) remains one of the rarer forms of pancreatitis but has become increasingly well recognized and widely diagnosed as it is an important differential, particularly due to the dramatic response to appropriate therapy. It is now best considered as part of a multisystem disease and the notion of “IgG4-related systemic sclerosing disease” has become widely recognized as the number of extra-pancreatic associations of AIP grows. More recently AIP has been classified into two subtypes: lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct-centric pancreatitis (IDCP) with distinct geographical, age and sex distributions for the two subtypes, in addition to different pathological characteristics. The role of imaging is crucial in AIP and should be considered in conjunction with clinical, serological, and histopathological findings to make the diagnosis. Radiologists are uniquely placed to raise the possibility of AIP and aid the exclusion of significant differentials to allow the initiation of appropriate management and avoidance of unnecessary intervention. Radiological investigation may reveal a number of characteristic imaging findings in AIP but appearances can vary considerably and the focal form of AIP may appear as a pancreatic mass, imitating pancreatic carcinoma. This review will illustrate typical and atypical appearances of AIP on all imaging modes. Emphasis will be placed on the imaging features that are likely to prove useful in discriminating AIP from other causes prior to histopathological confirmation. In addition, examples of relevant differential diagnoses are discussed and illustrated

  4. Azathioprine Induced Pancreatitis in a Patient with Co-Existing Autoimmune Pancreatitis and Hepatitis

    Directory of Open Access Journals (Sweden)

    Preethi GK Venkatesh

    2011-05-01

    Full Text Available Context Azathioprine induced pancreatitis usually runs a benign self limited course with rapid disappearance of signs and symptoms upon with drawl of the drug. Azathioprine is used in treating relapses in patients with autoimmune pancreatitis and maintenance of remission in autoimmune hepatitis. Acute pancreatitis complicated by symptomatic pseudocysts requiring drainage is not usually associated with drug induced pancreatitis. The risk of azathioprine use in patients with underlying disease of pancreas including autoimmune pancreatitis is unclear. Case report We report here a case of an African American patient with co-existing autoimmune pancreatitis and autoimmune hepatitis who developed azathioprine induced acute pancreatitis complicated by a large symptomatic pseudocyst compressing the duodenum requiring a cystoduodenostomy. Conclusions Future studies to investigate the risk of azathioprine induced pancreatitis in the presence of underlying disease of the pancreas including autoimmune pancreatitis are required to further understand the safety of azathioprine in this sub group of patients.

  5. Early over expression of messenger RNA for multiple genes, including insulin, in the Pancreatic Lymph Nodes of NOD mice is associated with Islet Autoimmunity

    Directory of Open Access Journals (Sweden)

    Eisenbarth George

    2009-10-01

    Full Text Available Abstract Background Autoimmune diabetes (T1D onset is preceded by a long inflammatory process directed against the insulin-secreting β cells of the pancreas. Deciphering the early autoimmune mechanisms represents a challenge due to the absence of clinical signs at early disease stages. The aim of this study was to identify genes implicated in the early steps of the autoimmune process, prior to inflammation, in T1D. We have previously established that insulin autoantibodies (E-IAA predict early diabetes onset delineating an early phenotypic check point (window 1 in disease pathogenesis. We used this sub-phenotype and applied differential gene expression analysis in the pancreatic lymph nodes (PLN of 5 weeks old Non Obese Diabetic (NOD mice differing solely upon the presence or absence of E-IAA. Analysis of gene expression profiles has the potential to provide a global understanding of the disease and to generate novel hypothesis concerning the initiation of the autoimmune process. Methods Animals have been screened weekly for the presence of E-IAA between 3 and 5 weeks of age. E-IAA positive or negative NOD mice at least twice were selected and RNAs isolated from the PLN were used for microarray analysis. Comparison of transcriptional profiles between positive and negative animals and functional annotations of the resulting differentially expressed genes, using software together with manual literature data mining, have been performed. Results The expression of 165 genes was modulated between E-IAA positive and negative PLN. In particular, genes coding for insulin and for proteins known to be implicated in tissue remodelling and Th1 immunity have been found to be highly differentially expressed. Forty one genes showed over 5 fold differences between the two sets of samples and 30 code for extracellular proteins. This class of proteins represents potential diagnostic markers and drug targets for T1D. Conclusion Our data strongly suggest that the

  6. Autoimmune pancreatitis in Japan. Overview and perspective

    International Nuclear Information System (INIS)

    Since the rediscovery and definition of autoimmune pancreatitis (AIP) by Yoshida et al. in 1995, the disease has been attracting attention because of its unique clinical features and practical issues. This disease shows very impressive imaging findings, serological changes, and characteristic histopathology. It occurs most commonly in elderly males with painless jaundice or mild abdominal pain; resemblance in imaging findings between AIP and pancreatobiliary cancers poses an important practical issue of differentiation. With increasing recognition of AIP and accumulation of cases, another important feature of this disease has been revealed, id est (i.e.), association of extrapancreatic organ involvements. Initially misunderstood because it can be accompanied by other autoimmune disorders, such as Sjogren's syndrome or primary sclerosing cholangitis (PSC), AIP is now known to be associated with unique types of sialadenitis and cholangitis distinct from Sjogren's syndrome or PSC. Now the concept of 'IgG4-related sclerosing disease' has become widely accepted and the list of organs involved continues to increase. With worldwide recognition, an emerging issue is the clinical definition of other possible types of autoimmune-related pancreatitis called 'idiopathic duct-centric chronic pancreatitis (IDCP)' and AIP with granulocyte epithelial lesion (GEL)' and their relation to AIP with lymphoplasmacytic sclerosing pancreatitis (LPSP). The time has arrived to establish clinical diagnostic criteria of AIP based on international consensus and to discuss regional and racial differences in the clinicopathological features of AIP. Consensus guidelines are also required for the ideal use of steroids in the treatment of AIP to suppress recurrence efficiently with minimal side effects. There are many issues to be settled in AIP; international collaboration of experts in the pancreas field is necessary to clarify the entire picture of this unique and important disease. (author)

  7. Differentiation of autoimmune pancreatitis from suspected pancreatic cancer by fluorine-18 fluorodeoxyglucose positron emission tomography

    International Nuclear Information System (INIS)

    Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been widely used for the diagnosis of pancreatic cancer. Because autoimmune pancreatitis is easily misdiagnosed as pancreatic cancer and can be tested for by FDG-PET analysis based on the presence of suspected pancreatic cancer, we attempted to clarify the differences in FDG-PET findings between the two conditions. We compared FDG-PET findings between 15 patients with autoimmune pancreatitis and 26 patients with pancreatic cancer. The findings were evaluated visually or semiquantitatively using the maximum standardized uptake value and the accumulation pattern of FDG. FDG uptake was found in all 15 patients with autoimmune pancreatitis, whereas it was found in 19 of 26 patients (73.1%) with pancreatic cancer. An accumulation pattern characterized by nodular shapes was significantly more frequent in pancreatic cancer, whereas a longitudinal shape indicated autoimmune pancreatitis. Heterogeneous accumulation was found in almost all cases of autoimmune pancreatitis, whereas homogeneous accumulation was found in pancreatic cancer. Significantly more cases of pancreatic cancer showed solitary localization, whereas multiple localization in the pancreas favored the presence of autoimmune pancreatitis. FDG uptake by the hilar lymph node was significantly more frequent in autoimmune pancreatitis than in pancreatic cancer, and uptake by the lachrymal gland, salivary gland, biliary duct, retroperitoneal space, and prostate were seen only in autoimmune pancreatitis. FDG-PET is a useful tool for differentiating autoimmune pancreatitis from suspected pancreatic cancer, if the accumulation pattern and extrapancreatic involvement are considered. IgG4 measurement and other current image tests can further confirm the diagnosis. (author)

  8. A Case of Pancreatic Cancer in the Setting of Autoimmune Pancreatitis with Nondiagnostic Serum Markers

    OpenAIRE

    Chandrasegaram, Manju D; Chiam, Su C.; Nguyen, Nam Q; Andrew Ruszkiewicz; Adrian Chung; Neo, Eu L; Chen, John W; Worthley, Christopher S.; Brooke-Smith, Mark E.

    2013-01-01

    Background. Autoimmune pancreatitis (AIP) often mimics pancreatic cancer. The diagnosis of both conditions is difficult preoperatively let alone when they coexist. Several reports have been published describing pancreatic cancer in the setting of AIP. Case Report. The case of a 53-year-old man who presented with abdominal pain, jaundice, and radiological features of autoimmune pancreatitis, with a “sausage-shaped” pancreas and bulky pancreatic head with portal vein impingement, is presented. ...

  9. Diagnostic criteria for autoimmune chronic pancreatitis revisited

    Institute of Scientific and Technical Information of China (English)

    Kyu-Pyo Kim; Myung-Hwan Kim; Jong Cheol Kim; Sang Soo Lee; Dong Wan Seo; Sung Koo Lee

    2006-01-01

    Autoimmune chronic pancreatitis (AIP) is increasingly being recognized worldwidely, as knowledge of this entity builds up. Above all, AIP is a very attractive disease to clinicians in terms of its dramatic response to the oral steroid therapy in contrast to ordinary chronic pancreatitis. Although many characteristic findings of AIP have been described, definite diagnostic criteria have not been fully established. In the year 2002, the Japan Pancreas Society published the diagnostic criteria of AIP and many clinicians around the world use these criteria for the diagnosis of AIP. The diagnostic criteria proposed by the Japan Pancreas Society, however, are not completely satisfactory and some groups use their own criteria in reporting AIP. This review discusses several potential limitations of current diagnostic criteria for this increasingly recognized condition. The manuscript is organized to emphasize the need for convening a consensus to develop improved diagnostic criteria.

  10. Sclerosing cholecystitis associated with autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Terumi Kamisawa; Yuyang Tu; Hitoshi Nakajima; Naoto Egawa; Kouji Tsuruta; Atsutake Okamoto; Shinichirou Horiguchi

    2006-01-01

    AIM: To evaluate the histopathological and radiological findings of the gallbladder in patients with autoimmune pancreatitis (AIP).METHODS: The radiological findings of the gallbladder of 19 AIP patients were retrospectively reviewed.Resected gallbladders of 8 AIP patients were examined histologically and were immunostained with antiIgG4 antibody. Controls consisted of gallbladders resected for symptomatic gallstones (n=10) and those removed during pancreatoduodenectomy for pancreatic carcinoma (n=10), as well as extrahepatic bile ducts and pancreases removed by pancreatoduodenectomy for pancreatic carcinoma (n=10).RESULTS: Thickening of the gallbladder wall was detected by ultrasound and/or computed tomography in 10 patients with AIP (3 severe and 7 moderate);in these patients severe stenosis of the extrahepatic bile duct was also noted. Histologically, thickening of the gallbladder was detected in 6 of 8 (75%) patients with AIP; 4 cases had transmural lymphoplasmacytic infiltration with fibrosis, and 2 cases had mucosal-based lymphoplasmacytic infiltration. Considerable transmural thickening of the extrahepatic bile duct wall with dense fibrosis and diffuse ly rnphoplasmacytic infiltration was detected in 7 patients. Immunohistochemically, severe or moderate infiltration of IgG4-positive plasma cells was detected in the gallbladder, bile duct, and pancreas of all 8 patients, but was not detected in controls.CONCLUSION: Gallbladder wall thickening with fibrosis and abundant infiltration of IgG4-positive plasma cells is frequently detected in patients with AIR We propose the use of a new term, sclerosing cholecystitis, for these cases that are induced by the same mechanism as sclerosing pancreatitis or sclerosing cholangitis in AIP.

  11. Autoimmune Pancreatitis: An Update on Diagnosis and Management.

    Science.gov (United States)

    Madhani, Kamraan; Farrell, James J

    2016-03-01

    There is an evolving understanding that autoimmune pancreatitis (AIP) is an immunoglobulin (Ig) G4 systemic disease. It can manifest as primarily a pancreatic disorder or in association with other disorders of presumed autoimmune cause. Classic clinical characteristics include obstructive jaundice, abdominal pain, and acute pancreatitis. Thus, AIP can be difficult to distinguish from pancreatic malignancy. However, AIP may respond to therapy with corticosteroids, and has a strong association with other immune mediated diseases. Although primarily a pathologic diagnosis, attempts have been made to reliably diagnose AIP clinically. AIP can be classified as either type 1 or type 2. PMID:26895679

  12. Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis

    Energy Technology Data Exchange (ETDEWEB)

    Fujinaga, Yasunari, E-mail: fujinaga@shinshu-u.ac.jp [Department of Radiology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621 (Japan); Kadoya, Masumi [Department of Radiology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621 (Japan); Kawa, Shigeyuki [Center of Health, Safety and Environmental Management, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621 (Japan); Hamano, Hideaki [Department of Medicine, Gastroenterology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621 (Japan); Ueda, Kazuhiko; Momose, Mitsuhiro; Kawakami, Satoshi; Yamazaki, Sachie; Hatta, Tomoko; Sugiyama, Yukiko [Department of Radiology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621 (Japan)

    2010-11-15

    Purpose: Autoimmune pancreatitis is a unique form of chronic pancreatitis characterized by a variety of extra-pancreatic involvements which are frequently misdiagnosed as lesions of corresponding organs. The purpose of this study was to clarify the diagnostic imaging features of extra-pancreatic lesions associated with autoimmune pancreatitis. Materials and methods: We retrospectively analyzed diagnostic images of 90 patients with autoimmune pancreatitis who underwent computer-assisted tomography, magnetic resonance imaging, and/or gallium-67 scintigraphy before steroid therapy was initiated. Results: AIP was frequently (92.2%) accompanied by a variety of extra-pancreatic lesions, including swelling of lachrymal and salivary gland lesions (47.5%), lung hilar lymphadenopathy (78.3%), a variety of lung lesions (51.2%), wall thickening of bile ducts (77.8%), peri-pancreatic or para-aortic lymphadenopathy (56.0%), retroperitoneal fibrosis (19.8%), a variety of renal lesions (14.4%), and mass lesions of the ligamentum teres (2.2%). Characteristic findings in CT and MRI included lymphadenopathies of the hilar, peri-pancreatic, and para-aortic regions; wall thickening of the bile duct; and soft tissue masses in the kidney, ureters, aorta, paravertebral region, ligamentum teres, and orbit. Conclusions: Recognition of the diagnostic features in the images of various involved organs will assist in the diagnosis of autoimmune pancreatitis and in differential diagnoses between autoimmune pancreatitis-associated extra-pancreatic lesions and lesions due to other pathologies.

  13. Expression of innate immunity genes and damage of primary human pancreatic islets by epidemic strains of Echovirus: implication for post-virus islet autoimmunity.

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    Luis Sarmiento

    Full Text Available Three large-scale Echovirus (E epidemics (E4,E16,E30, each differently associated to the acute development of diabetes related autoantibodies, have been documented in Cuba. The prevalence of islet cell autoantibodies was moderate during the E4 epidemic but high in the E16 and E30 epidemic. The aim of this study was to evaluate the effect of epidemic strains of echovirus on beta-cell lysis, beta-cell function and innate immunity gene expression in primary human pancreatic islets. Human islets from non-diabetic donors (n = 7 were infected with the virus strains E4, E16 and E30, all isolated from patients with aseptic meningitis who seroconverted to islet cell antibody positivity. Viral replication, degree of cytolysis, insulin release in response to high glucose as well as mRNA expression of innate immunity genes (IFN-b, RANTES, RIG-I, MDA5, TLR3 and OAS were measured. The strains of E16 and E30 did replicate well in all islets examined, resulting in marked cytotoxic effects. E4 did not cause any effects on cell lysis, however it was able to replicate in 2 out of 7 islet donors. Beta-cell function was hampered in all infected islets (P<0.05; however the effect of E16 and E30 on insulin secretion appeared to be higher than the strain of E4. TLR3 and IFN-beta mRNA expression increased significantly following infection with E16 and E30 (P<0.033 and P<0.039 respectively. In contrast, the expression of none of the innate immunity genes studied was altered in E4-infected islets. These findings suggest that the extent of the epidemic-associated islet autoimmunity may depend on the ability of the viral strains to damage islet cells and induce pro-inflammatory innate immune responses within the infected islets.

  14. Autoimmune Pancreatitis Presenting as Simultaneous Masses in the Pancreatic Head and Gallbladder

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    Andrew A Gumbs

    2005-09-01

    Full Text Available Context Autoimmune pancreatitis is a rare variant of chronic pancreatitis characterized by pancreatic ductal narrowing and pancreatic parenchymal edema on computed tomography and rarely with intermittent attacks of abdominal pain. Recently, it has been found to be a systemic disease with lymphoplasmacytic infiltration that has been associated with several autoimmune diseases and described in multiple organs including the extrahepatic bile duct, liver and gallbladder. Case report We describe the clinical, radiographic and histopathologic aspects of a patient who presented with synchronous masses in the pancreatic head and gallbladder. Postoperatively, the patient's jaundice subsided and IgG4 levels, which were drawn one week postoperatively, were all within normal limits. Nonetheless, immunohistochemical staining for IgG4 was positive. Conclusion Autoimmune pancreatitis is the most common benign entity identified in patients that underwent pancreaticoduodenectomy for presumed pancreatic adenocarcinoma. Our patient with autoimmune pancreatitis presented with simultaneous inflamematory masses in the gallbladder and pancreatic head, an association not previously reported. Preoperative evaluation of IgG4 or autoantibody levels may have obviated the need for an operation. Therefore, we have begun screening for elevated serum IgG4 concentrations to identify patients with possible autoimmune pancreatitis who present without definitive pathological or radiographic evidence for malignancy. If preoperative diagnosis is not made, immunohistochemical staining of pathology specimens can confirm the diagnosis.

  15. Autoimmune Pancreatitis and Treatment Approaches with Case Reports

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    Şafak Öztürk

    2012-12-01

    Full Text Available Objective: In this study, we aimed to review retrospectively the data of 10 patient who were treated and followed-up in our clinic and to review the current approaches in the diagnosis and treatment of autoimmune pancreatitis (AIP.Material and Methods: We reviewed 10 patients retrospectively who were operated on and had the diagnosis of AIP histopathologically in the Ege University School of Medicine Department of General Surgery.Results: Between June 2001-November 2010, 10 patients who were diagnosed as AIP were examined retrospectively. Radiologically, a pancreatic mass was found in the pancreatic head with ultrasound in 7 (70% of 10 patients and suspicious lesions were identified in the head of the pancreas in 3 (30% patients. All patients were operated on in our clinic with the preliminary diagnosis of pancreatic head tumor; 8 patients underwent Whipple’s procedure, 1 patient underwent pylorus preserving pancreaticoduodenectomy, and in 1 patient an exploratory pancreatic biopsy (frozen section was carried out.Conclusion: Autoimmune pancreatitis is a disease with increasing incidence and characterized by lymphoplasmocytic cell infiltration and fibrosis. Patients with a pancreatic mass, if there is an autoimmune disease or chronic pancreatitis suspected in the detailed history, it is necessary to evaluate patients in terms of AIP serologically to protect the patients from an incoorectng diagnosis and morbidity of surgery.

  16. Autoimmune Pancreatitis Complicated by Spontaneous Subcapsular Splenic Haemorrhage

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    Mina S Hanna

    2013-09-01

    Full Text Available Context Autoimmune pancreatitis is a rare but increasingly reco gnised condition with unique clinical, immunologica l and histological features. We report the first case of auto immune pancreatitis associated with spontaneous sple nic haemorrhage. Case report A 75-year-old man presented with severe epigastric pa in radiating to the back associated with nausea and vomiting. A CT-scan of his abdomen showed a large ps eudocyst within the pancreatic tail as well as a sub capsular splenic haemorrhage. His IgG4 levels were elevated and clinica l history and investigations were consistent with se vere acute pancreatitis, but were negative for other known causes of pancreatic disease. The patient was started on ste roid therapy and improved dramatically clinically, immunologically and radiologically thus confirming the diagnosis of auto immune pancreatitis. His splenic haemorrhage was managed cons ervatively in view of his haemodynamic stablity and eventually self- resolved. Conclusion Autoimmune pancreatitis should not be overlooked in cases of acute pancreatitis without other obvious etiology. Furthermore, superimposed splenic hae morrhage is a rare but important complication of autoimm une pancreatitis.

  17. Autoimmune Pancreatitis: Etiology, Pathogenesis, Clinical Findings and Treatment. The Japanese Experience

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    Okazaki K

    2005-01-01

    Full Text Available A concept of "autoimmune pancreatitis" has recently been proposed. Computed tomography, magnetic resonance imaging or ultrasonography can demonstrate the diffusely enlarged pancreas with its so called "sausage-like" appearance. Hypergammaglobulinemia, increased serum levels of total IgG or IgG4, positive autoantibodies such as antinuclear antibody, anti-lactoferrin antibody, anti-CA-II antibody and rheumatoid factor have often been observed in patients with autoimmune pancreatitis. Microscopic findings have shown fibrotic changes involving infiltration of lymphocytes and plasmacytes, and often obliterative phlebitis in the pancreas. The major lymphocytes infiltrating the zone around the pancreatic duct were T cells producing IFN-g. HLA-DR was also expressed on the pancreatic duct and acinar cells as were lymphocytes. It is important to make the diagnosis of a diffusely enlarged pancreas based on clinical laboratory findings and pancreatic imaging such as narrowing pancreatogram. Laboratory data, pancreatic images and diabetes mellitus in most patients improved after steroid treatment.In conclusion, autoimmune pancreatitis appears to be a unique clinical entity.

  18. A Case of Pancreatic Cancer in the Setting of Autoimmune Pancreatitis with Nondiagnostic Serum Markers

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    Manju D. Chandrasegaram

    2013-01-01

    Full Text Available Background. Autoimmune pancreatitis (AIP often mimics pancreatic cancer. The diagnosis of both conditions is difficult preoperatively let alone when they coexist. Several reports have been published describing pancreatic cancer in the setting of AIP. Case Report. The case of a 53-year-old man who presented with abdominal pain, jaundice, and radiological features of autoimmune pancreatitis, with a “sausage-shaped” pancreas and bulky pancreatic head with portal vein impingement, is presented. He had a normal serum IgG4 and only mildly elevated Ca-19.9. Initial endoscopic ultrasound-(EUS- guided fine-needle aspiration (FNA of the pancreas revealed an inflammatory sclerosing process only. A repeat EUS guided biopsy following biliary decompression demonstrated both malignancy and features of autoimmune pancreatitis. At laparotomy, a uniformly hard, bulky pancreas was found with no sonographically definable mass. A total pancreatectomy with portal vein resection and reconstruction was performed. Histology revealed adenosquamous carcinoma of the pancreatic head and autoimmune pancreatitis and squamous metaplasia in the remaining pancreas. Conclusion. This case highlights the diagnostic and management difficulties in a patient with pancreatic cancer in the setting of serum IgG4-negative, Type 2 AIP.

  19. Immunoglobulin G4-related disease: autoimmune pancreatitis and extrapancreatic manifestations*

    Science.gov (United States)

    Fernandes, Daniel Alvarenga; Kido, Ricardo Yoshio Zanetti; Barros, Ricardo Hoelz de Oliveira; Martins, Daniel Lahan; Penachim, Thiago José; Caserta, Nelson Marcio Gomes

    2016-01-01

    We present a case of immunoglobulin G4 (IgG4)-related disease with pancreatic and extrapancreatic involvement, including the biliary and renal systems. Given the importance of imaging methods for the diagnosis of IgG4-related disease and its differentiation from pancreatic adenocarcinoma, we emphasize important abdominal computed tomography and magnetic resonance imaging findings related to this recently recognized systemic autoimmune disease. PMID:27141136

  20. Endoscopic Ultrasonography Findings in Autoimmune Pancreatitis: Be Aware of the Ambiguous Features and Look for the Pivotal Ones

    Directory of Open Access Journals (Sweden)

    Stefania De Lisi

    2010-01-01

    Full Text Available Autoimmune pancreatitis is a form of chronic pancreatitis caused by an autoimmune process. The classical appearance of autoimmune pancreatitis in abdominal imaging is diffuse pancreatic enlargement, but the focal form appears as a mass and often involves the pancreatic head; this scenario represents a challenging diagnostic problem because these features also resemble pancreatic cancer. We present the endoscopic ultrasound findings of seven patients with autoimmune pancreatitis in order to highlight the ambiguous features and the features pivotal for the diagnosis.

  1. Endoscopic Ultrasonography Findings in Autoimmune Pancreatitis: Be Aware of the Ambiguous Features and Look for the Pivotal Ones

    OpenAIRE

    Stefania De Lisi; Elisabetta Buscarini; Fernanda Menozzi; Alessandro Zambelli; Paolo Giorgio Arcidiacono; Mara Petrone; Pier Alberto Testoni

    2010-01-01

    Autoimmune pancreatitis is a form of chronic pancreatitis caused by an autoimmune process. The classical appearance of autoimmune pancreatitis in abdominal imaging is diffuse pancreatic enlargement, but the focal form appears as a mass and often involves the pancreatic head; this scenario represents a challenging diagnostic problem because these features also resemble pancreatic cancer. We present the endoscopic ultrasound findings of seven patients with autoimmune pancreatitis in order to hi...

  2. Perfusion computed tomography imaging of autoimmune pancreatitis

    International Nuclear Information System (INIS)

    Perfusion computed tomography (P-CT) is now available for the analysis of pancreatic blood flow. The aim of this study was to clarify pancreatic blood perfusion in AIP patients and the changes after steroid treatment. Color map imaging of P-CT and pancreatic time CT density curve (TDC) demonstrated that the pancreatic blood flow was attenuated in AIP patients. Pancreatic volumetric blood flow FV values of 11 AIP patients (82.7/min) were significantly lower than those of 12 normal controls (163.5/min, p=0.0006). AIP patients received steroid treatment and were re-examined, of these, 9 patients showed significantly elevated FV values after treatment (76.2/min and 109.8/min, p=0.0391, respectively). However, the changes of the values after the treatment differed in varying degrees among the individuals. P-CT is a useful method for the analysis of the blood flow in pancreatic diseases. (author)

  3. Clinical study on IgG4-related autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    吴庆军

    2013-01-01

    Objective To investigate the clinical features of IgG4-related autoimmune pancreatitis(IgG4-related AIP). Methods A prospective cohort study on IgG4 related disease(IgG4-RD) was carried out in Peking Union Medical College Hospital during December 2010 to June

  4. Autoimmune pancreatitis. An update; Autoimmunpankreatitis. Ein Update

    Energy Technology Data Exchange (ETDEWEB)

    Helmberger, T. [Klinikum Bogenhausen, Staedt. Klinikum, Institut fuer Diagnostische und Interventionelle Radiologie, Neuroradiologie und Nuklearmedizin, Muenchen (Germany)

    2016-04-15

    Autoimmune pancreatitis (AIP) is a rare disease, the pathophysiological understanding of which has been greatly improved over the last years. The most common form, type 1 AIP belongs to the IgG4-related diseases and must be distinguished from type 2 AIP, which is a much rarer entity associated with chronic inflammatory bowel disease. Clinically, there is an overlap with pancreatic cancer. Imaging and further criteria, such as serological and histological parameters are utilized for a differentiation between both entities in order to select the appropriate therapy and to avoid the small but ultimately unnecessary number of pancreatectomies. The diagnostics of AIP are complex, whereby the consensus criteria of the International Association of Pancreatology have become accepted as the parameters for discrimination. These encompass five cardinal criteria and one therapeutic criterion. By applying these criteria AIP can be diagnosed with a sensitivity of 84.9 %, a specificity of 100 % and an accuracy of 93.8 %. The diagnosis of AIP is accomplished by applying several parameters of which two relate to imaging. As for the routine diagnostics of the pancreas these are ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). Important for the differential diagnosis is the exclusion of signs of local and remote tumor spread for which CT and MRI are established. The essential diagnostic parameter of histology necessitates sufficient sample material, which cannot usually be acquired by a fine needle biopsy. CT or MRI are the reference standard methods for identification of the optimal puncture site and imaging-assisted (TruCut) biopsy. In patients presenting with unspecific upper abdominal pain, painless jaundice combined with the suspicion of a pancreatic malignancy in imaging but a mismatch of secondary signs of malignancy, AIP should also be considered as a differential diagnosis. As the diagnosis of AIP only partially relies on imaging radiologists also

  5. [Autoimmune pancreatitis. Evidence based management guidelines of the Hungarian Pancreatic Study Group].

    Science.gov (United States)

    Dubravcsik, Zsolt; Farkas, Gyula; Hegyi, Péter; Hritz, István; Kelemen, Dezső; Lásztity, Natália; Morvay, Zita; Oláh, Attila; Pap, Ákos; Párniczky, Andrea; Sahin-Tóth, Miklós; Szentkereszti, Zsolt; Szmola, Richárd; Takács, Tamás; Tiszlavicz, László; Szücs, Ákos; Czakó, László

    2015-02-22

    Autoimmune pancreatitis is a rare disease which can even mimic pancreatic tumor, however, unlike the latter, it requires not surgical but conservative management. Correct diagnosis and differential diagnosis of autoimmune pancreatitis and treatment of these patients requires up-to-date and evidence based management guidelines. The Hungarian Pancreatic Study Group proposed to prepare an evidence based guideline based on the available international guidelines and evidences. The preparatory and consultation task force appointed by the Hungarian Pancreatic Study Group translated and complemented and/or modified the international guidelines if it was necessary. 29 relevant clinical questions in 4 topics were defined (Basics; Diagnosis; Differential diagnostics; Therapy). Evidence was classified according to the UpToDate(®) grading system. The draft of the guidelines was presented and discussed at the consensus meeting on September 12, 2014. All clinial questions were accepted with almost total (more than 95%) agreement. The present guideline is the first evidence based autoimmune pancreatitis guideline in Hungary. The guideline may provide very important and helpful data for tuition of autoimmune pancreatitis, for everyday practice and for establishing proper finance. Therefore, the authors believe that these guidelines will widely become a basic reference in Hungary.

  6. Strategy to differentiate autoimmune pancreatitis from pancreas cancer

    Institute of Scientific and Technical Information of China (English)

    Kensuke Takuma; Terumi Kamisawa; Rajesh Gopalakrishna; Seiichi Hara; Taku Tabata; Yoshihiko Inaba; Naoto Egawa

    2012-01-01

    Autoimmune pancreatitis (AIP) is a newly described entity of pancreatitis in which the pathogenesis appears to involve autoimmune mechanisms.Based on histological and immunohistochemical examinations of various organs of AIP patients,AIP appears to be a pancreatic lesion reflecting a systemic "IgG4-related sclerosing disease".Clinically,AIP patients and patients with pancreatic cancer share many features,such as preponderance of elderly males,frequent initial symptom of painless jaundice,development of new-onset diabetes mellitus,and elevated levels of serum tumor markers.It is of uppermost importance not to misdiagnose AIP as pancreatic cancer.Since there is currently no diagnostic serological marker for AIP,and approach to the pancreas for histological examination is generally difficult,AIP is diagnosed using a combination of clinical,serological,morphological,and histopathological features.Findings suggesting AIP rather than pancreatic cancer include:fluctuating obstructive jaundice; elevated serum IgG4 levels; diffuse enlargement of the pancreas; delayed enhancement of the enlarged pancreas and presence of a capsule-like rim on dynamic computed tomography; low apparent diffusion coefficient values on diffusion-weighted magnetic resonance image; irregular narrowing of the main pancreatic duct on endoscopic retrograde cholangiopancreatography; less upstream dilatation of the main pancreatic duct on magnetic resonance cholangiopancreatography,presence of other organ involvement such as bilateral salivary gland swelling,retroperitoneal fibrosis and hilar or intrahepatic sclerosing cholangitis;negative work-up for malignancy including endoscopic ultrasound-guided fine needle aspiration; and steroid responsiveness.Since AIP responds dramatically to steroid therapy,accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection.

  7. The long-term impact of autoimmune pancreatitis on pancreatic function, quality of life, and life expectancy

    NARCIS (Netherlands)

    Buijs, Jorie; Cahen, Djuna L.; Van Heerde, Marianne J.; Rauws, Erik A.; De Buy Wenniger, Lucas J Maillette; Hansen, Bettina E.; Biermann, Katharina; Verheij, Joanne; Vleggaar, FP; Brink, Menno A.; Beuers, Ulrich H W; Van Buuren, Henk R.; Bruno, Marco J.

    2015-01-01

    Objective: To evaluate the long-termoutcome of autoimmune pancreatitis. Methods: Patients with at least 2 years of follow-up were included. Information was collected regarding disease characteristics, treatment outcome, diagnosedmalignancies, andmortality. In addition, pancreatic function and qualit

  8. Lack of an Association between Autoimmune Pancreatitis and Varicella Zoster Virus

    Directory of Open Access Journals (Sweden)

    Neal C Patel

    2011-11-01

    Full Text Available Dear Sir: Autoimmune pancreatitis is a form of chronic pancreatitis that was first described by Sarles et al. in 1961, and later coined in 1995 by Yoshida et al. [1, 2]. Subsequently, two types of autoimmune pancreatitis have been described. Autoimmune pancreatitis type 1 fits the classic description of the disease and is associated with a lymphoplasmacytic sclerosing pancreatitis and an elevated level of immunoglobulin G4 subclass of IgG. Autoimmune pancreatitis type 2 is characterized by a distinct neutrophilic obliterating lesion of the ductal epithelium [3]. Although the histopathological findings of autoimmune pancreatitis are well studied, the risk factors, pathogenesis, and treatments are still not well understood. There have been many hypotheses to the etiology of autoimmune pancreatitis, which are still being studied. One proposed theory is that of microbial mimicry leading to an autoimmune disorder. Several studies have been conducted to evaluate for a link with autoimmune pancreatitis and infectious causes, such as Helicobacter Pylori, without identifying a clear relationship [4]. Additionally, there has been a reported link between viral infections and acute pancreatitis, such as Coxackievirus [5].

  9. Newly developed autoimmune cholangitis without relapse of autoimmune pancreatitis after discontinuing prednisolone

    Institute of Scientific and Technical Information of China (English)

    Ji Hun Kim; Jae Hyuck Chang; Sung Min Nam; Mi Jeong Lee; Il Ho Maeng; Jin Young Park; Yun Sun Im

    2012-01-01

    A 57-year-old man presented with a 2-wk history of painless jaundice and weight loss.He had a large illdefined enhancing mass-like lesion in the uncinate process of the pancreas with stricture of the distal common bile duct.Aspiration cytology of the pancreatic mass demonstrated inflammatory cells without evidence of malignancy.Total serum immunoglobulin G level was slightly elevated,but IgG4 level was normal.After the 2-wk 40 mg prednisolone trial,the patient's symptoms and bilirubin level improved significantly.A follow-up computed tomography (CT) scan showed a dramatic resolution of the pancreatic lesion.A low dose steroid was continued.After six months he self-discontinued prednisolone for 3 wk,and was presented with jaundice again.ACT scan showed newly developed intrahepatic biliary dilatation and marked concentric wall thickening of the common hepatic duct and the proximal common bile duct without pancreatic aggravation.The patient' s IgG4 level was elevated to 2.51 g/L.Prednisolone was started again,after which his serum bilirubin level became normal and the thickening of the bile duct was resolved.This case suggests that autoimmune pancreatitis can progress to other organs that are not involved at the initial diagnosis,even with sustained pancreatic remission.

  10. Diffusion-weighted magnetic resonance imaging in autoimmune pancreatitis

    International Nuclear Information System (INIS)

    The aim of this study was to investigate the usefulness of diffusion-weighted magnetic resonance imaging (DWI MRI) for the diagnosis and evaluation of autoimmune pancreatitis (AIP). A total of 4 consecutive patients with AIP, 5 patients with chronic alcoholic pancreatitis (CP), and 13 patients without pancreatic disease (controls) were studied. DWI was performed in the axial plane with spin-echo echo-planar imaging single-shot sequence. Apparent diffusion coefficients (ADCs) were measured in circular regions of interest in the pancreas. In AIP patients, abdominal MRI was performed before, and 2-4 weeks after steroid treatment. Follow-up study was performed chronologically for up to 11 months in two patients. The correlation between ADCs of the pancreas and the immunoglobulin G4 (IgG4) index (serum IgG4 value/serum IgG4 value before steroid treatment) was evaluated. In the AIP patients, DWI of the pancreas showed high signal intensity, and the ADCs of the pancreas (mean±standard deviation (SD): 0.97±0.18 x 10-3 mm2/s) were significantly lower than those in patients with CP (1.45±0.10 x 10-3 mm2/s) or the controls (1.45±0.16 x 10-3 mm2/s) (Mann-Whitney U-test, Ps=-0.80, P<0.05). Autoimmune pancreatitis showed high signal intensity on DWI, which improved after steroid treatment. ADCs reflected disease activity. Thus, diffusion-weighted MRI might be useful for diagnosing AIP, determining the affected area, and evaluating the effect of treatment. (author)

  11. MRI findings of pancreatic lymphoma and autoimmune pancreatitis: A comparative study

    International Nuclear Information System (INIS)

    Purpose: To clarify whether there are differences in MRI findings between pancreatic lymphomas and autoimmune pancreatitis (AIP). Materials and methods: MRI of 8 patients with pancreatic lymphomas and 21 patients with AIP were retrospectively reviewed. For multifocal pancreatic lymphomas (n = 2) and AIP (n = 4), the largest 2 lesions were evaluated. Ten pancreatic lymphomas and 25 AIP were compared on three bases: the signal intensity on T2-weighted images, internal homogeneity, and presence or absence of capsule-like rim. In 8 lymphomas and 19 AIP, the enhancement pattern on dynamic MRI was compared, as well. Results: On T2-weighted images, pancreatic lymphomas comprised 5, 5 and 4 lesions with low (iso), slightly high, and moderately high intensity, respectively, while the numbers for AIP were 14, 10, and 1 (P < 0.01). Nine of 10 (90%) lymphomas appeared homogenous, and 11 of 25 (44%) AIP were homogenous (P < 0.05). A capsule-like rim was present in 9 of 25 (36%) AIP, but was not seen in lymphomas (P < 0.05). On dynamic MRI, 18 of 19 (94.7%) AIP showed persistent (n = 5) or delayed enhancement (n = 13), and 6 of 8 (75%) lymphomas showed low intensity without delayed enhancement (P < 0.001). Conclusion: MRI findings for pancreatic lymphomas and AIP were significantly different, which may be helpful for the differential diagnosis of these two diseases.

  12. MRI findings of pancreatic lymphoma and autoimmune pancreatitis: A comparative study

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    Ishigami, Kousei, E-mail: Ishigamikousei@aol.co [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 (Japan); Tajima, Tsuyoshi; Nishie, Akihiro; Ushijima, Yasuhiro [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 (Japan); Fujita, Nobuhiro [Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University (Japan); Asayama, Yoshiki; Kakihara, Daisuke; Irie, Hiroyuki [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 (Japan); Ito, Tetsuhide; Igarashi, Hisato [Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University (Japan); Nakamura, Masafumi [Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University (Japan); Honda, Hiroshi [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 (Japan)

    2010-06-15

    Purpose: To clarify whether there are differences in MRI findings between pancreatic lymphomas and autoimmune pancreatitis (AIP). Materials and methods: MRI of 8 patients with pancreatic lymphomas and 21 patients with AIP were retrospectively reviewed. For multifocal pancreatic lymphomas (n = 2) and AIP (n = 4), the largest 2 lesions were evaluated. Ten pancreatic lymphomas and 25 AIP were compared on three bases: the signal intensity on T2-weighted images, internal homogeneity, and presence or absence of capsule-like rim. In 8 lymphomas and 19 AIP, the enhancement pattern on dynamic MRI was compared, as well. Results: On T2-weighted images, pancreatic lymphomas comprised 5, 5 and 4 lesions with low (iso), slightly high, and moderately high intensity, respectively, while the numbers for AIP were 14, 10, and 1 (P < 0.01). Nine of 10 (90%) lymphomas appeared homogenous, and 11 of 25 (44%) AIP were homogenous (P < 0.05). A capsule-like rim was present in 9 of 25 (36%) AIP, but was not seen in lymphomas (P < 0.05). On dynamic MRI, 18 of 19 (94.7%) AIP showed persistent (n = 5) or delayed enhancement (n = 13), and 6 of 8 (75%) lymphomas showed low intensity without delayed enhancement (P < 0.001). Conclusion: MRI findings for pancreatic lymphomas and AIP were significantly different, which may be helpful for the differential diagnosis of these two diseases.

  13. Hypermethylation of MST1 in IgG4-related autoimmune pancreatitis and rheumatoid arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Fukuhara, Takataro; Tomiyama, Takashi [Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, JST CREST, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010 (Japan); Yasuda, Kaneki [Department of Urology and Andrology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010 (Japan); Ueda, Yoshihiro [Department of Molecular Genetics, Institute of Biomedical Science, and JST CREST, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010 (Japan); Ozaki, Yoshio; Son, Yonsu; Nomura, Shosaku [Department of the First Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010 (Japan); Uchida, Kazushige; Okazaki, Kazuichi [Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, JST CREST, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010 (Japan); Kinashi, Tatsuo, E-mail: kinashi@takii.kmu.ac.jp [Department of Molecular Genetics, Institute of Biomedical Science, and JST CREST, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010 (Japan)

    2015-08-07

    The serine/threonine kinase Mst1 plays important roles in the control of immune cell trafficking, proliferation, and differentiation. Previously, we reported that Mst1 was required for thymocyte selection and regulatory T-cell functions, thereby the prevention of autoimmunity in mice. In humans, MST1 null mutations cause T-cell immunodeficiency and hypergammaglobulinemia with autoantibody production. RASSF5C(RAPL) is an activator of MST1 and it is frequently methylated in some tumors. Herein, we investigated methylation of the promoter regions of MST1 and RASSF5C(RAPL) in leukocytes from patients with IgG4-related autoimmune pancreatitis (AIP) and rheumatoid arthritis (RA). Increased number of CpG methylation in the 5′ region of MST1 was detected in AIP patients with extrapancreatic lesions, whereas AIP patients without extrapancreatic lesions were similar to controls. In RA patients, we detected a slight increased CpG methylation in MST1, although the overall number of methylation sites was lower than that of AIP patients with extrapancreatic lesions. There were no significant changes of the methylation levels of the CpG islands in the 5′ region of RASSF5C(RAPL) in leukocytes from AIP and RA patients. Consistently, we found a significantly down-regulated expression of MST1 in regulatory T cells of AIP patients. Our results suggest that the decreased expression of MST1 in regulatory T cells due to hypermethylation of the promoter contributes to the pathogenesis of IgG4-related AIP. - Highlights: • Mst1 controls immune cells trafficking, cell proliferation and differentiation. • Autoimmune pancreatitis (AIP) is an idiopathic pancreatitis affecting multiple organs. • Decreased MST1 expression and increased CpG methylation of promoter of MST1 in AIP. • Slight increased CpG methylation of MST1 in rheumatoid arthritis patients. • MST1 contributes pathogenesis of IgG4-related AIP.

  14. Hypermethylation of MST1 in IgG4-related autoimmune pancreatitis and rheumatoid arthritis

    International Nuclear Information System (INIS)

    The serine/threonine kinase Mst1 plays important roles in the control of immune cell trafficking, proliferation, and differentiation. Previously, we reported that Mst1 was required for thymocyte selection and regulatory T-cell functions, thereby the prevention of autoimmunity in mice. In humans, MST1 null mutations cause T-cell immunodeficiency and hypergammaglobulinemia with autoantibody production. RASSF5C(RAPL) is an activator of MST1 and it is frequently methylated in some tumors. Herein, we investigated methylation of the promoter regions of MST1 and RASSF5C(RAPL) in leukocytes from patients with IgG4-related autoimmune pancreatitis (AIP) and rheumatoid arthritis (RA). Increased number of CpG methylation in the 5′ region of MST1 was detected in AIP patients with extrapancreatic lesions, whereas AIP patients without extrapancreatic lesions were similar to controls. In RA patients, we detected a slight increased CpG methylation in MST1, although the overall number of methylation sites was lower than that of AIP patients with extrapancreatic lesions. There were no significant changes of the methylation levels of the CpG islands in the 5′ region of RASSF5C(RAPL) in leukocytes from AIP and RA patients. Consistently, we found a significantly down-regulated expression of MST1 in regulatory T cells of AIP patients. Our results suggest that the decreased expression of MST1 in regulatory T cells due to hypermethylation of the promoter contributes to the pathogenesis of IgG4-related AIP. - Highlights: • Mst1 controls immune cells trafficking, cell proliferation and differentiation. • Autoimmune pancreatitis (AIP) is an idiopathic pancreatitis affecting multiple organs. • Decreased MST1 expression and increased CpG methylation of promoter of MST1 in AIP. • Slight increased CpG methylation of MST1 in rheumatoid arthritis patients. • MST1 contributes pathogenesis of IgG4-related AIP

  15. The Long-Term Impact of Autoimmune Pancreatitis on Pancreatic Function, Quality of Life, and Life Expectancy

    NARCIS (Netherlands)

    J. Buijs (Jan); D.L. Cahen; M. van Heerde (Marianne); Rauws, EA; L.J.M. De Buy Wenniger (Lucas J. Maillette); B.E. Hansen (Bettina); K. Biermann (Katharina); J. Verheij (Joanne); F.P. Vleggaar (Frank); M.A. Brink (Menno); U. Beuers (Ulrich); H.R. van Buuren (Henk); M.J. Bruno (Marco)

    2015-01-01

    textabstractObjective To evaluate the long-term outcome of autoimmune pancreatitis. Methods Patients with at least 2 years of follow-up were included. Information was collected regarding disease characteristics, treatment outcome, diagnosed malignancies, and mortality. In addition, pancreatic functi

  16. Autoimmune pancreatocholangitis, non-autoimmune pancreatitis and primary sclerosing cholangitis: a comparative morphological and immunological analysis.

    Directory of Open Access Journals (Sweden)

    Irene Esposito

    Full Text Available BACKGROUND: Autoimmune pancreatocholangitis (AIPC is an emerging, not completely characterized disease. Aim of this study was the comprehensive evaluation of a series of AIPC patients, who were diagnosed and treated in a European institution between January 2003 and July 2006. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-three patients with histologically confirmed AIPC were analyzed and compared to 20 patients with non-autoimmune chronic pancreatitis (CP and 14 patients with primary sclerosing cholangitis (PSC. Clinical features and conventional histopathology were taken into account. Immunohistochemistry and real-time quantitative PCR were used for the characterization of the inflammatory infiltrate and the stromal reaction. AIPC was localized in the pancreatic head in 94% of the patients. Intra- and/or extrapancreatic biliary tract involvement was present in 64% of the cases. The number of infiltrating T-lymphocytes, macrophages and total plasma cells was significantly higher in AIPC than in CP (3-, 4- and 8-fold increase, respectively. The absolute number of IgG4-positive plasma cells was higher in AIPC than in CP and PSC (7-fold and 35-fold increase, respectively, but significance was only reached in comparison with PSC. CXCR5- and CXCL13-positive cells were almost exclusively detected in AIPC. CONCLUSIONS/SIGNIFICANCE: AIPC is mainly a disease of the pancreatic head with possible extension into the periphery of the gland and/or into the biliary tract/gallbladder. The morphology of AIPC, as well as the immune- and stromal reaction is characteristic and comparable between cases with and without biliary tract involvement. Immunological markers (IgG4, CXCR5, CXCL13 can be of diagnostic relevance in specific settings.

  17. Autoimmune pancreatitis with atypical imaging fi ndings that mimicked an endocrine tumor

    Institute of Scientific and Technical Information of China (English)

    Cindy; Neuzillet; Céline; Lepère; Mostafa; El; Hajjam; Laurent; Palazzo; Monique; Fabre; Hajer; Turki; Pascal; Hammel; Philippe; Rougier; Emmanuel; Mitry

    2010-01-01

    Autoimmune pancreatitis(AIP) is a rare cause of recurrent acute pancreatitis or chronic pancreatitis in middleaged patients,and is characterised by a marked infiltration of lymphocytes and plasma cells in pancreatic tissue.Diagnosis of focal forms can be diff icult as AIP may mimic pancreatic adenocarcinoma.Pediatric cases of AIP are exceptional.We report the case of a 15-yearold girl who had a focal AIP and associated cholangitis,with a very unusual vascularized mass that mimicked a pancreatic endocrine tu...

  18. IgG4-Seronegative Autoimmune Pancreatitis and Sclerosing Cholangitis

    Directory of Open Access Journals (Sweden)

    Allon Kahn

    2015-01-01

    Full Text Available IgG4-related disease is a relatively novel clinical entity whose gastrointestinal manifestations include type 1 autoimmune pancreatitis (AIP and IgG4-associated sclerosing cholangitis. The presence of elevated serum IgG4 is suggestive but not essential for the diagnosis of type 1 AIP and is a pervasive feature of the proposed diagnostic criteria. The differential diagnosis of type 1 AIP includes malignant conditions, emphasizing the importance of a deliberate, comprehensive evaluation. Management of patients with a suggestive clinical presentation, but without serum IgG4 elevation, is difficult. Here we present three cases of IgG4-seronegative AIP and sclerosing cholangitis that responded to empiric steroid therapy and discuss approach considerations. These cases demonstrate the value of meticulous application of existing diagnostic algorithms to achieve a clinical diagnosis and avoid surgical intervention.

  19. Renal lesions associated with autoimmune pancreatitis: CT findings

    International Nuclear Information System (INIS)

    Background: Autoimmune pancreatitis (AIP) is a chronic inflammatory condition characterized by IgG4-positive plasma cells. Recent evidence suggests that it is a systemic disease affecting various organs. Tubulointerstitial nephritis has been reported in association with AIP. Purpose: To investigate the incidence and types of renal involvement in patients with AIP. Material and Methods: Eighteen patients with no history of renal disease and a diagnosis of AIP (on the basis of histopathologic findings or a combination of characteristic imaging features, increased serum IgG4 levels, and response to steroid treatment) were included. All patients underwent computed tomography (CT) imaging and follow-up ranged from 6 months to 2 years. CT images were reviewed for the presence of renal lesions. Results: Seven patients had renal involvement (38.8%). None of the lesions was visible on non-contrast-enhanced CT scan. Parenchymal lesions appeared as multiple nodules showing decreased enhancement (four cases). Pyelonephritis, lymphoma, and metastases were considered in the differential diagnosis. An ill-defined low-attenuation mass-like lesion was found in one patient, while diffuse thickening of the renal pelvis wall was evident in the last two cases. Renal lesions regressed in all patients after steroid treatment, the larger one leaving a fibrous cortical scar. Conclusion: Different types of renal lesions in patients with AIP are relatively common, appearing as multiple nodules with decreased enhancement. These findings support the proposed concept of an IgG4-related systemic disease. Autoimmune disease should be suspected in cases of renal involvement in association with pancreatic focal or diffuse enlargement.

  20. Renal lesions associated with autoimmune pancreatitis: CT findings

    Energy Technology Data Exchange (ETDEWEB)

    Triantopoulou, Charikleia; Maniatis, Petros; Siafas, Ioannis; Papailiou, John (CT and Radiology Dept., ' Konstantopouleion' General Hospital, Athens (Greece)), e-mail: ctriantopoulou@gmail.com; Malachias, George; Anastopoulos, John (Radiology Dept., ' Sismanogleio' General Hospital, Athens (Greece))

    2010-07-15

    Background: Autoimmune pancreatitis (AIP) is a chronic inflammatory condition characterized by IgG4-positive plasma cells. Recent evidence suggests that it is a systemic disease affecting various organs. Tubulointerstitial nephritis has been reported in association with AIP. Purpose: To investigate the incidence and types of renal involvement in patients with AIP. Material and Methods: Eighteen patients with no history of renal disease and a diagnosis of AIP (on the basis of histopathologic findings or a combination of characteristic imaging features, increased serum IgG4 levels, and response to steroid treatment) were included. All patients underwent computed tomography (CT) imaging and follow-up ranged from 6 months to 2 years. CT images were reviewed for the presence of renal lesions. Results: Seven patients had renal involvement (38.8%). None of the lesions was visible on non-contrast-enhanced CT scan. Parenchymal lesions appeared as multiple nodules showing decreased enhancement (four cases). Pyelonephritis, lymphoma, and metastases were considered in the differential diagnosis. An ill-defined low-attenuation mass-like lesion was found in one patient, while diffuse thickening of the renal pelvis wall was evident in the last two cases. Renal lesions regressed in all patients after steroid treatment, the larger one leaving a fibrous cortical scar. Conclusion: Different types of renal lesions in patients with AIP are relatively common, appearing as multiple nodules with decreased enhancement. These findings support the proposed concept of an IgG4-related systemic disease. Autoimmune disease should be suspected in cases of renal involvement in association with pancreatic focal or diffuse enlargement.

  1. Autoimmune pancreatitis results from loss of TGFβ signalling in S100A4-positive dendritic cells

    OpenAIRE

    Boomershine, C S; Chamberlain, A; Kendall, P.; Afshar-Sharif, A-R; Huang, H; Washington, M.K.; Lawson, W.E.; Thomas, J. W.; Blackwell, T S; Bhowmick, N A

    2009-01-01

    Background and aims: Autoimmune pancreatitis (AIP) is a poorly understood human disease affecting the exocrine pancreas. The goal of the present study was to elucidate the pathogenic mechanisms underlying pancreatic autoimmunity in a murine disease model. Methods: A transgenic mouse with an S100A4/fibroblast-specific protein 1 (FSP1) Cre-mediated conditional knockout of the transforming growth factor β (TGFβ) type II receptor, termed Tgfbr2 fspKO , was used to determine the direct role of TGF...

  2. Pancreatic duct abnormalities in focal autoimmune pancreatitis: MR/MRCP imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Negrelli, Riccardo; Manfredi, Riccardo; Pedrinolla, Beatrice; Boninsegna, Enrico; Ventriglia, Anna; Mehrabi, Sara; Pozzi Mucelli, Roberto [G.B. Rossi University Hospital, University of Verona, Department of Radiology, Verona (Italy); Frulloni, Luca [Universita di Verona, Department of Gastroenterology, Policlinico G.B. Rossi, Verona (Italy)

    2014-08-09

    To evaluate the magnetic resonance (MR) imaging-MR cholangiopancreatographic (MRCP) findings of focal forms of autoimmune pancreatitis (AIP) to describe ductal involvement at diagnosis. MR examinations of 123 patients affected by AIP were analysed. We included 26 patients who satisfied International Consensus Diagnostic Criteria and were suffering from focal AIP. Image analysis included: site of parenchymal enlargement, main pancreatic duct (MPD) diameter, MPD stenosis, stricture length, presence of upstream dilation within the stricture, signal intensity, and pancreatic enhancement. Signal intensity abnormalities were localized in the head in 10/26 (38.5 %) and in the body-tail in 16/26 (61.5 %) patients. MRCP showed a single MPD stenosis in 12/26 (46.1 %) and multiple MPD stenosis in 14/26 (53.8 %) patients, without a dilation of the upstream MPD (mean: 3.83 mm). Lesions showed hypointensity on T1-weighted images in all patients, and hyperintensity on T2-weighted images in 22/26 (84.6 %) patients. The affected parenchyma was hypovascular during the arterial phase in 25/26 (96.2 %) patients with contrast retention. MR-MRCP are effective techniques for the diagnosis of AIP showing the loss of the physiological lobulation and the typical contrastographic appearance. The presence of multiple, long stenoses without an upstream MPD dilation at MRCP suggests the diagnosis of AIP, and can be useful in differential diagnosis of pancreatic adenocarcinoma. (orig.)

  3. Renal Cell Carcinoma Mimicking Igg4-Related Pseudotumor in Autoimmune Pancreatitis

    Directory of Open Access Journals (Sweden)

    Muhammad Ali Khan

    2014-09-01

    Full Text Available Context Autoimmune pancreatitis is classified into two distinct clinical profiles. Care report Type 1 autoimmunepancreatitis (AIP is considered to be a manifestation of a novel clinicopathological entity called IgG4 related sclerosingdisease, diagnosed using the Mayo Clinic HISORt criteria. Extra-pancreatic manifestations can include involvement of bileducts, salivary gland, lung nodules, thyroiditis, tubulointerstitial nephritis, renal masses, and retroperitoneal fibrosis. Type2 autoimmune pancreatitis on the other hand is confirmed by histologically seen duct centric pancreatitis without elevationof IgG4 or involvement of other organs. In type 1 autoimmune pancreatitis, extrapancreatic manifestations like bile ductstrictures, tubulointerstitial nephritis, renal nodules, retroperitoneal fibrosis respond to steroid therapy. Conclusion Wepresent a case of type 1 autoimmune pancreatitis in which the renal mass did not respond to steroid therapy and was later on found to be renal cell carcinoma. To the best of our knowledge this is only the third reported case of autoimmune pancreatitis in which the patient had renal cell carcinoma. Our case highlights the importance of close follow up of lesions that do not respond to steroid treatment which in this case proved to be renal cell cancer.

  4. Are Dysregulated Inflammatory Responses to Commensal Bacteria Involved in the Pathogenesis of Hepatobiliary-Pancreatic Autoimmune Disease? An Analysis Using Mice Models of Primary Biliary Cirrhosis and Autoimmune Pancreatitis

    OpenAIRE

    Naoko Yanagisawa; Ikuko Haruta; Ken Kikuchi; Noriyuki Shibata; Junji Yagi

    2011-01-01

    The etiopathogenesis of many autoimmune disorders has not been identified. The aim of this paper is to focus on the involvement of bacterial exposure in the pathogenesis of primary biliary cirrhosis (PBC) and autoimmune pancreatitis (AIP), both of which are broadly categorized as autoimmune disorders involving hepatobiliary-pancreatic lesions. Avirulent and/or commensal bacteria, which may have important role(s) as initiating factors in the pathogenesis of autoimmune disorders such as PBC and...

  5. Autoimmune pancreatitis metachronously associated with retroperitoneal fibrosis with IgG4-positive plasma cell infiltration

    Institute of Scientific and Technical Information of China (English)

    Terumi Kamisawa; Pong Yui Chen; Yuyang Tu; Hitoshi Nakajima; Naoto Egawa

    2006-01-01

    Retroperitoneal fibrosis is an uncommon disorder characterized by the formation of a dense plaque of fibrous tissue in the retroperitoneum, and its etiology remains unknown. Autoimmune pancreatitis is a rare type of chronic pancreatitis characterized by fibrosis with abundant infiltration of IgG4-positive plasma cells and lymphocytes and obliterative phlebitis in the pancreas. We present a case of autoimmune pancreatitis that developed 10 mo after the occurrence of retroperitoneal fibrosis. Histological findings of the resected retroperitoneal mass were marked periureteral fibrosis with abundant infiltration of IgG4-positive plasma cells and lymphocytes and obliterative phlebitis.These findings suggest a common pathophysiological mechanism for retroperitoneal fibrosis and autoimmune pancreatitis in this case. Some cases of retroperitoneal fibrosis might be a retroperitoneal lesion of IgG4-related sclerosing disease.

  6. Autoimmune pancreatitis results from loss of TGFβ signalling in S100A4-positive dendritic cells

    Science.gov (United States)

    Boomershine, C S; Chamberlain, A; Kendall, P; Afshar-Sharif, A-R; Huang, H; Washington, M K; Lawson, W E; Thomas, J W; Blackwell, T S; Bhowmick, N A

    2009-01-01

    Background and aims: Autoimmune pancreatitis (AIP) is a poorly understood human disease affecting the exocrine pancreas. The goal of the present study was to elucidate the pathogenic mechanisms underlying pancreatic autoimmunity in a murine disease model. Methods: A transgenic mouse with an S100A4/fibroblast-specific protein 1 (FSP1) Cre-mediated conditional knockout of the transforming growth factor β (TGFβ) type II receptor, termed Tgfbr2fspKO, was used to determine the direct role of TGFβ in S100A4+ cells. Immunohistochemical studies suggested that Tgfbr2fspKO mice develop mouse AIP (mAIP) characterised by interlobular ductal inflammatory infiltrates and pancreatic autoantibody production. Fluorescence-activated cell sorting (FACS)-isolated dendritic cells (DCs) from diseased pancreata were verified to have S100A4-Cre-mediated DNA recombination. Results: The Tgfbr2fspKO mice spontaneously developed mAIP by 6 weeks of age. DCs were confirmed to express S100A4, a previously reported protein expressed by fibroblasts. Adoptive transfer of bone marrow-derived DCs from Tgfbr2fspKO mice into 2-week-old syngenic wild-type C57BL/6 mice resulted in reproduction of pancreatitis within 6 weeks. Similar adoptive transfer of wild-type DCs had no effect on pancreas pathology of the host mice. The inability to induce pancreatitis by adoptive transfer of Tgfbr2fspKO DCs in adult mice suggested a developmental event in mAIP pathogenesis. Tgfbr2fspKO DCs undergo elevated maturation in response to antigen and increased activation of naïve CD4-positive T cells. Conclusion: The development of mAIP in the Tgfbr2fspKO mouse model illustrates the role of TGFβ in maintaining myeloid DC immune tolerance. The loss of immune tolerance in myeloid S100A4+ DCs can mediate mAIP and may explain some aspects of AIP disease pathogenesis. PMID:19625278

  7. Gene expression profiling in autoimmune diseases

    DEFF Research Database (Denmark)

    Bovin, Lone Frier; Brynskov, Jørn; Hegedüs, Laszlo;

    2007-01-01

    A central issue in autoimmune disease is whether the underlying inflammation is a repeated stereotypical process or whether disease specific gene expression is involved. To shed light on this, we analysed whether genes previously found to be differentially regulated in rheumatoid arthritis (RA...... differences in peripheral blood mononuclear cell (MNC) gene expression patterns between 15 newly diagnosed HT patients and 15 matched healthy controls. However, the MNC expression levels of five genes were significantly upregulated in 25 IBD patients, compared to 18 matched healthy controls (CD14, FACL2, FCN1...... immunoinflammatory diseases, but only if accompanied by pronounced systemic manifestations. This suggests that at least some of the genes activated in RA are predominantly or solely related to general and disease-nonspecific autoimmune processes...

  8. An unusual case of autoimmune pancreatitis presenting as pancreatic mass and obstructive jaundice: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Conley Barbara A

    2011-06-01

    Full Text Available Abstract Background Autoimmune pancreatitis is a rare chronic inflammatory pancreatic disease that is increasingly being diagnosed worldwide. As a result of overlap in clinical and radiological features, it is often misdiagnosed as pancreatic cancer. We report the case of a patient with autoimmune pancreatitis that was initially misdiagnosed as pancreatic cancer. Case presentation A 31-year-old Caucasian man presented to our hospital with epigastric pain, jaundice and weight loss. His CA 19-9 level was elevated, and computed tomography and endoscopic ultrasound revealed a pancreatic head mass abutting the portal vein. Endoscopic retrograde cholangiopancreaticography showed narrowing of the biliary duct and poor visualization of the pancreatic duct. Fine-needle aspiration biopsy revealed atypical ductal epithelial cells, which raised clinical suspicion of adenocarcinoma. Because of the patient's unusual age for the onset of pancreatic cancer and the acuity of his symptoms, he was referred to a tertiary care center for further evaluation. His immunoglobulin G4 antibody level was 365 mg/dL, and repeat computed tomography showed features typical of autoimmune pancreatitis. The patient's symptoms resolved with corticosteroid therapy. Conclusion Autoimmune pancreatitis is a rare disease with an excellent response to corticosteroid therapy. Its unique histological appearance and response to corticosteroid therapy can reduce unnecessary surgical procedures. A thorough evaluation by a multidisciplinary team is important in rendering the diagnosis of autoimmune pancreatitis.

  9. Autoimmune pancreatitis: Assessment of the enhanced duct sign on multiphase contrast-enhanced computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Kawai, Yuichi, E-mail: kawai.yuichi@a.mbox.nagoya-u.ac.jp [Department of Radiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Suzuki, Kojiro, E-mail: kojiro@med.nagoya-u.ac.jp [Department of Radiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Itoh, Shigeki, E-mail: shigeito@nagoya-1st.jrc.or.jp [Department of Diagnostic Radiology, Japan Red Cross Nagoya Daiichi Hospital, 3-35 Michishita-cho, Nakamura-ku, Nagoya 453-8511 (Japan); Takada, Akira, E-mail: takadaa@med.nagoya-u.ac.jp [Department of Radiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Mori, Yoshine, E-mail: yoshine@med.nagoya-u.ac.jp [Department of Radiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Naganawa, Shinji, E-mail: naganawa@med.nagoya-u.ac.jp [Department of Radiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan)

    2012-11-15

    Purpose: To assess the usefulness of the computed tomography (CT) finding of main pancreatic duct (MPD) wall enhancement, termed the 'enhanced duct sign', for diagnosis of autoimmune pancreatitis (AIP) in comparison with diagnosis of pancreatic carcinoma and chronic pancreatitis. Materials and methods: Two radiologists independently evaluated the presence or absence of the enhanced duct sign on multiphase contrast-enhanced CT in patients with AIP (n = 55), pancreatic carcinoma (n = 50), and chronic pancreatitis (n = 50). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of AIP were calculated. In patients demonstrating the enhanced duct sign, additional findings were evaluated by consensus. Results: The enhanced duct sign was more frequently observed in patients with AIP (37/55, 67%) than in patients with pancreatic carcinoma (5/50, 10%) or chronic pancreatitis (0/50, 0%) (P < 0.05). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the finding were 0.67, 0.95, 0.85, 0.88, and 0.84, respectively. In AIP, the lumen within the enhanced duct was completely or partially invisible in 29 of 37 (78%) patients, and the enhanced duct was observed within the affected pancreatic parenchyma in 35 of 37 (95%) patients. In pancreatic carcinoma, the lumen within the enhanced duct was visible in all patients (5/5, 100%), and the enhanced duct was observed downstream of the tumor (5/5, 100%). Conclusion: The enhanced duct sign is highly specific of AIP.

  10. Mycophenolate mofetil for maintenance of remission in steroid-dependent autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Jamie B Sodikoff; Steven A Keilin; Qiang cai; Sheila J Bharmal; Melinda M Lewis; Gottumukkala S Raju; Field F Willingham

    2012-01-01

    Systemic corticosteroids represent the standard treatment for autoimmune pancreatitis with IgG4-associated cholangitis.For steroid-dependent disease,azathioprine has been used for maintenance of remission.Mycophenolate mofetil has been used for transplant immunosuppression and more recently for autoimmune hepatitis; however,there are no case reports to date on the use of mycophenolate mofetil in adult patients with autoimmune pancreatitis.A patient with IgG4-mediated autoimmune pancreatitis and IgG4-associated cholangitis refractory to steroids and intolerant of azathioprine was treated with mycophenolate mofetil,which inhibits de novo guanosine synthesis and blockade of both B and T lymphocyte production.Introduction of mycophenolate mofetil and uptitration to 1000 mg by mouth twice daily over a treatment period of 4 mo was associated with improvement in the patient's energy level and blood glucose control and was not associated with any adverse events.The patient was managed without a biliary stent.However,there was a return of symptoms,jaundice,increase in transaminases,and hyperbilirubinemia when the prednisone dose reached 11 mg per day.In the first report of mycophenolate mofetil use in an adult patient with IgG4-associated autoimmune pancreatitis and IgG4-associated cholangitis,the introduction of mycophenolate mofetil was safe and well-tolerated without adverse events,but it did not enable discontinuation of the steroids.Mycophenolate mofetil and other immunomodulatory therapies should continue to be studied for maintenance of remission in the large subset of patients with refractory or recurrent autoimmune pancreatitis.

  11. Diagnosis and differential diagnosis value of magnetic resonance imaging in autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    汪建华

    2014-01-01

    Objective To investigate the diagnosis and differential diagnosis value of multi-sequences magnetic resonance imaging(MRI)in autoimmune pancreatitis(AIP).Methods The MRI data of twelve AIP patients were retrospectively analyzed.The sequences of MRI included T1-weighted imaging,T2-weighted imaging,magnetic resonance cholangiopancreatography(MRCP),diffusionweighted imaging(DWI)and dynamic enhancement ima-

  12. Autoimmune Pancreatitis and IgG4 Related Disease in Three Children

    Science.gov (United States)

    Chong, Sze Yee; Coleman, Lee; MacGregor, Duncan; Hardikar, Winita; Oliver, Mark R.

    2016-01-01

    We report 3 children who presented with fever and abdominal pain, deranged liver function tests, and on abdominal ultrasound were found to have an enlarged pancreas, substantial abdominal lymphadenopathy, and extrahepatic biliary duct dilatation. After ruling out malignancy, probable immunoglobulin G4-related disease (IgG4RD) associated with autoimmune pancreatitis was considered. This condition was first described in the adults and often mimics pancreatic cancer. It can involve multiple organs, either synchronously or metachronously, and is rarely reported in children. The disorder mostly responds to corticosteroid therapy and other immune suppression. We highlight the difficulty in diagnosing autoimmune pancreatitis/IgG4-related disease in children and illustrate the difference between pediatric and adult presentation. PMID:27622194

  13. Autoimmune Pancreatitis and IgG4 Related Disease in Three Children.

    Science.gov (United States)

    Bolia, Rishi; Chong, Sze Yee; Coleman, Lee; MacGregor, Duncan; Hardikar, Winita; Oliver, Mark R

    2016-07-01

    We report 3 children who presented with fever and abdominal pain, deranged liver function tests, and on abdominal ultrasound were found to have an enlarged pancreas, substantial abdominal lymphadenopathy, and extrahepatic biliary duct dilatation. After ruling out malignancy, probable immunoglobulin G4-related disease (IgG4RD) associated with autoimmune pancreatitis was considered. This condition was first described in the adults and often mimics pancreatic cancer. It can involve multiple organs, either synchronously or metachronously, and is rarely reported in children. The disorder mostly responds to corticosteroid therapy and other immune suppression. We highlight the difficulty in diagnosing autoimmune pancreatitis/IgG4-related disease in children and illustrate the difference between pediatric and adult presentation. PMID:27622194

  14. Analysis of VH gene rearrangement and somatic hypermutation in type 1 autoimmune pancreatitis.

    Science.gov (United States)

    Okumura, Fumihiro; Sakuma, Hidenori; Nakazawa, Takahiro; Hayashi, Kazuki; Naitoh, Itaru; Miyabe, Katsuyuki; Yoshida, Michihiro; Yamashita, Hiroaki; Ohara, Hirotaka; Inagaki, Hiroshi; Joh, Takashi

    2012-05-01

    Type 1 autoimmune pancreatitis (AIP) is the pancreatic manifestation of systemic fibroinflammatory disease called immunoglobulin G4-associated systemic disease. Although this inflammatory process is considered to be a disease with an autoimmune mechanism, its pathogenesis still remains unclear. To clarify the characteristics of B cells infiltrating the lesion, we analyzed the immunoglobulin heavy chain variable region (VH) gene rearrangement and somatic hypermutation of invasive lymphoid cells in type 1 AIP (n= 3), in comparison with obstructive pancreatitis (n= 3) as a control. DNA was extracted from the affected inflammatory lesions. After PCR amplification of the rearranged VH gene, the clones were subcloned, and recombinant clones were randomly selected and sequenced. More than 60 clones per case were analyzed. Monoclonal VH rearrangement was not detected in any of the cases examined. There was no VH family or VH fragment specific to type 1 AIP and obstructive pancreatitis. However, the rate of unmutated VH fragments in type 1 AIP (17%) was higher than that in obstructive pancreatitis (5.1%) (P= 0.010). Our study suggests that an increased rate of unmutated or less mutated VH genes may be characteristic of type 1 AIP and might play a role in the development of this disease.

  15. Localized 18F-fluorodeoxyglucose uptake at the pancreatic head during remission phase of autoimmune pancreatitis: A case report

    Science.gov (United States)

    Yonenaga, Yoshikuni; Kushihata, Fumiki; Watanabe, Jota; Tohyama, Taiji; Inoue, Hitoshi; Sugita, Atsuro; Takada, Yasutsugu

    2016-01-01

    Autoimmune pancreatitis (AIP) is a unique form of pancreatitis, histopathologically characterized by dense lymphoplasmacytic infiltration and fibrosis of the pancreas with obliterative phlebitis. AIP is associated with a good response to steroid therapy. Differentiation between AIP and pancreatic cancer to determine a preoperative diagnosis is often challenging, despite the use of various diagnostic modalities, including computed tomography (CT), magnetic resonance imaging and endoscopic retrograde cholangiopancreatography. It has been reported that 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/CT may be a useful tool for distinguishing between the two diseases. In the present case report, a 71-year-old male patient presented with a well-circumscribed, solitary, nodular and homogenous 18F-FDG uptake at the pancreatic head, while receiving maintenance steroid therapy in the remission phase of AIP; preoperatively, the patient had been strongly suspected of having pancreatic cancer. Pathological examination revealed post-treatment relapse of AIP. The present case highlights the diagnostic and management difficulties with AIP in the remission phase. In certain cases, it remains challenging to differentiate the two diseases, even using the latest modalities.

  16. Review of the diagnosis,classification and management of autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Derek; A; O’Reilly; Deep; J; Malde; Trish; Duncan; Madhu; Rao; Rafik; Filobbos

    2014-01-01

    Autoimmune pancreatitis(AIP)is a rare form of chronic pancreatitis,with as yet undetermined incidence and prevalence in the general population.Our understanding of it continues to evolve.In the last few years,2separate subtypes have been identified:type 1 AIP has been recognised as the pancreatic manifestation of a multiorgan disease,named immunoglobulin G4(IgG4)-related disease while type 2 AIP is a pancreas specific disorder not associated with IgG4.International criteria for the diagnosis of AIP have been defined:the HISORt criteria from the Mayo clinic,the Japan consensus criteria and,most recently,the international association of pancreatology"International Consensus Diagnostic Criteria".Despite this,in clinical practice it can still be very difficult to confirm the diagnosis and differenti-ate AIP from a pancreatic cancer.There are no large studies into the long-term prognosis and management of relapses of AIP,and there is even less information at present regarding the Type 2 AIP subtype.Further studies are necessary to clarify the pathogenesis,treatment and long-term outcomes of this disease.Critically for clinicians,making the correct diagnosis and differentiating the disease from pancreatic cancer is of the utmost importance and the greatest challenge.

  17. CT findings in autoimmune pancreatitis: assessment using multiphase contrast-enhanced multisection CT

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, K., E-mail: Kojiro@med.nagoya-u.ac.j [Department of Radiology, Nagoya University Graduate School of Medicine, Nagoya (Japan); Itoh, S. [Department of Radiology, Nagoya Hirokoji Clinic, Nagoya (Japan); Nagasaka, T. [Departments of Medical Technology, Nagoya University School of Health Science, Nagoya (Japan); Ogawa, H.; Ota, T.; Naganawa, S. [Department of Radiology, Nagoya University Graduate School of Medicine, Nagoya (Japan)

    2010-09-15

    Aim: To assess the spectrum of findings using multiphase contrast-enhanced computed tomography (CT) in patients with autoimmune pancreatitis (AIP). Materials and methods: Fifty patients (four female and 46 male, mean age 65 years) were retrospectively identified from consecutive patients with abnormal CT findings of the pancreas and negative work-up for known causes. These patients had at least one finding supporting the diagnosis of AIP: serological abnormality, histopathological abnormality, or response to steroid. Two radiologists evaluated multiphase contrast-enhanced CT images in consensus. Results: The pancreas showed diffuse enlargement (n = 16; 32%), focal enlargement (n = 18; 36%), or no enlargement (n = 16; 32%). Forty-nine (98%) patients showed abnormal contrast enhancement in the affected pancreatic parenchyma, including hypoattenuation during the pancreatic phase (n = 45; 90%) and hyperattenuation during the delayed phase (n = 39; 87%). The following findings were also seen in the pancreas: a capsule-like rim (n = 24; 48%); no visualization of the main pancreatic duct lumen (n = 48; 96%); ductal enhancement (n = 26; 52%); upstream dilatation of the main pancreatic duct (n = 27; 54%); upstream atrophy of the pancreatic parenchyma (n = 27; 54%); calcification (n = 7; 14%); and cysts (n = 5; 10%). Forty-two (84%) patients showed one or more of the following extrapancreatic findings: biliary duct or gallbladder abnormality (n = 40; 80%); peripancreatic (n = 8; 16%) or para-aortic (n = 10; 20%) soft-tissue proliferation; and renal involvement (n = 15; 30%). Conclusion: Patients with AIP presented with a variety of CT findings in the pancreas and the extrapancreatic organs. The present study highlights pancreatic ductal enhancement in a subset of patients with AIP.

  18. Differentiation of focal-type autoimmune pancreatitis from pancreatic carcinoma: assessment by multiphase contrast-enhanced CT

    Energy Technology Data Exchange (ETDEWEB)

    Furuhashi, Naohiro; Suzuki, Kojiro; Sakurai, Yusuke; Naganawa, Shinji [Nagoya University Graduate School of Medicine, Department of Radiology, Nagoya (Japan); Ikeda, Mitsuru [Nagoya University Graduate School of Medicine, Department of Radiological Technology, Nagoya (Japan); Kawai, Yuichi [Japanese Red Cross Nagoya Daiichi Hospital, Department of Diagnostic Radiology, Nagoya (Japan)

    2015-05-01

    To evaluate the utility of multiphase contrast-enhanced computed tomography (CT) findings alone and in combination for differentiating focal-type autoimmune pancreatitis (f-AIP) from pancreatic carcinoma (PC). The study group comprised 22 f-AIP lesions and 61 PC lesions. Two radiologists independently evaluated CT findings. Frequencies of findings were compared between f-AIP and PC. Statistical, univariate and multivariate analyses were performed. Homogeneous enhancement during the portal phase (AIP, 59 % vs. PC, 3 %; P < 0.001), dotted enhancement during the pancreatic phase (50 % vs. 7 %; P < 0.001), duct-penetrating sign (46 % vs. 2 %; P < 0.001), enhanced duct sign (36 % vs. 2 %; P < 0.001) and capsule-like rim (46 % vs. 3 %; P < 0.001) were more frequently observed in AIP. Ring-like enhancement during the delayed phase (5 % vs. 46 %; P < 0.001) and peripancreatic strands with a length of at least 10 mm (5 % vs. 39 %; P = 0.001) were more frequently observed in PC. AIP was identified with 82 % sensitivity and 98 % specificity using four of these seven findings. Multivariate analysis revealed significant differences in dotted enhancement (P = 0.004), duct-penetrating sign (P < 0.001) and capsule-like rim (P = 0.007). The combination of CT findings may allow improvements in differentiating f-AIP from PC. (orig.)

  19. Pyogenic liver abscess after choledochoduodenostomy for biliary obstruction caused by autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Nobuyuki Toshikuni; Hirofumi Morishita; Koichi Uesaka; Shiro Yuasa; Kyohei Kai; Shizo Sato; Motoko Kitano; Masayoshi Fujisawa; Hiroaki Okushin; Kazuhiko Morii; Shinjiro Takagi; Masahiro Takatani

    2006-01-01

    A 68-year-old man underwent cholecystectomy and choledochoduodenostomy for biliary obstruction and nephrectomy for a renal tumor. Based on clinical and histopathologic findings, autoimmune pancreatitis (AIP) was diagnosed. The renal tumor was diagnosed as a renal cell cancer. Steroid therapy was started and thereafter pancreatic inflammation improved. Five years after surgery, the patient was readmitted because of pyrexia in a preshock state. A Klebsiella pneumoniae liver abscess complicated by sepsis was diagnosed. The patient recovered with percutaneous abscess drainage and administration of intravenous antibiotics. Liver abscess recurred 1 mo later but was successfully treated with antibiotics. There has been little information on long-term outcomes of patients with AIP treated with surgery. To our knowledge, this is the second case of liver abscess after surgical treatment of AIP.

  20. Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model.

    Science.gov (United States)

    Zhang, Baihao; Chikuma, Shunsuke; Hori, Shohei; Fagarasan, Sidonia; Honjo, Tasuku

    2016-07-26

    PD-1 (programmed-death 1), an immune-inhibitory receptor required for immune self-tolerance whose deficiency causes autoimmunity with variable severity and tissue specificity depending on other genetic factors, is expressed on activated T cells, including the transcription factor FoxP3(+) Treg cells known to play critical roles in maintaining immune tolerance. However, whether PD-1 expression by the Treg cells is required for their immune regulatory function, especially in autoimmune settings, is still unclear. We found that mice with partial FoxP3 insufficiency developed early-onset lympho-proliferation and lethal autoimmune pancreatitis only when PD-1 is absent. The autoimmune phenotype was rescued by the transfer of FoxP3-sufficient T cells, regardless of whether they were derived from WT or PD-1-deficient mice, indicating that Treg cells dominantly protect against development of spontaneous autoimmunity without intrinsic expression of PD-1. The absence of PD-1 combined with partial FoxP3 insufficiency, however, led to generation of ex-FoxP3 T cells with proinflammatory properties and expansion of effector/memory T cells that contributed to the autoimmune destruction of target tissues. Altogether, the results suggest that PD-1 and FoxP3 work collaboratively in maintaining immune tolerance mostly through nonoverlapping pathways. Thus, PD-1 is modulating the activation threshold and maintaining the balance between regulatory and effector T cells, whereas FoxP3 is sufficient for dominant regulation through maintaining the integrity of the Treg function. We suggest that genetic or environmental factors that even moderately affect the expression of both PD-1 and FoxP3 can cause life-threatening autoimmune diseases by disrupting the T-cell homeostasis. PMID:27410049

  1. Clinical analysis of high serum IgE in autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Kenji; Hirano; Minoru; Tada; Hiroyuki; Isayama; Kazumichi; Kawakubo; Hiroshi; Yagioka; Takashi; Sasaki; Hirofumi; Kogure; Yousuke; Nakai; Naoki; Sasahira; Takeshi; Tsujino; Nobuo; Toda; Kazuhiko; Koike

    2010-01-01

    AIM: To clarify the clinical significance of high serum IgE in autoimmune pancreatitis (AIP). METHODS: Forty-two AIP patients, whose IgE was measured before steroid treatment, were analyzed. To evaluate the relationship between IgE levels and the disease activity of AIP, we examined (1) Frequency of high IgE (> 170 IU/mL) and concomitant allergic dis-eases requiring treatment; (2) Correlations between IgG, IgG4, and IgE; (3) Relationship between the presence of extrapancreatic lesions and IgE; (4) Re-lation...

  2. Expression of CD44 in pancreatic cancer and its significance

    OpenAIRE

    Li, Xiao-Ping; Zhang, Xiao-Wei; Zheng, Lei-Zhen; Guo, Wei-Jian

    2015-01-01

    Background: CD44 is a potentially interesting prognostic marker and therapeutic target in pancreatic cancer. The expression of CD44 has been reported to correlate with poor prognosis of pancreatic cancer in most literatures. The purpose of this study is to investigate the roles of CD44 in pancreatic caner, and their correlation with the prognosis of pancreatic cancer patients. Methods: 67 pancreatic cancer samples were collected in Xinhua hospital affiliated to Shanghai Jiaotong University da...

  3. The role of endoscopic ultrasound (EUS) in relation to other imaging modalities in the differential diagnosis between mass forming chronic pancreatitis, autoimmune pancreatitis and ductal pancreatic adenocarcinoma Papel de la endoscopia en relación con otras modalidades de imagen en el diagnóstico diferencial entre pancreatitis crónica en forma de masa, pancreatitis autoinmune y adenocarcinoma pancreático

    OpenAIRE

    Julio Iglesias-García; Björn Lindkvist; José Lariño-Noia; J. Enrique Domínguez-Muñoz

    2012-01-01

    Differential diagnosis of solid pancreatic lesions remains as an important clinical challenge, mainly for the differentiation between mass forming chronic pancreatitis, autoimmune pancreatitis and pancreatic adenocarcinoma. Endoscopic ultrasound (EUS), computed tomography (CT) and magnetic resonance imaging (MRI) can all provide valuable and complementary information in this setting. Among them, EUS has the unique ability to obtain specimens for histopathological diagnosis and can therefore p...

  4. Diagnostic Dilemma in a Patient with Jaundice: How to Differentiate between Autoimmune Pancreatitis, Primary Sclerosing Cholangitis and Pancreas Carcinoma

    Directory of Open Access Journals (Sweden)

    Matthias Buechter

    2012-04-01

    Full Text Available A 68-year-old male patient was referred to our institution in May 2011 for a suspected tumor in the pancreatic head with consecutive jaundice. Using magnetic resonance imaging, further differentiation between chronic inflammation and a malignant process was not possible with certainty. Apart from cholestasis, laboratory studies showed increased values for CA 19-9 to 532 U/ml (normal <37 U/ml and hypergammaglobulinemia (immunoglobulin G, IgG of 19.3% (normal 8.0–15.8% with an elevation of the IgG4 subtype to 2,350 mg/l (normal 52–1,250 mg/l. Endoscopic retrograde cholangiopancreatography revealed a prominent stenosis of the distal ductus hepaticus communis caused by pancreatic head swelling and also a bihilar stenosis of the main hepatic bile ducts. Cytology demonstrated inflammatory cells without evidence of malignancy. Under suspicion of autoimmune pancreatitis with IgG4-associated cholangitis, immunosuppressive therapy with steroids and azathioprine was started. Follow-up endoscopic retrograde cholangiopancreatography after 3 months displayed regressive development of the diverse stenoses. Jaundice had disappeared and blood values had returned to normal ranges. Moreover, no tumor of the pancreatic head was present in the magnetic resonance control images. Due to clinical and radiological similarities but a consecutive completely different prognosis and therapy, it is of fundamental importance to differentiate between pancreatic cancer and autoimmune pancreatitis. Especially, determination of serum IgG4 levels and associated bile duct lesions induced by inflammation should clarify the diagnosis of autoimmune pancreatitis and legitimate immunosuppressive therapy.

  5. Abdominal extrapancreatic lesions associated with autoimmune pancreatitis: Radiological findings and changes after therapy

    International Nuclear Information System (INIS)

    Purpose: To evaluate imaging findings of abdominal extrapancreatic lesions associated with autoimmune pancreatitis (AIP) and changes after steroid therapy. Methods and materials: This study included nine AIP patients with abdominal extrapancreatic lesions, which were determined by retrospective radiological review. CT (initial and follow-up, n = 9) and MR imaging (initial, n = 5) were reviewed by two radiologists in consensus to determine imaging characteristics (i.e., size, number, attenuation or signal intensity, and contrast enhancement of the lesions, and the presence of overlying capsule retraction) and evaluate changes with steroid therapy of abdominal extrapancreatic lesions associated with AIP. Results: The most common abdominal extrapancreatic lesion associated with AIP was retroperitoneal fibrosis (RPF) in six patients. In five patients, CT and MR imaging revealed single or multiple, round- or wedge-shaped, hypoattenuating or hypointense, enhancing lesions in the renal cortex or pelvis. Other lesions included a geographic, ill-defined, hypoattenuating lesion with or without overlying capsule retraction in the liver in two and bile duct dilatation with or without bile duct wall thickening in four. Over a follow-up period of 6-81 months, CT exams of eight patients demonstrated partial or complete improvement of the abdominal extrapancreatic lesions, albeit their improvement in general lagged behind that of the pancreatic lesion. Conclusion: On CT or MR imaging, the abdominal extrapancreatic lesions associated with AIP are various in the retroperitoneum, liver, kidneys and bile ducts, and are reversible with steroid therapy

  6. Quantitative perfusion analysis in pancreatic contrast enhanced ultrasound (DCE-US): a promising tool for the differentiation between autoimmune pancreatitis and pancreatic cancer.

    Science.gov (United States)

    Vitali, F; Pfeifer, L; Janson, C; Goertz, R S; Neurath, M F; Strobel, D; Wildner, D

    2015-10-01

    In the work-up of focal pancreatic lesions autoimmune pancreatitis (AIP) is a rare differential diagnosis to pancreatic cancer (PC) with similar clinical constellations. The aim of our study was to compare differences between proven AIP and PC using transabdominal dynamic contrast enhanced ultrasound (DCE-US). Therefore we recorded 3-minute-clips of CEUS examinations and analyzed perfusion parameters with VueBox®-quantification software. To obtain DCE-US Parameters, Regions-of-Interest were selected within the lesions and the surrounding pancreas parenchyma, serving as reference tissue. We compared 3 patients with AIP (mean age: 58 years; lesion mean size: 40 mm) to 17 patients with PC (mean age: 68 years; lesion mean size: 35.9 mm). Significant differences between PC and parenchyma could be found in the following parameters: Peak-Enhancement (PE), Wash-in-and-Wash-out-AUC, Wash-in Perfusion-Index. PE of AIP was comparable to normal parenchyma. The relation of PE between parenchyma and lesion (ΔPE) AIP and PC was significantly different [AIP: 0.21 (±0.06); PC: 0.81 (±0.1); p<0.01]. PE of neoplastic lesions was significantly lower as AIP and normal parenchyma (p<0.01). Therefore perfusion analysis in DCE-US can help to differentiate hypovascular PC from AIP presenting nearly isovascular time intensity curves. Diagnostic accuracy of DCE-US in this setting has to be validated in future prospective studies in comparison to CT and MRI. PMID:26480053

  7. Pancreatitis

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    2010355 Oxymatrine enhances the expression of collagen I and α-SMA in rat chronic pancreatitis. WANG Yuliang(王昱良),et al. Dept Gastroenterol ,Huanghe Hosp,Sanmenxia 472000. World Chin J Digestol 2010;18(13):1331-36. Objective To investigate the treatment effects of oxymatrine (OM) against chronic pancreatitis in rats and to explore the potential

  8. Aberrant expression of Wnt antagonist SFRP1 in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    BU Xian-min; ZHAO Cheng-hai; DAI Xian-wei

    2008-01-01

    @@ Pancreatic cancer is one of the malignant tumor with a very poor prognosis. Both genetic and epigenetic alterations are involved in the pathogenetic mechanisms of pancreatic cancer. Hypermethylation and subsequent loss of expression of some tumor suppressor genes and tumor-related genes occur frequently in pancreatic cancer, such as loss of expression of pl6,1 RASSF1A,2 SOCS-1,3 and hMLH14 genes were repoted.

  9. Emodin promoted pancreatic claudin-5 and occludin expression in experimental acute pancreatitis rats

    Institute of Scientific and Technical Information of China (English)

    Xian-Ming Xia; Bang-Ku Li; Shi-Mei Xing; Hai-Ling Ruan

    2012-01-01

    AIM:To investigate the effect of emodin on pancreatic claudin-5 and occludin expression,and pancreatic paracellular permeability in acute pancreatitis (AP).METHODS:Experimental pancreatitis was induced by retrograde injection of 5% sodium taurocholate into the biliopancreatic duct.Emodin was injected via the external jugular vein 0 or 6 h after induction of AP.Rats from sham operation and AP groups were injected with normal saline at the same time.Samples of pancreas were obtained 6 or 12 h after drug administration.Pancreatic morphology was examined with hematoxylin and eosin staining.Pancreatic edema was estimated by measuring tissue water content.Tumor necrosis factor (TNF)-α and interleukin (IL)-6 level were measured by enzyme-linked immunosorbent assay.Pancreatic paracellular permeability was assessed by tissue dye extravasation.Expression of pancreatic claudin-5 and occludin was examined by immunohistology,quantitative real-time reverse transcriptase polymerase chain reaction and western blotting.RESULTS:Pancreatic TNF-α and IL-6 levels,wet/dry ratio,dye extravasation,and histological score were significantly elevated at 3,6 and 12 h following sodium taurocholate infusion; treatment with emodin prevented these changes at all time points.Immunostaining of claudin-5 and occludin was detected in rat pancreas,which was distributed in pancreatic acinar cells,ductal cells and vascular endothelial cells,respectively.Sodium taurocholate infusion significantly decreased pancreatic claudin-5 and occludin mRNA and protein levels at 3,6 and 12 h,and that could be promoted by intravenous administration of emodin at all time points.CONCLUSION:These results demonstrate that emodin could promote pancreatic claudin-5 and occludin expression,and reduce pancreatic paracellular permeability.

  10. Somatostatin receptor expression and biological functions in endocrine pancreatic cells: review based on a doctoral thesis.

    Science.gov (United States)

    Ludvigsen, Eva

    2007-01-01

    Type 1 diabetes is resulting from the selective destruction of insulin-producing betacells within the pancreatic islets. Somatostatin acts as an inhibitor of hormone secretion through specific receptors (sst1-5). All ssts were expressed in normal rat and mouse pancreatic islets, although the expression intensity and the co-expression pattern varied between ssts as well as between species. This may reflect a difference in response to somatostatin in islet cells of the two species. The Non-Obese Diabetic (NOD) mouse model is an experimental model of type 1 diabetes, with insulitis accompanied by spontaneous hyperglycaemia. Pancreatic specimens from NOD mice at different age and stage of disease were stained for ssts. The islet cells of diabetic NOD mice showed increased islet expression of sst2-5 compared to normoglycemic NOD mice. The increase in sst2-5 expression in the islets cells may suggest either a contributing factor in the process leading to diabetes, or a defense response against ongoing beta-cell destruction. Somatostatin analogues were tested on a human endocrine pancreatic tumour cell line and cultured pancreatic islets. Somatostatin analogues had an effect on cAMP accumulation, chromogranin A secretion and MAP kinase activity in the cell line. Treatment of rat pancreatic islets with somatostatin analogues with selective receptor affinity was not sufficient to induce an inhibition of insulin and glucagon secretion. However, a combination of selective analogues or non-selective analogues via costimulation of receptors can cause inhibition of hormone production. For insulin and glucagon, combinations of sst2 + sst5 and sst1 + sst2, respectively, showed a biological effect. In summary, knowledge of islet cell ssts expression and the effect of somatostatin analogues with high affinity to ssts may be valuable in the future attempts to influence beta-cell function in type 1 diabetes mellitus, since down-regulation of beta-cell function may promote survival of

  11. Pancreas duodenal homeobox-1 expression and significance in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Tao Liu; Shan-Miao Gou; Chun-You Wang; He-Shui Wu; Jiong-Xin Xiong; Feng Zhou

    2007-01-01

    AIM: To study the correlations of Pancreas duodenal homeobox-1 with pancreatic cancer characteristics,incluling pathological grading, TNM grading, tumor metastasis and tumor cell proliferation.METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect PDX-1 mRNA expression in pancreatic cancer tissue and normal pancreatic tissue. The expression of PDX-1 protein was measured by Western blot and immunohistochemistry.Immunohistochemistry was also used to detect proliferative cell nuclear antigen (PCNA). Correlations of PDX-1 with pancreatic cancer characteristics, including pathological grading, TNM grading, tumor metastasis and tumor cell proliferation, were analyzed by using χ2 test.RESULTS: Immunohistochemistry showed that 41.1% of pancreatic cancers were positive for PDX-1 expression,but normal pancreatic tissue except islets showed no staining for PDX-1. In consistent with the result of imunohistochemistry, Western blot showed that 37.5% of pancreatic cancers were positive for PDX-1. RT-PCR showed that PDX-1 expression was significantly higher in pancreatic cancer tissues than normal pancreatic tissues (2-3.56 ± 0.35 vs 2-8.76 ± 0.14, P< 0.01). Lymph node metastasis (P < 0.01), TNM grading (P < 0.05), pathological grading (P < 0.05) and tumor cell proliferation (P < 0.01) were significantly correlated with PDX-1 expression levels.CONCLUSION: PDX-1 is re-expressed in pancreatic cancer, and PDX-1-positive pancreatic cancer cells show more malignant potential compared to PDX-1-negative cells. Therefore, PDX-1-positive cells may be tumor stem cells and PDX-1 may act as alternate surface marker of pancreatic cancer stem cells.

  12. Autoimmune Oophoritis with Multiple Molecular Targets Mitigated by Transgenic Expression of Mater

    OpenAIRE

    Otsuka, Noriyuki; Tong, Zhi-Bin; Vanevski, Konstantina; Tu, Wei; Cheng, Mickie H.; Nelson, Lawrence M.

    2011-01-01

    Transgenic expression of the MATER autoantigen in antigen-presenting cells significantly mitigates autoimmune oophoritis in mice with implications for diagnosis and tolerance induction in human autoimmune primary ovarian insufficiency.

  13. Allergic diseases, immunoglobulin E, and autoimmune pancreatitis: a retrospective study of 22 patients

    Institute of Scientific and Technical Information of China (English)

    Zhang Li; Guo Limei; Huang Yonghui; Wang Tianli; Shi Xueying; Chang Hong; Yao Wei

    2014-01-01

    Background Autoimmune pancreatitis (ALP) is a chronic inflammatory disease of pancreas.We evaluated the clinical manifestations,imaging,and histological presentations of AlP in Chinese patients,and investigated the roles of immunoglobulin E (IgE) and allergic diseases in the diagnosis and pathogenesis of AIP.Methods The clinical records of 22 patients diagnosed with AlP were reviewed and analyzed.All patients with AlP fulfilled the 2006 revised diagnostic criteria proposed by Japan Pancreas Society or the Korean Criteria for AIP.Results Half (11/22) of AlP patients had allergic diseases.Twenty-one patients had elevated serum IgE levels,and 14 patients had IgE levels more than 3 times that of normal.There were no significant differences between the patients with higher or lower IgE,with or without allergic disease,in clinical features,laboratory tests,diffuse or focal lesions,or the choice of treatment methods; however,more complaints of body weight loss were observed in patients with higher IgE levels.Patients with higher IgE levels and with allergic diseases were more likely to have onset in March,April,May,August,September,or October.IgE levels decreased after therapy,but increased again during recurrence.Increased number of mast cells was found in the pancreatic tissue in AIP.Conclusions IgE maybe a useful marker for monitoring therapeutic response and recurrence of AlP.Allergic processes may play an important role in the pathogenesis of AIP.

  14. LRP1 expression in microglia is protective during CNS autoimmunity.

    Science.gov (United States)

    Chuang, Tzu-Ying; Guo, Yong; Seki, Scott M; Rosen, Abagail M; Johanson, David M; Mandell, James W; Lucchinetti, Claudia F; Gaultier, Alban

    2016-01-01

    Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis. Supporting its central role in Multiple sclerosis pathology, we find that LRP1 expression is increased in Multiple sclerosis lesions in comparison to the surrounding healthy tissue. Using two genetic mouse models, we show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis, an animal model of Multiple sclerosis. We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus. At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α. We also show that LRP1 functions as a robust inhibitor of NF-kB activation in myeloid cells via a MyD88 dependent pathway, potentially explaining the increase in disease severity observed in mice lacking LRP1 expression in microglia. Taken together, our data suggest that the function of LRP1 in microglia is to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in Multiple sclerosis. PMID:27400748

  15. Sclerosing cholangitis associated with autoimmune pancreatitis differs from primary sclerosing cholangitis

    Institute of Scientific and Technical Information of China (English)

    Terumi Kamisawa; Kensuke Takuma; Hajime Anjiki; Naoto Egawa; Masanao Kurata; Goro Honda; Kouji Tsuruta

    2009-01-01

    AIM: To clarify the characteristic features of biliary lesions in patients with autoimmune pancreatitis (AIP) and compare them with those of primary sclerosing cholangitis (PSC). METHODS: The clinicopathological characteristics of 34 patients with sclerosing cholangitis (SC) associated with AIP were compared with those of 4 patients with PSC. RESULTS: SC with AIP occurred predominantly in elderly men. Obstructive jaundice was the most frequent initial symptom in SC with AIP. Only SC patients with AIP had elevated serum IgG4 levels, and sclerosing diseases were more frequent in these patients. SC patients with AIP responded well to steroid therapy. Segmental stenosis of the lower bile duct was observed only in SC patients with AIP, but a beaded and prunedtree appearance was detected only in PSC patients. Dense infiltration of IgG4-positive plasma cells was detected in the bile duct wall and the periportal area, as well as in the pancreas, of SC patients with AIP. CONCLUSION: SC with AIP is distinctly different from PSC. The two diseases can be discriminated based on cholangiopancreatographic findings and serum IgG4 levels.

  16. Autoimmune pancreatitis complicated by gastric varices: A report of 3 cases

    Institute of Scientific and Technical Information of China (English)

    Norihiro Goto; Jun Mimura; Toshinao Itani; Motohito Hayashi; Yukari Shimada; Tomoaki Matsumori

    2012-01-01

    We present three cases of autoimmune pancreatitis (AIP) complicated by gastric varices.Case 1:A 57-yearold man was diagnosed with AIP complicated by gastric varices and splenic vein obstruction.Splenomegaly was not detected at the time of the diagnosis.The AIP improved using steroid therapy,the splenic vein was reperfused,and the gastric varices disappeared; case 2:A 55-year-old man was diagnosed with AIP complicated by gastric varices,splenic vein obstruction,and splenomegaly.Although the AIP improved using steroid therapy,the gastric varices and splenic vein obstruction did not resolve; case 3:A 68-year-old man was diagnosed with AIP complicated by gastric varices,splenic vein obstruction,and splenomegaly.The gastric varices,splenic vein obstruction,and AIP did not improve using steroid therapy.These three cases suggest that gastric varices or splenic vein obstruction without splenomegaly may be an indication for steroid therapy in patients with AIP because the complications will likely become irreversible over time.

  17. P15: The expression of Tc17 cells in thymoma accompany with autoimmune diseases or autoimmune disorders

    Science.gov (United States)

    Zhang, Peng

    2015-01-01

    Background Thymoma is thymic epithelial cell tumor. Studies have shown that thymoma associated with autoimmune disorders and possible mechanisms of autoimmune diseases is the central immune tolerance and peripheral tolerance obstacles have resulted in the breaking of the autoimmune response activation and immune tolerance. Tc17 cells and Th17 cells have been shown play an important role in tumor and autoimmune diseases’ development process. This study test the distribution of Tc17cells in thymoma and the expression of RORγt in thymus of thymoma patients with myasthenia gravis (MG) or other autoimmune diseases, the frequency of Th17/Tc17 in PBMCs, to explore the expression of Th17/Tc17 cells in thymoma accompany with autoimmune diseases or autoimmune disorders. Methods In this study, grouped as follows: (I) thymoma non gravis group (Tm groups); (II) thymoma with MG group thymoma with MG (MG group); (III) thymoma with MG associated with other autoimmune diseases group or anti- nuclear antibodies abnormal elevation of the group (AD group), to analyze the basic differences between the groups. In this study, we examined the RT-PCR to detect RORγt in the thymoma tissue, immunohistochemical double staining method to detect Tc17 cells expression and localization in the thymoma tissue distribution expression Th17/Tc17 in PBMCs by flow cytometry [Interleukin (IL)-17-producing CD8+ cells as Thl7 cells and IL-17-producing CD4+ cells as Tcl7 cells], analysis of differential expression of three in each group thymoma; and explore of Th17/Tc17 expression. Results (I) Tm groups and AD group serum CD8+ cells was statistically significant (PTc17 cells in MG/AD group was significantly higher than that in Tm, was statistically significant (PTc17 cells have risen trend in Tm groups and MG/AD group. Conclusions (I) CD8+ cells, CD4+/CD8+ T ratio, immunoglobulin, CRP and complement C3 levels can be used as indicators of evaluation of the role of the immune status of patients with

  18. The efficacy of whole-body FDG-PET or PET/CT for autoimmune pancreatitis and associated extrapancreatic autoimmune lesions

    Energy Technology Data Exchange (ETDEWEB)

    Nakajo, Masatoyo [Atsuchi Memorial Clinic PET Center, Department of Radiology, Kagoshima City (Japan); Graduate School of Medical and Dental Sciences, Kagoshima University, Department of Radiology, Kagoshima (Japan); Jinnouchi, Seishi; Tateno, Rie [Atsuchi Memorial Clinic PET Center, Department of Radiology, Kagoshima City (Japan); Fukukura, Yoshihiko; Tanabe, Hiroaki; Nakajo, Masayuki [Graduate School of Medical and Dental Sciences, Kagoshima University, Department of Radiology, Kagoshima (Japan)

    2007-12-15

    The aim of this study was to evaluate retrospectively the efficacy of whole-body {sup 18}F-fluorodeoxyglucose positron emission tomography (FDG-PET) for autoimmune pancreatitis (AIP) and associated extrapancreatic autoimmune lesions. Whole-body FDG-PET or PET/computed tomography (CT) findings were reviewed in six patients with AIP. The initial PET scans were performed 1 h and 2 h after FDG injection in all six patients. Follow-up PET scans were performed during or following steroid therapy in five patients and in one patient who did not have steroid therapy. The initial PET scans revealed intense FDG uptake by AIP in all six patients. The maximum standardized uptake value (SUVmax) increased in four patients and was stable in two patients. The intense uptake in the pancreas disappeared during or following steroid therapy in five patients and in one patient who showed spontaneous remission of AIP. Abnormal FDG uptake by extrapancreatic autoimmune diseases was observed in five of the six patients: sclerosing sialadenitis (n = 5), lymphadenopathy (n = 5), retroperitoneal fibrosis (n = 2), interstitial nephritis (n = 2) and sclerosing cholecystitis (n = 1). Abnormal FDG uptake disappeared in the salivary glands (n = 4), lymph nodes (n = 4), retroperitoneum (n = 2), kidneys (n = 1) and gallbladder (n = 1) during or following steroid therapy and remained in the salivary glands and lymph nodes of a spontaneous remission patient. These results suggest that whole-body FDG-PET may be useful for detecting AIP and associated extrapancreatic autoimmune lesions and for monitoring their disease activity but that dual time point imaging may not be useful for differentiating malignancy from AIP. (orig.)

  19. Potential Role of NO in Modulation of COX-2 Expression and PGE2 Production in Pancreatic β-cells

    Institute of Scientific and Technical Information of China (English)

    Jia-Jian LING; Yu-Jie SUN; Dong-Ya ZHU; Qi CHEN; Xiao HAN

    2005-01-01

    Cytokines have been implicated in pancreatic β-cell destruction leading to type 1 diabetes.Exposure to interleuken-1 β (IL-1 β) of pancreatic β-cells induces expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Subsequent formation of nitric oxide (NO) and prostaglandin E2 (PGE2) may impair β-cell function. Using NOS inhibitor NG-monomethyl-L-arginine (L-NMMA), we have further investigated the relation between NO formation and COX-2 expression. IL-1 β stimulated the formation of NO and PGE2 by pancreatic β-cells. L-NMMA completely inhibited IL- 1 β-induced NO formation and attenuated PGE2 production. COX-2 gene transcription level and protein expression were determined by real-time PCR, Western blot and luciferase analysis. L-NMMA inhibited IL-1 β-induced promoter activity, gene transcription and protein expression of COX-2 in pancreatic β-cells. Therefore, we concluded that NO-affected COX-2 activity is directly linked to COX-2 gene transcription and protein expression in pancreatic β-cells. The identification of a novel interaction of NO on the COX signaling pathway in β-cells provides a strategy of intervention for further evaluating the role of NO and PGE2 in autoimmune diabetes.

  20. Overexpression of c-met in the early stage of pancreatic carcinogenesis; altered expression is not sufficient for progression from chronic pancreatitis to pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Jun Yu; Eishi Nagai; Masao Tanaka; Kenoki Ohuchida; Kazuhiro Mizumoto; Nami Ishikawa; Yasuhiro Ogura; Daisuke Yamada; Takuya Egami; Hayato Fujita; Seiji Ohashi

    2006-01-01

    AIM: To investigate c-met expression during early pancreatic carcinogenesis.METHODS: We used 46 bulk tissues and 36 microdissected samples, including normal pancreas, chronic pancreatitis, and pancreatic cancer, for quantitative real time reverse transcription-polymerase chain reaction.RESULTS: In bulk tissue analyses, pancreatic cancer tissues expressed significantly higher levels of c-met than did chronic pancreatitis and normal pancreas tissues.c-met levels did not differ between chronic pancreatitis and normal pancreas tissues. In microdissection-based analyses, c-met was expressed at higher levels in microdissected pancreatic cancer cells and pancreatitisaffected epithelial cells than in normal ductal epithelial cells (both, P < 0.01). Interestingly, pancreatitis-affected epithelial cells expressed levels of c-met similar to those of pancreatic cancer cells.CONCLUSION: Overexpression of c-met occurs during the early stage of pancreatic carcinogenesis, and a single alteration of c-met expression is not sufficient for progression of chronic pancreatitis-affected epithelial cells to pancreatic cancer cells.

  1. Expression of Survivin in pancreatic cancer and its correlation to expression of Bcl-2

    Institute of Scientific and Technical Information of China (English)

    Jian-Guo Qiao; Yu-Qing Zhang; Yu-Chun Yin; Zui Tan

    2004-01-01

    AIM: To investigate the expression of Survivin in pancreatic cancer and its correlation to the expression of Bcl-2.METHODS: Survivin and Bcl-2 expressions were examined by immunohistochemistry in 42 tissue samples from pancreatic cancer and 10 from normal pancrease. RESULTS: No survivin expression was detected in the tissue samples from normal pancrease, while it was detected in 34 of 42 tissue samples from pancreatic cancer (81.95%).There was a correlation between survivin expression and differentiation and stages of pancreatic cancer. Survivin positive cases were strongly correlated to Bcl-2 expression (28/30 vs 6/12, P<0.05).CONCLUSION: Overexpression of survivin plays an important role in the development and progression of pancreatic cancer, and correlates to the expression of Bcl-2. Survivin expression can be used as a prognostic factor.

  2. Helicobacter pylori and pancreatic diseases

    Institute of Scientific and Technical Information of China (English)

    Milutin; Bulajic; Nikola; Panic; Johannes; Matthias; L?hr

    2014-01-01

    A possible role for Helicobacter pylori(H. pylori) infec-tion in pancreatic diseases remains controversial. H. pylori infection with antral predomination leading to an increase in pancreatic bicarbonate output and induc-ing ductal epithelial cell proliferation could contribute to the development of pancreatic cancer via complex interactions with the ABO genotype, dietary and smok-ing habits and N-nitrosamine exposure of the host. Although the individual study data available so far is inconsistent, several meta-analyses have reported an increased risk for pancreatic cancer among H. pylori seropositive individuals. It has been suggested that H. pylori causes autoimmune pancreatitis due to molecu-lar mimicry between H. pylori a-carbonic anhydrase(a-CA) and human CA type Ⅱ, and between H. pylori plasminogen-binding protein and human ubiquitin-protein ligase E3 component n-recognin 2, enzymes that are highly expressed in the pancreatic ductal andacinar cells, respectively. Future studies involving large numbers of cases are needed in order to examine the role of H. pylori in autoimmune pancreatitis more fully. Considering the worldwide pancreatic cancer burden, as well as the association between autoimmune pan-creatitis and other autoimmune conditions, a complete elucidation of the role played by H. pylori in the gen-esis of such conditions could have a substantial impact on healthcare.

  3. Autoimmune pancreatitis with IgG4-positive plasma cell infiltration in salivary glands and biliary tract

    Institute of Scientific and Technical Information of China (English)

    Masashi Taguchi; Gentaro Aridome; Shintaro Abe; Keiichiro Kume; Mitsuo Tashiro; Mitsuyoshi Yamamoto; Yasuyuki Kihara; Hayato Nakamura; Makoto Otsuki

    2005-01-01

    A 62-year-old male was referred to our hospital because of liver dysfunction, diffuse pancreatic swelling, and trachelophyma. At admission, the patient was free of pain.Physical examination showed enlarged and palpable bilateral submandibular masses, but no palpable mass or organomegaly in the abdomen. Laboratory findings were as follows: total protein 90 g/L with γ-globulin of 37.3% (33 g/L), total bilirubin 4 mg/L, aspartate aminotransferase 39 IU/L, alanine aminotransferase 67 IU/L, γ-glutamyl transpeptidase 1 647 IU/L, and amylase 135 IU/L. Autoantibodies were negative, and tumor markers were within the normal range. Serum IgG4 level was markedly elevated (18 900 mg/L). Computed tomography (CT) showed diffuse swelling of the pancreas and dilatation of both common and intra-hepatic bile ducts. Endoscopic retrograde pancreatography (ERP) revealed diffuse irregular and narrow main pancreatic duct and stenosis of the lower common bile duct. Biopsy specimens from the pancreas, salivary gland and liver showed marked periductal IgG4-positive plasma cell infiltration with fibrosis. We considered this patient to be autoimmune pancreatitis (AIP) with fibrosclerosis of the salivary gland and biliary tract, prescribed prednisolone at an initial dose of 40 mg/d. Three months later, the laboratory data improved almost to normal. Abdominal CT reflected prominent improvement in the pancreatic lesion. Swelling of the salivary gland also improved. At present, the patient is on 10 mg/d of prednisolone without recurrence of the pancreatitis. We present here a case of AIP with fibrosclerosis of salivary gland and biliary tract.

  4. Retrospective comparison between preoperative diagnosis by International Consensus Diagnostic Criteria and histological diagnosis in patients with focal autoimmune pancreatitis who underwent surgery with suspicion of cancer

    DEFF Research Database (Denmark)

    Ikeura, Tsukasa; Detlefsen, Sönke; Zamboni, Giuseppe;

    2014-01-01

    OBJECTIVE: The objective of this study was to compare the preoperative diagnosis by International Consensus Diagnostic Criteria (ICDC) with histological diagnosis in patients with focal autoimmune pancreatitis (AIP) who underwent surgery. METHODS: Thirty patients (type 1 AIP in 23 and type 2 AIP ...

  5. Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice.

    Science.gov (United States)

    Rastellini, Cristiana; Han, Song; Bhatia, Vandanajay; Cao, Yanna; Liu, Ka; Gao, Xuxia; Ko, Tien C; Greeley, George H; Falzon, Miriam

    2015-10-01

    Chronic pancreatitis (CP) is a devastating disease with no treatments. Experimental models have been developed to reproduce the parenchyma and inflammatory responses typical of human CP. For the present study, one objective was to assess and compare the effects of pancreatic duct ligation (PDL) to those of repetitive cerulein (Cer)-induced CP in mice on pancreatic production of bone morphogenetic protein-2 (BMP2), apelin, and parathyroid hormone-related protein (PTHrP). A second objective was to determine the extent of cross talk among pancreatic BMP2, apelin, and PTHrP signaling systems. We focused on BMP2, apelin, and PTHrP since these factors regulate the inflammation-fibrosis cascade during pancreatitis. Findings showed that PDL- and Cer-induced CP resulted in significant elevations in expression and peptide/protein levels of pancreatic BMP2, apelin, and PTHrP. In vivo mouse and in vitro pancreatic cell culture experiments demonstrated that BMP2 stimulated pancreatic apelin expression whereas apelin expression was inhibited by PTHrP exposure. Apelin or BMP2 exposure inhibited PTHrP expression, and PTHrP stimulated upregulation of gremlin, an endogenous inhibitor of BMP2 activity. Transforming growth factor-β (TGF-β) stimulated PTHrP expression. Together, findings demonstrated that PDL- and Cer-induced CP resulted in increased production of the pancreatic BMP2, apelin, and PTHrP signaling systems and that significant cross talk occurred among pancreatic BMP2, apelin, and PTHrP. These results together with previous findings imply that these factors interact via a pancreatic network to regulate the inflammation-fibrosis cascade during CP. More importantly, this network communicated with TGF-β, a key effector of pancreatic pathophysiology. This novel network may be amenable to pharmacologic manipulations during CP in humans. PMID:26229008

  6. Clinical significance of clusterin expression in pancreatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Jin Junshuo

    2012-07-01

    Full Text Available Abstract Background Clusterin is known to be expressed in many human neoplasms, and is believed to participate in the regeneration, migration, and anti-apoptosis of tumor cells. However, few reports have addressed the relationship between the manifestation of clusterin and clinicopathologic parameters in pancreas cancer patients. In the present study, the authors investigated the expression of clusterin and its clinical significance in pancreatic adenocarcinoma. Methods Immunohistochemical staining was performed for clusterin in tumor tissues obtained from patients who received pancreatic resection with radical intent, and the associations of clusterin expression with various clinicopathologic parameters were analyzed in addition to the relation between its expression and survival. Results Immunoreactivity for clusterin was observed in 17 of the 52 (33% pancreatic adenocarcinomas examined. In addition, clusterin positivity was found to be associated with preoperative serum carcinoembryonic antigen level, perineural invasion, and, most strongly, lymph node metastasis. The survival analysis identified tumor differentiation and lymph node metastasis as the only significant prognostic factors. Conclusion Although not an independent prognostic factor, clusterin immunoreactivity can be used in conjunction with lymph node metastasis to predict survival in cases of pancreatic adenocarcinoma.

  7. Gene expression profiling and endothelin in acute experimental pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Helieh S Oz; Ying Lu; Louis P Vera-Portocarrero; Pei Ge; Ada Silos-Santiago; Karin N Westlund

    2012-01-01

    AIM:To analyze gene expression profiles in an experimental pancreatitis and provide functional reversal of hypersensitivity with candidate gene endothelin-1 antagonists.METHODS:Dibutyltin dichloride (DBTC) is a chemical used as a polyvinyl carbonate stabilizer/catalyzer,biocide in agriculture,antifouling agent in paint and fabric.DBTC induces an acute pancreatitis flare through generation of reactive oxygen species.Lewis-inbred rats received a single i.v.injection with either DBTC or vehicle.Spinal cord and dorsal root ganglia (DRG) were taken at the peak of inflammation and processed for transcriptional profiling with a cDNA microarray biased for rat brain-specific genes.In a second study,groups of animals with DBTC-induced pancreatitis were treated with endothelin (ET) receptor antagonists [ET-A (BQ123) and ET-B BQ788)].Spontaneous pain related mechanical and thermal hypersensitivity were measured.Immunohistochemical analysis was performed using anti-ET-A and ET-B antibodies on sections from pancreatic tissues and DRG of the T10-12 spinal segments.RESULTS:Animals developed acute pancreatic inflammation persisting 7-10 d as confirmed by pathological studies (edema in parenchyma,loss of pancreatic architecture and islets,infiltration of inflammatory cells,neutrophil and mononuclear cells,degeneration,vacuolization and necrosis of acinar cells) and the painrelated behaviors (cutaneous secondary mechanical and thermal hypersensitivity).Gene expression profile was different in the spinal cord from animals with pancreatitis compared to the vehicle control group.Over 260 up-regulated and 60 down-regulated unique genes could be classified into 8 functional gene families:circulatory/acute phase/immunomodulatory; extracellular matrix; structural; channel/receptor/transporter; signaling transduction; transcription/translation-related; antioxidants/chaperones/heat shock; pancreatic and other enzymes.ET-1 was among the 52 candidate genes upregulated greater than 2-fold in

  8. Diagnosis of pancreatic neoplasms using a novel method of DNA methylation analysis of mucin expression in pancreatic juice.

    Directory of Open Access Journals (Sweden)

    Seiya Yokoyama

    Full Text Available Mucins (MUC play crucial roles in carcinogenesis and tumor invasion in pancreatic ductal adenocarcinoma (PDAC and intraductal papillary mucinous neoplasms (IPMNs. Our immunohistochemistry (IHC studies have shown a consensus position on mucin expression profiles in pancreatic neoplasms as follows: MUC1-positive but MUC2-negative expression in PDACs; MUC1-negative but MUC2-positive expression in intestinal-type IPMNs (dangerous type; MUC1-negative and MUC2-negative expression in gastric-type IPMNs (safe type; High MUC4 expression in PDAC patients with a poor outcome; and MUC4-positive expression in intestinal-type IPMNs. We also showed that three mucin genes (MUC1, MUC2 and MUC4 expression in cancer cell line was regulated by DNA methylation. We have developed a novel 'methylation-specific electrophoresis (MSE' method to analyze the DNA methylation status of mucin genes by high sensitivity and resolution. By using the MSE method, we evaluated pancreatic juice samples from 45 patients with various pancreatic lesions. The results were compared with final diagnosis of the pancreatic lesions including IHC of mucin expression in the paired pancreatic tissues. The results indicated that the DNA methylation status of MUC1, MUC2 and MUC4 in pancreatic juice matched with the mucin expression in tissue. Analyses of the DNA methylation status of MUC1, MUC2 and MUC4 were useful for differential diagnosis of human pancreatic neoplasms, with specificity and sensitivity of 87% and 80% for PDAC; 100% and 88% for intestinal-type IPMN; and 88% and 77% for gastric-type IPMN, respectively. In conclusion, MSE analysis of human pancreatic juice may provide useful information for selection of treatment for pancreatic neoplasms.

  9. Autoimmun pankreatitis

    DEFF Research Database (Denmark)

    Fjordside, Eva; Novovic, Srdan; Schmidt, Palle Nordblad;

    2015-01-01

    Autoimmune pancreatitis (AIP) is a rare inflammatory disease. AIP has characteristic histology, serology and imaging findings. Two types of AIP exist, type 1, which is a part of the systemic immunoglobulin G4-related disease, and type 2, which is only localized to the pancreas. Patients with type 1...... are predominantly older men, have involvement of other organs and more often experience relapse than patients with type 2. Both types respond well to steroid treatment. The most important differential diagnose is pancreatic cancer....

  10. MicroRNAs: Novel Players in the Dialogue between Pancreatic Islets and Immune System in Autoimmune Diabetes

    OpenAIRE

    Giuliana Ventriglia; Laura Nigi; Guido Sebastiani; Francesco Dotta

    2015-01-01

    MicroRNAs are small noncoding RNA molecules that regulate gene expression in all cell types. Therefore, these tiny noncoding RNA molecules are involved in a wide range of biological processes, exerting functional effects at cellular, tissue, and organ level. In pancreatic islets of Langerhans, including beta-cells, microRNAs are involved in cell differentiation as well as in insulin secretion, while in immune cells they have been shown to play pivotal roles in development, activation, and res...

  11. Sensitization to and Challenge with Gliadin Induce Pancreatitis and Extrapancreatic Inflammation in HLA-DQ8 Mice: An Animal Model of Type 1 Autoimmune Pancreatitis

    Science.gov (United States)

    Moon, Sung-Hoon; Kim, Jihun; Kim, Mi-Young; Park, Do Hyun; Song, Tae Jun; Kim, Sun A; Lee, Sang Soo; Seo, Dong Wan; Lee, Sung Koo; Kim, Myung-Hwan

    2016-01-01

    Background/Aims The aim of this study was to establish a pathogenetic mechanism of pancreatitis in celiac disease and IgG4-related disease using gluten-sensitive human leukocyte antigen (HLA)-DQ8 transgenic mice. Methods Transgenic mice expressing HLA-DQ8 genes were utilized. Control mice were not sensitized but were fed gliadin-free rice cereal. Experimental groups consisted of gliadin-sensitized and gliadin-challenged mice; nonsensitized mice with cerulein hyperstimulation; and gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation. Results Gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation showed significant inflammatory cell infiltrates, fibrosis and acinar atrophy compared with the control mice and the other experimental groups. The immunohistochemical analysis showed greater IgG1-positive plasma cells in the inflammatory infiltrates of gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation compared with the control mice and the other experimental groups. Gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation or gliadin-sensitized and gliadin-challenged mice showed IgG1-stained inflammatory cell infiltrates in the extrapancreatic organs, including the bile ducts, salivary glands, kidneys, and lungs. Conclusions Gliadin-sensitization and cerulein hyperstimulation of gluten-sensitive HLA-DQ8 transgenic mice resulted in pancreatitis and extrapancreatic inflammation. This animal model suggests that chronic gliadin ingestion in a susceptible individual with the HLA-DQ8 molecule may be associated with pancreatitis and extrapancreatic inflammation. PMID:27114422

  12. Expression of thyroid stimulating hormone β splice variant in thyroid of mouse with autoimmune thyroiditis

    Institute of Scientific and Technical Information of China (English)

    袁继红

    2014-01-01

    Objective To investigate the expression of marrowderived thyroid stimulating hormoneβ(TSHβ)splice variant in thyroid of mouse with autoimmune thyroiditis induced by thyroglobulin(Tg)immunization,and to analyze whether TSHβsplice variant participated in the pathological process of autoimmune thyroiditis.Methods Using random number table,forty-eight mice(24 females and 24 males)of 7 to 8 weeks old with body mass 20 to25 g were randomly divided into 4 groups(12 females

  13. Autoimmun pankreatitis

    DEFF Research Database (Denmark)

    Fjordside, Eva; Novovic, Srdan; Schmidt, Palle Nordblad;

    2015-01-01

    Autoimmune pancreatitis (AIP) is a rare inflammatory disease. AIP has characteristic histology, serology and imaging findings. Two types of AIP exist, type 1, which is a part of the systemic immunoglobulin G4-related disease, and type 2, which is only localized to the pancreas. Patients with type 1...

  14. LRP1 expression in microglia is protective during CNS autoimmunity

    OpenAIRE

    Chuang, Tzu-Ying; Guo, Yong; Seki, Scott M.; Rosen, Abagail M.; Johanson, David M.; Mandell, James W.; Lucchinetti, Claudia F.; Gaultier, Alban

    2016-01-01

    Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the i...

  15. Alterations in integrin expression modulates invasion of pancreatic cancer cells.

    LENUS (Irish Health Repository)

    Walsh, Naomi

    2009-01-01

    BACKGROUND: Factors mediating the invasion of pancreatic cancer cells through the extracellular matrix (ECM) are not fully understood. METHODS: In this study, sub-populations of the human pancreatic cancer cell line, MiaPaCa-2 were established which displayed differences in invasion, adhesion, anoikis, anchorage-independent growth and integrin expression. RESULTS: Clone #3 displayed higher invasion with less adhesion, while Clone #8 was less invasive with increased adhesion to ECM proteins compared to MiaPaCa-2. Clone #8 was more sensitive to anoikis than Clone #3 and MiaPaCa-2, and displayed low colony-forming efficiency in an anchorage-independent growth assay. Integrins beta 1, alpha 5 and alpha 6 were over-expressed in Clone #8. Using small interfering RNA (siRNA), integrin beta1 knockdown in Clone #8 cells increased invasion through matrigel and fibronectin, increased motility, decreased adhesion and anoikis. Integrin alpha 5 and alpha 6 knockdown also resulted in increased motility, invasion through matrigel and decreased adhesion. CONCLUSION: Our results suggest that altered expression of integrins interacting with different extracellular matrixes may play a significant role in suppressing the aggressive invasive phenotype. Analysis of these clonal populations of MiaPaCa-2 provides a model for investigations into the invasive properties of pancreatic carcinoma.

  16. MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma

    DEFF Research Database (Denmark)

    Schultz, Nicolai A; Werner, Jens; Willenbrock, Hanni;

    2012-01-01

    MicroRNAs have potential as diagnostic cancer biomarkers. The aim of this study was (1) to define microRNA expression patterns in formalin-fixed parafin-embedded tissue from pancreatic ductal adenocarcinoma, ampullary adenocarcinoma, normal pancreas and chronic pancreatitis without using micro......, normal pancreas and duodenal adenocarcinoma. In all, 43 microRNAs had higher and 41 microRNAs reduced expression in pancreatic cancer compared with normal pancreas. In all, 32 microRNAs were differently expressed in pancreatic adenocarcinoma compared with chronic pancreatitis (17 higher; 15 reduced......-dissection and (2) to discover new diagnostic microRNAs and combinations of microRNAs in cancer tissue. The expression of 664 microRNAs in tissue from 170 pancreatic adenocarcinomas and 107 ampullary adenocarcinomas were analyzed using a commercial microRNA assay. Results were compared with chronic pancreatitis...

  17. Pancreatitis

    Science.gov (United States)

    ... the hormones insulin and glucagon into the bloodstream. Pancreatitis is inflammation of the pancreas. It happens when digestive enzymes start digesting the pancreas itself. Pancreatitis can be acute or chronic. Either form is ...

  18. Pancreatitis

    Institute of Scientific and Technical Information of China (English)

    1997-01-01

    970359 CT diagnosis of pancreatic carcinoma andchronic pancreatitis. LUAN Baoqing(栾宝庆), et al,Dept Radiol, Beijing Friendship Hosp, Capital Med U-niv, Beijing, 100050. Chin J Radiol 1997; 31(2): 114-118. Objective: To improve the diagnostic accuracy ofpancreatic carcinoma and chronic pancreatitis. Materi-

  19. Expression of anti-SRP19 antibody in muscle tissues from patients with autoimmune necrotizing myopathy.

    Science.gov (United States)

    Wang, Q; Duan, F; Liu, P; Wang, P F; Wang, M X

    2016-01-01

    This study aimed to investigate the role of anti-SRP19 antibody in muscle tissues of patients with autoimmune necrotizing myopathy. Immunohistochemistry staining was used to determine the expression of anti-SRP19 antibodies in muscle tissues of autoimmune necrotizing myopathy patients. Results demonstrated that anti-SRP19 antibody was expressed in 71.4% (20/28) of muscle tissue specimens from patients with autoimmune necrotizing myopathy. Anti-SRP19 antibody expression was mainly localized in cytoplasm of necrotic muscle fibers surrounding the small blood vessels and interstitial cells. There were no significant differences in the age, course of disease, muscle, and creatine kinase levels between patients with positive or negative expression of anti-SRP19 antibodies. The expression levels of anti-SRP19, serum anti-nuclear antibodies, as well as anti-Ro-52, anti- SSA, anti-Sm, and anti-Jo-1 antibodies were not significantly different among groups. This study demonstrates that anti-SRP19 antibody is highly expressed in muscle tissues of patients with autoimmune necrotizing myopathy, and suggests that this protein may be involved in the origin and progression of the disease. PMID:27525944

  20. Pancreatitis

    Institute of Scientific and Technical Information of China (English)

    1995-01-01

    950347 Pancreatic endorcine response to parenteralnutrition in experimental acute pancreatitis.SUN Xi-aoguang(孙晓光),et al.Dept Nucl Med,ZhongshanHosp,Shanghai Med Univ,Shanghai.Shanghai Med J1995;18(2),74-70.In order to study the pancreatic endocrine responseto parenteral nutrition (PN) in acute pancreatitis,thedisease was induced in dogs by injecting 4% tauro-cholate sodium 0.5ml/kg plus trypsin 0.5mg/kg into the pancreatic duct.Intravenous infusion of PN wasinitiated one hour after the establishment of the dis-

  1. Differential expression of metallothioneins in the CNS of mice with experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, C; Carrasco, J; Hidalgo, J;

    2001-01-01

    Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. Metallothioneins-I+II are antioxidant proteins induced in the CNS by immobilisation stress, trauma or degenerative diseases which have been postulated to play a neuroprotective role, while the CNS isoform metallothionein......-III has been related to Alzheimer's disease. We have analysed metallothioneins-I-III expression in the CNS of mice with experimental autoimmune encephalomyelitis. Moreover, we have examined the putative role of interferon-gamma, a pro-inflammatory cytokine, in the control of metallothioneins expression...... during experimental autoimmune encephalomyelitis in interferon-gamma receptor knockout mice with two different genetic backgrounds: 129/Sv and C57BL/6x129/Sv.Mice with experimental autoimmune encephalomyelitis showed a significant induction of metallothioneins-I+II in the spinal cord white matter, and to...

  2. Pancreatitis autoinmune: pseudotumor inflamatorio, afectación multifocal, hipertensión portal y evolución a largo plazo Autoimmune pancreatitis: inflammatory pseudotumor, multifocal fibrosclerosis, portal hypertension, and long-term outcome

    Directory of Open Access Journals (Sweden)

    J. L. Beristain

    2008-10-01

    Full Text Available La pancreatitis autoinmune es una enfermedad recientemente caracterizada y que en la actualidad constituye un reto diagnóstico especialmente su diferenciación con el cáncer de páncreas. Su evolución a largo plazo es poco conocida, presentándose un caso estudiado a lo largo de 14 años y mostrando su evolución clínica, bioquímica y morfológica. Paciente mujer de 54 años que debuta con un cuadro de ictericia obstructiva y molestias abdominales inespecíficas y constatación en la TAC de un aumento de la cabeza del páncreas, todo ello sugestivo de neoplasia de páncreas. Fue intervenida evidenciándose un aumento difuso de todo el páncreas descartándose malignidad intraoperatoriamente, realizando únicamente colecistectomía y coledocoduodenostomía, quedando diagnosticada entonces como pancreatitis crónica. Durante los años posteriores fueron apareciendo diferentes procesos autoinmunes como asma, sialoadenitis y colangitis esclerosante secundaria, así como episodios recurrentes de ictericia e insuficiencia pancreática endocrina y exocrina. La aparición de estas complicaciones y la detección de niveles séricos elevados de IgG4 y de anticuerpos antianhidrasa carbónica II condujo a la reevaluación de la histología inicial concluyendo finalmente con el diagnóstico de pancreatitis autoinmune al evidenciarse una infiltración linfocitaria y plasmacitaria IgG4+, así como fibrosis y flebitis obliterativa. En los últimos años se ha añadido a las anteriores complicaciones una fibrosis retroperitoneal con hipertensión portal, varices esofágicas y esplenomegalia.Autoimmune pancreatitis is a recently characterized disease that still constitutes a diagnostic challenge, especially regarding differential diagnosis from neoplasia. Long-term outcome is poorly known. We herein report a case of a patient with autoimmune pancreatitis and 14 years of follow-up, and show its clinical, biochemical, and morphological characteristics. A 54

  3. Expression and significance of CD44 and p-AKT in pancreatic head cancer

    OpenAIRE

    Xiaoping, Li; Xiaowei, Zhang; Leizhen, Zheng; Weijian, Guo

    2015-01-01

    Background CD44 and phosphorylated AKT (p-AKT) is a potentially interesting prognostic marker and therapeutic target in pancreatic cancer. The expression of CD44 and p-AKT has been reported to correlate with poor prognosis of pancreatic cancer in most literatures. The purpose of this study is to investigate the roles of CD44 and p-AKT in pancreatic head cancer and their correlation with the prognosis of pancreatic head cancer patients. Methods Forty-eight pancreatic head cancer samples were c...

  4. Sclerosing cholangitis with autoimmune pancreatitis versus primary sclerosing cholangitis: comparison on endoscopic retrograde cholangiography, MR cholangiography, CT, and MRI

    Energy Technology Data Exchange (ETDEWEB)

    Kim; Jin Hee; Byun, Jae Ho; Kim, So Yeon; Lee, Seung Soo; Kim, Hyoung Jung; Lee, Moon-Gyu [Dept. of Radiology and Research Inst. of Radiology, Univ. of Ulsan Coll. of Medicine, Asan Medical Center, Seoul (Korea, Republic of)], e-mail: jhbyun@amc.seoul.kr; Kim, Myung-Hwan [Dept. of Internal Medicine, Univ. of Ulsan Coll. of Medicine, Asan Medical Center, Seoul (Korea, Republic of)

    2013-07-15

    Background: It is essential to differentiate sclerosing cholangitis with autoimmune pancreatitis (SC-AIP) from primary sclerosing cholangitis (PSC) as the treatment and prognosis of the two diseases are totally different. Purpose: To compare image findings of SC-AIP and PSC on endoscopic retrograde cholangiography (ERC), magnetic resonance cholangiography (MRC), computed tomography (CT), and magnetic resonance imaging (MRI). Material and Methods: Two radiologists retrospectively reviewed ERC, MRC, CT, and MRI in 28 SC-AIP and 23 PSC patients in consensus. Factors evaluated included the length, location, and multiplicity of bile duct stricture, the presence of characteristic cholangiographic features of PSC on ERC and MRC, and the presence, location, thickness, and pattern of bile duct wall thickening on CT and MRI. Results: On ERC, focal stricture, multifocal and intrahepatic bile duct stricture, and beaded, pruned-tree, and diverticulum-like appearance were more frequent in PSC than in SC-AIP patients (P = 0.006). On MRC, multifocal and intrahepatic bile duct stricture and pruned-tree appearance were more frequent in PSC than in SC-AIP patients (P = 0.044). On CT and MRI, the bile duct wall was thicker (5.1 mm vs. 3.1 mm; P = 0.033 and 4.3 mm vs. 3.0 mm; P = 0.01, respectively) in SC-AIP than in PSC patients. PSC was more frequently associated with intrahepatic bile duct wall thickening on both CT (93% vs. 50%; P = 0.024) and MRI (100% vs. 50%; P = 0.023) than SC-AIP. Conclusion: The combination of ERC or MRC with cross-sectional images, including CT and MRI, may be helpful in differentiating between SC-AIP and PSC.

  5. Gene expression profiling in autoimmune diseases: chronic inflammation or disease specific patterns?

    DEFF Research Database (Denmark)

    Bovin, Lone Frier; Brynskov, Jørn; Hegedüs, Laszlo;

    2007-01-01

    A central issue in autoimmune disease is whether the underlying inflammation is a repeated stereotypical process or whether disease specific gene expression is involved. To shed light on this, we analysed whether genes previously found to be differentially regulated in rheumatoid arthritis (RA...

  6. Imaging Axl expression in pancreatic and prostate cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Nimmagadda, Sridhar, E-mail: snimmag1@jhmi.edu [Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD 21287 (United States); Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287 (United States); Pullambhatla, Mrudula; Lisok, Ala [Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD 21287 (United States); Hu, Chaoxin [Department of Pathology, Johns Hopkins University, Baltimore, MD 21287 (United States); Maitra, Anirban [Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287 (United States); Department of Pathology, Johns Hopkins University, Baltimore, MD 21287 (United States); Pomper, Martin G, E-mail: mpomper@jhmi.edu [Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD 21287 (United States); Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287 (United States)

    2014-01-10

    Highlights: •Axl is overexpressed in a variety of cancers. •Axl overexpression confers invasive phenotype. •Axl imaging would be useful for therapeutic guidance and monitoring. •Axl expression imaging is demonstrated in pancreatic and prostate cancer xenografts. •Graded levels of Axl expression imaging is feasible. -- Abstract: The receptor tyrosine kinase Axl is overexpressed in and leads to patient morbidity and mortality in a variety of cancers. Axl–Gas6 interactions are critical for tumor growth, angiogenesis and metastasis. The goal of this study was to investigate the feasibility of imaging graded levels of Axl expression in tumors using a radiolabeled antibody. We radiolabeled anti-human Axl (Axl mAb) and control IgG1 antibodies with {sup 125}I with high specific radioactivity and radiochemical purity, resulting in an immunoreactive fraction suitable for in vivo studies. Radiolabeled antibodies were investigated in severe combined immunodeficient mice harboring subcutaneous CFPAC (Axl{sup high}) and Panc1 (Axl{sup low}) pancreatic cancer xenografts by ex vivo biodistribution and imaging. Based on these results, the specificity of [{sup 125}I]Axl mAb was also validated in mice harboring orthotopic Panc1 or CFPAC tumors and in mice harboring subcutaneous 22Rv1 (Axl{sup low}) or DU145 (Axl{sup high}) prostate tumors by ex vivo biodistribution and imaging studies at 72 h post-injection of the antibody. Both imaging and biodistribution studies demonstrated specific and persistent accumulation of [{sup 125}I]Axl mAb in Axl{sup high} (CFPAC and DU145) expression tumors compared to the Axl{sup low} (Panc1 and 22Rv1) expression tumors. Axl expression in these tumors was further confirmed by immunohistochemical studies. No difference in the uptake of radioactivity was observed between the control [{sup 125}I]IgG1 antibody in the Axl{sup high} and Axl{sup low} expression tumors. These data demonstrate the feasibility of imaging Axl expression in pancreatic

  7. MicroRNA Expression Analyses in Preoperative Pancreatic Juice Samples of Pancreatic Ductal Adenocarcinoma

    OpenAIRE

    Yoshihiko Sadakari; Takao Ohtsuka; Kenoki Ohuchida; Kosuke Tsutsumi; Shunichi Takahata; Masafumi Nakamura; Kazuhiro Mizumoto; Masao Tanaka

    1999-01-01

    Context Cytological assessment of pancreatic juice is commonly used to diagnose pancreatic ductal adenocarcinoma; however, the sensitivity of cytological assessment has been reported to be low. MicroRNAs are small RNAs regulating various cellular processes and have recently been identified as possible markers of malignant diseases including pancreatic ductal adenocarcinoma. Objective The purposes of this study were to prove the existence of microRNAs in pancreatic juice and to determine wheth...

  8. Advances in imaging diagnosis of autoimmune pancreatitis%自身免疫性胰腺炎影像诊断进展

    Institute of Scientific and Technical Information of China (English)

    张斌斌; 郑新; 靳二虎

    2014-01-01

    Autoimmune pancreatitis (AIP) is a special type of chronic inflammation of the pancreas caused by autoimmune abnormality, responds to steroid therapy very well, and it is considered to be pancreatic involvement of IgG4-related disease. Other organs may also be involved, including the bile duct, gallbladder, kidney, retroperitoneal tissue, salivary glands, etc. The main imaging manifestations of AIP are diffuse or localized swelling of the pancreas and irregular stenosis of the pancreatic duct. It is difficult to differentiate AIP from pancreatic cancer and other diseases. Since there is no specific diagnostic methods, AIP usually requires a comprehensive evaluation, thus familiar with the imaging characteristics of the disease is very important for the early diagnosis and treatment.%自身免疫性胰腺炎是由自身免疫异常引发的特殊类型的慢性胰腺炎,类固醇治疗效果显著,被认为是IgG4相关性全身性疾病的胰腺受累表现,其他受累器官包括胆管、胆囊、肾脏、腹膜后组织、涎腺等。主要的影像表现是弥漫性或局限性胰腺肿大以及胰管不规则狭窄,有时与胰腺癌等疾病鉴别困难。由于没有特异性诊断方法,自身免疫性胰腺炎通常需要综合性诊断,因此从影像诊断学上提高对该病的认识,对于该病的早期诊断和治疗相当重要。

  9. Genetic architecture of early pre-inflammatory stage transcription signatures of autoimmune diabetes in the pancreatic lymph nodes of the NOD mouse reveals significant gene enrichment on chromosomes 6 and 7

    Directory of Open Access Journals (Sweden)

    Beatrice Regnault

    2015-12-01

    Full Text Available Autoimmune diseases are characterized by the stimulation of an excessive immune response to self-tissues by inner and/or outer organism factors. Common characteristics in their etiology include a complex genetic predisposition and environmental triggers as well as the implication of the major histocompatibility (MHC locus on human chromosome 6p21. A restraint number of non-MHC susceptibility genes, part of the genetic component of type 1 diabetes have been identified in human and in animal models, while the complete spectrum of genes involved remains unknown. We elaborate herein patterns of chromosomal organization of 162 genes differentially expressed in the pancreatic lymph nodes of Non-Obese Diabetic mice, carefully selected by early sub-phenotypic evaluation (presence or absence of insulin autoantibodies. Chromosomal assignment of these genes revealed a non-random distribution on five chromosomes (47%. Significant gene enrichment was observed in particular for two chromosomes, 6 and 7. While a subset of these genes coding for secreted proteins showed significant enrichment on both chromosomes, the overall pool of genes was significantly enriched on chromosome 7. The significance of this unexpected gene distribution on the mouse genome is discussed in the light of novel findings indicating that genes affecting common diseases map to recombination “hotspot” regions of mammalian genomes. The genetic architecture of transcripts differentially expressed in specific stages of autoimmune diabetes offers novel venues towards our understanding of patterns of inheritance potentially affecting the pathological disease mechanisms.

  10. [Pancreatic Diseases].

    Science.gov (United States)

    Schöfl, Rainer

    2016-06-22

    The author presents his personal choice of practical relevant papers of pancreatic diseases from 2014 to 2015. Nutritional factors and hypertriglycidemia are discussed as causes of acute pancreatitis. Tools to avoid post-ERCP(endoscopic retrograde cholangiopancreatography) pancreatitis are described and the natural course of fluid collections and pseudocysts is demonstrated. The value of secretin-MRCP(magnetic resonance cholangiopancreatography) for diagnosis of chronic pancreatitis is illustrated. Data help to choose the minimally effective prednisolone dose in autoimmune pancreatitis. The increased prevalence of fractures in patients with chronic pancreatitis highlights the necessity of screening for bone density loss. The association of vitamin D intake with pancreatic cancer is described. The probability of cancer in IPNM is shown and innovative surgical concepts to reduce the loss of pancreatic function are presented. Finally neoadjuvant concepts for the treatment of pancreatic cancer are highlighted. PMID:27329710

  11. Regulation of Pancreatic microRNA-7 Expression

    Directory of Open Access Journals (Sweden)

    Sharon Kredo-Russo

    2012-01-01

    Full Text Available Genome-encoded microRNAs (miRNAs provide a posttranscriptional regulatory layer, which is important for pancreas development. Differentiation of endocrine cells is controlled by a network of pancreatic transcription factors including Ngn3 and NeuroD/Beta2. However, how specific miRNAs are intertwined into this transcriptional network is not well understood. Here, we characterize the regulation of microRNA-7 (miR-7 by endocrine-specific transcription factors. Our data reveal that three independent miR-7 genes are coexpressed in the pancreas. We have identified conserved blocks upstream of pre-miR-7a-2 and pre-miR-7b and demonstrated by functional assays that they possess promoter activity, which is increased by the expression of NeuroD/Beta2. These data suggest that the endocrine specificity of miR-7 expression is governed by transcriptional mechanisms and involves members of the pancreatic endocrine network of transcription factors.

  12. Effect of IL-4 on altered expression of complement activation regulators in rat pancreatic cells during severe acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Cheng Zhang; Chun-Lin Ge; Ren-Xuan Guo; San-Guang He

    2005-01-01

    AIM: To investigate the effect of IL-4 on the altered expression of complement activation regulators in pancreas and pancreatic necrosis during experimental severe acute pancreatitis (SAP).METHODS: SAP model of rats was established by retrograde injection of 5% sodium taurocholate (1 mL/kg)into the pancreatic duct. We immunohistochemically assayed the expression of three complement activation regulators: decay accelerating factor (DAF; CD55), 20ku homologous restriction factor (HRF20; CD59) and membrane cofactor protein (MCP; CD46), in the pancreatic acinar cells of rats at 0, 3, 6, 12, and 24 h after the induction of SAP model. Meanwhile the levels of amylase and lipase were determined, and morphological examination was performed. Then, 61 rats were randomly divided into three groups. Group A (n = 21) received notreatment after the SAP model was established; group B (n = 20) was given IL-4 (8 μg/animal) intraperitoneally 0.5 h before the SAP model was established; group C (n = 20) was given IL-4 (8 μg/animal) intraperitoneally 0.5 h after the SAP model was established. Plasma amylase and lipase, extent of pancreatic necrosis and expression of complement activation regulators were investigated 6 h after the induction of SAP model.RESULTS: Three complement activation regulators were all expressed in pancreatic acinar cells. MCP was not found on the basolateral surface as reported. Contrary to the gradually increasing plasma level of amylase and lipase, expression of complement activation regulators decreased after SAP model was set up. At the same time, the severity of pancreatic necrosis was enhanced.A strong negative correlation was found between the expression of MCP, DAF, CD59 in pancreatic acinar cells and the severity of pancreatic necrosis (r = -0.748, -0.827,-0.723; P<0.01). In the second series of experiments,no matter when the treatment of IL-4 was given (before or after the induction of SAP model), the serum level of amylase or lipase Was decreased

  13. Clinicopathologic characteristics of fibrous mass-forming chronic pancreatitis

    Institute of Scientific and Technical Information of China (English)

    常雪姣

    2013-01-01

    Objective To investigate clinicopathological features of fibrous mass-forming chronic pancreatitis (FMCP) ,to compare clinicopathological and immunohistochemical characteristics between autoimmune pancreatitis (AIP) and fibrous mass-forming non-autoimmune pancreatitis

  14. Etiopathogenesis of insulin autoimmunity.

    OpenAIRE

    Åke Lenmark; Moustakas, Antonis K; Papadopoulos, George K; Norio Kanatsuna

    2012-01-01

    Autoimmunity against pancreatic islet beta cells is strongly associated with proinsulin, insulin, or both. The insulin autoreactivity is particularly pronounced in children with young age at onset of type 1 diabetes. Possible mechanisms for (pro)insulin autoimmunity may involve beta-cell destruction resulting in proinsulin peptide presentation on HLA-DR-DQ Class II molecules in pancreatic draining lymphnodes. Recent data on proinsulin peptide binding to type 1 diabetes-associated HLA-DQ2 and ...

  15. Relationship between the Apoptosis and Notch-1 Expression in Acute Pancreatitis

    Institute of Scientific and Technical Information of China (English)

    ZHANG Weikang; WANG Chunyou; YANG Ming; WAN Chidan

    2007-01-01

    In order to investigate the expression of Notch-1 in rats with acute pancreatitis (AP) and its relation with apoptosis of pancreatic cells, mild AP (MAP) and severe AP (SAP) models were established by retrograde injection of different concentrations of sodium taurocholae into pancreatic duct. The apoptosis index and the expression of Notch-1 protein and mRNA were detected by using TUNEL, Western blot and real-time PCR in MAP and SAP at different time intervals. The results showed that in MAP group the apoptosis index was significantly elevated during 4 to 24 h after induction of pancreatitis, but there was no significant difference among different time intervals. In SAP group, the apoptosis index reached the peak at 4th h after induction of pancreatitis, then gradually declined. There was significant difference in apoptosis index between MAP and SAP groups. Starting from 4th after induction of pancreatitis, the expression of Notch-1 in both MAP and SAP group was increased at different time intervals, but that in SAP group was significantly higher than in MAP group (P<0.05). The expression of Notch in MAP and SAP groups reached the peak at 12th and 8th h respectively after induction of pancreatitis. It was concluded that there was significant difference in apoptosis index and the Notch-1 expression in different types of AP. The overexpression of Notch-1 could aggravate AP by inhibiting the apoptosis of pancreatic cells.

  16. NBL1 and anillin (ANLN genes over-expression in pancreatic carcinoma.

    Directory of Open Access Journals (Sweden)

    Dariusz Lange

    2009-12-01

    Full Text Available The aim of the study was to analyze the gene expression profile of pancreatic cancer to derive novel molecular markers of this malignancy. The snap-frozen or RNA-later preserved samples of 18 pancreatic adenocarcinomas, 5 chronic pancreatitis cases and 6 specimens of grossly normal pancreas were used for microarray analysis by HG-U133 Plus 2.0 oligonucleotide Affymetrix arrays. Validation was carried out by real-time quantitative PCR (Q-PCR in the set of 66 samples: 31 of pancreatic cancer, 14 of chronic pancreatitis and 21 of macroscopically unchanged pancreas. By Principal Component Analysis of the microarray data we found a very consistent expression pattern of normal samples and a less homogenous one in chronic pancreatitis. By supervised comparison (corrected p-value 0.001 we observed 11094 probesets differentiating between cancer and normal samples, while only seventy six probesets were significant for difference between cancer and chronic pancreatitis. The only gene occurring within the best 10 genes in both comparisons was S100 calcium binding protein P (S100P, already indicated for its utility as pancreatic cancer marker by earlier microarray-based studies. For validation we selected two genes which appeared as valuable candidates for molecular markers of pancreatic cancer: neuroblastoma, suppression of tumorigenicity 1 (NBL1 and anillin (ANLN. By Q-PCR, we confirmed statistically significant differences in these genes with a 9.5 fold-change difference between NBL1 expression in cancer/normal comparison and a relatively modest difference between cancer and pancreatitis. For ANLN even more distinct differences were observed (cancer/normal 19.8-fold, cancer/pancreatitis 4.0-fold. NBL1 and anillin are promising markers for pancreatic carcinoma molecular diagnostics.

  17. Comparative proteomic analysis of differentially expressed proteins in human pancreatic cancer tissue

    Institute of Scientific and Technical Information of China (English)

    Jian-Hua Chen; Run-Zhou Ni; Ming-Bing Xiao; Ji-Guang Guo; Jia-Wei Zhou

    2009-01-01

    BACKGROUND:Pancreatic cancer is one of the most common malignant tumors. Early diagnosis of pancreatic cancer is dififcult because of the latent onset and lack of good biomarkers. This study aimed to look for and identify differentially expressed proteins in tissues of pancreatic cancer and adjacent noncancerous tissues by proteomic approaches so as to provide information about possible pancreatic cancer markers and therapeutic targets. METHODS:Proteins extracted from 3 paired adjacent noncancerous and cancerous pancreatic tissue specimens were separated by two-dimensional gel electrophoresis (2-DE). The protein spots exhibiting statistical alternations between the two groups through computerized image analysis were then identiifed by matrix-assisted laser desorption ionization time-of-lfight mass spectrometry (MALDI-TOF-MS). In addition, Western blotting and immunohistochemistry were performed to verify the expression of certain candidate proteins. RESULTS:Twelve proteins were signiifcantly upregulated and 4 were downregulated between cancerous and paired adjacent noncancerous pancreatic tissues. Several proteins (S100A11, Ig gamma-1 chain C region, GSTO1 and peroxiredoxin 4) were found for the ifrst time to be associated with pancreatic cancer. Differential expression of some identiifed proteins was further conifrmed by Western blotting analysis and/or immunohistochemical analysis.CONCLUSIONS:Comparative proteomic analysis using 2-DE and MALDI-TOF-MS is an effective method for identifying differentially expressed proteins that may be the potential diagnostic biomarkers and therapeutic targets for pancreatic cancer.

  18. Molecular mechanisms of pancreatic stone formation in chronic pancreatitis.

    Directory of Open Access Journals (Sweden)

    Shigeru B.H. Ko

    2012-11-01

    Full Text Available Chronic pancreatitis (CP is a progressive inflammatory disease in which the pancreatic secretory parenchyma is destroyed and replaced by fibrosis. The presence of intraductal pancreatic stone(s is important for the diagnosis of CP; however, the precise molecular mechanisms of pancreatic stone formation in CP were left largely unknown. CFTR is a chloride channel expressed in the apical plasma membrane of pancreatic duct cells and plays a central role in HCO3- secretion. In previous studies, we have found that CFTR is largely mislocalized to the cytoplasm of pancreatic duct cells in all forms of CP and corticosteroids normalizes the localization of CFTR to the proper apical membrane at least in autoimmune pancreatitis. From these observations, we could conclude that the mislocalization of CFTR is a cause of protein plug formation in CP, subsequently resulting in pancreatic stone formation.Considering our observation that the mislocalization of CFTR also occurs in alcoholic or idiopathic CP, it is very likely that these pathological conditions can also be treated by corticosteroids, thereby preventing pancreatic stone formation in these patients. Further studies are definitely required to clarify these fundamental issues.

  19. Serum miRNA expression profiles change in autoimmune vitiligo in mice.

    Science.gov (United States)

    Shi, Yu-Ling; Weiland, Matthew; Lim, Henry W; Mi, Qing-Sheng; Zhou, Li

    2014-02-01

    It is widely believed that non-segmental vitiligo results from the autoimmune destruction of melanocytes. MicroRNAs (miRNAs), a class of small non-coding RNAs that negatively regulate gene expression, are involved in the immune cell development and function and regulate the development of autoimmune diseases. Recent studies demonstrate that functional miRNAs can be detected in the serum and serve as biomarkers of various diseases. In the present study, we used a mouse autoimmune vitiligo model, in which melanocyte autoreactive CD4+ T cells were adoptively transferred into Rag1(-/-) host mice. Serum miRNA expression was profiled in vitiligo developed mice and control mice using TaqMan RT-PCR arrays. We have found that the expressions of 20 serum miRNAs were changed in vitiligo mice compared to control mice. Three increased miRNAs, miR-146a, miR-191, and miR-342-3p, were further confirmed by a single TaqMan RT-PCR. Our findings suggest that miRNAs may be involved in vitiligo development and serum miRNAs could serve as serum biomarkers for vitiligo in mice.

  20. Alteration of somatostatin receptor subtype 2 gene expression in pancreatic tumor angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Ren-Yi Qin; Ru-Liang Fang; Manoj Kumar Gupta; Zheng-Ren Liu; Da-Yu Wang; Qing Chang; Yi-Bei Chen

    2004-01-01

    AIM: To explore the difference of somatostatin receptorsubtype 2 (SST2R) gene expression in pancreatic canceroustissue and its adjacent tissue, and the relationship betweenthe change of SST2R gene expression and pancreatic tumorangiogenesis related genes.METHODS: The expressions of SST2R, DPC4, p53 and ras genes in cancer tissues of 40 patients with primary pancreatic cancer, and the expression of SST2R gene in its adjacent tissue were determined by immunohistochemiscal LSAB method and EnVisionTM method. Chi-square test was used to analyze the difference in expression of SST2R in pancreatic cancer tissue and its adjacent tissue, and the correlation of SST2R gene expression with the expression of p53, ras and DPC4 genes.RESULTS: Of the tissue specimens from 40 patients with primary pancreatic cancer, 35 (87.5%) cancer tissues showed a negative expression of SST2R gene, whereas 34 (85%) a positive expression of SST2R gene in its adjacent tissues.Five (12.5%) cancer tissues and its adjacent tissues simultaneously expressed SST2R. The expression of SST2R gene was markedly higher in pancreatic tissues adjacent to cancer than in pancreatic cancer tissues (P<0.05). The expression rates of p53, ras and DPC4 genes were 50%,60% and 72.5%, respectively. There was a significant negative correlation of SST2R with p53 and ras genes (X12=9.33,X22=15.43, P<0.01), but no significant correlation with DPC4 gene (X2=2.08, P >0.05).CONCLUSION: There was a significant difference of SST2R gene expression in pancreatic cancer tissues and its adjacent tissues, which might be one cause for the different therapeutic effects of somatostatin and its analogs on pancreatic cancer patients. There were abnormal expressions of SST2R, DPC4, p53 and ras genes in pancreatic carcinogenesis, and moreover, the loss or decrease of SST2R gene expression was significantly negatively correlated with the overexpression of tumor angiogenesis correlated p53 and ras genes, suggesting that SST2R gene

  1. Clinicopathological significance of p53 and mdm2 protein expression in human pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Ming Dong; Gang Ma; Wei Tu; Ke-Jian Guo; Yu-Lin Tian; Yu-Ting Dong

    2005-01-01

    AIM: To study the clinicopathological significance of p53 and mdm2 protein expression in human pancreatic cancer. METHODS: To investigate the expression of p53 and mdm2 in pancreatic cancer by immunohistochemistry, and the relationships between the p53 and mdm2 protein expression and clinicopathological parameters in pancreatic cancer.RESULTS: The positive expression of p53 protein was found in 40 of 59 patients (67.8%) and that of mdm2 protein in 17 of 59 patients (28.8%). No obvious relationships were found between p53 as well as mdm2 expression and sex, tumor site, TNM staging and histological differentiation. p53 expression was increased in patients younger than 65 years old, while mdm2 had no relationship with age. The survival time of the patients with the positive expression of p53 and mdm2 proteins was obviously shorter than the other groups. CONCLUSION: Both p53 and mdm2 presented relatively high expression in human pancreatic cancer. The overexpression of p53 and mdm2 might reflect the malignant proliferation of pancreatic cancer and their co-expression might be helpful to evaluate the prognosis of the patients with pancreatic cancer.

  2. Prognostic significance of S100A4 and vascular endothelial growth factor expression in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Kai-Xing Ai; Lin-Yuan Lu; Xin-Yu Huang; Wei Chen; Hui-Zhen Zhang

    2008-01-01

    AIM:To investigate the expression of vascular endothelial growth factor (VEGF) and calcium-binding protein S100A4 in pancreatic cancer and their relationship to the clinicopathological parameters and prognosis of pancreatic cancer.METHODS: Expression status of VEGF and S100A4 was examined in 62 surgical specimens of primary pancreatic cancer by immunohistochemistry. Correlation between the expression of VEGF and S100A4 and clinicopathological parameters was analyzed.RESULTS: Thirty-eight of 62 (61.3%) specimens of primary pancreatic cancer were positive for S100A4. Thirty-seven (59.7%) specimens showed positive expression of VEGF. The positive correlation between S100A4 and VEGF expression was significant in cancer tissues(P < 0.001). S100A4 expression was significantly correlated with tumor size, TNM stage and poorer prognosis. VEGF expression had a significant correlation with poorer prognosis. The prognosis of 17 S100A4- and VEGF-negative cancer patients was significantly better than that of other patients (P < 0.05). Distant metastasis(P = 0.001), S100A4- (P = 0.008) and VEGF-positive expression (P= 0.016) were significantly independent prognostic predictors (P<0.05).CONCLUSION: Over-expression of S100A4 and VEGF plays an important role in the development of pancreatic cancer. Combined examination of the two molecules might be useful in evaluating the outcome of patients with pancreatic cancer.

  3. The role of stress in the clinical expression of thyroid autoimmunity.

    Science.gov (United States)

    Tsatsoulis, Agathocles

    2006-11-01

    During stress, activation of the hypothalamic-pituitary-adrenal axis and the sympathoadrenal system leads to increased secretion of glucocorticoids and catecholamines, respectively, in order to maintain homeostasis. Recent evidence suggests that stress hormones, acting on antigen-presenting immune cells, may influence the differentiation of bipotential T helper (Th) cells away from Th1 and toward a Th2 phenotype. This results in suppression of cellular immunity and potentiation of humoral immunity. Thyroid autoimmunity is clinically expressed as Hashimoto's thyroiditis (HT) and its variants (sporadic or postpartum thyroiditis) or as Grave's disease (GD). The different phenotypic expression of thyroid autoimmunity is largely dependent on the balance of Th1 versus Th2 immune response. A predominantly Th1-mediated immune activity may promote apoptotic pathways on thyroid follicular cells leading to thyroid cell destruction and HT. Conversely, predominance of Th2-mediated immune response may induce antigen-specific B lymphocytes to produce anti-TSH receptor (TSHr) antibodies causing GD. The weight of evidence from epidemiological and case-control studies supports an association between stress and GD. On the other hand, there is little information available on the effect of stress on HT, but there is evidence for an increase in postpartum thyroiditis, following the cellular immune suppressive effect of pregnancy. Whether stress has a causative effect on GD remains elusive. Circumstantial evidence supports the hypothesis that stress may influence the clinical expression of thyroid autoimmunity in susceptible individuals favoring the development of GD by shifting the Th1-Th2 balance away for Th1 and toward Th2. Conversely, recovery from stress or the immune suppressive effect of pregnancy may induce a Th2 to Th1 "return shift" leading to autoimmune (sporadic) or postpartum thyroiditis, respectively. PMID:17192582

  4. Regulations of Gene Expression in Medullary Thymic Epithelial Cells Required for Preventing the Onset of Autoimmune Diseases

    OpenAIRE

    Akiyama, Taishin; Shinzawa, Miho; Qin, Junwen; Akiyama, Nobuko

    2013-01-01

    Elimination of potential self-reactive T cells in the thymus is crucial for preventing the onset of autoimmune diseases. Epithelial cell subsets localized in thymic medulla [medullary thymic epithelial cells (mTECs)] contribute to this process by supplying a wide range of self-antigens that are otherwise expressed in a tissue-specific manner (TSAs). Expression of some TSAs in mTECs is controlled by the autoimmune regulator (AIRE) protein, of which dysfunctional mutations are the causative fac...

  5. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.

    Science.gov (United States)

    Cros, J; Hentic, O; Rebours, V; Zappa, M; Gille, N; Theou-Anton, N; Vernerey, D; Maire, F; Lévy, P; Bedossa, P; Paradis, V; Hammel, P; Ruszniewski, P; Couvelard, A

    2016-08-01

    Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

  6. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ishan Roy

    Full Text Available Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

  7. Expression of Ki-67, p53, and K-ras in chronic pancreatitis and pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Seok Jeong; Young Bae Kim; Don Haeng Lee; Jung Il Lee; Jin-Woo Lee; Kye Sook Kwon; Pum-Soo Kim; Hyung Gil Kim; Yong Woon Shin; Young Soo Kim

    2005-01-01

    AIM: To examine surgical specimens of pancreas with either chronic pancreatitis or pancreatic cancer in order to study whether ductal hyperplasia and dysplasia in pancreas represent precursor lesions for pancreatic cancer.METHODS: We examined expression of Ki-67, CEA,p53, and K-ras, in the surgical specimens of pancreas with adenocarcinomas (n = 11) and chronic pancreatitis (n = 12). Cellular proliferation was assessed by Ki-67proliferation index using the proliferation marker Ki-67.In specimens with pancreas cancer, we divided pancreas epithelium into normal (n=7), ductal hyperplasia (n=3), dysplasia (n=4), and cancerous lesion (n=11) after hematoxylin and eosin staining, Ki-67, and CEA immunohistochemical staining. In cases with chronic pancreatitis, the specimen was pathologically examined as in cases with pancreas cancer, and they were also determined as normal (n=10), ductal hyperplasia (n=4), or dysplasia (n= 5). p53 and K-ras expression were also studied by immunohistochemical staining.RESULTS: In pancreatic cancer, the Ki-67 index was 3.73±3.58 in normal site, 6.62±4.39 in ductalhyperplasia, 13.47±4.02 in dysplasia and 37.03±10.05in cancer tissue, respectively. Overall, p53 was positive in normal ducts, ductal hyperplasia, dysplasia, and carcinoma cells in 0 of 14 (0%), 0 of 7 (0%), 7 of 9 (78%),and 10 of 11 (91%), respectively, and K-ras was positive in 0 of 8 (0%), 1 of 3 (33%), 4 of 6 (67%), 4 of 5 (80%),respectively.CONCLUSION: Our results favorably support the hypothesis that ductal hyperplasia and dysplasia of the pancreas might be precursor lesions for pancreas cancer.Further evaluation of oncogenes by the molecular study is needed.

  8. Changes in gene expression of pancreatitis-associated protein and pancreatic secretory trypsin inhibitors in experimental pancreatitis produced by pancreatic duct occlusion in rats: comparison with gene expression of cholecystokinin and secretin.

    Science.gov (United States)

    Funakoshi, A; Miyasaka, K; Jimi, A; Nakamura, E; Teraoka, H

    1995-08-01

    Pancreatic duct occlusion is known to produce a sustained increase in the plasma cholecystokinin (CCK) concentration and to affect the tissue content of CCK in the rat. The tissue content of CCK is correlated with regenerative changes in the pancreas after pancreatic duct occlusion. In the present study, we examined the changes in mRNA levels of pancreatic secretory trypsin inhibitors (PSTIs), pancreatitis-associated protein (PAP), and amylase in the pancreas in comparison with changes in CCK and secretin mRNA levels in the intestine and the histological changes produced by pancreatic duct ligation. Rats with an internal bile fistula and with obstruction of pancreatic flow were prepared and were sacrificed 1, 3, 7, 10, 14, and 28 days later. Then mRNA levels of CCK, secretin, PSTIs, PAP, and amylase were determined by slot-blot analysis. The CCK mRNA level gradually increased to a peak on day 10, was slightly lower on day 14, and returned to the control level on day 28. The level of secretin mRNA did not change. The mRNA levels of PSTIs increased significantly on day 3 after occlusion. PAP mRNA was detectable on days 1 and 3, being maximal on day 1. The mRNA level of amylase was markedly decreased on days 1 and 3, then remained lower than the control level. Histological examination showed acute inflammatory changes in the pancreas on days 1 and 3 and regenerative changes from day 7. These results suggest that a change in gene expression of PAP reflects acute inflammatory changes in the pancreas most sensitively.

  9. Pancreatitis

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008318 Proteomics of hyperlipidemia-associated pancreatitis using differential gel electrophoresis and tandem mass spectrometry: experiment with rats. ZHANG Wei(张伟), et al. Dept Gastroenterol, Shanghai 1st Hosp, Shanghai Jiaotong Univ, Shanghai 200080. Natl Med J China 2008;88(16):1132-1131.Objective To analyze the injury mechanismof hyperlipidemia-associated acute pancreatitis utilizing pro-teomics.Methods Ten SD rats were fed with high fat feed to establish hyperlipidemic models,and 10 SD rats were fed with normal feed to be used as control group.

  10. Expression and signifi cance of TLR4 and HIF-1α in pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To investigate the expression of toll-like receptor(TLR) 4,nuclear factor-κB(NF-κB) p65 and hypoxiainducible transcription factor 1α(HIF-1α) in pancreatic ductal adenocarcinoma and their clinical significance.METHODS:The mRNA of TLR4 and HIF-1α were investigated by real-time polymerase chain reaction in 30 cases of pancreatic ductal adenocarcinoma and its adjacent tissues,and expression of TLR4,NF-κB p65 and HIF-1α protein were detected by immunohistochemistry in 65 cases of pancreatic ductal adenocarci...

  11. Comparative analysis of clinicopathological correlations of cyclooxygenase-2 expression in resectable pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Marketa; Hermanova; Petr; Karasek; Jiri; Tomasek; Jiri; Lenz; Jiri; Jarkovsky; Petr; Dite

    2010-01-01

    AIM:To perform a comparative analysis of clinicopathological correlations of cyclooxygenase2 (COX2) expression in pancreatic cancer, examined by monoclonal and polyclonal antibodies.METHODS: The COX2 expression in 85 resection specimens of pancreatic ductal adenocarcinoma was immunohistochemically examined using both monoclonal and polyclonal antibodies. The final immunoscores were obtained by multiplying the percentage of positive cells with the numeric score reflecting the staining intensity.COX2 expressi...

  12. PDX-1 Expression in Pancreatic Ductal Cells after Partial Pancreatectomy in Adult Rats

    Institute of Scientific and Technical Information of China (English)

    刘涛; 王春友; 万赤丹; 熊炯忻; 许逸卿; 周峰

    2004-01-01

    To investigate the protein and mRNA expression of pancreas/duodenal homeobox-1(PDX-1), a transcription factor as a marker for pancreatic stem cells, in pancreatic ductal cells of rats after partial (90 %) pancreatectomy and evaluated the significance of the PDX-1 expression.Western blot and Reverse transcriptase-polymerase chain reaction (RT-PCR) were used to detect the expression of PDX-1 protein and mRNA respectively. PDX-1 protein was only faintly detected in pancreatic ductal cells on the day 1 after partial pancreatectomy. On the day 2 and 3 after operation in operation group, a 2-3 fold increased PDX-1 protein was observed, corresponding to the characteristic 42-kD protein in Western blot. There was significant difference between operation group and sham-operation group (P<0.05). PDX-1 protein expression on the day 5 and 7 after operation had already been no difference from control group (P>0.05). RT-PCR revealed the PDX-1mRNA expression showed no significant difference between operation group at various time points and sham-operation group (P>0.05). These results indicate that there was overexpression of PDX-1 in the cells of pancreatic epithelium during the regeneration of remnant pancreas after partial pancreatectomy in adult rats, suggesting the pancreatic stem cells in pancreatic ductal epithelial cells are involved in the regeneration of remnant pancreas and the expression of PDX-1 in ductal cells was regulated posttranscription.

  13. Proteomic analysis of differential protein expression in early process of pancreatic regeneration in pancreatectomized rats

    Institute of Scientific and Technical Information of China (English)

    Ming YANG; Wei LIU; Chun-you WANG; Tao LIU; Feng ZHOU; Jing TAO; Yang WANG; Ming-tao LI

    2006-01-01

    Aim: A broad-range proteomic approach was applied to investigate the complexity of the mechanisms involved in pancreatic regeneration for identification of new targets of diabetes treatment and potential markers of pancreatic stem cells. Methods: A regeneration pancreatic model was induced by 90% partial pancreatectomy (Px) in rats. Changes in the protein expression in regenerating rat pancreas on the third day after Px, as compared with rats that received sham surgery, were analyzed by using 2-D gel electrophoresis (2-DE), mass spectrometry(MS), and mass fingerprinting. Results: 2-DE revealed 91 spots with at least 1.5-fold increases in expression at 3 d after pancreatectomy and 53 differentially expressed proteins that were identified by peptide mass fingerprinting (PMF). These included cell growth-related, lipid and energy metabolism-related, protein and amino acid metabolism-related proteins, and signal transduction proteins. Vimentin, CK8, L-plastin. hnRNP A2/B1, and AGAT are associated with embryogenesis and cell differentiation, and may be new potential pancreatic stem cells markers. Conclusion: The proteome profiling technique provided a broad-based and effective approach for the rapid assimilation and identification of adaptive protein changes during pancreas regeneration induced by pancreatectomy. Our data clarify the global proteome during the pancreatic proliferation and differentiation processes, which is important for better understanding of pancreatic regeneration and for discovering of protein biomarkers for pancreatic stem cells.

  14. Serum expression of HA and LN in lewis rat models of autoimmune myocarditis

    International Nuclear Information System (INIS)

    Objective: To study the clinical significance of dynamic changes of serum expressions of hyaluronic acid (HA) and laminin (LN) in Lewis rat models of experimental autoimmune myocarditis (EAM). Methods: Fifty Lewis rat models of experimental autoimmune myocarditis (EAM) were established with injection of recombinant cardiac C protein with complete freund adjuvant into two foot-pads plus intraperitoneal injection of pertussis toxin. At 1w, 2w, 4w, 6w and 8w, 10 models were sacrificed each time;cardiac tissues were examined with HE stain for myocardial inflammatory score and examined with picrosirius red stain for myocardial fibrosis score, also, serum HA and LN expressions were determined with RIA. These examinations were performed in 10 undisturbed animals as controls. Results: The myocardial inflammatory scores of the models at 1w were about the same as those in the controls, but the scores rapidly increased from 2w on to 4w then fell gradually. The myocardial fibrosis scores of the models at 1wk were also not much different from those in controls. The fibrosis scores increased rapidly at 4w and maintained at high level up to 8w. The changes of serum expressions of HA and LN roughly paralleled those of myocardial fibrosis scores i. e. rapidly increased at 4w up to 8w. Conclusion: Serum expressions of HA and LN could faithfully reflect the degree of myocardial fibrosis in rat models of EAM. HA and LN were useful markers of myocardial fibrois and were of prognostic importance. (authors)

  15. The role of endoscopic ultrasound (EUS in relation to other imaging modalities in the differential diagnosis between mass forming chronic pancreatitis, autoimmune pancreatitis and ductal pancreatic adenocarcinoma Papel de la endoscopia en relación con otras modalidades de imagen en el diagnóstico diferencial entre pancreatitis crónica en forma de masa, pancreatitis autoinmune y adenocarcinoma pancreático

    Directory of Open Access Journals (Sweden)

    Julio Iglesias-García

    2012-06-01

    Full Text Available Differential diagnosis of solid pancreatic lesions remains as an important clinical challenge, mainly for the differentiation between mass forming chronic pancreatitis, autoimmune pancreatitis and pancreatic adenocarcinoma. Endoscopic ultrasound (EUS, computed tomography (CT and magnetic resonance imaging (MRI can all provide valuable and complementary information in this setting. Among them, EUS has the unique ability to obtain specimens for histopathological diagnosis and can therefore play a crucial role in the evaluation patients with inconclusive findings on initial examinations. Nowadays, new developed techniques associated to EUS, like elastography and contrast enhancement, have shown promising results for the differential diagnosis of these pancreatic lesions.El diagnóstico diferencial de las lesiones sólidas pancreáticas permanece como un reto clínico importante, sobre todo para la diferenciación entre la masa de conformación pancreatitis crónica, pancreatitis autoinmune y el adenocarcinoma de páncreas. Ecografía endoscópica (USE, la tomografía computarizada (TC y la resonancia magnética (MRI pueden proporcionar información valiosa y complementaria en este entorno. Entre ellos, la USE tiene la capacidad única de obtener muestras para diagnóstico histopatológico y por lo tanto, puede desempeñar un papel crucial en la evaluación de los pacientes con resultados poco concluyentes en los exámenes iniciales. Hoy en día, las nuevas técnicas desarrolladas asociadas a la USE, como la elastografía y realce de contraste, han mostrado resultados prometedores para el diagnóstico diferencial de las lesiones pancreáticas.

  16. Key metalloproteinases are expressed by specific cell types in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Toft-Hansen, Henrik; Nuttall, Robert K; Edwards, Dylan R;

    2004-01-01

    Metalloproteinases (MPs) include matrix metalloproteinases (MMPs) and metalloproteinase-disintegrins (ADAMs). Their physiological inhibitors are tissue inhibitor of metalloproteinases (TIMPs). MPs are thought to be mediators of cellular infiltration in the pathogenesis of multiple sclerosis and its...... animal model, experimental autoimmune encephalomyelitis (EAE). We used real-time RT-PCR to profile the expression of all 22 known mouse MMPs, seven ADAMs, and all four known TIMPs in spinal cord from SJL/J mice and mice with adoptively transferred myelin basic protein (MBP)-specific EAE. A significant...

  17. Ribosomal protein s6-ps240 is expressed in lesional skin from patients with autoimmune skin blistering diseases

    Directory of Open Access Journals (Sweden)

    Ana Maria Abreu Velez

    2013-01-01

    Full Text Available Background: The in situ signaling transduction within skin biopsies from patients affected by autoimmune skin blistering diseases is not well-characterized. Aim : In autoimmune skin blistering diseases, autoantibodies seem to trigger several intracellular signaling pathways and we investigated the presence of the phosphorylated form of ribosomal protein S6-pS240 within autoimmune skin blistering diseases biopsies. Materials and Methods: We utilized immunohistochemistry to evaluate the presence of S6-pS240 in lesional skin biopsies of patients affected by autoimmune skin blistering diseases including patients with an endemic and nonendemic pemphigus foliaceus (non EPF, with bullous pemphigoid (BP, pemphigus vulgaris (PV, dermatitis herpetiformis (DH, and the respective controls. Results: Most autoimmune bullous skin diseases biopsies stained positive for S6-pS240 around lesional blisters, including adjacent areas of the epidermis; and within upper dermal inflammatory infiltrates, and/or mesenchymal-endothelial cell junctions within the dermis. Conclusions: We document that S6-pS240 is expressed in lesional areas of skin biopsies from patients with autoimmune skin blistering diseases, as well as on eccrine glands and piloerector muscles. Thus, the role of this molecule in autoimmune skin blistering diseases warrants further study.

  18. Frequency Of Pancreatic Beta-Cell Autoimmunity Markers In Patients With Autoimmune Thyroid Disease Frecuencia de marcadores de autoinmunidad beta pancreática en pacientes con enfermedad tiroidea autoinmune

    Directory of Open Access Journals (Sweden)

    María E. Primo

    2008-02-01

    Full Text Available A total of 305 ambulatory patients recruited at the Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, with autoimmune thyroid disease (AITD were studied to search for associations between autoimmune thyroid disease and presence of serum markers of autoimmune diabetes mellitus. Screening for markers of pancreatic beta-cell autoimmunity was performed by radioligand binding assays (RBA as follows: autoantibodies to glutamic acid decarboxylase (GADA and proinsulin (PAA were determined in all sera, whereas autoantibodies to protein tyrosine phosphatase (IA-2A and insulin (IAA were additionally measured in 200 sera randomly selected from the total collection. In addition, every GADA positive serum among the remaining 105 sera was systematically tested for the presence of IA-2A and IAA. In the cohort of 305 AITD patients 22 (7.2% were previously diagnosed as type 1, type 2 or insulin-requiring type 2 diabetics. Ten of these patients presented serum marker positivity specific for β-cell autoantigens and 12 were marker negative. On the other hand, considering the majority of non-diabetic AITD patients (n=283, β-cell marker positivity was detected in 17 individuals (6.0%. The prevalence of autoimmune diabetes markers was much higher in the studied population than in the general population utilized as a control group, and GADA was the most frequent marker.Se investigó la asociación entre enfermedad tiroidea autoinmune y la presencia de marcadores séricos de diabetes mellitus en 305 pacientes ambulatorios con enfermedad tiroidea autoinmune reclutados en la División Endocrinología. La búsqueda de marcadores de autoinmunidad contra las células beta pancreáticas se realizó por la técnica de unión de radioligandos (RBA como se detalla a continuación: se determinaron autoanticuerpos contra la decarboxilasa del ácido glutámico (GADA y proinsulina (PAA en todos los sueros, mientras que los anticuerpos contra la prote

  19. Thymosin beta-10 is aberrantly expressed in pancreatic cancer and induces JNK activation.

    Science.gov (United States)

    Li, Min; Zhang, Yuqing; Zhai, Qihui; Feurino, Louis W; Fisher, William E; Chen, Changyi; Yao, Qizhi

    2009-03-01

    Thymosin beta-10 (T beta 10) has been shown to be associated with several cancers; however, its role in pancreatic cancer is not understood. The expression of T beta 10 was determined by immunohistochemistry and real-time polymerase chain reaction. The phosphorylation of JNK and the cytokine secretion was determined by using the Bio-Plex phosphoprotein and cytokines assays. Pancreatic cancer tissues and cells expressed higher amounts of T beta 10 than normal surrounding tissues and human pancreatic duct epithelial cells. Exogenous T beta 10 caused the phosphorylation of JNK and increased the secretion of cytokines interleukin (IL)-7 and IL-8 in BxPC-3 cells. T beta 10 might be a promising marker and a novel therapeutic target for pancreatic cancer. PMID:19194824

  20. Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer

    OpenAIRE

    Xiaojia Guo; Lindsay Hollander; Douglas MacPherson; Ling Wang; Heino Velazquez; John Chang; Robert Safirstein; Charles Cha; Fred Gorelick; Desir, Gary V.

    2016-01-01

    An essential feature of cancer is dysregulation of cell senescence and death. Renalase, a recently discovered secreted flavoprotein, provides cytoprotection against ischemic and toxic cellular injury by signaling through the PI3K-AKT and MAPK pathways. Here we show that renalase expression is increased in pancreatic cancer tissue and that it functions as a growth factor. In a cohort of patients with pancreatic ductal adenocarcinoma, overall survival was inversely correlated with renalase expr...

  1. Pancreatic Stellate Cells and Chronic Alcoholic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Raffaele Pezzilli

    2007-03-01

    Full Text Available Chronic pancreatitis is a disease often characterized by recurrent episodes of abdominal pain accompanied by progressive pancreatic exocrine and endocrine insufficiency [1] and it sometimes requires multiple hospitalizations. Obstructive jaundice, duodenal stenosis, left-sided portal hypertension, pseudocyst and mass formation, and pancreatic carcinoma may occur as complications of chronic pancreatitis. The disease is frequently the result of chronic alcohol abuse, even if other factors such as genetic alterations, autoimmune disorders, and obstructive disease of the biliary tract and the pancreas may cause the disease [2]. Medical therapy is the treatment of choice for most patients and it is based on substitutive therapy for either exocrine or endocrine insufficiency and on analgesics for pain control. In the presence of intractable pain, surgical management is the main option [3] even if, in recent years, other therapeutic options such as endoscopic therapy [4], thoracoscopic splanchnicectomy [5], and extracorporeal shockwave lithotripsy have been applied in clinical practice [6]. From a pathological point of view, chronic pancreatitis is characterized by irregular sclerosis with destruction and loss of the exocrine parenchyma, and complete replacement of acinar, ductal and endocrine tissue by fibrotic tissue. It has recently been reported that acute alcoholic pancreatitis develops in a pancreas already affected by chronic pancreatitis [7]. In 1982, Watari et al. [8] reported the presence of vitamin A-containing cells in the vitamin A-fed rat pancreas. These were later described and characterized as stellate cells in the rat and the human pancreas [9, 10]. Pancreatic stellate cells are morphologically similar to hepatic stellate cells. They bear long cytoplasmic processes and are situated close to the pancreatic acini. In the quiescent state, these cells contain lipid droplets, store vitamin A and express markers such as desmin, glial

  2. Selenium status and over-expression of interleukin-15 in celiac disease and autoimmune thyroid diseases

    Directory of Open Access Journals (Sweden)

    Anna Velia Stazi

    2010-12-01

    Full Text Available In celiac disease (CD, for its multifactorial nature, the target organs are not limited to the gut, but include thyroid, liver, skin and reproductive and nervous systems. Between the extraintestinal symptoms associated with CD, autoimmune thyroid diseases (AITDs are more evident, underlining as CD-related autoimmune alterations can be modulated not only by gluten but also by various concurrent endogenous (genetic affinity, over-expression of cytokines and exogenous (environment, nutritional deficiency factors. In their pathogenesis a central role for over-expression of interleukin-15 (IL-15 is shown, by inhibiting apoptosis, leading to the perpetuation of inflammation and tissue destruction. Thyroid is particularly sensitive to selenium deficiency because selenoproteins are significant in biosynthesis and activity of thyroid hormones; besides, some selenoproteins as glutathione peroxidase are involved in inhibiting apoptosis. Thus, selenium malabsorption in CD can be thought as a key factor directly leading to thyroid and intestinal damage. Considering the complexity of this interaction and on the basis of available evidence, the aim of this review is to assess as preventive and therapeutic target the role of IL-15 and selenium in the pathogeneses of both CD and AITD.

  3. Kinetics of expression of costimulatory molecules and their ligands in murine relapsing experimental autoimmune encephalomyelitis in vivo

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Navikas, V; Schaub, M;

    1998-01-01

    We studied the kinetics of expression of costimulatory molecules and cytokines in the central nervous system (CNS) in murine relapsing experimental autoimmune encephalomyelitis (EAE). During the natural course of EAE, B7-2 expression in the CNS correlated with clinical signs, while B7-1 was exclu...

  4. Pancreatic Expression database: a generic model for the organization, integration and mining of complex cancer datasets

    Directory of Open Access Journals (Sweden)

    Lemoine Nicholas R

    2007-11-01

    Full Text Available Abstract Background Pancreatic cancer is the 5th leading cause of cancer death in both males and females. In recent years, a wealth of gene and protein expression studies have been published broadening our understanding of pancreatic cancer biology. Due to the explosive growth in publicly available data from multiple different sources it is becoming increasingly difficult for individual researchers to integrate these into their current research programmes. The Pancreatic Expression database, a generic web-based system, is aiming to close this gap by providing the research community with an open access tool, not only to mine currently available pancreatic cancer data sets but also to include their own data in the database. Description Currently, the database holds 32 datasets comprising 7636 gene expression measurements extracted from 20 different published gene or protein expression studies from various pancreatic cancer types, pancreatic precursor lesions (PanINs and chronic pancreatitis. The pancreatic data are stored in a data management system based on the BioMart technology alongside the human genome gene and protein annotations, sequence, homologue, SNP and antibody data. Interrogation of the database can be achieved through both a web-based query interface and through web services using combined criteria from pancreatic (disease stages, regulation, differential expression, expression, platform technology, publication and/or public data (antibodies, genomic region, gene-related accessions, ontology, expression patterns, multi-species comparisons, protein data, SNPs. Thus, our database enables connections between otherwise disparate data sources and allows relatively simple navigation between all data types and annotations. Conclusion The database structure and content provides a powerful and high-speed data-mining tool for cancer research. It can be used for target discovery i.e. of biomarkers from body fluids, identification and analysis

  5. Differential Expression of Glucocorticoid Receptor Noncoding RNA Repressor Gas5 in Autoimmune and Inflammatory Diseases.

    Science.gov (United States)

    Mayama, T; Marr, A K; Kino, T

    2016-08-01

    Glucocorticoids have strong regulatory actions on the immune system and act as potent therapeutic compounds for autoimmune and inflammatory diseases. We previously reported that the long noncoding RNA growth arrest-specific 5 (Gas5), which accumulates inside the cells in response to cellular starvation/growth arrest, functions as a potent repressor of the glucocorticoid receptor (GR) through its RNA "glucocorticoid response element (GRE)". To evaluate potential roles of Gas5 in immune-related disorders, we examined Gas5 RNA levels in various autoimmune, inflammatory, and infectious diseases using the microarray data available in the Gene Expression Omnibus. We found that Gas5 levels were altered in whole blood or leukocytes of the patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and sarcoidosis. Gas5 levels were also altered in infectious diseases, such as by the human immunodeficiency virus type-1 and influenza virus, and bacterial sepsis. In our experimental analysis using mice, Gas5 levels were kept at high basal levels and did not respond to fasting in immune organs, such as spleen and thymus, while its levels in metabolic organs, including liver, fat, and skeletal muscles, were low at baseline and were highly elevated upon this treatment, possibly through suppression of the mTOR pathway. These results suggest that Gas5 plays a role in the regulation of immune functions and pathogenesis/pathophysiology of autoimmune, inflammatory, and infectious diseases in part through modulation of the GR transcriptional activity via its decoy RNA "GRE". Changes in the Gas5 levels may also influence disease response to immunosuppressive glucocorticoid therapy. PMID:27214311

  6. Hypermethylation and aberrant expression of secreted fizzled-related protein genes in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Xian-Min Bu; Cheng-Hai Zhao; Ning Zhang; Feng Gao; Shuai Lin; Xian-Wei Dai

    2008-01-01

    AIM:To determine the methylation status and aberrant expression of some secreted frizzled-related protein (SFRP) genes in pancreatic cancer and explore their role in pancreatic carcinogenesis. METHODS:Methylation status and expression of SFRP genes were detected by methylation-specific PCR (MSPCR) and reverse-transcription PCR (RT-PCR) respectively. RESULTS:The frequencies of methylation for SFRP genes 1,2,4,5 were 70%, 48.3%,60% and 76.7% in pancreatic cancer samples, and 21.7%, 20%,10% and 36.7% in matched cancer adjacent normal tissue samples,respectively (χ2=28.23,P<0.0001 for SFRP gene 1; χ2=10.71,P=0.001 for SFRP gene 2;χ2=32.97,P<0.0001 for SFRP gene 4;χ2=19.55,P<0.0001 for SFRP gene 5). Expression loss of SFRP genes 1,2,4 and 5 was found in 65%,40%,55% and 71.7% of 60 pancreatic cancer samples, and 25%,15%,18.3% and 31.7% of matched cancer adjacent normal tissue samples,respectively (χ2=19.39,P<0.0001 for SFRP gene 1;χ2=9.40,P=0.002 for SFRP gene 2;χ2=17.37,P<0.0001 for SFRP gene 4;χ2=19.22,P<0.0001 for SFRP gene 5).SFRP gene 1 was methylated but not expressed in PC-3 and PANC-1,SFRP gene 2 was methylated but not expressed in PANC-1 and CFPAC-1,SFRP gene 4 was methylated but not expressed in PC-3,and SFRP gene 5 was methylated but not expressed in CFPAC-1. CONCLUSION:Hypermethylation and aberrant expression of SFRP genes are common in pancreatic cancer,which may be involved in pancreatic carcinogenesis.

  7. Usefulness of biopsying the major duodenal papilla to diagnose autoimmune pancreatitis: A prospective study using TgG4-immunostaining

    Institute of Scientific and Technical Information of China (English)

    Terumi Kamisawa; Yuyang Tu; Hitoshi Nakajima; Naoto Egawa; Kouji Tsuruta; Atsutake Okamoto

    2006-01-01

    AIM: To examine the histological and immunohistochemical findings of biopsy specimens taken from the major duodenal papilla of autoirnrnune pancreatitis (AIP)patients.METHODS: The major duodenal papilla in the resected pancreas of 3 patients with AIP and of 5 control patients [pancreatic carcinoma (n = 3) and chronic alcoholic pancreatitis (n = 2)] was irnrnunostained using anti-CD4-T cell, CD8-T cell and IgG4 antibodies. Forceps biopsy specimens taken from the major duodenal papilla of 2patients with AIP and 5 control patients with suspected papillitis were prospectively taken during duodenoscopy and immunohistochernically examined.RESULTS: Moderate or severe lyrnphoplasrnacytic infiltration including many CD4-positive or CD8-positive T lymphocytes and IgG4-positive plasma cells (≥10/HPF),was observed in the major duodenal papilla of all 3 patients with AIP. The same findings were also detected in the biopsy specimens taken from the major duodenal papilla of 2 patients with AIP, but in controls, there were only a few (≤3/HPF) IgG4-positive plasma cells infiltrating the major duodenal papilla.CONCLUSIONS: An abundant infiltration of IgG4-positive plasma cells is specifically detected in the major duodenal papilla of patients with AIP. Although this is a preliminary study, IgG4-irnmunostaining of biopsy specimens taken from the major duodenal papilla may support the diagnosis of AIP.

  8. Identification of gene expression patterns crucially involved in experimental autoimmune encephalomyelitis and multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Martin M. Herrmann

    2016-10-01

    Full Text Available After encounter with a central nervous system (CNS-derived autoantigen, lymphocytes leave the lymph nodes and enter the CNS. This event leads only rarely to subsequent tissue damage. Genes relevant to CNS pathology after cell infiltration are largely undefined. Myelin-oligodendrocyte-glycoprotein (MOG-induced experimental autoimmune encephalomyelitis (EAE is an animal model of multiple sclerosis (MS, a chronic autoimmune disease of the CNS that results in disability. To assess genes that are involved in encephalitogenicity and subsequent tissue damage mediated by CNS-infiltrating cells, we performed a DNA microarray analysis from cells derived from lymph nodes and eluted from CNS in LEW.1AV1 (RT1av1 rats immunized with MOG 91-108. The data was compared to immunizations with adjuvant alone or naive rats and to immunizations with the immunogenic but not encephalitogenic MOG 73-90 peptide. Here, we show involvement of Cd38, Cxcr4 and Akt and confirm these findings by the use of Cd38-knockout (B6.129P2-Cd38tm1Lnd/J mice, S1P-receptor modulation during EAE and quantitative expression analysis in individuals with MS. The hereby-defined underlying pathways indicate cellular activation and migration pathways mediated by G-protein-coupled receptors as crucial events in CNS tissue damage. These pathways can be further explored for novel therapeutic interventions.

  9. Expression of the Autoimmune Regulator Gene and Its Relevance to the Mechanisms of Central and Peripheral Tolerance

    Directory of Open Access Journals (Sweden)

    Roberto Perniola

    2012-01-01

    Full Text Available The autoimmune polyendocrine syndrome type 1 (APS-1 is a monogenic disease due to pathogenic variants occurring in the autoimmune regulator (AIRE gene. Its related protein, AIRE, activates the transcription of genes encoding for tissue-specific antigens (TsAgs in a subset of medullary thymic epithelial cells: the presentation of TsAgs to the maturating thymocytes induces the apoptosis of the autoreactive clones and constitutes the main form of central tolerance. Dysregulation of thymic AIRE expression in genetically transmitted and acquired diseases other than APS-1 may contribute to further forms of autoimmunity. As AIRE and its murine homolog are also expressed in the secondary lymphoid organs, the extent and relevance of AIRE participation in the mechanisms of peripheral tolerance need to be thoroughly defined.

  10. NDRG2 expression and mutation in human liver and pancreatic cancers

    Institute of Scientific and Technical Information of China (English)

    Xiao-Lan Hu; Xin-Ping Liu; Shu-Xin Lin; Yan-Chun Deng; Na Liu; Xia Li; Li-Bo Yao

    2004-01-01

    AIM: To investigate the expression of NDRG2 and mutation of the entire coding region of NDRG2 in human liver and pancreatic cancers, and to further discuss the possible causes of NDRG2 distinct expression patterns.METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze the expression of NDRG2 mRNA in 37 fresh cancer specimens (including 8 cases of pancreatic cancer and 29 cases of liver cancer) and adjacent normal tissues collected from clinical operation. In addition,mutation analysis of the whole coding region of NDRG2 in these cancers was examined by polymerase chain reactionsingle strand conformational polymorphism (PCR-SSCP).RESULTS: Compared with adjacent normal tissues, the expression levels of NDRG2 mRNA in corresponding cancer tissues reduced significantly (pancreatic cancer: 0.680±0.112vs2.089±0.214, P<0.01)(liver cancer: 0.894±0.098 vs 1.345±0.177, P<0.05). Using PCR-SSCP, the mutation of the whole coding region of NDRG2 was not found in those cancer tissues where the expression of NDRG2 mRNA reduced markedly.CONCLUSION: NDRG2 gene might express differently between normal tissues and cancer tissues, and might play an important role in the development of pancreatic cancer and liver cancer. Low expression of NDRG2 might be unrelated to the mutation of coding region of NDRG2.

  11. Expression of dynamin immunoreactivity in experimental pancreatic tumors induced in rat by mancozeb-nitrosomethylurea.

    Science.gov (United States)

    Valentich, M A; Cook, T; Urrutia, R

    1996-04-19

    Dynamins are GTPases which support receptor-mediated endocytosis and bind to several tyrosine kinase receptor-associated proteins known to mediate cell proliferation and differentiation. We have recently established that dynamin expression correlates with normal neuronal (Torre et al., J. Biol. Chem., 269 (1994) 32411-32417) and acinar pancreatic cell differentiation (Cook et al., Mol. Biol. Cell, 6 (1995) 405a). To begin to understand the role of dynamin in neoplastic pancreatic cell differentiation, we have followed the expression of this protein by immunohistochemistry during the development of pancreatic tumors in a mancozeb-nitrosomethylurea (NMU)-based carcinogenesis model recently developed in our laboratory (Monis and Valentich, Carcinogenesis, 14 (1993) 929-933). After a single intraperitoneal injection (50 mg/g body wt) of this carcinogen, rats fed with mancozeb develop pancreatic focal acinar hyperplasia (FACH), dysplastic foci (DYF) displaying acinar-like and ductular-like structures, and ductular-like carcinoma in situ (CIS). After histochemical staining using a monoclonal anti-dynamin antibody, high levels of this protein are consistently observed in well-differentiated acinar tumors (FACH). In contrast, dynamin immunoreactivity is almost undetectable in more advanced lesions showing a ductular-like phenotype (ductular-like DYF and CIS). This change in the expression pattern of dynamin during the progression of acinar into ductular-like DYF and CIS lesions correlates with recent findings from our laboratory showing a differential expression pattern for dynamin in pancreatic cells during embryonic development, with ductular-like precursor cells expressing low levels of this protein. Based upon these results, we conclude that more advanced ductular-like neoplastic cells induced by the carcinogen NMU in rat pancreas behave phenotypically like pancreatic precursor cells in their pattern of expression for dynamin. PMID:8603375

  12. Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer.

    Science.gov (United States)

    Guo, Xiaojia; Hollander, Lindsay; MacPherson, Douglas; Wang, Ling; Velazquez, Heino; Chang, John; Safirstein, Robert; Cha, Charles; Gorelick, Fred; Desir, Gary V

    2016-01-01

    An essential feature of cancer is dysregulation of cell senescence and death. Renalase, a recently discovered secreted flavoprotein, provides cytoprotection against ischemic and toxic cellular injury by signaling through the PI3K-AKT and MAPK pathways. Here we show that renalase expression is increased in pancreatic cancer tissue and that it functions as a growth factor. In a cohort of patients with pancreatic ductal adenocarcinoma, overall survival was inversely correlated with renalase expression in the tumor mass, suggesting a pathogenic role for renalase. Inhibition of renalase signaling using siRNA or inhibitory anti-renalase antibodies decreased the viability of cultured pancreatic ductal adenocarcinoma cells. In two xenograft mouse models, either the renalase monoclonal antibody m28-RNLS or shRNA knockdown of renalase inhibited pancreatic ductal adenocarcinoma growth. Inhibition of renalase caused tumor cell apoptosis and cell cycle arrest. These results reveal a previously unrecognized role for the renalase in cancer: its expression may serve as a prognostic maker and its inhibition may provide an attractive therapeutic target in pancreatic cancer. PMID:26972355

  13. The expressions and significance of MMP-2 and TIMP-2 in human pancreatic carcinoma

    Institute of Scientific and Technical Information of China (English)

    Dong Bo; Ma Qingyong; Li Ming

    2007-01-01

    Objective To study the expressions of MMP-2 and TIMP-2 in pancreatic carcinoma and their relationship with tumor invasion, local metastasis and prognosis of the carcinoma. Methods The expressions of MMP-2 and TIMP-2 were examined in 32 patients with pancreatic carcinomas by S-P immunohistochemical technique and the correlation with pathological tumor parameters were analyzed. Survival analysis was made by using the Kaplan-Meier method. Results The positive rates of MMP-2, TIMP-2 in 32 patients with pancreatic carcinoma were 56.25% and 75.00%, which were significantly higher than those of the controls(P<0.05). Expressions of MMP-2 and TIMP-2 were independent of sex, age, histological grading and type, but well correlated with the lymph node metastasis and TNM clinical staging(Ⅰ and Ⅲ, Ⅱ and Ⅲ). There was a significant association between MMP-2, TIMP-2 and prognosis in pancreatic carcinoma. Conclusion MMP-2 and TIMP-2 might be useful markers for biological aggressiveness of this malignancy and might contribute to the invasive properties of pancreatic carcinoma, which can be used to evaluate the prognosis of patients.

  14. Dipeptidyl peptidase-4 expression in pancreatic tissue from patients with congenital hyperinsulinism.

    Science.gov (United States)

    Rahman, Sofia A; Senniappan, Senthil; Sherif, Maha; Tahir, Sophia; Hussain, Khalid

    2015-01-01

    Congenital hyperinsulinism (CHI) is caused by unregulated insulin release and leads to hyperinsulinaemic-hypoglycaemia (HH). Glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY) and the enzyme; dipeptidyl peptidase-4 (DPP-4) all regulate appetite and glucose homeostasis. These proteins have been identified as possible contributors to HH but the mechanism remains poorly understood. We aimed to look at the expression pattern of pancreatic DPP-4 in children with focal and diffuse CHI (FCHI and DCHI, respectively). Using immunohistochemistry; we determined DPP-4 expression patterns in the pancreas of CHI patients. DPP-4 was found to be expressed in the pancreatic β, α and δ-cells in and around the focal area. However, it was predominantly co-localised with β-cells in the paediatric tissue samples. Additionally, proliferating β-cells expressed DPP-4 in DCHI, which was absent in the FCHI pancreas. Insulin was found to be present in the exocrine acini and duct cells of the DCHI pancreas suggestive of exocrine to endocrine transdifferentiation. Furthermore, 6 medically-unresponsive DCHI pancreatic samples showed an up-regulation of total pancreatic DPP-4 expression. In conclusion; the expression studies have shown DPP-4 to be altered in HH, however, further work is required to understand the underlying role for this enzyme.

  15. Enhanced expression of constitutive and inducible forms of nitric oxide synthase in autoimmune encephalomyelitis.

    Science.gov (United States)

    Kim, S; Moon, C; Wie, M B; Kim, H; Tanuma, N; Matsumoto, Y; Shin, T

    2000-06-01

    To elucidate the role of nitric oxide synthase (NOS) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), we analyzed the expression of constitutive neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS) in the spinal cords of rats with EAE. We further examined the structural interaction between apoptotic cells and spinal cord cells including neurons and astrocytes, which are potent cell types of nitric oxide (NO) production in the brain. Western blot analysis showed that three forms of NOS significantly increased in the spinal cords of rats at the peak stage of EAE, while small amounts of these enzymes were identified in the spinal cords of rats without EAE. Immunohistochemical study showed that the expression of either nNOS or eNOS increased in the brain cells including neurons and astrocytes during the peak and recovery stages of EAE, while the expression of iNOS was found mainly in the inflammatory macrophages in the perivascular EAE lesions. Double labeling showed that apoptotic cells had intimate contacts with either neurons or astrocytes, which are major cell types to express nNOS and eNOS constitutively. Our results suggest that the three NOS may play an important role in the recovery of EAE. PMID:14612615

  16. Complement activation and expression during chronic relapsing experimental autoimmune encephalomyelitis in the Biozzi ABH mouse.

    Science.gov (United States)

    Ramaglia, V; Jackson, S J; Hughes, T R; Neal, J W; Baker, D; Morgan, B P

    2015-06-01

    Chronic relapsing experimental autoimmune encephalomyelitis (crEAE) in mice recapitulates many of the clinical and histopathological features of human multiple sclerosis (MS), making it a preferred model for the disease. In both, adaptive immunity and anti-myelin T cells responses are thought to be important, while in MS a role for innate immunity and complement has emerged. Here we sought to test whether complement is activated in crEAE and important for disease. Disease was induced in Biozzi ABH mice that were terminated at different stages of the disease to assess complement activation and local complement expression in the central nervous system. Complement activation products were abundant in all spinal cord areas examined in acute disease during relapse and in the progressive phase, but were absent in early disease remission, despite significant residual clinical disease. Local expression of C1q and C3 was increased at all stages of disease, while C9 expression was increased only in acute disease; expression of the complement regulators CD55, complement receptor 1-related gene/protein y (Crry) and CD59a was reduced at all stages of the disease compared to naive controls. These data show that complement is activated in the central nervous system in the model and suggest that it is a suitable candidate for exploring whether anti-complement agents might be of benefit in MS.

  17. Gene expression profiles in primary pancreatic tumors and metastatic lesions of Ela-c-myc transgenic mice

    Directory of Open Access Journals (Sweden)

    Liao Dezhong J

    2008-01-01

    Full Text Available Abstract Background Pancreatic carcinoma usually is a fatal disease with no cure, mainly due to its invasion and metastasis prior to diagnosis. We analyzed the gene expression profiles of paired primary pancreatic tumors and metastatic lesions from Ela-c-myc transgenic mice in order to identify genes that may be involved in the pancreatic cancer progression. Differentially expressed selected genes were verified by semi-quantitative and quantitative RT-PCR. To further evaluate the relevance of some of the selected differentially expressed genes, we investigated their expression pattern in human pancreatic cancer cell lines with high and low metastatic potentials. Results Data indicate that genes involved in posttranscriptional regulation were a major functional category of upregulated genes in both primary pancreatic tumors (PT and liver metastatic lesions (LM compared to normal pancreas (NP. In particular, differential expression for splicing factors, RNA binding/pre-mRNA processing factors and spliceosome related genes were observed, indicating that RNA processing and editing related events may play critical roles in pancreatic tumor development and progression. High expression of insulin growth factor binding protein-1 (Igfbp1 and Serine proteinase inhibitor A1 (Serpina1, and low levels or absence of Wt1 gene expression were exclusive to liver metastatic lesion samples. Conclusion We identified Igfbp1, Serpina1 and Wt1 genes that are likely to be clinically useful biomarkers for prognostic or therapeutic purposes in metastatic pancreatic cancer, particularly in pancreatic cancer where c-Myc is overexpressed.

  18. Differential diagnosis of sclerosing cholangitis with autoimmune pancreatitis and periductal infiltrating cancer in the common bile duct at dynamic CT, endoscopic retrograde cholangiography and MR cholangiography

    International Nuclear Information System (INIS)

    To compare findings at dynamic computed tomography (CT), endoscopic retrograde cholangiography (ERC) and magnetic resonance cholangiography (MRC) in patients with sclerosing cholangitis with autoimmune pancreatitis (SC-AIP) and periductal infiltrating cancer in the common bile duct (CBD), and to evaluate the diagnostic performance of ERC and MRC in differentiating between the two diseases. Bile duct changes at dynamic CT, ERC and MRC were compared in 58 patients with SC-AIP and CBD involvement and 93 patients with periductal infiltrating CBD cancer. Two radiologists rated their confidence in differentiating between the two diseases and the diagnostic performances of ERC and MRC were compared. At CT, SC-AIP was more frequently associated with intrapancreatic CBD involvement, thinner CBD walls, concentric wall thickening, smooth outer margins, and lower degrees of upstream ductal dilatation and contrast enhancement (P ≤ 0.05) than CBD cancer. At ERC and MRC, SC-AIP was more frequently associated with smooth margins, gradual and symmetric narrowing, multifocal involvement and hourglass appearance (P ≤ 0.027) than CBD cancer. MRC showed good diagnostic performance comparable to ERC. Dynamic CT, ERC and MRC can be helpful in distinguishing SC-AIP from periductal infiltrating CBD cancer. MRC may be a useful diagnostic alternative to ERC in differentiating between the two diseases. (orig.)

  19. Differential diagnosis of sclerosing cholangitis with autoimmune pancreatitis and periductal infiltrating cancer in the common bile duct at dynamic CT, endoscopic retrograde cholangiography and MR cholangiography

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Hee; Byun, Jae Ho; Lee, So Jung; Park, Seong Ho; Kim, Hyoung Jung; Lee, Seung Soo; Lee, Moon-Gyu [University of Ulsan College of Medicine, Asan Medical Center, Department of Radiology and Research Institute of Radiology, Asanbyeongwon-gil 86, Songpa-Gu, Seoul (Korea, Republic of); Kim, Myung-Hwan [University of Ulsan College of Medicine, Asan Medical Center, Department of Internal Medicine, Asanbyeongwon-gil 86, Songpa-Gu, Seoul (Korea, Republic of); Kim, Jihun [University of Ulsan College of Medicine, Asan Medical Center, Department of Diagnostic Pathology, Asanbyeongwon-gil 86, Songpa-Gu, Seoul (Korea, Republic of)

    2012-11-15

    To compare findings at dynamic computed tomography (CT), endoscopic retrograde cholangiography (ERC) and magnetic resonance cholangiography (MRC) in patients with sclerosing cholangitis with autoimmune pancreatitis (SC-AIP) and periductal infiltrating cancer in the common bile duct (CBD), and to evaluate the diagnostic performance of ERC and MRC in differentiating between the two diseases. Bile duct changes at dynamic CT, ERC and MRC were compared in 58 patients with SC-AIP and CBD involvement and 93 patients with periductal infiltrating CBD cancer. Two radiologists rated their confidence in differentiating between the two diseases and the diagnostic performances of ERC and MRC were compared. At CT, SC-AIP was more frequently associated with intrapancreatic CBD involvement, thinner CBD walls, concentric wall thickening, smooth outer margins, and lower degrees of upstream ductal dilatation and contrast enhancement (P {<=} 0.05) than CBD cancer. At ERC and MRC, SC-AIP was more frequently associated with smooth margins, gradual and symmetric narrowing, multifocal involvement and hourglass appearance (P {<=} 0.027) than CBD cancer. MRC showed good diagnostic performance comparable to ERC. Dynamic CT, ERC and MRC can be helpful in distinguishing SC-AIP from periductal infiltrating CBD cancer. MRC may be a useful diagnostic alternative to ERC in differentiating between the two diseases. (orig.)

  20. Gene expression analysis of pancreatic cystic neoplasm in SV40Tag transgenic mice model

    Institute of Scientific and Technical Information of China (English)

    Jie Feng; Qiang Sun; Cheng Gao; Juan Dong; Xiao-Luan Wei; Hua Xing; Hou-Da Li

    2007-01-01

    AIM: To study the gene expression changes in pancreatic cystic neoplasm in SV40Tag transgenic mice model and to provide information about the prevention,clinical diagnosis and therapy of pancreatic cancer.METHODS: Using the pBC-SV40Tag transgenic mice model of pancreatic cystic neoplasm, we studied the gene expression changes by applying high-density microarrays. Validation of part gene expression profiling data was performed using real-time PCR.RESULTS: By using high-density oligonucleotide microarray, of 14113 genes, 453 were increased and 760 decreased in pancreatic cystic neoplasm, including oncogenes, cell-cycle-related genes, signal transduction-related genes, skeleton-related genes and metabolism-related genes. Among these, we confirmed the changes in Igf, Shh and Wnt signal pathways with real-time PCR.The results of real-time PCR showed similar expression changes in gene chip.CONCLUSION: all the altered expression genes are associated with cell cycle, DNA damage and repair, signal pathway, and metabolism. SV40Tag may cooperate with several proteins in promoting tumorigenesis.

  1. Expression analysis of MAC30 in human pancreatic cancer and tumors of the gastrointestinal tract

    OpenAIRE

    Kayed, Hany; Kleeff, Jörg; Ding, J.; Hammer, J.; Giese, T; Zentgraf, H; Büchler, M W; Friess, Helmut

    2004-01-01

    Meningioma-associated protein, MAC30, is a protein with unknown function and cellular localization that is differentially expressed in certain malignancies. In the present study, the expression of MAC30 in a variety of normal and cancerous human gastrointestinal tissues, with special emphasis on pancreatic tissues was analyzed. Quantitative RT-PCR was utilized to compare MAC30 expression levels. In situ hybridization and immunohistochemistry were carried ou...

  2. Interleukin-8 increases vascular endothelial growth factor and neuropilin expression and stimulates ERK activation in human pancreatic cancer.

    Science.gov (United States)

    Li, Min; Zhang, Yuqing; Feurino, Louis W; Wang, Hao; Fisher, William E; Brunicardi, F Charles; Chen, Changyi; Yao, Qizhi

    2008-04-01

    Interleukin-8 (IL-8) is associated with tumorigenesis by promoting angiogenesis and metastasis. Although up-regulation of IL-8 is indicated in many cancers, its function in pancreatic cancer has not been well characterized. In this study we examined the expression of IL-8 on pancreatic cancer cells and clinical tissue specimens, and investigated the effect of exogenous IL-8 on gene expression, and signaling in human pancreatic cancer cells. We found that pancreatic cancer cells expressed higher amount of IL-8 mRNA than normal human pancreatic ductal epithelium cells. IL-8 mRNA was also substantially overexpressed in 11 of 14 (79%) clinical pancreatic-adenocarcinoma samples compared with that in their surrounding normal tissues. Exogenous IL-8 up-regulated the expression of vascular endothelial growth factor(165), and neuropilin (NRP)-2 in BxPC-3 cells, one of human pancreatic cancer cell lines. IL-8 expression was inducible by hypoxia mimicking reagent cobalt chloride. In addition, IL-8 activated extracellular signal-regulated kinase (ERK)1/2 signaling pathway in BxPC-3 cells. Our studies suggest that IL-8 might be a malignant factor in human pancreatic cancer by induction of vascular endothelial growth factor and NRP-2 expression and ERK activation. Targeting IL-8 along with other antiangiogenesis therapy could be an effective treatment for this malignancy. PMID:18307536

  3. Interleukin-8 increases vascular endothelial growth factor and neuropilin expression and stimulates ERK activation in human pancreatic cancer.

    Science.gov (United States)

    Li, Min; Zhang, Yuqing; Feurino, Louis W; Wang, Hao; Fisher, William E; Brunicardi, F Charles; Chen, Changyi; Yao, Qizhi

    2008-04-01

    Interleukin-8 (IL-8) is associated with tumorigenesis by promoting angiogenesis and metastasis. Although up-regulation of IL-8 is indicated in many cancers, its function in pancreatic cancer has not been well characterized. In this study we examined the expression of IL-8 on pancreatic cancer cells and clinical tissue specimens, and investigated the effect of exogenous IL-8 on gene expression, and signaling in human pancreatic cancer cells. We found that pancreatic cancer cells expressed higher amount of IL-8 mRNA than normal human pancreatic ductal epithelium cells. IL-8 mRNA was also substantially overexpressed in 11 of 14 (79%) clinical pancreatic-adenocarcinoma samples compared with that in their surrounding normal tissues. Exogenous IL-8 up-regulated the expression of vascular endothelial growth factor(165), and neuropilin (NRP)-2 in BxPC-3 cells, one of human pancreatic cancer cell lines. IL-8 expression was inducible by hypoxia mimicking reagent cobalt chloride. In addition, IL-8 activated extracellular signal-regulated kinase (ERK)1/2 signaling pathway in BxPC-3 cells. Our studies suggest that IL-8 might be a malignant factor in human pancreatic cancer by induction of vascular endothelial growth factor and NRP-2 expression and ERK activation. Targeting IL-8 along with other antiangiogenesis therapy could be an effective treatment for this malignancy.

  4. Analysis of Pancreatic Cancer Microenvironment: Role of Macrophage Infiltrates and Growth Factors Expression

    Directory of Open Access Journals (Sweden)

    Katarzyna Gardian, Sława Janczewska, Waldemar L. Olszewski, Marek Durlik

    2012-01-01

    Full Text Available Background: Research over the last twenty years has yielded much insight into pancreatic cancer biology, but it has neither improved diagnostics methods nor the way of treatment. The question remains as to what the critical deciding factor is in making pancreatic cancer such an aggressive disease.Methods: Pancreatic tumor tissue came from 36 patients. To assess lymphatic vessels color lymphangiography and immunohistochemistry were used. Activity of matrix metalloproteinases was studied with gel and in situ zymography. Expression of growth factors and infiltrating immune cells were investigated using immunohistochemistry.Results: Our study revealed that the structures that correspond to lymphatic vessels were not observed in tumor center but only at the edge of the tumor. All studied growth factors were present in tumor tissue. We found that the difference in expression between G2 and G3 stage was statistically relevant in cases of c-Met receptor. Inflammatory cells were present around neoplastic glands and also strongly around nerves infiltrated by cancer cells. The number of infiltrating macrophages in tumor tissue was significantly higher in group with metastases to lymph nodes.Conclusion: We showed two factors that influence pancreatic cancer progression and invasion: c-Met receptors and macrophages infiltrating tumor tissue. Based on our analysis, this indicates that epithelial-mesenchymal transition might be crucial in the progression of pancreatic cancer.

  5. Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer

    International Nuclear Information System (INIS)

    Costimulatory signaling has been implicated as a potential regulator of antitumor immunity in various human cancers. In contrast to the negative prognostic value of aberrant B7-H1 expression by pancreatic cancer cells, the role of B7-H3 is still unknown. Therefore, we investigated the expression pattern and clinical significance of B7-H3 expression in human pancreatic cancer. B7-H3 expression was evaluated by immunohistochemistry in 68 patients with pancreatic cancer who underwent surgical tumor resection. Expression data was correlated with clinicopathologic features and with the number of tumor-infiltrating T cells. B7-H3 expression was significantly upregulated in pancreatic cancer compared to normal pancreas (p < 0.05). In 60 of 68 examined tumors B7-H3 protein was detectable in pancreatic cancer cells. Patients with high tumor B7-H3 levels had a significantly better postoperative prognosis than patients with low tumor B7-H3 levels (p = 0.0067). Furthermore, tumor B7-H3 expression significantly correlated with the number of tumor-infiltrating CD8+ T cells (p = 0.018). We demonstrate for the first time that B7-H3 is abundantly expressed in pancreatic cancer and that tumor-associated B7-H3 expression significantly correlates with prolonged postoperative survival. Our findings suggest that B7-H3 might play an important role as a potential stimulator of antitumor immune response in pancreatic cancer

  6. Oral Treatment with Lactococcus lactis Expressing Staphylococcus hyicus Lipase Enhances Lipid Digestion in Pigs with Induced Pancreatic Insufficiency

    OpenAIRE

    Drouault, Sophie; Juste, Catherine; Marteau, Philippe; Renault, Pierre; Corthier, Gérard

    2002-01-01

    The Staphylococcus hyicus lip gene was cloned in Lactococcus lactis. Pancreatic insufficiency was induced by ligation of the pancreatic duct in pigs. In pigs who had undergone pancreatic ligation, the coefficient of fat absorption was higher after consumption of lipase-expressing L. lactis (91.9% ± 3.7%) than that after consumption of the inactive control strain (78.4% ± 2.4%).

  7. Gene Expression in the Spinal Cord in Female Lewis Rats with Experimental Autoimmune Encephalomyelitis Induced with Myelin Basic Protein

    OpenAIRE

    Inglis, Hayley R.; Judith M. Greer; Pamela A. McCombe

    2012-01-01

    Background Experimental autoimmune encephalomyelitis (EAE), the best available model of multiple sclerosis, can be induced in different animal strains using immunization with central nervous system antigens. EAE is associated with inflammation and demyelination of the nervous system. Micro-array can be used to investigate gene expression and biological pathways that are altered during disease. There are few studies of the changes in gene expression in EAE, and these have mostly been done in a...

  8. Relationship between expression of E-cadherin-catenin complex and clinicopathologic characteristics of pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Yu-Jun Li; Xiang-Rui Ji

    2003-01-01

    AIM: To investigate the expression of E-cadherin and alpha-catenin and beta-catenin in pancreatic carcinoma and itsrelationship with the clinicopathologic characteristics, andclarify the mechanism of invasion and metastasis ofpancreatic cancer.METHODS: The expression of E-cadherin and alpha-, beta-catenin was examined in 47 cases of infiltrative ductaladenocarcinoma of pancreas and 12 adult normal pancreatictissues by immunohistochemical technique.RESULTS: The immunoreactivity of E-cadherin and alpha-,beta-catenin was expressed by normal ductal and acinarcells with strong membranous staining at the intercellularborder in 12 cases of adult normal pancreatic tissues. Abnormalexpression of E-cadherin and alpha-, beta-catenin in 47pancreatic carcinoma tissues was demonstrated in 53.2 %,61.7 % and 68.1%, respectively. Both abnormal expressionof E-cadherin and alpha-catenin significantly correlated withdifferentiation, lymph node and liver metastases (P<0.05,respectively), whereas aberrant beta-catenin expression onlycorrelated with lymph node and liver metastases (P<0.001).Abnormal E-cadherin and alpha-, beta-catenin expressionwas not associated with tumor size, invasion and survivaltime of patients (P>0.05, all).CONCLUSION: Pancreatic cancer likely occurs in case ofE-cadherin-catenin complex genes mutations or deletionsand abnormal expression of proteins, which significantlycorrelate with the biologic character of the tumor and lymphnode and liver metastases. It is suggested that the abnormalE-cadherin-catenin complex expression plays an importantrole in the development and progression of tumor, and thusmay become a new marker in pancreatic cancer metastasis.

  9. Environmental effects on molecular biomarkers expression in pancreatic and brain cancer

    Science.gov (United States)

    Mensah, Lawrence; Mallidi, Srivalleesha; Massodi, Iqbal; Anbil, Sriram; Mai, Zhiming; Hasan, Tayyaba

    2013-03-01

    A complete understanding of the biological mechanisms regulating devastating disease such as cancer remains elusive. Pancreatic and brain cancers are primary among the cancer types with poor prognosis. Molecular biomarkers have emerged as group of proteins that are preferentially overexpressed in cancers and with a key role in driving disease progression and resistance to chemotherapy. The epidermal growth factor receptor (EGFR), a cell proliferative biomarker is particularly highly expressed in most cancers including brain and pancreatic cancers. The ability of EGFR to sustain prolong cell proliferation is augmented by biomarkers such as Bax, Bcl-XL and Bcl-2, proteins regulating the apoptotic process. To better understand the role and effect of the microenvironment on these biomarkers in pancreatic cancer (PaCa); we analysed two pancreatic tumor lines (AsPc-1 and MiaPaCa-2) in 2D, 3D in-vitro cultures and in orthotopic tumors at different growth stages. We also investigated in patient derived glioblastoma (GBM) tumor cultures, the ability to utilize the EGFR expression to specifically deliver photosensitizer to the cells for photodynamic therapy. Overall, our results suggest that (1) microenvironment changes affect biomarker expression; thereby it is critical to understand these effects prior to designing combination therapies and (2) EGFR expression in tumor cells indeed could serve as a reliable and a robust biomarker that could be used to design targeted and image-guided photodynamic therapy.

  10. 自身免疫性胰腺炎的多层螺旋CT表现(附5例分析)%MSCT Characteristics of Autoimmune Pancreatitis (Imaging Findings in Five Cases)

    Institute of Scientific and Technical Information of China (English)

    周健; 彭振鹏; 冯仕庭; 李子平

    2015-01-01

    目的:探讨自身免疫性胰腺炎(autoimmune pancreatitis,AIP)的多层螺旋CT表现。方法回顾性分析5例经病理证实或临床治疗后随访证实的自身免疫性胰腺炎的64层螺旋CT表现。结果5例自身免疫性胰腺炎中3例(60%)胰腺弥漫性肿大,呈“腊肠状”,其中1例(20%)胰头部明显肿大,疑似肿物形成。1例(20%)胰腺体尾部局限性肿大。1例(20%)胰腺未见明显肿大。3例(60%)胰周筋膜模糊,其中2例(40%)胰周见少许渗出性积液,1例(20%)胰周见低密度环状包膜影,即“胶囊征”。4例(80%)胰腺密度均匀。1例(20%)胰头部见斑点状钙化。5例(100%)胰腺中度均匀强化。4例(80%)胆总管胰腺段逐渐变窄,肝内外胆管“串珠样”改变,其中2例(40%)伴有胰管轻度扩张。1例(20%)仅表现胰管轻度扩张。2例(40%)累及单侧肾周筋膜,肾周筋膜模糊。1例(20%)累及单侧肾盂,表现为肾盂增大,内见低密度软组织肿块影,增强扫描肿块轻度强化。结论多层螺旋CT可以用于诊断自身免疫性胰腺炎,可用于评估胰腺外病变及胰腺治疗后改变。%Objective To evaluate the MSCT characteristics of autoimmune pancreatitis. Methods Five autoimmune pancreatitis patients confirmed by pathology or clinical were retrospectively analyzed by the 64-slice spiral CT.Results Diffuse swelling of pancreas was found in three patients, just as sausage-shaped. Among them one case of the pancreatic head show obvious swelling, suspected neoplasm. Obvious pancreatic body and tail swelling in one patient. No significant swelling of the pancreas in one patient. Minimal peripancreatic stranding in three patients, peripancreatic fluid collection in two patients, focal enlargement with a capsule-like rim in one patient. Four patients showed homogeneous pancreatic density. One patient can be seen calification in the the pancreatic head . Pancreas showed mild homogeneous enhancement in all five

  11. Correlation between ECT2 gene expression and methylation change of ECT2 promoter region in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Mang-Li Zhang; Sen Lu; Lin Zhou; Shu-Sen Zheng

    2008-01-01

    BACKGROUND: Pancreatic cancer is closely related to epigenetic abnormality. The epithelial cell transforming sequence 2 gene (ECT2) plays a critical role in Rho activation during cytokinesis, and thus may play a role in the pathogenesis of pancreatic cancer. In this study, we investigated the relationships between aberrant expression and epigenetic changes of the ECT2 gene in pancreatic cancer. METHODS: Four cell lines (PANC-1, Colo357, T3M-4 and PancTuⅠ) and pancreatic ductal adenocarcinoma (PDAC) tissues were used for mRNA detection. After restriction isoschizomer endonucleases (MspⅠ/HpaⅡ) were used to digest the DNA sequence (5'-CCGG-3'), PCR was made to amplify the product. And RT-PCR was applied to determine the expression of the gene. RESULTS: The mRNA expression of the ECT2 gene was higher in pancreatic tumor tissue than in normal tissue. The gene was also expressed in the 4 PDAC cell lines. The methylation states of the upstream regions of the ECT2 gene were almost identical in normal, tumor pancreatic tissues, and the 4 PDAC cell lines. Some of the 5'-CCGG-3' areas in the upstream region of ECT2 were methylated, while others were unmethylated. CONCLUSIONS: The oncogene ECT2 is overexpressed in pancreatic tumor tissues as veriifed by RT-PCR detection. The methylation status of DNA in promoter areas is involved in the gene expression, along with other factors, in pancreatic cancer.

  12. Relationship between expression of COX-2, TNF-α, IL-6 and autoimmune-type recurrent miscarriage

    Institute of Scientific and Technical Information of China (English)

    Fu Hua; Chang-Hua Li; Hong Wang; Hong-Ge Xu

    2013-01-01

    Objective:To investigate the roles ofCOX-2,TNF-α,IL-6 in the pathogenesis of autoimmune-type recurrent spontaneous abortion(RSA).Methods:RT-PCR was used to detect the mRNA ofCOX-2,TNF-α,IL-6 in the trophoblast cells of murineRSA and normal pregnant models. TheCOX-2,TNF-α,IL-6 protein expressions were determined by using immunohistochemisry staining method.TheCOX-2,TNF-α,IL-6 protein expressions were determined byELISA. Results:The embryo loss rates in experiment group was significantly higher than that in normal pregnancy control group,the expression ofCOX-2,TNF-α,IL-6 in the trophoblast cells of murineRSA and normal pregnant models.The expression ofCOX-2 in autoimmune-type recurrent spontaneous abortion was significantly lesser than in normal pregnant models. The expression ofTNF-α,IL-6 in autoimmune-type recurrent spontaneous abortion was significantly higher than in normal pregnant models.There was a positively correlation between TNF-α andIL-6.There was no relationship betweenCOX-2,TNF-α andIL-6.Conclusions:The abnormal expression ofCOX-2,TNF-α andIL-6 may result inRSA.

  13. Impaired growth of pancreatic exocrine cells in transgenic mice expressing human activin βE subunit

    International Nuclear Information System (INIS)

    Activins, TGF-β superfamily members, have multiple functions in a variety of cells and tissues. Recently, additional activin β subunit genes, βC and βE, have been identified. To explore the role of activin E, we created transgenic mice overexpressing human activin βE subunit. There were pronounced differences in the pancreata of the transgenic animals as compared with their wild-type counterparts. Pancreatic weight, expressed relative to total body weight, was significantly reduced. Histologically, adipose replacement of acini in the exocrine pancreas was observed. There was a significant decrease in the number of PCNA-positive cells in the acinar cells, indicating reduced proliferation in the exocrine pancreas of the transgenic mice. However, quantitative pancreatic morphometry showed that the total number and mass of the islets of the transgenic mice were comparable with those of the nontransgenic control mice. Our findings suggest a role for activin E in regulating the proliferation of pancreatic exocrine cells

  14. Caerulin-induced pancreatitis in rats: Histological and genetic expression changes from acute phase to recuperation

    Institute of Scientific and Technical Information of China (English)

    Javier Maga(n)a-Gómez; Guillermo López-Cervantes; Ana María Calderón de la Barca

    2006-01-01

    AIM: To study the histological and pancreatitis-associated protein mRNA accumulation changes of pancreas from acute phase of caerulin-induced pancreatitis to recuperation in rats.METHODS: Acute pancreatitis was induced by caerulein in male Wistar rats and followed up for 90 d by histologicai and mRNA analyses of pancreas. Pancreases were dissected at 0, 9, 24 h and 3, 5, 15, 30, 60, 90 d post-induction. Edema (E), polymorphonuclear neutrophil (PMN) infiltration, cytoplasmic vacuolization (V), zymogen granule depletion (ZD) and acinar disorganization (AD) were microscopically evaluated. Accumulation of pancreatitisassociated protein (PAP) and L13A mRNAs were quantifled by real-time PCR.RESULTS: The main histological changes appeared at 9 h post-induction for PMN infiltration and cytoplasmic V, while at 24 h and 3 d for E and ZD, respectively. All the parameters were recovered after 5 d, except for ZD which delayed more than 30 d. The main AD was observed after 15 d and values returned to normal after 30 d. Similarly to histological changes, accumulation of the PAP mRNA was increased at 9 h with the highest accumulation at 24 h and differences disappeared after 5 d.CONCLUSION: From the acute phase to recuperation of pancreatitis, regeneration and re-differentiation of pancreas occur and PAP expression is exclusively an acute response of pancreatitis.

  15. Oligonucleotide microarray identifies genes differentially expressed during tumorigenesis of DMBA-induced pancreatic cancer in rats.

    Directory of Open Access Journals (Sweden)

    Jun-Chao Guo

    Full Text Available The extremely dismal prognosis of pancreatic cancer (PC is attributed, at least in part, to lack of early diagnosis. Therefore, identifying differentially expressed genes in multiple steps of tumorigenesis of PC is of great interest. In the present study, a 7,12-dimethylbenzanthraene (DMBA-induced PC model was established in male Sprague-Dawley rats. The gene expression profile was screened using an oligonucleotide microarray, followed by real-time quantitative polymerase chain reaction (qRT-PCR and immunohistochemical staining validation. A total of 661 differentially expressed genes were identified in stages of pancreatic carcinogenesis. According to GO classification, these genes were involved in multiple molecular pathways. Using two-way hierarchical clustering analysis, normal pancreas, acute and chronic pancreatitis, PanIN, early and advanced pancreatic cancer were completely discriminated. Furthermore, 11 upregulated and 142 downregulated genes (probes were found by Mann-Kendall trend Monotone test, indicating homologous genes of rat and human. The qRT-PCR and immunohistochemistry analysis of CXCR7 and UBe2c, two of the identified genes, confirmed the microarray results. In human PC cell lines, knockdown of CXCR7 resulted in decreased migration and invasion. Collectively, our data identified several promising markers and therapeutic targets of PC based on a comprehensive screening and systemic validation.

  16. Expression of the "stem cell marker" CD133 in pancreas and pancreatic ductal adenocarcinomas

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    Sakariassen Per

    2008-02-01

    Full Text Available Abstract Background It has been suggested that a small population of cells with unique self-renewal properties and malignant potential exists in solid tumors. Such "cancer stem cells" have been isolated by flow cytometry, followed by xenograft studies of their tumor-initiating properties. A frequently used sorting marker in these experiments is the cell surface protein CD133 (prominin-1. The aim of this work was to examine the distribution of CD133 in pancreatic exocrine cancer. Methods Fifty-one cases of pancreatic ductal adenocarcinomas were clinically and histopathologically evaluated, and immunohistochemically investigated for expression of CD133, cytokeratin 19 and chromogranin A. The results were interpreted on the background of CD133 expression in normal pancreas and other normal and malignant human tissues. Results CD133 positivity could not be related to a specific embryonic layer of organ origin and was seen mainly at the apical/endoluminal surface of non-squamous, glandular epithelia and of malignant cells in ductal arrangement. Cytoplasmic CD133 staining was observed in some non-epithelial malignancies. In the pancreas, we found CD133 expressed on the apical membrane of ductal cells. In a small subset of ductal cells and in cells in centroacinar position, we also observed expression in the cytoplasm. Pancreatic ductal adenocarcinomas showed a varying degree of apical cell surface CD133 expression, and cytoplasmic staining in a few tumor cells was noted. There was no correlation between the level of CD133 expression and patient survival. Conclusion Neither in the pancreas nor in the other investigated organs can CD133 membrane expression alone be a criterion for "stemness". However, there was an interesting difference in subcellular localization with a minor cell population in normal and malignant pancreatic tissue showing cytoplasmic expression. Moreover, since CD133 was expressed in shed ductal cells of pancreatic tumors and was

  17. Correlation between Protein Expression of PTEN in Human Pancreatic Cancer and the Proliferation, Infiltration, Metastasis and Prognosis

    Institute of Scientific and Technical Information of China (English)

    TAO Jing; XIONG Jiongxin; LI Tao; YANG Zhiyong; LI Xiaohui; LI Kai; WU Heshui; WANG Chunyou

    2006-01-01

    In order to investigate the correlation between protein expression of PTEN and the proliferation, infiltration, metastasis and prognosis in pancreatic cancer, immunohistochemical SP method was used to examine the protein expression of PTEN, PCNA, MVD, MMP-2, MMP-9 and TUNEL method to detect the levels of apoptosis of pancreatic cells in 41 pancreatic head cancers from regional pancreatectomy (RP) and 10 normal pancreatic tissues. The results showed that among 41 cases of pancreatic cancers, the positive staining of PTNE (39.02 %) was significantly weaker than that in normal pancreatic tissues (P<0.05). The levels of PCNA labeling index (LI), apoptotic index(AI), microvessel density (MVD), MMP-2 LI and MMP-9 LI were decreased gradually with the increase of the expression intensity of PTEN, and there was a significant difference in the above parameters among the patients having different expression levels of PTEN (P<0.01 or P<0.05). There was a negative correlation between the expression of PTEN and PCNA LI, MVD, MMP-2 LI,MMP-9 LI, and a positive correlation between AI and the expression of PTEN. The expression intensity of PTEN was correlated with the postoperative survival of the patients with pancreatic cancer(x2=22.3400, P<0.0001, RR=2.030). It was suggested that the expression levels of PTEN protein were closely related with proliferation, infiltration and metastasis in human pancreatic cancer, and the expression of PTEN protein was one of the prognostic factors for pancreatic cancer following RP.

  18. Type 1 diabetes and polyglandular autoimmune syndrome:A review

    Institute of Scientific and Technical Information of China (English)

    Martin P Hansen; Nina Matheis; George J Kahaly

    2015-01-01

    Type 1 diabetes (T1D) is an autoimmune disorder causedby inflammatory destruction of the pancreatic tissue. Theetiopathogenesis and characteristics of the pathologicprocess of pancreatic destruction are well described. Inaddition, the putative susceptibility genes for T1D as amonoglandular disease and the relation to polyglandularautoimmune syndrome (PAS) have also been wellexplored. The incidence of T1D has steadily increasedin most parts of the world, especially in industrializednations. T1D is frequently associated with autoimmuneendocrine and non-endocrine diseases and patients withT1D are at a higher risk for developing several glandularautoimmune diseases. Familial clustering is observed,which suggests that there is a genetic predisposition.Various hypotheses pertaining to viral- and bacterialinducedpancreatic autoimmunity have been proposed,however a definitive delineation of the autoimmunepathomechanism is still lacking. In patients with PAS,pancreatic and endocrine autoantigens either colocalizeon one antigen-presenting cell or are expressed on two/various target cells sharing a common amino acid, whichfacilitates binding to and activation of T cells. The mostprevalent PAS phenotype is the adult type 3 variant orPAS type Ⅲ, which encompasses T1D and autoimmunethyroid disease. This review discusses the findings ofrecent studies showing noticeable differences in thegenetic background and clinical phenotype of T1D eitheras an isolated autoimmune endocrinopathy or within thescope of polyglandular autoimmune syndrome.

  19. Interdependence of Gemcitabine Treatment, Transporter Expression, and Resistance in Human Pancreatic Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Wolfgang Hagmann

    2010-09-01

    Full Text Available Gemcitabine is widely used as first-line chemotherapeutic drug in the treatment of pancreatic cancer. Our previous experimental chemotherapy studies have shown that treatment of human pancreatic carcinoma cells with 5-fluorouracil (5-FU alters the cellular transporter expression profile and that modulation of the expression of multidrug resistance protein 5 (MRP5; ABCC5 influences the chemoresistance of these tumor cells. Here, we studied the influence of acute and chronic gemcitabine treatment on the expression of relevant uptake and export transporters in pancreatic carcinoma cells by reverse transcription-polymerase chain reaction (RT-PCR, quantitative RT-PCR, and immunoblot analyses. The specific role of MRP5 in cellular gemcitabine sensitivity was studied by cytotoxicity assays using MRP5-overexpressing and MRP5-silenced cells. Exposure to gemcitabine (12 nM for 3 days did not alter the messenger RNA (mRNA expression of MRP1, MRP3, MRP5, and equilibrative nucleoside transporter 1 (ENT1, whereas high dosages of the drug (20 µM for 1 hour elicited up-regulation of these transporters in most cell lines studied. In cells with acquired gemcitabine resistance (up to 160 nM gemcitabine, the mRNA or protein expression of the gemcitabine transporters MRP5 and ENT1 was upregulated in several cell lines. Combined treatment with 5-FU and gemcitabine caused a 5- to 40-fold increase in MRP5 and ENT1 expressions. Cytotoxicity assays using either MRP5-overexpressing (HEK and PANC-1 or MRP5-silenced (PANC1/shMRP5 cells indicated that MRP5 contributes to gemcitabine resistance. Thus, our novel data not only on drug-induced alterations of transporter expression relevant for gemcitabine uptake and export but also on the link between gemcitabine sensitivity and MRP5 expression may lead to improved strategies of future chemotherapy regimens using gemcitabine in pancreatic carcinoma patients.

  20. Expression of basic fibroblast growth factor and its receptor in human pancreatic carcinomas.

    OpenAIRE

    Ohta, T.(Research Center for Nuclear Physics, Osaka University, Ibaraki, Osaka 567-0047, Japan); Yamamoto, M.; Numata, M; Iseki, S.; Tsukioka, Y.; Miyashita, T; Kayahara, M.; Nagakawa, T.; Miyazaki, I.; Nishikawa, K.; Yoshitake, Y

    1995-01-01

    We examined the expression of basic fibroblast growth factor (FGF) and FGF receptor by immunohistochemistry in 32 human pancreatic ductal adenocarcinomas. Mild to marked basic FGF immunoreactivity was noted in 19 (59.4%) of the 32 tumours examined, and 30 (93.3%) of the tumours exhibited a cytoplasmic staining pattern against FGF receptor. The tumours were divided into two groups according to the proportion of positively stained tumour cells: a low expression group (positive cells < 25%) and ...

  1. Aberrant expression of mucin core proteins and o-linked glycans associated with progression of pancreatic cancer

    DEFF Research Database (Denmark)

    Remmers, Neeley; Anderson, Judy M; Linde, Erin M;

    2013-01-01

    Mucin expression is a common feature of most adenocarcinomas and features prominently in current attempts to improve diagnosis and therapy for pancreatic cancer and other adenocarcinomas. We investigated the expression of a number of mucin core proteins and associated O-linked glycans expressed...... in pancreatic adenocarcinoma-sialyl Tn (STn), Tn, T antigen, sialyl Lewis A (CA19-9), sialyl Lewis C (SLeC), Lewis X (LeX), and sialyl LeX (SLeX)-during the progression of pancreatic cancer from early stages to metastatic disease....

  2. Effects of Thymoquinone in the Expression of Mucin 4 in Pancreatic Cancer Cells: Implications for the Development of Novel Cancer Therapies

    OpenAIRE

    Torres, Maria P.; Moorthy P Ponnusamy; Chakraborty, Subhankar; Smith, Lynette M.; Das, Srustidhar; Arafat, Hwyda A.; Batra, Surinder K.

    2010-01-01

    Pancreatic cancer is one of the most lethal cancers in the world, as it continues to be resistant to any therapeutic approaches. The high molecular weight glycoprotein mucin 4 (MUC4) is aberrantly expressed in pancreatic cancer and contributes to the regulation of differentiation, proliferation, metastasis, and the chemoresistance of pancreatic cancer cells. The absence of its expression in the normal pancreatic ductal cells makes MUC4 a promising target for novel cancer therapeutics. Natural...

  3. Modulation of fibronectin expression in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis

    Directory of Open Access Journals (Sweden)

    De-Carvalho M.C.A.

    1999-01-01

    Full Text Available Fibronectin (FN, a large family of plasma and extracellular matrix (ECM glycoproteins, plays an important role in leukocyte migration. In normal central nervous system (CNS, a fine and delicate mesh of FN is virtually restricted to the basal membrane of cerebral blood vessels and to the glial limitans externa. Experimental autoimmune encephalomyelitis (EAE, an inflammatory CNS demyelinating disease, was induced in Lewis rats with a spinal cord homogenate. During the preclinical phase and the onset of the disease, marked immunolabelling was observed on the endothelial luminal surface and basal lamina of spinal cord and brainstem microvasculature. In the paralytic phase, a discrete labelling was evident in blood vessels of spinal cord and brainstem associated or not with an inflammatory infiltrate. Conversely, intense immunolabelling was present in cerebral and cerebellar blood vessels, which were still free from inflammatory cuffs. Shortly after clinical recovery minimal labelling was observed in a few blood vessels. Brainstem and spinal cord returned to normal, but numerous inflammatory foci and demyelination were still evident near the ventricle walls, in the cerebral cortex and in the cerebellum. Intense expression of FN in brain vessels ascending from the spinal cord towards the encephalon preceded the appearance of inflammatory cells but faded away after the establishment of the inflammatory cuff. These results indicate an important role for FN in the pathogenesis of CNS inflammatory demyelinating events occurring during EAE.

  4. Cloning and functional expression of a human pancreatic islet glucose-transporter cDNA

    International Nuclear Information System (INIS)

    Previous studies have suggested that pancreatic islet glucose transport is mediated by a high-Km, low-affinity facilitated transporter similar to that expressed in liver. To determine the relationship between islet and liver glucose transporters, liver-type glucose-transporter cDNA clones were isolated from a human liver cDNA library. The liver-type glucose-transporter cDNA clone hybridized to mRNA transcripts of the same size in human liver and pancreatic islet RNA. A cDNA library was prepared from purified human pancreatic islet tissue and screened with human liver-type glucose-transporter cDNA. The authors isolated two overlapping cDNA clones encompassing 2600 base pairs, which encode a pancreatic islet protein identical in sequence to that of the putative liver-type glucose-transporter protein. Xenopus oocytes injected with synthetic mRNA transcribed from a full-length cDNA construct exhibited increased uptake of 2-deoxyglucose, confirming the functional identity of the clone. These cDNA clones can now be used to study regulation of expression of the gene and to assess the role of inherited defects in this gene as a candidate for inherited susceptibility to non-insulin-dependent diabetes mellitus

  5. The Expression of the Thrombin Receptors PAR-3 and PAR-4 is Downregulated in Pancreatic Cancer Cell Lines

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    Claudia Rudroff

    2015-05-01

    Full Text Available Background: Patients with pancreatic cancer frequently suffer from thrombosis as a consequence of excess thrombin generation. In addition to its role in the plasmatic coagulation cascade, thrombin induces numerous cellular effects by activating a unique group of G-protein-coupled receptors on the cell membrane, the proteinase-activated receptors (PARs. At present, PAR-1, PAR-3 and PAR-4 are known to be activated by thrombin. We previously demonstrated a putative role for PAR-1 in pancreatic cancer progression, but little is known about the physiological and pathophysiological roles of PAR-3 and PAR-4. In the present study, we examined the expression patterns of PAR-3 and PAR-4 in pancreatic tissue and pancreatic cancer cells. Methods: Tissue samples from three patients with pancreatic adenocarcinoma and six human pancreatic carcinoma cell lines were examined. Gene expression was analysed by RT-PCR and quantified by HPLC. Protein expression was determined by Western blot analysis. Data analysis was performed using ANOVA in SPSS. Results and Conclusion: In contrast to PAR-1, both PAR-3 and PAR-4 were expressed in healthy pancreases but downregulated in pancreatic cancer. The contrasting expression patterns of PAR-3 and PAR-4 compared with PAR-1 indicate that the mechanism that regulates the cellular effects of thrombin on tumor progression remains to be fully elucidated.

  6. Glycyrrhizin suppresses the expressions of HMGB1 and relieves the severity of traumatic pancreatitis in rats.

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    Ke Xiang

    Full Text Available High mobility group box 1 (HMGB1 plays important roles in a large variety of diseases; glycyrrhizin (GL is recognized as an HMGB1 inhibitor. However, few studies have focused on whether glycyrrhizin can potentially improve the outcome of traumatic pancreatitis (TP by inhibiting HMGB1.A total of 60 male Wistar rats were randomly divided into three groups (n = 20 in each: Control group, TP group and TP-GL group. Pancreatic trauma was established with a custom-made biological impact machine-III, and GL was administered at 15 minutes after the accomplishment of operation. To determine survival rates during the first 7 days after injury, another 60 rats (n = 20 in each were grouped and treated as mentioned above. At 24 hours of induction of TP, the histopathological changes in pancreas were evaluated and serum amylase levels were tested. Serum tumor necrosis factor α (TNF-α, interleukin 6 (IL-6, and HMGB1 were measured using enzyme linked immunosorbent assay. HMGB1 expressions in pancreas were measured using immunohistochemical staining, Western blot and Real-Time PCR analysis.Serum levels of HMGB1, TNF-α and IL-6 were increased dramatically in TP group at 24 hours after induction of TP. However, these indicators were reduced significantly by GL administration in TP-GL group comparing with TP group (P < 0.05. Meanwhile, survival analysis showed that the seven-day survival rate in TP-GL group was significantly higher than that in TP group (85% versus 65%, P < 0.05. GL treatment significantly decreased the pancreatic protein and mRNA expressions of HMGB1 and ameliorated the pancreatic injury in rats with TP.Glycyrrhizin might play an important role in improving survival rates and ameliorating pancreatic injury of TP by suppression of the expressions of HMGB1 and other proinflammatory cytokine.

  7. Microarray analysis of gene expression profile of multidrug resistance in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    ZHAO Yu-pei; CHEN Ge; FENG Bin; ZHANG Tai-ping; MA En-ling; WU Yuan-de

    2007-01-01

    Background Chemotherapy is the most frequently adopted adjuvant therapy of pancreatic ductal adenocarcinoma (PDAC), but the development of drug resistance reduces its effectiveness. Clarification of the mechanism of multidrug resistance (MDR) development in PDAC is needed to improve the therapeutic effect of chemotherapy. This study was aimed to investigate the molecular mechanism of MDR of PDAC and to identify genes associated with MDR development.Methods The gene expression profiles of cell line SW1990 and three drug-selected pancreatic chemoresistant sub-lines, SW1990/5-Fu, SW1990/ADM and SW1990/GEM, were obtained using an oligonucleotide microarray (Affymetrix HG U133 2.0 plus) that contained approximately 38 000 human genes. The microarray results were validated by real-time quantitative polymerase chain reaction and Western blot analysis.Results There were 165 genes and expressed sequence tags, some of which have never been linked to drug resistance, that were up- or down-regulated at least 2-fold in all resistant sub-lines when compared with SW1990.According to Gene Ontology annotation, differentially expressed genes related to MDR in pancreatic cancer belong to many functional families and with diverse biological processes. Genes related to antioxidant activity, apoptosis, the cell cycle, signal transduction and intracellular adhesion may undergo epigenetic changes preceding MDR development. A hierarchical clustering was conducted and several interesting clusters were discovered that may be primarily related to cell cycle and developmental regulation. A prediction rule was built from the expression profiles of 117 genes after support vector machine (SVM) analysis, and the prediction result was examined by cytotoxic testing. As a result, a differential gene expression pattern was constructed in multidrug resistant pancreatic cancer cells.Conclusions The findings of this study prove that construction of a chemoresistance prediction rule, based on gene

  8. High SIRT1 expression is a negative prognosticator in pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Several lines of evidence indicate that Sirt1, a class III histone deacetylase (HDAC) is implicated in the initiation and progression of malignancies and thus gained attraction as druggable target. Since data on the role of Sirt1 in pancreatic ductal adenocarcinoma (PDAC) are sparse, we investigated the expression profile and prognostic significance of Sirt1 in vivo as well as cellular effects of Sirt1 inhibition in vitro. Sirt1 expression was analyzed by immunohistochemistry in a large cohort of PDACs and correlated with clinicopathological and survival data. Furthermore, we investigated the impact of overexpression and small molecule inhibition on Sirt1 in pancreatic cancer cell culture models including combinatorial treatment with chemotherapy and EGFR-inhibition. Cellular events were measured quantitatively in real time and corroborated by conventional readouts including FACS analysis and MTT assays. We detected nuclear Sirt1 expression in 36 (27.9%) of 129 PDACs. SIRT1 expression was significantly higher in poorly differentiated carcinomas. Strong SIRT1 expression was a significant predictor of poor survival both in univariate (p = 0.002) and multivariate (HR 1.65, p = 0.045) analysis. Accordingly, overexpression of Sirt1 led to increased cell viability, while small molecule inhibition led to a growth arrest in pancreatic cancer cells and impaired cell survival. This effect was even more pronounced in combinatorial regimens with gefitinib, but not in combination with gemcitabine. Sirt1 is an independent prognosticator in PDACs and plays an important role in pancreatic cancer cell growth, which can be levered out by small molecule inhibition. Our data warrant further studies on SIRT1 as a novel chemotherapeutic target in PDAC

  9. Silencing Mist1 Gene Expression Is Essential for Recovery from Acute Pancreatitis.

    Directory of Open Access Journals (Sweden)

    Anju Karki

    Full Text Available Acinar cells of the exocrine pancreas are tasked with synthesizing, packaging and secreting vast quantities of pro-digestive enzymes to maintain proper metabolic homeostasis for the organism. Because the synthesis of high levels of hydrolases is potentially dangerous, the pancreas is prone to acute pancreatitis (AP, a disease that targets acinar cells, leading to acinar-ductal metaplasia (ADM, inflammation and fibrosis-events that can transition into the earliest stages of pancreatic ductal adenocarcinoma. Despite a wealth of information concerning the broad phenotype associated with pancreatitis, little is understood regarding specific transcriptional regulatory networks that are susceptible to AP and the role these networks play in acinar cell and exocrine pancreas responses. In this study, we examined the importance of the acinar-specific maturation transcription factor MIST1 to AP damage and organ recovery. Analysis of wild-type and Mist1 conditional null mice revealed that Mist1 gene transcription and protein accumulation were dramatically reduced as acinar cells underwent ADM alterations during AP episodes. To test if loss of MIST1 function was primarily responsible for the damaged status of the organ, mice harboring a Cre-inducible Mist1 transgene (iMist1 were utilized to determine if sustained MIST1 activity could alleviate AP damage responses. Unexpectedly, constitutive iMist1 expression during AP led to a dramatic increase in organ damage followed by acinar cell death. We conclude that the transient silencing of Mist1 expression is critical for acinar cells to survive an AP episode, providing cells an opportunity to suppress their secretory function and regenerate damaged cells. The importance of MIST1 to these events suggests that modulating key pancreas transcription networks could ease clinical symptoms in patients diagnosed with pancreatitis and pancreatic cancer.

  10. 自身免疫性胰腺炎16例的临床分析%Clinical features of autoimmune pancreatitis: a case series of 16 patients

    Institute of Scientific and Technical Information of China (English)

    吕红; 蒋卫忠; 钱家鸣; 杨爱明; 秦明伟; 舒崽君; 丁辉

    2010-01-01

    Objective To summarize the clinical features, diagnosis and treatment of autoimmune pancreatitis (AIP). Methods From March 2003 to January 2008, a total of 16 cases of AIP were reviewed retrospectively. Results The ratio of male: female was 15:1, with a mean age of 61 years old (range:47-79 years old). Jaundice was the main clinical presentation in 81.2% patients. 68.8% patients presented with high serum gammaglobulin, while 66.7% with high serum IgG, 56.2% with elevated ESR, 50.0% with positive rheumatoid factor(RF), 43.7% with eosinophilia, 26.7% with positive antinuclear antigen(ANA),31.2% with elevated lipase, 18.7% with elevated amylase, and 25.0% with elevated CA19-9. 93.7%patients showed diffuse swelling of the pancreas on CT and/or endoscopic ultrasound. Stricture of the main pancreatic duct was seen in 100% patients. Distal common bile duct stricture was seen in 87.5%, while thickened wall of bile duct was seen in 50%. Histological findings of the pancreas EUS-FNA showed nonspecific results in one patient, while no tumor cell was detected in other 5 patients; lymphocytes infiltration was noted in 3 patients; pancreatic fibrosis was seen in 2 patients. 75.0% patients was found to have diabetes or abnormal sugar tolerance, enlargement of the celiac lymph nodes in 43.7%, splenic vein or inferior cava vein involvement in 42.9%, swelling of the maxillary glands in 18.7%, the lacrimal glands in 12%. Prednisone was given to 11 patients, among them 5 patients underwent endoscopic stent placement, and 10 patients responded well while 1 patient discontinued therapy due to intolerance. 2 patients underwent endoscopic stent placement alone and jaundice disappeared. 3 patients received conventional medical treatment. Steroid therapy exerted different effects on levels of the blood glucose, the enlarged maxillary and lacrimal glands improved after steroid therapy. Conclusions AIP occurred in middle aged and senior male predominantly, painless obstructive jaundice was

  11. UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets

    DEFF Research Database (Denmark)

    Dalgaard, Louise Torp

    2012-01-01

    Uncoupling Protein 2 (UCP2) is expressed in the pancreatic β-cell, where it partially uncouples the mitochondrial proton gradient, decreasing both ATP-production and glucose-stimulated insulin secretion (GSIS). Increased glucose levels up-regulate UCP2 mRNA and protein levels, but the mechanism for...... UCP2 up-regulation in response to increased glucose is unknown. The aim was to examine the effects of glucokinase (GK) deficiency on UCP2 mRNA levels and to characterize the interaction between UCP2 and GK with regard to glucose-stimulated insulin secretion in pancreatic islets. UCP2 mRNA expression...... was reduced in GK+/- islets and GK heterozygosity prevented glucose-induced up-regulation of islet UCP2 mRNA. In contrast to UCP2 protein function UCP2 mRNA regulation was not dependent on superoxide generation, but rather on products of glucose metabolism, because MnTBAP, a superoxide dismutase...

  12. Role of intrapancreatic SPINK1/Spink3 expression in the development of pancreatitis

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    Masaki eOhmuraya

    2012-05-01

    Full Text Available Studies on hereditary pancreatitis have provided evidence in favor of central role for trypsin activity in the disease. Identification of genetic variants of trypsinogen linked the protease to the onset of pancreatitis, and biochemical characterization proposed an enzymatic gain of function as the initiating mechanism. Mutations of serine protease inhibitor Kazal type 1gene (SPINK1 are shown to be associated with hereditary pancreatitis. We previously reported that Spink3 (a mouse homologue gene of human SPINK1 deficient mice showed excessive autophagy, followed by inappropriate trypsinogen activation in the exocrine pancreas. These data indicate that the role of SPINK1/Spink3 is not only trypsin inhibitor, but also negative regulator of autophagy. On the other hand, recent studies showed that high levels of SPINK1 protein detected in a serum or urine were associated with adverse outcome in various cancer types. It has been suggested that expression of SPINK1 and trypsin is balanced in normal tissue, but this balance could be disrupted during tumor progression. Based on the structural similarity between SPINK1 and epidermal growth factor (EGF, we showed that SPINK1 protein binds and activates EGF receptor, thus acting as a growth factor on tumor cell lines. In this review, we summarize the old and new roles of SPINK1/Spink3 in trypsin inhibition, autophagy, and cancer cell growth. These new functions of SPINK1/Spink3 may be related to the development of chronic pancreatitis.

  13. Transcriptional Regulation of Chemokine Genes: A Link to Pancreatic Islet Inflammation?

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    Susan J. Burke

    2015-05-01

    Full Text Available Enhanced expression of chemotactic cytokines (aka chemokines within pancreatic islets likely contributes to islet inflammation by regulating the recruitment and activation of various leukocyte populations, including macrophages, neutrophils, and T-lymphocytes. Because of the powerful actions of these chemokines, precise transcriptional control is required. In this review, we highlight what is known about the signals and mechanisms that govern the transcription of genes encoding specific chemokine proteins in pancreatic islet β-cells, which include contributions from the NF-κB and STAT1 pathways. We further discuss increased chemokine expression in pancreatic islets during autoimmune-mediated and obesity-related development of diabetes.

  14. Low Expression of ARHI Is Associated with Shorter Progression-Free Survival in Pancreatic Endocrine Tumors

    OpenAIRE

    Irene Dalai; Edoardo Missiaglia; Stefano Barbi; Giovanni Butturini; Claudio Doglioni; Massimo Falconi; Aldo Scarpa

    2007-01-01

    Little is known about the molecular anomalies involved in the development and progression of malignancy of pancreatic endocrine tumors (PETs). A recently identified member of the Ras family, Ras homologue member I (ARHI), has been shown to be involved in breast, ovary, and thyroid carcinogenesis. Unlike other members, it acts as a tumor suppressor gene that inhibits cell growth. Here we analyzed the mRNA expression of ARHI in 52 primary PETs and 16 normal pancreata using quantitative reverse ...

  15. Differential expression of pancreatic protein and chemosensing receptor mRNAs in NKCC1-null intestine

    Science.gov (United States)

    Bradford, Emily M; Vairamani, Kanimozhi; Shull, Gary E

    2016-01-01

    AIM: To investigate the intestinal functions of the NKCC1 Na+-K+-2Cl cotransporter (SLC12a2 gene), differential mRNA expression changes in NKCC1-null intestine were analyzed. METHODS: Microarray analysis of mRNA from intestines of adult wild-type mice and gene-targeted NKCC1-null mice (n = 6 of each genotype) was performed to identify patterns of differential gene expression changes. Differential expression patterns were further examined by Gene Ontology analysis using the online Gorilla program, and expression changes of selected genes were verified using northern blot analysis and quantitative real time-polymerase chain reaction. Histological staining and immunofluorescence were performed to identify cell types in which upregulated pancreatic digestive enzymes were expressed. RESULTS: Genes typically associated with pancreatic function were upregulated. These included lipase, amylase, elastase, and serine proteases indicative of pancreatic exocrine function, as well as insulin and regenerating islet genes, representative of endocrine function. Northern blot analysis and immunohistochemistry showed that differential expression of exocrine pancreas mRNAs was specific to the duodenum and localized to a subset of goblet cells. In addition, a major pattern of changes involving differential expression of olfactory receptors that function in chemical sensing, as well as other chemosensing G-protein coupled receptors, was observed. These changes in chemosensory receptor expression may be related to the failure of intestinal function and dependency on parenteral nutrition observed in humans with SLC12a2 mutations. CONCLUSION: The results suggest that loss of NKCC1 affects not only secretion, but also goblet cell function and chemosensing of intestinal contents via G-protein coupled chemosensory receptors. PMID:26909237

  16. Clinical features of 11 cases diagnosed autoimmune pancreatitis%自身免疫性胰腺炎11例临床特征分析

    Institute of Scientific and Technical Information of China (English)

    陈雪; 张杰; 陈婧; 郭子皓; 李光; 郝建宇

    2012-01-01

    目的 探讨自身免疫性胰腺炎(AIP)的临床表现,血清学、影像学、组织学特征,诊断及治疗方案,以期提高对此病的认识.方法 回顾性分析2002~2012年收治的具有完整临床资料的AIP病例11例.结果 11例患者中,男7例,女4例,年龄49~77岁,平均年龄(65.2±8.9)岁,出现黄疸6例(54.5%),上腹部不适8例(72.7%),体重减轻8例(72.7%),无症状1例(9.1%).血清IgG4水平升高者10例(90.9%),CT显示胰腺弥漫肿大者8例(72.7%),胰头肿大2例(18.2%),胰腺体尾部肿大1例(9.1%),出现晕环征者7例(63.6%).6例行ERCP检查,显示主胰管不规则狭窄者6例(100%),胆管狭窄5例(83.3%),考虑为IgG4相关性胆管炎.8例行EUS-FNA,其中可见浆细胞、腺体及纤维素者3例(37.5%),见少量腺体、纤维素者4例(50%),仅见小簇状细胞者1例(12.5%).单纯激素治疗者7例(63.6%),激素联合熊去氧胆酸治疗4例(36.4%),因胆管狭窄放置支架4例,手术2例,其中胆肠吻合术1例,胰十二指肠切除术1例,经治疗后,所有患者黄疸消退,影像学显示胰腺恢复正常,9例血清IgG4恢复正常.结论 自身免疫性胰腺炎的诊断需要综合考虑,激素是首选的治疗方法,对于IgG4相关性胆管炎所致胆管狭窄,单用激素治疗效果不佳者,胆道支架植入或胆肠吻合手术可以作为减轻黄疸的有效方法.%Objective In order to increase the awareness of autoimmune pancreatitis(AIP) , we investigated the clinical manifestations, serological, radiological and histological features, diagnosis and treatment. Methods Clinical data of 11 cases from 2002 to 2012 in Beijing Chaoyang Hospital was reviewed. Results The age of AIP (male 7 ; female 4) ranged from 49 to 77 with a median age of (65.2±8.9) years in this series. Ofthell patients, 6 cases (54. 5% )had the symptom of painless jaundice, upper abdominal discomfort in 8 cases (72.7% ) , weight loss in 8 cases (72.7%), asymptom in 1 case (9. 1

  17. HLA-DPDQDR is expressed in all lesional skin from patients with autoimmune skin diseases

    Directory of Open Access Journals (Sweden)

    Ana Maria Abreu Velez

    2014-04-01

    Full Text Available Introduction: Human genes responsible for human antigen presentation and transplant rejection functions are located on the short arm of Chromosome 6 and are called the Major Histocompatibility Complex (MHC. Moreover, the primary physiologic function of MHC molecules is to present peptides to T lymphocytes. MHC molecules are integral components of the ligands that most T cells recognize, since the T cell receptor (TCR has specificity for complexes of foreign antigenic peptides, as well as self-MHC molecules. Aim: Our investigation attempts to investigate the presence of HLA-DPDQDR within lesional skin biopsies from patients affected by autoimmune skin blistering diseases (ABDs. Materials and Methods: We utilized immunohistochemistry (IHC to evaluate the presence of HLA-DPDQDR in lesional skin biopsies of patients affected by ABDs. We tested 30 patients with endemic pemphigus foliaceus (EPF, 15 controls from the EPF endemic area, and 15 biopsies from healthy controls from the USA. We also tested archival biopsies from patients with selected ABDs, including 30 patients with bullous pemphigoid (BP, 20 with pemphigus vulgaris (PV, 8 with pemphigus foliaceus (PF, 14 with dermatitis herpetiformis (DH and 2 with epidermolysis bullosa acquisita (EBA. Results: Most ABD biopsies stained positive for HLA-DPDQDR in the lesional blisters and/or inflamed neurovascular plexus in the superficial dermis, and also at mesenchymal-endothelial like-cell junctions in the dermis. In BP, EBA and EPF, the HLA-DPDQDR staining was also seen in the dermal eccrine sweat gland coils and and ducts. Conclusion: Here, we document that HLA-DPDQDR is expressed in several anatomic areas of lesional skin in patients with ABDs. Notably, HLA-DPDQDR positivity was also consistently present in areas of the classic immune response in pemphigus epidermal keratinocytic intercellular junctions, and at basement membrane sites in bullous pemphigoid and other subepidermal blistering diseases.

  18. Cannabinoids Regulate Bcl-2 and Cyclin D2 Expression in Pancreatic β Cells.

    Directory of Open Access Journals (Sweden)

    Jihye Kim

    Full Text Available Recent reports have shown that cannabinoid 1 receptors (CB1Rs are expressed in pancreatic β cells, where they induce cell death and cell cycle arrest by directly inhibiting insulin receptor activation. Here, we report that CB1Rs regulate the expression of the anti-apoptotic protein Bcl-2 and cell cycle regulator cyclin D2 in pancreatic β cells. Treatment of MIN6 and βTC6 cells with a synthetic CB1R agonist, WIN55,212-2, led to a decrease in the expression of Bcl-2 and cyclin D2, in turn inducing cell cycle arrest in G0/G1 phase and caspase-3-dependent apoptosis. Additionally, genetic deletion and pharmacological blockade of CB1Rs after injury in mice led to increased levels of Bcl-2 and cyclin D2 in pancreatic β cells. These findings provide evidence for the involvement of Bcl-2 and cyclin D2 mediated by CB1Rs in the regulation of β-cell survival and growth, and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and growth in diabetes.

  19. Expression of early growth response factor-1 in rats with cerulein-induced acute pancreatitis and its significance

    Institute of Scientific and Technical Information of China (English)

    Lan-Bo Gong; Li He; Yang Liu; Xue-Qing Chen; Bo Jiang

    2005-01-01

    AIM: To observe the expressions of early growth response factor-1 (Egr-L) and tissue factor (TF) in rats with cerulein-induced acute pancreatitis and to explore its significance.METHODS: A large dose of cerulein was used to create the experimental acute pancreatitis model in rats. The changes of Egr-1 mRNA and protein in rats were observed during 30 min to 4 h after the treatment and immunohistochemical method was used to observe the localized expression of Egr-1 in tissues. In addition to the mRNA expression of Egr-1 target gene, TF was also observed. A blank control group, and a bombesinadministered group were used for comparison.RESULTS: After the stimulation of a large dose of cerulein,the rats showed typical inflammatory changes of acute pancreatitis. Thirty minutes after the stimulation, the mRNA expression of Egr-1 in the pancreatic tissue reached its peak and then declined, while the expression of Egr-1protein reached its peak 2 h after the stimulation.Histologically, 2 h after the stimulation, almost all pancreatic acinar cells had the expression of Egr-1 protein,which was focused in the nuclei. The mRNA expression of TF occurred 1 h after the stimulation and gradually increased within 4 h. However, a large dose of bombesin only stimulated the pancreatic tissue to produce a little mRNA expression of Egr-1 and no mRNA expression of Egr-1 protein and TF.CONCLUSION: Egr-1 as a pro-inflammatory transcription factor may play an important role in the pathogenesis of acute pancreatitis by modulating the expression of TF.

  20. Profile of MMP and TIMP Expression in Human Pancreatic Stellate Cells: Regulation by IL-1α and TGFβ and Implications for Migration of Pancreatic Cancer Cells

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    Vegard Tjomsland

    2016-07-01

    Full Text Available Pancreatic ductal adenocarcinoma is characterized by a prominent fibroinflammatory stroma with both tumor-promoting and tumor-suppressive functions. The pancreatic stellate cell (PSC is the major cellular stromal component and the main producer of extracellular matrix proteins, including collagens, which are degraded by metalloproteinases (MMPs. PSCs interact with cancer cells through various factors, including transforming growth factor (TGFβ and interleukin (IL-1α. The role of TGFβ in the dual nature of tumor stroma, i.e., protumorigenic or tumor suppressive, is not clear. We aimed to investigate the roles of TGFβ and IL-1α in the regulation of MMP profiles in PSCs and the subsequent effects on cancer cell migration. Human PSCs isolated from surgically resected specimens were cultured in the presence of pancreatic cancer cell lines, as well as IL-1α or TGFβ. MMP production and activities in PSCs were quantified by gene array transcripts, mRNA measurements, fluorescence resonance energy transfer–based activity assay, and zymography. PSC-conditioned media and pancreatic cancer cells were included in a collagen matrix cell migration model. We found that production of IL-1α by pancreatic cancer cells induced alterations in MMP and tissue inhibitors of matrix metalloproteinase (TIMP profiles and activities in PSCs, upregulated expression and activation of MMP1 and MMP3, and enhanced migration of pancreatic cancer cells in the collagen matrix model. TGFβ counteracted the effects of IL-1α on PSCs, reestablished PSC MMP and TIMP profiles and activities, and inhibited migration of cancer cells. This suggests that tumor TGFβ has a role as a suppressor of stromal promotion of tumor progression through alterations in PSC MMP profiles with subsequent inhibition of pancreatic cancer cell migration.

  1. Expressions of Matrix Metalloproteinases 2, 7, and 9 in Carcinogenesis of Pancreatic Ductal Adenocarcinoma

    Science.gov (United States)

    Januszewska, Joanna; Sidorkiewicz, Iwona; Niewiński, Andrzej; Lewczuk, Łukasz; Kędra, Bogusław; Guzińska-Ustymowicz, Katarzyna

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease, usually diagnosed in an advanced stage which gives a slight chance of recovery. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that participate in tissue remodeling and stimulate neovascularization and inflammatory response. The aim of the study was to evaluate the expression of MMP-2, MMP-7, and MMP-9 in normal ducts, tumor pancreatic adenocarcinoma cells, and peritumoral stroma in correlation with clinicohistopathological parameters. The study material was obtained from 29 patients with pancreatic ductal adenocarcinoma. The expressions of MMP-2, MMP-7, and MMP-9 were performed by immunohistochemical technique. Microvessel density (MVD) was visualized by special immunostaining. The expressions of MMP-2, MMP-7, and MMP-9 were mainly observed in tumor cells and peritumoral stroma. MMP-2 expression in cancer cells was correlated with female gender, stronger inflammation, and histopathological type of cancer (R = 0.460, p = 0.013; R = 0.690, p = 0.0001; R = −0.440, p = 0.005, resp.). The expression of MMP-7 in tumor cells was found to positively correlate with the presence of necrosis and negatively correlate with MVD (R = 0.402, p = 0.031; R = −0.682, p = 0.000). We also showed that positive MMP-9 expression in tumor cells was associated with MVD (R = 0.368, p = 0.084); however, it was not statistically significant. Our results demonstrate that MMP-2, MMP-7, and MMP-9 expressions correlate with various morphological features of the PDAC tumor such as inflammation, necrosis, and formation of the new blood vessels.

  2. Extracellular matrix composition significantly influences pancreatic stellate cell gene expression pattern: role of transgelin in PSC function.

    Science.gov (United States)

    Apte, Minoti V; Yang, Lu; Phillips, Phoebe A; Xu, Zhihong; Kaplan, Warren; Cowley, Mark; Pirola, Romano C; Wilson, Jeremy S

    2013-09-15

    Activated pancreatic stellate cells (PSCs) are responsible for the fibrotic matrix of chronic pancreatitis and pancreatic cancer. In vitro protocols examining PSC biology have usually involved PSCs cultured on plastic, a nonphysiological surface. However, PSCs cultured on physiological matrices, e.g., Matrigel (normal basement membrane) and collagen (fibrotic pancreas), may have distinctly different behaviors compared with cells cultured on plastic. Therefore, we aimed to 1) compare PSC gene expression after culture on plastic, Matrigel, and collagen I; 2) validate the gene array data for transgelin, the most highly dysregulated gene in PSCs grown on activating vs. nonactivating matrices, at mRNA and protein levels; 3) examine the role of transgelin in PSC function; and 4) assess transgelin expression in human chronic pancreatitis sections. Culture of PSCs on different matrices significantly affected their gene expression pattern. 146, 619, and 432 genes, respectively, were differentially expressed (P PSC proliferation and also reduced platelet-derived growth factor-induced PSC migration. Notably, transgelin was highly expressed in chronic pancreatitis in stromal areas and periacinar spaces but was absent in acinar cells. These findings suggest that transgelin is a potentially useful target protein to modulate PSC function so as to ameliorate pancreatic fibrosis.

  3. Analysis of the Expression of Fas, FasL and Bcl-2 in the Pathogenesis of Autoimmune Thyroid Disorders

    Institute of Scientific and Technical Information of China (English)

    Shenren Chen; S.M.Fazle Akbar; Zhichao Zhen; Yiping Luo; Lijuan Deng; Haihua Huang; Linxin Chen; Wei Li

    2004-01-01

    To investigate the expression of apoptosis-related protein (Fas, FasL, and Bcl-2) in the pathogenesis of autoimmune thyroid disorders (ATDs), immunohistochemical staining was performed on 20 Hashimoto's thyroiditis (HT), 20 Graves' disease (GD), and 20 thyroid follicular adenoma (TFA, as control). All the cases expressed Fas, mainly on the cell surface and cytoplasm. FasL was found in 17 cases of the TFA. Bcl-2 was detected in 15 cases of HT, 19 of GD and 17 of TFA. In TFA, a moderate Fas expression and a minimal or no FasL expression was detected on follicular cells. In HT, the follicles adjacent to infiltrating lymphocytes showed increased levels of Fas and FasL expression. A weaker staining of Fas and FasL was exhibited on infiltrating lymphocytes than on thyrocytes. In a comparison of GD with HT, thyrocytes and lymphocytes showed similar Fas staining, but for FasL the staining was rather weaker in HT. The expression of Bcl-2 was nearly identical in GD and TFA, but much weaker on the follicular cells in vicinity of lymphocytes and on the lymphocytes located in germinal centers of HT tissues. The expression of Fas, FasL, Bcl-2 in Hashimoto's thyroiditis and Graves' disease were almost same. FasL strong expression and Bcl-2 weak expression on the follicles in HT may induce apoptosis. These results provided evidence for expression of Fas, FasL and Bcl-2 in the pathogenesis of autoimmune thyroid disease. The lymphocytes seem not to be directly engaged in the process via their own FasL, but they may provide some cytokines that, in turn, upregulate Fas and/or FasL expression to induce apoptosis.

  4. Pancreatic expression of human insulin gene in transgenic mice.

    OpenAIRE

    Bucchini, D; Ripoche, M A; Stinnakre, M G; Desbois, P; Lorès, P; Monthioux, E; Absil, J; Lepesant, J A; Pictet, R; Jami, J

    1986-01-01

    We have investigated the possibility of obtaining integration and expression of a native human gene in transgenic mice. An 11-kilobase (kb) human chromosomal DNA fragment including the insulin gene (1430 base pairs) was microinjected into fertilized mouse eggs. This fragment was present in the genomic DNA of several developing animals. One transgenic mouse and its progeny were analyzed for expression of the foreign gene. Synthesis and release of human insulin was revealed by detection of the ...

  5. Promoter Hypermethylation and Decreased Expression of Syncytin-1 in Pancreatic Adenocarcinomas.

    Directory of Open Access Journals (Sweden)

    Qinsheng Lu

    Full Text Available Syncytin-1 is a member of human endogenous retroviral W gene family (HERVW1. Known to be expressed in human placental trophoblast, syncytin-1 protein mediates the fusion of cytotrophoblasts for the formation of syncytiotrophoblasts, the terminally differentiated form of trophoblast lineage. In addition, in vitro studies indicate that syncytin-1 possessed nonfusogenic functions such as those for immune suppression, cell cycle regulation and anti-apoptotic activities. Overexpression of syncytin-1 has been observed in various malignant tissues including breast, endometrial and ovarian cancers. It was reported that syncytin-1 gene expression is associated with dynamic changes of DNA hypomethylation in the 5' LTR. In this study, applying the real-time PCR, Western blot analysis and immunohistochemistry methods, we demonstrate a constitutive expression of syncytin-1 in normal pancreas tissues as well as normal tissues adjacent to cancer lesions. Moreover, a reduced expression is found in the pancreatic adenocarcinoma tissues. The expression levels of syncytin-1 are not correlated with the stage, historical grade and gender, but inversely correlated with patients' age. Furthermore, COBRA and bisulfite sequencing results indicated that the lower expression of syncytin-1 is correlated with the hypermethylation of two CpG dinucleotides in the 5' LTR of syncytin-1 gene. The nonfusogenic function of syncytin-1 in normal pancreas as well as its role(s in the pathogenesis and progression of pancreatic cancers remains to be investigated. Identification of the two CpG dinucleotides around transcription start site as key epigenetic elements has provided valuable information for further studies on the epigenetic regulation of syncytin-1 in pancreatic cancer cells.

  6. SIGNIFICANCE OF EXPRESS OF SOME NONHORMONAL ANTIGENS IN PANCREATIC ENDOCRINE TUMORS

    Institute of Scientific and Technical Information of China (English)

    Yu Jiyao

    1998-01-01

    Objective: To study the express of some nonhormonal antigens in pancreatic endocrine tumors. Methods: The nonhormonal antigens including Alpha-subunit of human chorionic gonadotropin (α-HCG), progesterone receptors (PR), 7B2, HISL-19, in normal pancreatic islets and in 52cases of pancreatic endocrine tumors (PET) were investigated by immunohistochemistry. Results: It was found that HCG can be detected in PET but not in normal islet cells. HCG immunoreactivity was expressed by 3 of 28 (10.7%) benign PET and by 14 of 24 (58.3%)malignant PET. PR was found by 20 of 28 (71.4%) benign PET and by 7 of 24 (29%) malignant PET. 7B2 was detected by 23 of 28 (82.1%) benign PET and by 13 of 24(54.2%) malignant PET. HISL-19 was appeared by 23 of 28 benign PET and by 11 of 24 (46%) malignant PET.Golgitype persisted in 87.5% malignant tumors.Conclusion: The assay of nonhormonal antigens may be well defined the clinico-pathological characteristics of PET.

  7. Aberrantly Over-Expressed TRPM8 Channels in Pancreatic Adenocarcinoma: Correlation with Tumor Size/Stage and Requirement for Cancer Cells Invasion

    Directory of Open Access Journals (Sweden)

    Nelson S. Yee

    2014-05-01

    Full Text Available The transient receptor potential melastatin-subfamily member 8 (TRPM8 channels control Ca2+ homeostasis. Recent studies indicate that TRPM8 channels are aberrantly expressed and required for cellular proliferation in pancreatic adenocarcinoma. However, the functional significance of TRPM8 in pancreatic tissues is mostly unknown. The objectives of this study are to examine the expression of TRPM8 in various histopathological types of pancreatic tissues, determine its clinical significance in pancreatic adenocarcinoma, and investigate its functional role in cancer cells invasion. We present evidence that, in normal pancreatic tissues, anti-TRPM8 immunoreactivity is detected in the centroacinar cells and the islet endocrine cells. In pre-malignant pancreatic tissues and malignant neoplasms, TRPM8 is aberrantly expressed to variable extents. In the majority of pancreatic adenocarcinoma, TRPM8 is expressed at moderate or high levels, and anti-TRPM8 immunoreactivity positively correlates with the primary tumor size and stage. In the pancreatic adenocarcinoma cell lines that express relatively high levels of TRPM8, short hairpin RNA-mediated interference of TRPM8 expression impaired their ability of invasion. These data suggest that aberrantly expressed TRPM8 channels play contributory roles in pancreatic tumor growth and metastasis, and support exploration of TRPM8 as a biomarker and target of pancreatic adenocarcinoma.

  8. Raloxifene suppresses experimental autoimmune encephalomyelitis and NF-κB-dependent CCL20 expression in reactive astrocytes.

    Directory of Open Access Journals (Sweden)

    Rui Li

    Full Text Available Recent clinical data have led to the consideration of sexual steroids as new potential therapeutic tools for multiple sclerosis. Selective estrogen receptor modulators can exhibit neuroprotective effects like estrogen, with fewer systemic estrogen side effects than estrogen, offering a more promising therapeutic modality for multiple sclerosis. The important role of astrocytes in a proinflammatory effect mediated by CCL20 signaling on inflammatory cells has been documented. Their potential contribution to selective estrogen receptor modulator-mediated protection is still unknown. Using a mouse model of chronic neuroinflammation, we report that raloxifene, a selective estrogen receptor modulator, alleviated experimental autoimmune encephalomyelitis-an animal model of multiple sclerosis-and decreased astrocytic production of CCL20. Enzyme-linked immunosorbent assay, immunohistochemistry imaging and transwell migration assays revealed that reactive astrocytes express CCL20, which promotes Th17 cell migration. In cultured rodent astrocytes, raloxifene inhibited IL-1β-induced CCL20 expression and chemotaxis ability for Th17 migration, whereas the estrogen receptor antagonist ICI 182,780 blocked this effect. Western blotting further indicated that raloxifene suppresses IL-1β-induced NF-κB activation (phosphorylation of p65 and translocation but does not affect phosphorylation of IκB. In conclusion, these data demonstrate that raloxifene provides robust neuroprotection against experimental autoimmune encephalomyelitis, partially via an inhibitory action on CCL20 expression and NF-κB pathways in reactive astrocytes. Our results contribute to a better understanding of the critical roles of raloxifene in treating experimental autoimmune encephalomyelitis and uncover reactive astrocytes as a new target for the inhibitory action of estrogen receptors on chemokine CCL20 expression.

  9. Decreased miR-26a expression correlates with the progression of podocyte injury in autoimmune glomerulonephritis.

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    Osamu Ichii

    Full Text Available MicroRNAs contribute to the pathogenesis of certain diseases and may serve as biomarkers. We analyzed glomerular microRNA expression in B6.MRLc1, which serve as a mouse model of autoimmune glomerulonephritis. We found that miR-26a was the most abundantly expressed microRNA in the glomerulus of normal C57BL/6 and that its glomerular expression in B6.MRLc1 was significantly lower than that in C57BL/6. In mouse kidneys, podocytes mainly expressed miR-26a, and glomerular miR-26a expression in B6.MRLc1 mice correlated negatively with the urinary albumin levels and podocyte-specific gene expression. Puromycin-induced injury of immortalized mouse podocytes decreased miR-26a expression, perturbed the actin cytoskeleton, and increased the release of exosomes containing miR-26a. Although miR-26a expression increased with differentiation of immortalized mouse podocytes, silencing miR-26a decreased the expression of genes associated with the podocyte differentiation and formation of the cytoskeleton. In particular, the levels of vimentin and actin significantly decreased. In patients with lupus nephritis and IgA nephropathy, glomerular miR-26a levels were significantly lower than those of healthy controls. In B6.MRLc1 and patients with lupus nephritis, miR-26a levels in urinary exosomes were significantly higher compared with those for the respective healthy control. These data indicate that miR-26a regulates podocyte differentiation and cytoskeletal integrity, and its altered levels in glomerulus and urine may serve as a marker of injured podocytes in autoimmune glomerulonephritis.

  10. Chemokine expression in GKO mice (lacking interferon-gamma) with experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Glabinski, A R; Krakowski, M; Han, Y;

    1999-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) considered to be an animal model for multiple sclerosis (MS). The detailed mechanism that specifies accumulation of inflammatory cells within the CNS in these conditions remains a subjec...

  11. Reduced experimental autoimmune encephalomyelitis after intranasal and oral administration of recombinant lactobacilli expressing myelin antigens

    NARCIS (Netherlands)

    C.B.M. Maassen (Kitty); J.D. Laman (Jon); C. van Holten-Neelen; L. Hoogteijling (L.); L. Groenewegen (Lizet); L. Visser (Lizette); M.M. Schellekens (M.); W.G. Boersma (Wim); H.J.H.M. Claassen (Eric)

    2003-01-01

    textabstractOral administration of autoantigens is a safe and convenient way to induce peripheral T-cell tolerance in autoimmune diseases like multiple sclerosis (MS). To increase the efficacy of oral tolerance induction and obviate the need for large-scale purification of human myelin proteins, we

  12. Reduced experimental autoimmune encephalomyelitis after intranasal and oral administration of recombinant lactobacilli expressing meyelin antigens

    NARCIS (Netherlands)

    Maassen, C.B.M.; Holten-Neelen, van J.C.P.A.; Groenewegen, L.; Hoogteijling, L.; Visser, L.; Boersma, W.J.A.

    2003-01-01

    Oral administration of autoantigens is a safe and convenient way to induce peripheral T-cell tolerance in autoimmune diseases like multiple sclerosis (MS). To increase the efficacy of oral tolerance induction and obviate the need for large-scale purification of human myelin proteins, we use genetica

  13. Analysis of gene expression profile of pancreatic carcinoma using CDNA microarray

    Institute of Scientific and Technical Information of China (English)

    ZhiJun Tan; Xian-Gui Hu; Gui-Song Cao; Yan Tang

    2003-01-01

    AIM: To identify new diagnostic markers and drug targets,the gene expression profiles of pancreatic cancer were compared with that of adjacent normal tissues utilizing cDNA microarray analysis.METHODS: cDNA probes were prepared by labeling mRNA from samples of six pancreatic carcinoma tissues with Cy5dUTP and mRNA from adjacent normal tissues with Cy3dUTP respectively through reverse transcription. The mixed probes of each sample were then hybridized with 12 800cDNA arrays (12 648 unique human cDNA sequences), and the fluorescent signals were scanned by ScanArray 3 000scanner (General Scanning, Inc.). The values of CyS-dUTP and Cy3-dUTP on each spot were analyzed and calculated by ImaGene 3.0 software (BioDiscovery, Inc.). Differentially expressed genes were screened according to the criterion that the absolute value of natural logarithm of the ratio of Cy5-dUTP to Cy3-dUTP was greater-than 0.69.RESETS: Among 6 samples investigated, 301 genes, which accounted for 2.38% of genes on the microarry slides,exhibited differentially expression at least in 5. There were 166 over-expressed genes including 136 having been registered in Genebank, and 135 under-expressed genes including 79 in Genebank in cancerous tissues.CONCLUSION: Microarray analysis may provide invaluable information on disease pathology, progression, resistance to treatment, and response to cellular microenvironments of pancreatic carcinoma and ultimately may lead to improving early diagnosis and discovering innovative therapeutic approaches for cancer.

  14. Transgenic expression of the human growth hormone minigene promotes pancreatic β-cell proliferation.

    Science.gov (United States)

    Baan, Mieke; Kibbe, Carly R; Bushkofsky, Justin R; Harris, Ted W; Sherman, Dawn S; Davis, Dawn Belt

    2015-10-01

    Transgenic mouse models are designed to study the role of specific proteins. To increase transgene expression the human growth hormone (hGH) minigene, including introns, has been included in many transgenic constructs. Until recently, it was thought that the hGH gene was not spliced, transcribed, and translated to produce functional hGH protein. We generated a transgenic mouse with the transcription factor Forkhead box M1 (FoxM1) followed by the hGH minigene, under control of the mouse insulin promoter (MIP) to target expression specifically in the pancreatic β-cell. Expression of FoxM1 in isolated pancreatic islets in vitro stimulates β-cell proliferation. We aimed to investigate the effect of FoxM1 on β-cell mass in a mouse model for diabetes mellitus. However, we found inadvertent coexpression of hGH protein from a spliced, bicistronic mRNA. MIP-FoxM1-hGH mice had lower blood glucose and higher pancreatic insulin content, due to increased β-cell proliferation. hGH signals through the murine prolactin receptor, and expression of its downstream targets tryptophan hydroxylase-1 (Tph1), tryptophan hydroxylase-2 (Tph2), and cytokine-inducible SH2 containing protein (Cish) was increased. Conversely, transcriptional targets of FoxM1 were not upregulated. Our data suggest that the phenotype of MIP-FoxM1-hGH mice is due primarily to hGH activity and that the FoxM1 protein remains largely inactive. Over the past decades, multiple transgenic mouse strains were generated that make use of the hGH minigene to increase transgene expression. Our work suggests that each will need to be carefully screened for inadvertent hGH production and critically evaluated for the use of proper controls. PMID:26202070

  15. Adenoviral vectors stimulate glucagon transcription in human mesenchymal stem cells expressing pancreatic transcription factors.

    Directory of Open Access Journals (Sweden)

    Arnaud Zaldumbide

    Full Text Available Viral gene carriers are being widely used as gene transfer systems in (transdifferentiation and reprogramming strategies. Forced expression of key regulators of pancreatic differentiation in stem cells, liver cells, pancreatic duct cells, or cells from the exocrine pancreas, can lead to the initiation of endocrine pancreatic differentiation. While several viral vector systems have been employed in such studies, the results reported with adenovirus vectors have been the most promising in vitro and in vivo. In this study, we examined whether the viral vector system itself could impact the differentiation capacity of human bone-marrow derived mesenchymal stem cells (hMSCs toward the endocrine lineage. Lentivirus-mediated expression of Pdx-1, Ngn-3, and Maf-A alone or in combination does not lead to robust expression of any of the endocrine hormones (i.e. insulin, glucagon and somatostatin in hMSCs. Remarkably, subsequent transduction of these genetically modified cells with an irrelevant early region 1 (E1-deleted adenoviral vector potentiates the differentiation stimulus and promotes glucagon gene expression in hMSCs by affecting the chromatin structure. This adenovirus stimulation was observed upon infection with an E1-deleted adenovirus vector, but not after exposure to helper-dependent adenovirus vectors, pointing at the involvement of genes retained in the E1-deleted adenovirus vector in this phenomenon. Lentivirus mediated expression of the adenovirus E4-ORF3 mimics the adenovirus effect. From these data we conclude that E1-deleted adenoviral vectors are not inert gene-transfer vectors and contribute to the modulation of the cellular differentiation pathways.

  16. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of {beta}-catenin

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Il-Rae [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Koh, Sang Seok [Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333 (Korea, Republic of); Department of Functional Genomics, University of Science and Technology, Daejeon 305-333 (Korea, Republic of); Malilas, Waraporn; Srisuttee, Ratakorn; Moon, Jeong [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Choi, Young-Whan [Department of Horticultural Bioscience, Pusan National University, Miryang 627-706 (Korea, Republic of); Horio, Yoshiyuki [Department of Pharmacology, Sapporo Medical University, Sapporo 060-8556 (Japan); Oh, Sangtaek [Department of Advanced Fermentation Fusion Science and Technology, Kookmin University, Seoul 136-702 (Korea, Republic of); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of)

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer SIRT1 inhibits protein levels of {beta}-catenin and its transcriptional activity. Black-Right-Pointing-Pointer Nuclear localization of SIRT1 is not required for the decrease of {beta}-catenin expression. Black-Right-Pointing-Pointer SIRT1-mediated degradation of {beta}-catenin is not required for GSK-3{beta} and Siah-1 but for proteosome. Black-Right-Pointing-Pointer SIRT1 activation inhibits proliferation of pancreatic cancer cells expressing PAUF. -- Abstract: Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of {beta}-catenin, we postulated that {beta}-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target {beta}-catenin in a colon cancer model, suppresses {beta}-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF). We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of {beta}-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced {beta}-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of {beta}-catenin. Treatment with MG132, a proteasomal inhibitor, restored {beta}-catenin protein levels, suggesting that SIRT1-mediated degradation of {beta}-catenin requires proteasomal activity. It was reported that inhibition of GSK-3{beta} or Siah-1 stabilizes {beta}-catenin in colon cancer cells, but suppression of GSK-3{beta} or Siah-1 using siRNA in the presence of resveratrol instead diminished {beta}-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3{beta} and Siah-1 are not involved in SIRT1

  17. Global gene expression profiling of pancreatic islets in mice during streptozotocin-induced β-cell damage and pancreatic Glp-1 gene therapy

    Directory of Open Access Journals (Sweden)

    Jason M. Tonne

    2013-09-01

    Streptozotocin (STZ, a glucosamine-nitrosourea compound, has potent genotoxic effects on pancreatic β-cells and is frequently used to induce diabetes in experimental animals. Glucagon-like peptide-1 (GLP-1 has β-cell protective effects and is known to preserve β-cells from STZ treatment. In this study, we analyzed the mechanisms of STZ-induced diabetes and GLP-1-mediated β-cell protection in STZ-treated mice. At 1 week after multiple low-dose STZ administrations, pancreatic β-cells showed impaired insulin expression, while maintaining expression of nuclear Nkx6.1. This was accompanied by significant upregulation of p53-responsive genes in islets, including a mediator of cell cycle arrest, p21 (also known as Waf1 and Cip1. STZ treatment also suppressed expression of a wide range of genes linked with key β-cell functions or diabetes development, such as G6pc2, Slc2a2 (Glut2, Slc30a8, Neurod1, Ucn3, Gad1, Isl1, Foxa2, Vdr, Pdx1, Fkbp1b and Abcc8, suggesting global β-cell defects in STZ-treated islets. The Tmem229B, Prss53 and Ttc28 genes were highly expressed in untreated islets and strongly suppressed by STZ, suggesting their potential roles in β-cell function. When a pancreas-targeted adeno-associated virus (AAV vector was employed for long-term Glp-1 gene delivery, pancreatic GLP-1 expression protected mice from STZ-induced diabetes through preservation of the β-cell mass. Despite its potent β-cell protective effects, however, pancreatic GLP-1 overexpression showed limited effects on the global gene expression profiles in the islets. Network analysis identified the programmed-cell-death-associated pathways as the most relevant network in Glp-1 gene therapy. Upon pancreatic GLP-1 expression, upregulation of Cxcl13 and Nptx2 was observed in STZ-damaged islets, but not in untreated normal islets. Given the pro-β-cell-survival effects of Cxcl12 (Sdf-1 in inducing GLP-1 production in α-cells, pancreatic GLP-1-mediated Cxcl13 induction might also play a

  18. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of β-catenin

    International Nuclear Information System (INIS)

    Highlights: ► SIRT1 inhibits protein levels of β-catenin and its transcriptional activity. ► Nuclear localization of SIRT1 is not required for the decrease of β-catenin expression. ► SIRT1-mediated degradation of β-catenin is not required for GSK-3β and Siah-1 but for proteosome. ► SIRT1 activation inhibits proliferation of pancreatic cancer cells expressing PAUF. -- Abstract: Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of β-catenin, we postulated that β-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target β-catenin in a colon cancer model, suppresses β-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF). We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of β-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced β-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of β-catenin. Treatment with MG132, a proteasomal inhibitor, restored β-catenin protein levels, suggesting that SIRT1-mediated degradation of β-catenin requires proteasomal activity. It was reported that inhibition of GSK-3β or Siah-1 stabilizes β-catenin in colon cancer cells, but suppression of GSK-3β or Siah-1 using siRNA in the presence of resveratrol instead diminished β-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3β and Siah-1 are not involved in SIRT1-mediated degradation of β-catenin in the cells. Finally, activation of SIRT1 inhibited the proliferation of Panc-PAUF cells by down-regulation of cyclin-D1, a target

  19. African Americans with pancreatic ductal adenocarcinoma exhibit gender differences in Kaiso expression.

    Science.gov (United States)

    Jones, Jacqueline; Mukherjee, Angana; Karanam, Balasubramanyam; Davis, Melissa; Jaynes, Jesse; Reams, R Renee; Dean-Colomb, Windy; Yates, Clayton

    2016-10-01

    Kaiso, a bi-modal transcription factor, regulates gene expression, and is elevated in breast, prostate, and colon cancers. Depletion of Kaiso in other cancer types leads to a reduction in markers for the epithelial-mesenchymal transition (EMT) (Jones et al., 2014), however its clinical implications in pancreatic ductal adenocarcinoma (PDCA) have not been widely explored. PDCA is rarely detected at an early stage but is characterized by rapid progression and invasiveness. We now report the significance of the subcellular localization of Kaiso in PDCAs from African Americans. Kaiso expression is higher in the cytoplasm of invasive and metastatic pancreatic cancers. In males, cytoplasmic expression of Kaiso correlates with cancer grade and lymph node positivity. In male and female patients, cytoplasmic Kaiso expression correlates with invasiveness. Also, nuclear expression of Kaiso increases with increased invasiveness and lymph node positivity. Further, analysis of the largest PDCA dataset available on ONCOMINE shows that as Kaiso increases, there is an overall increase in Zeb1, which is the inverse for E-cadherin. Hence, these findings suggest a role for Kaiso in the progression of PDCAs, involving the EMT markers, E-cadherin and Zeb1. PMID:27424525

  20. Analysis of long non-coding RNA expression profiles in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Fu, Xue-Liang; Liu, De-Jun; Yan, Ting-Ting; Yang, Jian-Yu; Yang, Min-Wei; Li, Jiao; Huo, Yan-Miao; Liu, Wei; Zhang, Jun-Feng; Hong, Jie; Hua, Rong; Chen, Hao-Yan; Sun, Yong-Wei

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients' clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC. PMID:27628540

  1. Global expression analysis during late stage of embryonic pancreatic development of rats with microarray technique

    Institute of Scientific and Technical Information of China (English)

    Qingxin Yuan; Chao Liu; Yan Zhong; Cuiping Liu; Li Yuan; Jinyong Zhou; Li-ping Teng; Jingjing Hu; Wei De

    2006-01-01

    Objective: To define gene expression profiles during late stage of embryonic pancreatic development of rats and to find out key genes in rat pancreatic functional development. Methods: Pancreata of rats in embryonic day 15.5(E15.5) and 18.5(E18.5)were dissected under microscope respectively. Genechips from Affymetrix company were applied to study gene expression profiles. Some differentially expressed genes were verified by RT-PCR. Results: Comparing El8.5 to El5.5, 8.3% genes were expressed differently 2-fold above, in which, 50.3% were up-regulated, including transcriptions related to metabolic development and various kinds of enzymes and hormones (both endocrine and exocrine) and 49.7% were down-regulated, including transcriptions related to cell differentiation. The percentage of genes having definite function was 63%, and that of expressed sequence tag(EST) was 37%. The result of RT-PCR is accordant to that of genechips. Conclusion: The metabolic function of rat pancreas may be further accomplished during late stage of embryonic day.

  2. ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor {alpha} Expression in Pancreatic {beta}-Cells

    DEFF Research Database (Denmark)

    Boergesen, Michael; Poulsen, Lars la Cour; Schmidt, Søren Fisker;

    2011-01-01

    Chronic exposure to elevated levels of glucose and fatty acids leads to dysfunction of pancreatic β-cells by mechanisms that are only partly understood. The transcription factor peroxisome proliferator-activated receptor α (PPARα) is an important regulator of genes involved in fatty acid metaboli...... of glucose repression of PPARα gene expression in pancreatic β-cells, suggesting that ChREBP may be important for glucose suppression of the fatty acid oxidation capacity of β-cells....

  3. Prospective Evaluation of Procalcitonin, Soluble Triggering Receptor Expressed on Myeloid Cells-1 and C-Reactive Protein in Febrile Patients with Autoimmune Diseases

    OpenAIRE

    Lin, Chou-Han; Hsieh, Song-Chou; Keng, Li-Ta; Lee, Ho-Sheng; Chang, Hou-Tai; Liao, Wei-Yu; Ho, Chao-Chi; Yu, Chong-Jen

    2016-01-01

    Background Both procalcitonin (PCT) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have been investigated separately as indicators of infection in patients with autoimmune diseases. Our study simultaneously evaluated both PCT and sTREM-1 along with C-reactive protein (CRP) in febrile patients with autoimmune diseases. Methods Fifty-nine patients were enrolled in the study. The patients were categorized into the infection group (n = 24) or the disease flare group (n = 3...

  4. Screening for genes and subnetworks associated with pancreatic cancer based on the gene expression profile.

    Science.gov (United States)

    Long, Jin; Liu, Zhe; Wu, Xingda; Xu, Yuanhong; Ge, Chunlin

    2016-05-01

    The present study aimed to screen for potential genes and subnetworks associated with pancreatic cancer (PC) using the gene expression profile. The expression profile GSE 16515 was downloaded from the Gene Expression Omnibus database, which included 36 PC tissue samples and 16 normal samples. Limma package in R language was used to screen differentially expressed genes (DEGs), which were grouped as up‑ and downregulated genes. Then, PFSNet was applied to perform subnetwork analysis for all the DEGs. Moreover, Gene Ontology (GO) and REACTOME pathway enrichment analysis of up‑ and downregulated genes was performed, followed by protein‑protein interaction (PPI) network construction using Search Tool for the Retrieval of Interacting Genes Search Tool for the Retrieval of Interacting Genes. In total, 1,989 DEGs including 1,461 up‑ and 528 downregulated genes were screened out. Subnetworks including pancreatic cancer in PC tissue samples and intercellular adhesion in normal samples were identified, respectively. A total of 8 significant REACTOME pathways for upregulated DEGs, such as hemostasis and cell cycle, mitotic were identified. Moreover, 4 significant REACTOME pathways for downregulated DEGs, including regulation of β‑cell development and transmembrane transport of small molecules were screened out. Additionally, DEGs with high connectivity degrees, such as CCNA2 (cyclin A2) and PBK (PDZ binding kinase), of the module in the protein‑protein interaction network were mainly enriched with cell‑division cycle. CCNA2 and PBK of the module and their relative pathway cell‑division cycle, and two subnetworks (pancreatic cancer and intercellular adhesion subnetworks) may be pivotal for further understanding of the molecular mechanism of PC. PMID:27035224

  5. Melatonin inhibits the expression of vascular endothelial growth factor in pancreatic cancer cells

    Institute of Scientific and Technical Information of China (English)

    Dong Lv; Pei-Lin Cui; Shi-Wei Yao; You-Qing Xu; Zhao-Xu Yang

    2012-01-01

    Objective:To investigate the effects of melatonin on cellular proliferation and endogenous vascular endothelial growth factor (VEGF) expression in pancreatic carcinoma cells (PANC-1).Methods:PANC-1 cells were cultured for this study.The secreted VEGF concentration in the culture medium was determined using ELISA method,VEGF production in the tumor cells was detected by immunocytochemistry,and VEGF mRNA expression was determined by RT-PCR.Results:Higher melatonin concentrations significantly inhibited cellular proliferation,with 1 mmol/L concentration exhibiting the highest inhibitory effect (P<0.01).VEGF concentrations in the cell culture supernatants and intra-cellules were all significantly reduced after melatonin (1 mmol/L) incubation (P<0.05).VEGF mRNA expression decreased markedly in a time-dependent manner during the observation period (P<0.05).Conclusions:High melatonin concentrations markedly inhibited the proliferation of pancreatic carcinoma cells.The endogenous VEGF expression was also suppressed by melatonin incubation.

  6. Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression.

    Science.gov (United States)

    Li, Min; Zhang, Yuqing; Liu, Zijuan; Bharadwaj, Uddalak; Wang, Hao; Wang, Xinwen; Zhang, Sheng; Liuzzi, Juan P; Chang, Shou-Mei; Cousins, Robert J; Fisher, William E; Brunicardi, F Charles; Logsdon, Craig D; Chen, Changyi; Yao, Qizhi

    2007-11-20

    Zinc is an essential trace element and catalytic/structural component used by many metalloenzymes and transcription factors. Recent studies indicate a possible correlation of zinc levels with the cancer risk; however, the exact role of zinc and zinc transporters in cancer progression is unknown. We have observed that a zinc transporter, ZIP4 (SLC39A4), was substantially overexpressed in 16 of 17 (94%) clinical pancreatic adenocarcinoma specimens compared with the surrounding normal tissues, and ZIP4 mRNA expression was significantly higher in human pancreatic cancer cells than human pancreatic ductal epithelium (HPDE) cells. This indicates that aberrant ZIP4 up-regulation may contribute to the pancreatic cancer pathogenesis and progression. We studied the effects of ZIP4 overexpression in pancreatic cancer cell proliferation in vitro and pancreatic cancer progression in vivo. We found that forced expression of ZIP4 increased intracellular zinc levels, increased cell proliferation by 2-fold in vitro, and significantly increased tumor volume by 13-fold in the nude mice model with s.c. xenograft compared with the control cells. In the orthotopic nude mice model, overexpression of ZIP4 not only increased the primary tumor weight (7.2-fold), it also increased the peritoneal dissemination and ascites incidence. Moreover, increased cell proliferation and higher zinc content were also observed in the tumor tissues that overexpressed ZIP4. These data reveal an important outcome of aberrant ZIP4 expression in contributing to pancreatic cancer pathogenesis and progression. It may suggest a therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth. PMID:18003899

  7. Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression.

    Science.gov (United States)

    Li, Min; Zhang, Yuqing; Liu, Zijuan; Bharadwaj, Uddalak; Wang, Hao; Wang, Xinwen; Zhang, Sheng; Liuzzi, Juan P; Chang, Shou-Mei; Cousins, Robert J; Fisher, William E; Brunicardi, F Charles; Logsdon, Craig D; Chen, Changyi; Yao, Qizhi

    2007-11-20

    Zinc is an essential trace element and catalytic/structural component used by many metalloenzymes and transcription factors. Recent studies indicate a possible correlation of zinc levels with the cancer risk; however, the exact role of zinc and zinc transporters in cancer progression is unknown. We have observed that a zinc transporter, ZIP4 (SLC39A4), was substantially overexpressed in 16 of 17 (94%) clinical pancreatic adenocarcinoma specimens compared with the surrounding normal tissues, and ZIP4 mRNA expression was significantly higher in human pancreatic cancer cells than human pancreatic ductal epithelium (HPDE) cells. This indicates that aberrant ZIP4 up-regulation may contribute to the pancreatic cancer pathogenesis and progression. We studied the effects of ZIP4 overexpression in pancreatic cancer cell proliferation in vitro and pancreatic cancer progression in vivo. We found that forced expression of ZIP4 increased intracellular zinc levels, increased cell proliferation by 2-fold in vitro, and significantly increased tumor volume by 13-fold in the nude mice model with s.c. xenograft compared with the control cells. In the orthotopic nude mice model, overexpression of ZIP4 not only increased the primary tumor weight (7.2-fold), it also increased the peritoneal dissemination and ascites incidence. Moreover, increased cell proliferation and higher zinc content were also observed in the tumor tissues that overexpressed ZIP4. These data reveal an important outcome of aberrant ZIP4 expression in contributing to pancreatic cancer pathogenesis and progression. It may suggest a therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth.

  8. Expression of EPO Receptor in Pancreatic Cells and Its Effect on Cell Apoptosis

    Institute of Scientific and Technical Information of China (English)

    Hongxia SHUAI; Ji ZHANG; Yikai YU; Muxun ZHANG

    2008-01-01

    In order to explore the expression of erythropoietin receptor (EPOR) in pancreatic cell ine NIT-1 and its effect on cell apoptosis after binding with erythropoietin (EPO), NIT-1 cells were cultured and expanded. The expression of EPOR was detected using electrophoresis. NIT-1 apoptosis was induced by cytokines and their effects on cell apoptosis and cell insulin secretion were assayed after binding of EPO to EPOR. The results showed that EPOR was expressed in NIT-1 cells. Recom- binant human EPO (rHuEPO) had no effect on cell apoptosis but significantly inhibited apoptosis in- duced by cytokines, rHuEPO had no effect on cell insulin secretion but significantly improved insulin secretion inhibited by cytokines. From these findings, it was concluded that EPOR was expressed in NIT-1 cells and EPO could protect N1T-1 cells from apoptosis induced by cytokines.

  9. Bioinformatics analysis of the factors controlling type I IFN gene expression in autoimmune disease and virus-induced immunity

    Directory of Open Access Journals (Sweden)

    Di eFeng

    2013-09-01

    Full Text Available Patients with systemic lupus erythematosus (SLE and Sjögren's syndrome (SS display increased levels of type I IFN-induced genes. Plasmacytoid dendritic cells (PDCs are natural interferon producing cells and considered to be a primary source of IFN-α in these two diseases. Differential expression patterns of type I IFN inducible transcripts can be found in different immune cell subsets and in patients with both active and inactive autoimmune disease. A type I IFN gene signature generally consists of three groups of IFN-induced genes - those regulated in response to virus-induced type I IFN, those regulated by the IFN-induced mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK pathway, and those by the IFN-induced phosphoinositide-3 kinase (PI-3K pathway. These three groups of type I IFN-regulated genes control important cellular processes such as apoptosis, survival, adhesion, and chemotaxis, that when dysregulated, contribute to autoimmunity. With the recent generation of large datasets in the public domain from next-generation sequencing and DNA microarray experiments, one can perform detailed analyses of cell type-specific gene signatures as well as identify distinct transcription factors that differentially regulate these gene signatures. We have performed bioinformatics analysis of data in the public domain and experimental data from our lab to gain insight into the regulation of type I IFN gene expression. We have found that the genetic landscape of the IFNA and IFNB genes are occupied by transcription factors, such as insulators CTCF and cohesin, that negatively regulate transcription, as well as IRF5 and IRF7, that positively and distinctly regulate IFNA subtypes. A detailed understanding of the factors controlling type I IFN gene transcription will significantly aid in the identification and development of new therapeutic strategies targeting the IFN pathway in autoimmune disease.

  10. Type 1 diabetes associated autoimmunity.

    Science.gov (United States)

    Kahaly, George J; Hansen, Martin P

    2016-07-01

    Diabetes mellitus is increasing in prevalence worldwide. The economic costs are considerable given the cardiovascular complications and co-morbidities that it may entail. Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the loss of insulin-producing pancreatic β-cells. The pathogenesis of T1D is complex and multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets. Genetic background may affect the risk for autoimmune disease and patients with T1D exhibit an increased risk of other autoimmune disorders such as autoimmune thyroid disease, Addison's disease, autoimmune gastritis, coeliac disease and vitiligo. Approximately 20%-25% of patients with T1D have thyroid antibodies, and up to 50% of such patients progress to clinical autoimmune thyroid disease. Approximately 0.5% of diabetic patients have concomitant Addison's disease and 4% have coeliac disease. The prevalence of autoimmune gastritis and pernicious anemia is 5% to 10% and 2.6% to 4%, respectively. Early detection of antibodies and latent organ-specific dysfunction is advocated to alert physicians to take appropriate action in order to prevent full-blown disease. Patients and family members should be educated to be able to recognize signs and symptoms of underlying disease.

  11. Comparative identification of Ca2+ channel expression in INS-1 and rat pancreatic β cells

    Institute of Scientific and Technical Information of China (English)

    Fei Li; Zong-Ming Zhang

    2009-01-01

    AIM: To identify and compare the profile of Ca2+ channel subunit expression in INS-1 and rat pancreatic β cells. METHODS: The rat insulin-secreting INS-1 cell line was cultured in RPMI-1640 with Wistar rats employed as islet donors. Ca2+ channel subunit expression in INS-1 and isolated rat β cells were examined by reverse transcription polymerase chain reaction (RT-PCR). Absolute real-time quantitative PCR was performed in a Bio-Rad iQ5 Gradient Real Time PCR system and the data analyzed using an iQ5 system to identify the expression level of the Ca2+ channel subunits. RESULTS: In INS-1 cells, the L-type Ca2+ channel 1C subunit had the highest expression level and the TPRM2 subunit had the second highest expression. In rat β cells, the TPRC4β subunit expression was dominant and the expression of the L-type 1C subunit exceeded the 1D subunit expression about two-fold. This result agreed with other studies, confirming the important role of the L-type 1C subunit in insulinsecreting cells, and suggested that non-voltageoperated Ca2+ channels may have an important role in biphasic insulin secretion. CONCLUSION: Twelve major Ca2+ channel subunit types were identified in INS-1 and rat β cells and significant differences were observed in the expression of certain subunits between these cells.

  12. High IFN-α expression is associated with the induction of experimental autoimmune uveitis (EAU) in Fischer 344 rat

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Thl-response plays a crucial role in determining pathogenesis of organ-specific autoimmune diseases. It is believed that both IL-12 and INF-α are initiators to regulate Th1- response. In our experimental autoimmune uveitis (EAU) model, both Lewis and Fischer 344 rats share the same MHC class ⅡI molecules,while Lewis rat is EAU susceptible and Fischer 344 rat is EAU resistant. However, under the same condition of immunization, if pertussis toxin (PTX) was injected intraperitoneally as an additional adjuvant, Fischer 344 rat can develop EAU. In this study we investigate which mechanisms are involved in the induction of EAU in CFA+R16+PTX-treated (CRP-treated) Fischer 344 rats. In vivo and in vitro data demonstrated that Thl-cytokine, IFN-γ mRNA expression was significantly increased in disease target tissue-eyes and in draining lymph node cells of CRP-treated Fischer 344 rat. When IL-12 and IFN-α mRNA expression were compared in the experimental groups, only IFN-α mRNA expression was associated with EAU development.To distinguish the sources of IFN-α producing cells, it was observed that IFN-α expression was mainly produced by macrophages. It was further confirmed that normal macrophage from Fischer 344 rat was able to produce significant IFN-α in the presence of PTX. The data strongly suggested that IFN-α might be involved in initiating Thl-cell differentiation and in turn contribute to the induction of EAU. High IFN-αexpression induced by PTX may represent a novel pathway to initiate Thl response in Fischer 344 rat.

  13. Low expression of ARHI is associated with shorter progression-free survival in pancreatic endocrine tumors.

    Science.gov (United States)

    Dalai, Irene; Missiaglia, Edoardo; Barbi, Stefano; Butturini, Giovanni; Doglioni, Claudio; Falconi, Massimo; Scarpa, Aldo

    2007-03-01

    Little is known about the molecular anomalies involved in the development and progression of malignancy of pancreatic endocrine tumors (PETs). A recently identified member of the Ras family, Ras homologue member I (ARHI), has been shown to be involved in breast, ovary, and thyroid carcinogenesis. Unlike other members, it acts as a tumor suppressor gene that inhibits cell growth. Here we analyzed the mRNA expression of ARHI in 52 primary PETs and 16 normal pancreata using quantitative reverse transcription-polymerase chain reaction. ARHI expression showed a statistically significant difference between either normal pancreas or well-differentiated endocrine tumors (WDET) and poorly differentiated endocrine carcinomas (PDECs) (P PET progression. Its mRNA expression seemed to be a prognostic factor for disease outcome and, in association with the proliferative index Ki67, a predictor for a rapid tumor relapse. PMID:17401457

  14. Identification of key transcription factors in caerulein-induced pancreatitis through expression profiling data.

    Science.gov (United States)

    Qi, Dachuan; Wu, Bo; Tong, Danian; Pan, Ye; Chen, Wei

    2015-08-01

    The current study aimed to isolate key transcription factors (TFs) in caerulein-induced pancreatitis, and to identify the difference between wild type and Mist1 knockout (KO) mice, in order to elucidate the contribution of Mist1 to pancreatitis. The gene profile of GSE3644 was downloaded from the Gene Expression Omnibus database then analyzed using the t-test. The isolated differentially expressed genes (DEGs) were mapped into a transcriptional regulatory network derived from the Integrated Transcription Factor Platform database and in the network, the interaction pairs involving at least one DEG were screened. Fisher's exact test was used to analyze the functional enrichment of the target genes. A total of 1,555 and 3,057 DEGs were identified in the wild type and Mist1KO mice treated with caerulein, respectively. DEGs screened in Mist1KO mice were predominantly enriched in apoptosis, mitogen-activated protein kinase signaling and other cancer-associated pathways. A total of 188 and 51 TFs associated with pathopoiesis were isolated in Mist1KO and wild type mice, respectively. Out of the top 10 TFs (ranked by P-value), 7 TFs, including S-phase kinase-associated protein 2 (Skp2); minichromosome maintenance complex component 3 (Mcm3); cell division cycle 6 (Cdc6); cyclin B1 (Ccnb1); mutS homolog 6 (Msh6); cyclin A2 (Ccna2); and cyclin B2 (Ccnb2), were expressed in the two types of mouse. These TFs were predominantly involved in phosphorylation, DNA replication, cell division and DNA mismatch repair. In addition, specific TFs, including minichromosome maintenance complex component 7 (Mcm7); lymphoid-specific helicase (Hells); and minichromosome maintenance complex component 6 (Mcm6), that function in the unwinding of DNA were identified to participate in Mist1KO pancreatitis. The DEGs, including Cdc6, Mcm6, Msh6 and Wdr1 are closely associated with the regulation of caerulein-induced pancreatitis. Furthermore, other identified TFs were also involved in this type of

  15. Tetracycline-inducible protein expression in pancreatic cancer cells: Effects of CapG overexpression

    Institute of Scientific and Technical Information of China (English)

    Sarah Tonack; Sabina Patel; Mehdi Jalali; Taoufik Nedjadi; Rosalind E Jenkins; Christopher Goldring; John Neoptolemos; Eithne Costello

    2011-01-01

    AIM: To establish stable tetracycline-inducible pancre-atic cancer cell lines.METHODS: Suit-2, MiaPaca-2, and Panc-1 cells were transfected with a second generation reverse tetra-cycline-controlled transactivator protein (rtTA2S-M2), under the control of either a cytomegalovirus (CMV) or a chicken β-actin promoter, and the resulting clones were characterised.RESULTS: Use of the chicken (β-actin) promoter proved superior for both the production and mainte-nance of doxycycline-inducible cell lines. The system proved versatile, enabling transient inducible expression of a variety of genes, including GST-P, CYP2E1, S100A6, and the actin capping protein, CapG. To determine the physiological utility of this system in pancreatic cancer cells, stable inducible CapG expressors were established. Overexpressed CapG was localised to the cytoplasm and the nuclear membrane, but was not observed in the nu-cleus. High CapG levels were associated with enhanced motility, but not with changes to the cell cycle, or cellu-lar proliferation. In CapG-overexpressing cells, the levels and phosphorylation status of other actin-moduating proteins (Cofilin and Ezrin/Radixin) were not altered. However, preliminary analyses suggest that the levels of other cellular proteins, such as ornithine aminotransfer-ase and enolase, are altered upon CapG induction. CONCLUSION: We have generated pancreatic-cancer derived cell lines in which gene expression is fully con-trollable.

  16. Low Expression of TBX4 Predicts Poor Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Meijuan Zong

    2011-08-01

    Full Text Available This study was designed to investigate the expression of the T-box transcription factor 4 (TBX4, a tumor biomarker that was previously identified by proteomics, in pancreatic ductal adenocarcinoma (PDAC and evaluate its clinical utility as a potential prognostic biomarkers for PDAC. The expression of TBX4 was detected in 77 stage II PDAC tumors by immunohistochemistry, and the results were analyzed with regard to clinicopathological characteristics and overall survival. Moreover, Tbx4 promoter methylation status in primary PDAC tumors and normal adjacent pancreas tissues was measured by bisulfite sequencing. Among 77 stage II PDAC tumors, 48 cases (62.3% expressed TBX4 at a high level. No significant correlation between TBX4 expression and other clinicopathological parameters, except tumor grade and liver metastasis recurrence, was found. The survival of patients with TBX4-high expression was significantly longer than those with TBX4-low expression (P = 0.010. In multivariate analysis, low TBX4 expression was an independent prognostic factor for overall survival in patients with stage II PDAC. TBX4 promoter methylation status was frequently observed in both PDAC and normal adjacent pancreas. We conclude that a low level of TBX4 expression suggests a worse prognosis for patients with stage II PDAC. Down-regulation of the TBX4 gene in pancreas is less likely to be regulated by DNA methylation.

  17. PPAR-γ ligands inhibit the expression of inflammatory cytokines and attenuate autoimmune myocarditis

    Institute of Scientific and Technical Information of China (English)

    YUAN Zu-yi 袁祖贻; LIU Yan 刘艳; LIU Yu 刘豫; ZHANG Ji-jun 张继军; Chiharu Kishimoto; WANG Yan-ni 王燕妮; MA Ai-qun 马爱群; LIU Zhi-quan 刘治全

    2004-01-01

    @@ Peroxisome proliferator-activated receptors (PPARs) are members of a nuclear hormone receptor superfamily of ligand-activated transcriptional factors. Recent data have shown that the prostaglandin (PG), 15-deoxy-△12,14-PGJ2 (15d-PGJ2), and synthetic antidiabetic thiazolidinedione (TZDs), which are PPAR-γ ligands, suppress T cell proliferative response in vitro and inhibit inflammatory cytokine production by cells of monocyte/macrophage lineage.1 Importantly, PPAR-γ ligands have been shown to ameliorate a variety of inflammatory conditions, including atherosclerosis, arthritis, inflammatory bowel disease and experimental autoimmune encephalomyelitis.2

  18. Autoimmune hepatitis

    Science.gov (United States)

    ... Sjogren syndrome Systemic lupus erythematosus Thyroiditis Type 1 diabetes Ulcerative colitis Autoimmune hepatitis may occur in family members of people with autoimmune diseases. There may be a genetic cause. This disease is most common in young girls ...

  19. Silymarin Induces Expression of Pancreatic Nkx6.1 Transcription Factor and β-Cells Neogenesis in a Pancreatectomy Model

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    Claudia Soto

    2014-04-01

    Full Text Available A physio-pathological feature of diabetes mellitus is a significant reduction of β-pancreatic cells. The growth, differentiation and function maintenance of these cells is directed by transcription factors. Nkx6.1 is a key transcription factor for the differentiation, neogenesis and maintenance of β-pancreatic cells. We reported that silymarin restores normal morphology and endocrine function of damaged pancreatic tissue after alloxan-induced diabetes mellitus in rats. The aim of this study was to analyze the effect of silymarin on Nkx6.1 transcription factor expression and its consequence in β cells neogenesis. Sixty male Wistar rats were partially pancreatectomized and divided into twelve groups. Six groups were treated with silymarin (200 mg/Kg p.o for periods of 3, 7, 14, 21, 42 and 63 days. Additionally, an unpancreatectomized control group was used. Nkx6.1 and insulin gene expression were assessed by RT-PCR assay in total pancreatic RNA. β-Cell neogenesis was determined by immunoperoxidase assay. Silymarin treated group showed an increase of Nkx6.1 and insulin genic expression. In this group, there was an increment of β-cell neogenesis in comparison to pancreatectomized untreated group. Silymarin treatment produced a rise in serum insulin and serum glucose normalization. These results suggest that silymarin may improve the reduction of β pancreatic cells observed in diabetes mellitus.

  20. Effect of Cell Adhesion Molecule 1 Expression on Intracellular Granule Movement in Pancreatic α Cells.

    Science.gov (United States)

    Yokawa, Satoru; Furuno, Tadahide; Suzuki, Takahiro; Inoh, Yoshikazu; Suzuki, Ryo; Hirashima, Naohide

    2016-09-01

    Although glucagon secreted from pancreatic α cells plays a role in increasing glucose concentrations in serum, the mechanism regulating glucagon secretion from α cells remains unclear. Cell adhesion molecule 1 (CADM1), identified as an adhesion molecule in α cells, has been reported not only to communicate among α cells and between nerve fibers, but also to prevent excessive glucagon secretion from α cells. Here, we investigated the effect of CADM1 expression on the movement of intracellular secretory granules in α cells because the granule transport is an important step in secretion. Spinning disk microscopic analysis showed that granules moved at a mean velocity of 0.236 ± 0.010 μm/s in the mouse α cell line αTC6 that expressed CADM1 endogenously. The mean velocity was significantly decreased in CADM1-knockdown (KD) cells (mean velocity: 0.190 ± 0.016 μm/s). The velocity of granule movement decreased greatly in αTC6 cells treated with the microtubule-depolymerizing reagent nocodazole, but not in αTC6 cells treated with the actin-depolymerizing reagent cytochalasin D. No difference in the mean velocity was observed between αTC6 and CADM1-KD cells treated with nocodazole. These results suggest that intracellular granules in pancreatic α cells move along the microtubule network, and that CADM1 influences their velocity. PMID:27262873

  1. Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression.

    Science.gov (United States)

    Botla, Sandeep K; Savant, Soniya; Jandaghi, Pouria; Bauer, Andrea S; Mücke, Oliver; Moskalev, Evgeny A; Neoptolemos, John P; Costello, Eithne; Greenhalf, William; Scarpa, Aldo; Gaida, Matthias M; Büchler, Markus W; Strobel, Oliver; Hackert, Thilo; Giese, Nathalia A; Augustin, Hellmut G; Hoheisel, Jörg D

    2016-07-15

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. ©2016 AACR.

  2. Expression of major histocompatibility complex class I-related chain A/B (MICA/B) in pancreatic carcinoma.

    Science.gov (United States)

    Dambrauskas, Zilvinas; Svensson, Helena; Joshi, Meghnad; Hyltander, Anders; Naredi, Peter; Iresjö, Britt-Marie

    2014-01-01

    Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind to the immunoreceptor NKG2D and play an important role in mediating cytotoxicity of NK and T cells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells and thus could be associated with more aggressive course of tumor growth. In this study, we investigated the expression of MICA/B in ductal pancreatic carcinoma and serum in relation to tumor stage, differentiation and survival. MICA/B expression in tumor tissues and sera from patients with pancreatic cancer were analyzed by immunohistochemical staining (IHC), western blotting and ELISA, respectively. MICA/B expression was present in 17 of 22 (77%) of the tumors but not in normal pancreatic ductal epithelial cells. Poorly differentiated tumors showed more pronounced MICA/B expression compared to differentiated tumors, but did not correlate significantly to other tumor characteristics. MICA/B-negative tumors displayed significantly lower incidence of lymph node metastases (pMICA/B expression were elevated in pancreatic cancer cells without elevated levels in serum, despite well-recognized acute phase reactants in serum. Poorly differentiated tumors showed high MICA/B expression, which was related to extended tumor lymph node metastases and less frequent long-term survival.

  3. Differential Expression of Metabolic Genes in Tumor and Stromal Components of Primary and Metastatic Loci in Pancreatic Adenocarcinoma

    Science.gov (United States)

    Chaika, Nina V.; Yu, Fang; Purohit, Vinee; Mehla, Kamiya; Lazenby, Audrey J.; DiMaio, Dominick; Anderson, Judy M.; Yeh, Jen Jen; Johnson, Keith R.; Hollingsworth, Michael A.; Singh, Pankaj K.

    2012-01-01

    Background Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States with a five-year survival rate of 6%. It is characterized by extremely aggressive tumor growth rate and high incidence of metastasis. One of the most common and profound biochemical phenotypes of animal and human cancer cells is their ability to metabolize glucose at high rates, even under aerobic conditions. However, the contribution of metabolic interrelationships between tumor cells and cells of the surrounding microenvironment to the progression of cancer is not well understood. We evaluated differential expression of metabolic genes and, hence, metabolic pathways in primary tumor and metastases of patients with pancreatic adenocarcinoma. Methods and Findings We analyzed the metabolic gene (those involved in glycolysis, tri-carboxylic acid pathway, pentose-phosphate pathway and fatty acid metabolism) expression profiles of primary and metastatic lesions from pancreatic cancer patients by gene expression arrays. We observed two principal results: genes that were upregulated in primary and most of the metastatic lesions; and genes that were upregulated only in specific metastatic lesions in a site-specific manner. Immunohistochemical (IHC) analyses of several metabolic gene products confirmed the gene expression patterns at the protein level. The IHC analyses also revealed differential tumor and stromal expression patterns of metabolic enzymes that were correlated with the metastasis sites. Conclusions Here, we present the first comprehensive studies that establish differential metabolic status of tumor and stromal components and elevation of aerobic glycolysis gene expression in pancreatic cancer. PMID:22412968

  4. Differential expression of metabolic genes in tumor and stromal components of primary and metastatic loci in pancreatic adenocarcinoma.

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    Nina V Chaika

    Full Text Available BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States with a five-year survival rate of 6%. It is characterized by extremely aggressive tumor growth rate and high incidence of metastasis. One of the most common and profound biochemical phenotypes of animal and human cancer cells is their ability to metabolize glucose at high rates, even under aerobic conditions. However, the contribution of metabolic interrelationships between tumor cells and cells of the surrounding microenvironment to the progression of cancer is not well understood. We evaluated differential expression of metabolic genes and, hence, metabolic pathways in primary tumor and metastases of patients with pancreatic adenocarcinoma. METHODS AND FINDINGS: We analyzed the metabolic gene (those involved in glycolysis, tri-carboxylic acid pathway, pentose-phosphate pathway and fatty acid metabolism expression profiles of primary and metastatic lesions from pancreatic cancer patients by gene expression arrays. We observed two principal results: genes that were upregulated in primary and most of the metastatic lesions; and genes that were upregulated only in specific metastatic lesions in a site-specific manner. Immunohistochemical (IHC analyses of several metabolic gene products confirmed the gene expression patterns at the protein level. The IHC analyses also revealed differential tumor and stromal expression patterns of metabolic enzymes that were correlated with the metastasis sites. CONCLUSIONS: Here, we present the first comprehensive studies that establish differential metabolic status of tumor and stromal components and elevation of aerobic glycolysis gene expression in pancreatic cancer.

  5. Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma:Correlation with microvessel density

    Institute of Scientific and Technical Information of China (English)

    Hans U. Kasper; Hella Wolf; Uta Drebber; Helmut K. Wolf; Michael A. Kern

    2004-01-01

    AIM: Cyclooxygenases (COX) are key enzymes for conversion of arachidonic acid to prostaglandins. Nitric oxide synthase (NOS) is the enzyme responsible for formation of nitric oxide.Both have constitutive and inducible isoforms. The inducible isoforms (iNOS and COX-2) are of great interest as regulators of tumor angiogenesis, tumorigenesis and inflammatory processes. This study was to clarify their role in pancreatic adenocarcinomas.METHODS: We investigated the immunohistochemical iNOS and COX-2 expression in 40 pancreatic ducal adenocarcinomas of different grade and stage. The results were compared with microvessel density and clinicopathological data.RESULTS: Twenty-one (52.5%) of the cases showed iNOS expression, 15 (37.5%) of the cases were positive for COX-2.The immunoreaction was heterogeneously distributed within the tumors. Staining intensity was different between the tumors. No correlation between iNOS and COX-2 expression was seen. There was no relationship with microvessel density.However, iNOS positive tumors developed more often distant metastases and the more malignant tumors showed a higher COX-2 expression. There was no correlation with other clinicopathological data.CONCLUSION: Approximately half of the cases expressed iNOS and COX-2. These two enzymes do not seem to be the key step in angiogenesis or carcinogenesis of pancreatic adenocarcinomas. Due to a low prevalence of COX-2expression, chemoprevention of pancreatic carcinomas by COX-2 inhibitors can only achieve a limited success.

  6. Reduced expression of DNA repair and redox signaling protein APE1/Ref-1 impairs human pancreatic cancer cell survival, proliferation, and cell cycle progression.

    Science.gov (United States)

    Jiang, Yanlin; Zhou, Shaoyu; Sandusky, George E; Kelley, Mark R; Fishel, Melissa L

    2010-11-01

    Pancreatic cancer is a deadly disease that is virtually never cured. Understanding the chemoresistance intrinsic to this cancer will aid in developing new regimens. High expression of APE1/Ref-1, a DNA repair and redox signaling protein, is associated with resistance, poor outcome, and angiogenesis; little is known in pancreatic cancer. Immunostaining of adenocarcinoma shows greater APE1/Ref-1 expression than in normal pancreas tissue. A decrease in APE1/Ref-1 protein levels results in pancreatic cancer cell growth inhibition, increased apoptosis, and altered cell cycle progression. Endogenous cell cycle inhibitors increase when APE1/ Ref-1 is reduced, demonstrating its importance to proliferation and growth of pancreatic cancer.

  7. Oral Tolerance Induction in Experimental Autoimmune Encephalomyelitis with Candida utilis Expressing the Immunogenic MOG35-55 Peptide.

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    Christoph Buerth

    Full Text Available Multiple sclerosis (MS is an autoimmune disease that attacks myelinated axons in the central nervous system. Induction of oral tolerance is a potent mechanism to prevent autoimmunity. The food yeast Candida utilis was used to test the therapeutic potential of oral tolerance induction in an animal model of human multiple sclerosis (MS. We constructed a C. utilis strain, which displays a fusion peptide composed of the encephalitogenic MOG35-55 peptide and the C. utilis Gas1 cell wall protein on its surface.By immunizing mice with MOG35-55 peptide experimental autoimmune encephalomyelitis (EAE was induced in a mouse model. Feeding of mice with C. utilis that expresses MOG35-55 peptide on its surface was started seven days prior to immunization and was continued for ten days. Control animals were treated with wild-type fungus or left untreated. Untreated mice developed first clinical symptoms ten days post immunization (p. i. with an ascending paralysis reaching maximal clinical disability at day 18 to 20 p. i.. Treatment with the wild-type strain demonstrated comparable clinical symptoms. In contrast, oral gavage of MOG35-55-presenting fungus ameliorated the development of EAE. In addition, incidence as well as maximal clinical disease severity were significantly reduced. Interestingly, reduction of disease severity also occurred in animals treated with heat-inactivated C. utilis cells indicating that tolerance induction was independent of fungal viability. Better disease outcome correlated with reduced demyelination and cellular inflammation in the spinal cord, lower T cell proliferation against rechallenge with MOG35-55 and more regulatory T cells in the lymph nodes. Our data demonstrate successful that using the food approved fungus C. utilis presenting the immunogenic MOG35-55 peptide on its surface induced an oral tolerance against this epitope in EAE. Further studies will reveal the nature and extent of an anti-inflammatory environment

  8. Low Expression of ARHI Is Associated with Shorter Progression-Free Survival in Pancreatic Endocrine Tumors

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    Irene Dalai

    2007-03-01

    Full Text Available Little is known about the molecular anomalies involved in the development and progression of malignancy of pancreatic endocrine tumors (PETs. A recently identified member of the Ras family, Ras homologue member I (ARHI, has been shown to be involved in breast, ovary, and thyroid carcinogenesis. Unlike other members, it acts as a tumor suppressor gene that inhibits cell growth. Here we analyzed the mRNA expression of ARHI in 52 primary PETs and 16 normal pancreata using quantitative reverse transcription-polymerase chain reaction. ARHI expression showed a statistically significant difference between either normal pancreas or well-differentiated endocrine tumors (WDET and poorly differentiated endocrine carcinomas (PDECs (P < .001 and P < .001, respectively. Moreover, ARHI expression among WDEC samples was more heterogeneous than in WDET, with several tumors showing level of expression analogous to that observed in PDECs. A significant correlation between lower ARHI expression and shorter survival (P = .020 was identified, and a low ARHI expression was associated to a shorter time to progression (P < .001, even considering the proliferation index Ki67 in the multivariate analysis. ARHI is involved in PET progression. Its mRNA expression seemed to be a prognostic factor for disease outcome and, in association with the proliferative index Ki67, a predictor for a rapid tumor relapse.

  9. Identification of novel highly expressed genes in pancreatic ductal adenocarcinomas through a bioinformatics analysis of expressed sequence tags.

    Science.gov (United States)

    Cao, Dengfeng; Hustinx, Steven R; Sui, Guoping; Bala, P; Sato, Norihiro; Martin, Sean; Maitra, Anirban; Murphy, Kathleen M; Cameron, John L; Yeo, Charles J; Kern, Scott E; Goggins, Michael; Pandey, Akhilesh; Hruban, Ralph H

    2004-11-01

    In most microarray experiments, a significant fraction of the differentially expressed mRNAs identified correspond to expressed sequence tags (ESTs) and are generally discarded from further analyses. We used careful bioinformatics analyses to characterize those ESTs that were found to be highly overexpressed in a series of pancreatic adenocarcinomas. cDNA was prepared from 60 non-neoplastic samples (normal pancreas [n = 20], normal colon [n = 10], or normal duodenal mucosal [n = 30]) and from 64 pancreatic cancers (resected cancers [n = 50] or cancer cell lines [n = 14]) and hybridized to the complete Affymetrix Human Genome U133 GeneChip(R) set (arrays U133A and B) for simultaneous analysis of 45,000 fragments corresponding to 33,000 known genes and 6,000 ESTs. The GeneExpress(R) software system Fold Change Analysis Tool was used and 60 ESTs were identified that were expressed at levels at least 3-fold greater in the pancreatic cancers as compared to normal tissues. Searches against the human genomic sequence and comparative genomic analysis of human and mouse genomes was carried out using basic local alignment search tools (BLAST), BLASTN, and BLASTX, for identifying protein coding genes corresponding to the ESTs. Subsequently, in order to pick the most relevant candidate genes for a more detailed analysis, we looked for domains/motifs in the open reading frames using SMART and Pfam programs. We were able to definitively map 43 of the 60 ESTs to known or novel genes, and 15 of the ESTs could be localized in close proximity to a gene in the human genome although we were unable to establish that the EST was indeed derived from those genes. The differential expression of a subset of genes was confirmed at the protein level by immunohistochemical labeling of tissue microarrays (inhibin beta A [INHBA] and CD29) and/or at the transcript level by RT-PCR (INHBA, AKAP12, ELK3, FOXQ1, EIF5A2, and EFNA5). We conclude that bioinformatics tools can be used to characterize

  10. Effect of gemcitabine on the expression of apoptosis-related genes in human pancreatic cancer cells

    Institute of Scientific and Technical Information of China (English)

    Pei-Hong Jiang; Yoshiharu Motoo; Norio Sawabu; Toshinari Minamoto

    2006-01-01

    AIM: To investigate the expression of genes involved in the gemcitabine-induced cytotoxicity in human pancreatic cancer cells.METHODS: A human pancreatic cancer cell line,PANC-1, was cultured. 1×104 PANC-1 cells were plated in 96-well microtiter plates. After being incubated for 24 h,gemcitabine was added to the medium at concentrations ranging 2.5 -1 000 mg/L. The AlamarBlue dye method was used for cell growth analysis. DNA fragmentation was quantitatively assayed using a DNA fragmentation enzyme-linked immunosorbent assay (ELISA) kit. PAP and TP53INP1 mRNA expression was determined using the reverse transcription-polymerase chain reaction with semi-quantitative analysis. The expression of GSK-3β and phospho-GSK-3β proteins was examined with Western blot analysis.RESULTS: The IC50 for the drug after a 48-h exposure to gemcitabine was 16 mg/L. The growth of PANC-1 cells was inhibited by gemcitabine in a concentrationdependent manner (P< 0.0001) and the cell growth was also inhibited throughout the time course (P<0.0001).The DNA fragmentation rate in the gemcitabine-treated group at 48 h was 44.7 %, whereas it was 25.3 % in the untreated group. The PAP mRNA expression was decreased after being treated with gemcitabine, whereas the TP53INP1 mRNA was increased by the gemcitabine treatment. Western blot analysis showed that phosphoGSK-3βser9 was induced by the gemcitabine treatment.CONCLUSION: Gemcitabine suppresses PANC-1cell proliferation and induces apoptosis. Apoptosis is considered to be associated with the inhibition of PAP and GSK-3β, and the activation of TP53INP1 and posphoGSK-33ser9 .

  11. Etiopathogenesis of Insulin Autoimmunity

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    Norio Kanatsuna

    2012-01-01

    Full Text Available Autoimmunity against pancreatic islet beta cells is strongly associated with proinsulin, insulin, or both. The insulin autoreactivity is particularly pronounced in children with young age at onset of type 1 diabetes. Possible mechanisms for (proinsulin autoimmunity may involve beta-cell destruction resulting in proinsulin peptide presentation on HLA-DR-DQ Class II molecules in pancreatic draining lymphnodes. Recent data on proinsulin peptide binding to type 1 diabetes-associated HLA-DQ2 and -DQ8 is reviewed and illustrated by molecular modeling. The importance of the cellular immune reaction involving cytotoxic CD8-positive T cells to kill beta cells through Class I MHC is discussed along with speculations of the possible role of B lymphocytes in presenting the proinsulin autoantigen over and over again through insulin-carrying insulin autoantibodies. In contrast to autoantibodies against other islet autoantigens such as GAD65, IA-2, and ZnT8 transporters, it has not been possible yet to standardize the insulin autoantibody test. As islet autoantibodies predict type 1 diabetes, it is imperative to clarify the mechanisms of insulin autoimmunity.

  12. The Expression Pattern of PDX-1, SHH, Patched and Gli-1 Is Associated with Pathological and Clinical Features in Human Pancreatic Cancer

    OpenAIRE

    Quint, Karl; Stintzing, Sebastian; Alinger, Beate; Hauser-Kronberger, Cornelia; Dietze, Otto; Gahr, Susanne; Hahn, Eckhart G.; Ocker, Matthias; Neureiter, Daniel

    2013-01-01

    Background and Aims: Pancreatic cancer cells have been shown to possess stem-cell-like properties, especially by reactivating embryonic transcription factors involved in tissue differentiation. We therefore investigated if and to what extent developmental genes of the human pancreas are expressed in pancreatic ductal adenocarcinomas and precursor lesions, pancreatic intraepithelial neoplasia (PanIN), and if this correlates or predicts response to treatment and overall survival. Material and M...

  13. Aberrant over-expression of TRPM7 ion channels in pancreatic cancer: required for cancer cell invasion and implicated in tumor growth and metastasis

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    Nelson S. Yee

    2015-03-01

    Full Text Available Our previous studies in zebrafish development have led to identification of the novel roles of the transient receptor potential melastatin-subfamily member 7 (TRPM7 ion channels in human pancreatic cancer. However, the biological significance of TRPM7 channels in pancreatic neoplasms was mostly unexplored. In this study, we determined the expression levels of TRPM7 in pancreatic tissue microarrays and correlated these measurements in pancreatic adenocarcinoma with the clinicopathological features. We also investigated the role of TRPM7 channels in pancreatic cancer cell invasion using the MatrigelTM-coated transwell assay. In normal pancreas, TRPM7 is expressed at a discernable level in the ductal cells and centroacinar cells and at a relatively high level in the islet endocrine cells. In chronic pancreatitis, pre-malignant tissues, and malignant neoplasms, there is variable expression of TRPM7. In the majority of pancreatic adenocarcinoma specimens examined, TRPM7 is expressed at either moderate-level or high-level. Anti-TRPM7 immunoreactivity in pancreatic adenocarcinoma significantly correlates with the size and stages of tumors. In human pancreatic adenocarcinoma cells in which TRPM7 is highly expressed, short hairpin RNA-mediated suppression of TRPM7 impairs cell invasion. The results demonstrate that TRPM7 channels are over-expressed in a proportion of the pre-malignant lesions and malignant tumors of the pancreas, and they are necessary for invasion by pancreatic cancer cells. We propose that TRPM7 channels play important roles in development and progression of pancreatic neoplasm, and they may be explored as clinical biomarkers and targets for its prevention and treatment.

  14. Expression of p57kip2, Rb protein and PCNA and their relationships with clinicopathology in human pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Hui Yue; Yan-Li Na; Xin-Li Feng; Shu-Ren Ma; Fu-Lin Song; Bo Yang

    2003-01-01

    AIM: To investigate the effects of inhibiting factor of cellcycle regulation p57kip2, retinoblastinoma protein (Rb protein)and proliferating cell nuclear antigen (PCNA) in the genesisand progression of human pancreatic cancer.METHODS: The expression of p57kip2, Rb protein and PCNAin tumor tissues and adjacent tissues of 32 patients withpancreatic cancer was detected with SP immunohistochemicaltechnique.RESULTS: p57kip2 protein positive-expression rate in tumortissues of pancreatic cancer was 46.9 %, which was lowerthan that in adjacent pancreatic tissues (75.0 %) (x2=5.317,P<0.05), p57kip2 protein positive-expression correlatedsignificantly with tumor cell differentiation (well-differentiationversus moderate or low-differentiation, P<0.05) but did notcorrelate significantly with lymph node metastasis (lymph nodemetastasis versus non-lymph node metastasis, P>0.05); Rbgene protein positive-expression rate in tumor tissues was50.0 %, which was also lower than that in adjacent pancreatictissues (78.1%) (x2=5.497, P<0.05); PCNA positive-expression rate was 71.9 %, being higher than that inadjacent pancreatic tissues (43.8 %) (x2=5.189, P<0.05),PCNA positive-expression also correlated significantly withtumor cell differentiation and lymph node metastasis (well-differentiation versus moderate or low- differentiation, lymphnode metastasis versus non-lymph node metastasis, P<0.05).Rb protein positive-expression rate in the tumor tissues ofp57kip2 protein positive-expression group was 53.3 %; andRb protein positive-expression rate in the tumor tissues ofp57kip2 protein negative-expression group was 47.1%. Therewas no significant relationship between the two groups(r=0.16507, P>0.05).CONCLUSION: The decreased expression of p57kip2, Rbprotein or over-expression of PCNA protein might contributeto the genesis or progression of pancreatic cancer, p57kip2,Rb protein and PCNA may play an important role in genesisand progression of pancreatic cancer.

  15. Expression of CD44, CD24 and ESA in pancreatic adenocarcinoma cell lines varies with local microenvironment

    Institute of Scientific and Technical Information of China (English)

    Hong-JiWei; TaoYin; ZhuZhu; Peng-FeiShi; YuanTian; Chun-YouWang

    2011-01-01

    BACKGROUND: Emerging evidence suggests that pancreatic adenocarcinoma is hierarchically organized and sustained by pancreatic cancer stem cells. Furthermore, elimination of these cells is possible and therapeutically relevant. This study aimed to investigate the expression patterns of pancreatic cancer stem cell surface markers CD44, CD24 and ESA in pancreatic adenocarcinoma cell lines and explore the influence of their local microenvironment. METHODS: Flow cytometry was used to analyze the expression patterns of CD44, CD24 and ESA in five pancreatic adenocarcinoma cell lines (PANC-1, PC-2, MIA-Paca-2, AsPC-1 and BxPC-3). In addition, the capacity for sphere-formation in serum-free medium of four cell lines (PANC-1, PC-2, MIA-Paca-2 and BxPC-3) was assessed. Then, the same assays were performed when tumor cell spheres were developed. The role of sonic hedgehog (SHH) in cell spheres from PANC-1 and MIA-Paca-2 were also assessed by RT-PCR. RESULTS:  CD44 and CD24 were detected in PANC-1. Only CD44 expression was detected in PC-2, MIA-Paca-2 and AsPC-1. CD44, CD24 and ESA were all detected in BxPC-3. Tumor cell spheres developed in PANC-1 and MIA-Paca-2 in serum-free medium. This was accompanied by an increase in CD24 expression and a decrease in CD44 expression in PANC-1. Interestingly, the expression of CD44 and CD24 returned to initial levels once the medium was changed back from serum-free to serum-containing medium. No significant change in the expression of CD44 was detected in MIA-Paca-2. Furthermore, the relative quantification of SHH mRNA in PANC-1 cell spheres was significantly higher than that in cells cultured in the serum-containing medium. CONCLUSION: The expression patterns of the pancreatic cancer stem cell surface markers CD44, CD24 and ESA were diverse in different pancreatic adenocarcinoma cell lines and changed with their local microenvironment.

  16. Breviscapine attenuates acute pancreatitis by inhibiting expression of PKCα and NF-κB in pancreas

    Institute of Scientific and Technical Information of China (English)

    Hong Zhang; Cui-Zhu Cai; Xiao-Qin Zhang; Tao Li; Xiao-Yun Jia; Bao-Lan Li; Liang Song; Xiao-Jun Ma

    2011-01-01

    AIM: To study the effect of breviscapine (Bre) on activity of protein kinase Cα (PKCα) and nuclear factor (NF)-κB in pancreas, and the mechanism of Bre attenuating acute pancreatitis (AP).METHODS: One hundred and eight rats were randomly divided into acute necrotizing pancreatitis (ANP) group, Bre group (ANP + Bre group) and sham operation (SO) group, 36 rats in each group.ANP model was induced by a retrograde injection of 4% sodium deoxycholate into the bilio-pancreatic duct.Fifteen minutes after the ANP model was induced, the rats in Bre group were intraperitoneally injected with Bre (0.4 mg/100 g body weight or 0.1 mL/100 g body weight).Survival time and mortality of rats were calculated.Serum amylase and malondialdehyde levels were measured, volume of ascites was recorded and morphology of pancreas and lung was evaluated at 1, 5 and 10 h, after the ANP model was induced, respectively.Expressions of PKCα and subunit p65 of NF-κB in pancreas were detected by immunohistochemistry and Western blotting.RESULTS: The life span of rats was longer and the mortality was lower in Bre group than in ANP group 13.51 ± 5.46 vs 25.36 ± 8.11 (P < 0.05).The amylase and MDA levels as well as the volume of ascites were lower and the pathological changes in pancreas and lung were less in Bre group than ANP group (P < 0.05), indicating that the pancreatitis is less severe in Bre group than ANP group.The activation of PKCα and NF-κB p65 in pancreas was induced rapidly and reached their peak at 1 h or 5 h after ANP, but their activity in Bre group was significantly inhibited.CONCLUSION: Bre exerts its therapeutic effect on AP by inhibiting the activation of PKCα and NF-κB p65 in pancreas.

  17. Gene expression in the spinal cord in female lewis rats with experimental autoimmune encephalomyelitis induced with myelin basic protein.

    Directory of Open Access Journals (Sweden)

    Hayley R Inglis

    Full Text Available BACKGROUND: Experimental autoimmune encephalomyelitis (EAE, the best available model of multiple sclerosis, can be induced in different animal strains using immunization with central nervous system antigens. EAE is associated with inflammation and demyelination of the nervous system. Micro-array can be used to investigate gene expression and biological pathways that are altered during disease. There are few studies of the changes in gene expression in EAE, and these have mostly been done in a chronic mouse EAE model. EAE induced in the Lewis with myelin basic protein (MBP-EAE is well characterised, making it an ideal candidate for the analysis of gene expression in this disease model. METHODOLOGY/PRINCIPAL FINDINGS: MBP-EAE was induced in female Lewis rats by inoculation with MBP and adjuvants. Total RNA was extracted from the spinal cords and used for micro-array analysis using AffimetrixGeneChip Rat Exon 1.0 ST Arrays. Gene expression in the spinal cords was compared between healthy female rats and female rats with MBP-EAE. Gene expression in the spinal cord of rats with MBP-EAE differed from that in the spinal cord of normal rats, and there was regulation of pathways involved with immune function and nervous system function. For selected genes the change in expression was confirmed with real-time PCR. CONCLUSIONS/SIGNIFICANCE: EAE leads to modulation of gene expression in the spinal cord. We have identified the genes that are most significantly regulated in MBP-EAE in the Lewis rat and produced a profile of gene expression in the spinal cord at the peak of disease.

  18. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

  19. Microwave & Magnetic (M2) Proteomics Reveals CNS-Specific Protein Expression Waves that Precede Clinical Symptoms of Experimental Autoimmune Encephalomyelitis

    Science.gov (United States)

    Raphael, Itay; Mahesula, Swetha; Purkar, Anjali; Black, David; Catala, Alexis; Gelfond, Jonathon A. L.; Forsthuber, Thomas G.; Haskins, William E.

    2014-09-01

    Central nervous system-specific proteins (CSPs), transported across the damaged blood-brain-barrier (BBB) to cerebrospinal fluid (CSF) and blood (serum), might be promising diagnostic, prognostic and predictive protein biomarkers of disease in individual multiple sclerosis (MS) patients because they are not expected to be present at appreciable levels in the circulation of healthy subjects. We hypothesized that microwave & magnetic (M2) proteomics of CSPs in brain tissue might be an effective means to prioritize putative CSP biomarkers for future immunoassays in serum. To test this hypothesis, we used M2 proteomics to longitudinally assess CSP expression in brain tissue from mice during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Confirmation of central nervous system (CNS)-infiltrating inflammatory cell response and CSP expression in serum was achieved with cytokine ELISPOT and ELISA immunoassays, respectively, for selected CSPs. M2 proteomics (and ELISA) revealed characteristic CSP expression waves, including synapsin-1 and α-II-spectrin, which peaked at day 7 in brain tissue (and serum) and preceded clinical EAE symptoms that began at day 10 and peaked at day 20. Moreover, M2 proteomics supports the concept that relatively few CNS-infiltrating inflammatory cells can have a disproportionally large impact on CSP expression prior to clinical manifestation of EAE.

  20. EFFECT OF STAT3 SPECIFIC SHRNA EXPRESSION VECTOR ON PROLIFERATION AND APOPTOSIS OF HUMAN PANCREATIC CANCER CELLS

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective To construct signal transduction and activators of transcription 3 (STAT3) short hairpin RNA (shRNA) expression vector and to investigate its inhibitory effects on STAT3 expression, cell proliferation and apoptosis of human pancreatic cancer. Methods Three pairs of hairpin-like oligonucleotide sequences specific for human STAT3 gene were designed and synthesized. The annealed oligonucleotide fragments were subcloned into pRNAT-U6.1/Neo plasmid. The STAT3 shRNA expressing vectors were confirmed by PCR and DNA sequencing. STAT3 mRNA and protein expression were examined by using reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. MTT assay and flow cytometry were performed to detect the state of cell proliferation and cell apoptosis, respectively. Results PCR and DNA sequencing showed that the oligonucleotide fragments were correctly inserted into pRNAT-U6.1/Neo plasmid. STAT3 expression and cell proliferation in the transfected cells was inhibited significantly by three STAT3 shRNA expressing vectors (P<0.05). ConclusionSTAT3 shRNA expression vector can effectively inhibit the expression of STAT3. Silencing of STAT3 with RNAi can significantly inhibit the proliferation and promotes the apoptosis of pancreatic cancer cells and may provide a novel therapeutic target for treating pancreatic cancer.

  1. The rescue of miR-148a expression in pancreatic cancer: an inappropriate therapeutic tool.

    Directory of Open Access Journals (Sweden)

    Yannick Delpu

    Full Text Available MicroRNAs are small non-coding RNAs that physiologically modulate proteins expression, and regulate numerous cellular mechanisms. Alteration of microRNA expression has been described in cancer and is associated to tumor initiation and progression. The microRNA 148a (miR-148a is frequently down-regulated in cancer. We previously demonstrated that its down-regulation by DNA hypermethylation is an early event in pancreatic ductal adenocarcinoma (PDAC carcinogenesis, suggesting a tumor suppressive function. Here, we investigate the potential role of miR-148a over-expression in PDAC as a therapeutic tool. We first report the consequences of miR-148a over-expression in PDAC cell lines. We demonstrate that miR-148a over-expression has no dramatic effect on cell proliferation and cell chemo-sensitivity in four well described PDAC cell lines. We also investigate the modulation of protein expression by a global proteomic approach (2D-DIGE. We show that despite its massive over-expression, miR-148a weakly modulates protein expression, thus preventing the identification of protein targets in PDAC cell lines. More importantly, in vivo data demonstrate that modulating miR-148a expression either in the epithelia tumor cells and/or in the tumor microenvironment does not impede tumor growth. Taken together, we demonstrate herein that miR-148a does not impact PDAC proliferation both in vitro and in vivo thus suggesting a weak potential as a therapeutic tool.

  2. Massive parallel gene expression profiling of RINm5F pancreatic islet beta-cells stimulated with interleukin-1beta

    DEFF Research Database (Denmark)

    Rieneck, K; Bovin, L F; Josefsen, K;

    2000-01-01

    Interleukin 1 (IL-1) is a pleiotropic cytokine with the potential to kill pancreatic beta-cells, and this unique property is thought to be involved in the pathogenesis of type I diabetes mellitus. We therefore determined the quantitative expression of 24,000 mRNAs of RINm5F, an insulinoma cell line...... derived from rat pancreatic beta-cells, before and after challenge with 30 and 1,000 pg/ml of recombinant human IL-1beta. The highest concentration resulted in decreased insulin production and cell death over a period of 4 days. Using three different time points, 2, 4 and 24 hours after challenge, we...

  3. Co-Expression of Cancer Stem Cell Markers Corresponds to a Pro-Tumorigenic Expression Profile in Pancreatic Adenocarcinoma

    Science.gov (United States)

    Skoda, Jan; Hermanova, Marketa; Loja, Tomas; Nemec, Pavel; Neradil, Jakub; Karasek, Petr; Veselska, Renata

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Its dismal prognosis is often attributed to the presence of cancer stem cells (CSCs) that have been identified in PDAC using various markers. However, the co-expression of all of these markers has not yet been evaluated. Furthermore, studies that compare the expression levels of CSC markers in PDAC tumor samples and in cell lines derived directly from those tumors are lacking. Here, we analyzed the expression of putative CSC markers—CD24, CD44, epithelial cell adhesion molecule (EpCAM), CD133, and nestin—by immunofluorescence, flow cytometry and quantitative PCR in 3 PDAC-derived cell lines and by immunohistochemistry in 3 corresponding tumor samples. We showed high expression of the examined CSC markers among all of the cell lines and tumor samples, with the exception of CD24 and CD44, which were enriched under in vitro conditions compared with tumor tissues. The proportions of cells positive for the remaining markers were comparable to those detected in the corresponding tumors. Co-expression analysis using flow cytometry revealed that CD24+/CD44+/EpCAM+/CD133+ cells represented a significant population of the cells (range, 43 to 72%) among the cell lines. The highest proportion of CD24+/CD44+/EpCAM+/CD133+ cells was detected in the cell line derived from the tumor of a patient with the shortest survival. Using gene expression profiling, we further identified the specific pro-tumorigenic expression profile of this cell line compared with the profiles of the other two cell lines. Together, CD24+/CD44+/EpCAM+/CD133+ cells are present in PDAC cell lines derived from primary tumors, and their increased proportion corresponds with a pro-tumorigenic gene expression profile. PMID:27414409

  4. Co-Expression of Cancer Stem Cell Markers Corresponds to a Pro-Tumorigenic Expression Profile in Pancreatic Adenocarcinoma.

    Science.gov (United States)

    Skoda, Jan; Hermanova, Marketa; Loja, Tomas; Nemec, Pavel; Neradil, Jakub; Karasek, Petr; Veselska, Renata

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Its dismal prognosis is often attributed to the presence of cancer stem cells (CSCs) that have been identified in PDAC using various markers. However, the co-expression of all of these markers has not yet been evaluated. Furthermore, studies that compare the expression levels of CSC markers in PDAC tumor samples and in cell lines derived directly from those tumors are lacking. Here, we analyzed the expression of putative CSC markers-CD24, CD44, epithelial cell adhesion molecule (EpCAM), CD133, and nestin-by immunofluorescence, flow cytometry and quantitative PCR in 3 PDAC-derived cell lines and by immunohistochemistry in 3 corresponding tumor samples. We showed high expression of the examined CSC markers among all of the cell lines and tumor samples, with the exception of CD24 and CD44, which were enriched under in vitro conditions compared with tumor tissues. The proportions of cells positive for the remaining markers were comparable to those detected in the corresponding tumors. Co-expression analysis using flow cytometry revealed that CD24+/CD44+/EpCAM+/CD133+ cells represented a significant population of the cells (range, 43 to 72%) among the cell lines. The highest proportion of CD24+/CD44+/EpCAM+/CD133+ cells was detected in the cell line derived from the tumor of a patient with the shortest survival. Using gene expression profiling, we further identified the specific pro-tumorigenic expression profile of this cell line compared with the profiles of the other two cell lines. Together, CD24+/CD44+/EpCAM+/CD133+ cells are present in PDAC cell lines derived from primary tumors, and their increased proportion corresponds with a pro-tumorigenic gene expression profile. PMID:27414409

  5. Ran GTPase protein promotes human pancreatic cancer proliferation by deregulating the expression of Survivin and cell cycle proteins

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Lin [State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi 710032 (China); Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710038 (China); Lu, Yuanyuan; Zhao, Xiaodi; Sun, Yi; Shi, Yongquan; Fan, Hongwei; Liu, Changhao; Zhou, Jinfeng; Nie, Yongzhan; Wu, Kaichun [State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi 710032 (China); Fan, Daiming, E-mail: daimingfan@fmmu.edu.cn [State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi 710032 (China); Guo, Xuegang, E-mail: xuegangguo@126.com [State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi 710032 (China)

    2013-10-18

    Highlights: •Overexpression of Ran in pancreatic cancer was correlated with histological grade. •Downregulation of Ran could induce cell apoptosis and inhibit cell proliferation. •The effects were mediated by cell cycle proteins, Survivin and cleaved Caspase-3. -- Abstract: Ran, a member of the Ras GTPase family, has important roles in nucleocytoplasmic transport. Herein, we detected Ran expression in pancreatic cancer and explored its potential role on tumour progression. Overexpressed Ran in pancreatic cancer tissues was found highly correlated with the histological grade. Downregulation of Ran led to significant suppression of cell proliferation, cell cycle arrest at the G1/S phase and induction of apoptosis. In vivo studies also validated that result. Further studies revealed that those effects were at least partly mediated by the downregulation of Cyclin A, Cyclin D1, Cyclin E, CDK2, CDK4, phospho-Rb and Survivin proteins and up regulation of cleaved Caspase-3.

  6. Ran GTPase protein promotes human pancreatic cancer proliferation by deregulating the expression of Survivin and cell cycle proteins

    International Nuclear Information System (INIS)

    Highlights: •Overexpression of Ran in pancreatic cancer was correlated with histological grade. •Downregulation of Ran could induce cell apoptosis and inhibit cell proliferation. •The effects were mediated by cell cycle proteins, Survivin and cleaved Caspase-3. -- Abstract: Ran, a member of the Ras GTPase family, has important roles in nucleocytoplasmic transport. Herein, we detected Ran expression in pancreatic cancer and explored its potential role on tumour progression. Overexpressed Ran in pancreatic cancer tissues was found highly correlated with the histological grade. Downregulation of Ran led to significant suppression of cell proliferation, cell cycle arrest at the G1/S phase and induction of apoptosis. In vivo studies also validated that result. Further studies revealed that those effects were at least partly mediated by the downregulation of Cyclin A, Cyclin D1, Cyclin E, CDK2, CDK4, phospho-Rb and Survivin proteins and up regulation of cleaved Caspase-3

  7. TGF-β Signaling Regulates Pancreatic β-Cell Proliferation through Control of Cell Cycle Regulator p27 Expression

    International Nuclear Information System (INIS)

    Proliferation of pancreatic β-cells is an important mechanism underlying β-cell mass adaptation to metabolic demands. Increasing β-cell mass by regeneration may ameliorate or correct both type 1 and type 2 diabetes, which both result from inadequate production of insulin by β-cells of the pancreatic islet. Transforming growth factor β (TGF-β) signaling is essential for fetal development and growth of pancreatic islets. In this study, we exposed HIT-T15, a clonal pancreatic β-cell line, to TGF-β signaling. We found that inhibition of TGF-β signaling promotes proliferation of the cells significantly, while TGF-β signaling stimulation inhibits proliferation of the cells remarkably. We confirmed that this proliferative regulation by TGF-β signaling is due to the changed expression of the cell cycle regulator p27. Furthermore, we demonstrated that there is no observed effect on transcriptional activity of p27 by TGF-β signaling. Our data show that TGF-β signaling mediates the cell-cycle progression of pancreatic β-cells by regulating the nuclear localization of CDK inhibitor, p27. Inhibition of TGF-β signaling reduces the nuclear accumulation of p27, and as a result this inhibition promotes proliferation of β-cells

  8. Extracting gene expression profiles common to colon and pancreatic adenocarcinoma using simultaneous nonnegative matrix factorization.

    Science.gov (United States)

    Badea, Liviu

    2008-01-01

    In this paper we introduce a clustering algorithm capable of simultaneously factorizing two distinct gene expression datasets with the aim of uncovering gene regulatory programs that are common to the two phenotypes. The siNMF algorithm simultaneously searches for two factorizations that share the same gene expression profiles. The two key ingredients of this algorithm are the nonnegativity constraint and the offset variables, which together ensure the sparseness of the factorizations. While cancer is a very heterogeneous disease, there is overwhelming recent evidence that the differences between cancer subtypes implicate entire pathways and biological processes involving large numbers of genes, rather than changes in single genes. We have applied our simultaneous factorization algorithm looking for gene expression profiles that are common between the more homogeneous pancreatic ductal adenocarcinoma (PDAC) and the more heterogeneous colon adenocarcinoma. The fact that the PDAC signature is active in a large fraction of colon adeocarcinoma suggests that the oncogenic mechanisms involved may be similar to those in PDAC, at least in this subset of colon samples. There are many approaches to uncovering common mechanisms involved in different phenotypes, but most are based on comparing gene lists. The approach presented in this paper additionally takes gene expression data into account and can thus be more sensitive. PMID:18229692

  9. Pax4 Expression does not Transduce Pancreatic Alpha Cells to Beta Cells

    Directory of Open Access Journals (Sweden)

    Ling Chen

    2015-07-01

    Full Text Available Background/Aims: The lack of available beta cells greatly limits the use of beta cell transplantation as a therapy for diabetes. Thus, generation of beta cells from other sources is substantially required. Pax4 has been shown to induce reprograming of alpha cells into beta cells during embryogenesis. Nevertheless, whether expression of Pax4 in adult alpha cells could trigger this alpha-to-beta cell reprogramming is unknown. Methods: Here we generated an adeno-associated virus carrying Pax4 and GFP under a CMV promoter (AAV-Pax4. We used AAV-Pax4 to transduce a mouse alpha cell line in vitro, and to transduce primary alpha cells in diabetic mice. Reprogramming was examined by double immunostaining and by changes in beta cell number. The effects on blood glucose were evaluated by fasting blood glucose and glucose response. Results: In vitro, Pax4 overexpression neither induced insulin expression, nor suppressed glucagon expression in alpha cells. In vivo, Pax4 overexpression failed to increase beta cell number, and did not alter hyperglycemia and glucose response in diabetic mice. Conclusion: Pax4 expression is not sufficient to transduce pancreatic alpha cells into beta cells. Overexpression of Pax4 in alpha cells may not increase functional beta cell number in diabetic patients.

  10. Matrine downregulates IL-33/ST2 expression in the central nervous system of rats with experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Zhao, Xiaoyu; Zhang, Xiaojian; Lv, Ying; Xu, Yuming; Li, Menglong; Pan, Qingxia; Chu, Yaojuan; Liu, Nan; Zhang, Guang-Xian; Zhu, Lin

    2016-10-01

    Interleukin (IL)-33 is a recently described member of the IL-1 family and functions as a ligand for ST2, a member of the IL-1 receptor family. The role of IL-33/ST2 axis in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), remains controversial. Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, the underlying immunoregulatory mechanisms have not been fully elucidated, and whether this effect of MAT is through inhibiting the function of the IL-33/ST2 axis is not known. In this study, we investigated the relationship between the therapeutic effects of MAT and IL-33/ST2 expression. MAT treatment successfully attenuated severe clinical deficit and histopathological changes, compared to untreated controls. While IL-33/ST2 mRNA expression was largely increased in spinal cord of EAE rats compared to naïve rats, this expression was significantly inhibited in rats treated with MAT. These results were further confirmed by their protein levels tested with immunohistochemistry. Together, our study demonstrates that MAT treatment regulates the inflammatory IL-33/ST2 axis, thus being a novel mechanism underlying the effect of MAT.

  11. Autoimmune epilepsy.

    Science.gov (United States)

    Greco, Antonio; Rizzo, Maria Ida; De Virgilio, Armando; Conte, Michela; Gallo, Andrea; Attanasio, Giuseppe; Ruoppolo, Giovanni; de Vincentiis, Marco

    2016-03-01

    Despite the fact that epilepsy is the third most common chronic brain disorder, relatively little is known about the processes leading to the generation of seizures. Accumulating data support an autoimmune basis in patients with antiepileptic drug-resistant seizures. Besides, recent studies show that epilepsy and autoimmune disease frequently co-occur. Autoimmune epilepsy is increasingly recognized in the spectrum of neurological disorders characterized by detection of neural autoantibodies in serum or spinal fluid and responsiveness to immunotherapy. An autoimmune cause is suspected based on frequent or medically intractable seizures and the presence of at least one neural antibody, inflammatory changes indicated in serum or spinal fluid or on MRI, or a personal or family history of autoimmunity. It is essential that an autoimmune etiology be considered in the initial differential diagnosis of new onset epilepsy, because early immunotherapy assures an optimal outcome for the patient. PMID:26626229

  12. Reduced Expression of the Polymeric Immunoglobulin Receptor in Pancreatic and Periampullary Adenocarcinoma Signifies Tumour Progression and Poor Prognosis

    OpenAIRE

    Richard Fristedt; Jacob Elebro; Alexander Gaber; Liv Jonsson; Margareta Heby; Yulyana Yudina; Björn Nodin; Mathias Uhlén; Jakob Eberhard; Karin Jirström

    2014-01-01

    The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically tre...

  13. “Warming yang and invigorating qi” acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis

    Science.gov (United States)

    Huang, Hai-peng; Pan, Hong; Wang, Hong-feng

    2016-01-01

    Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. “Warming yang and invigorating qi” acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following “warming yang and invigorating qi” acupuncture therapy. Needles were inserted at acupressure points Shousanli (LI10), Zusanli (ST36), Pishu (BL20), and Shenshu (BL23) once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These findings suggest that “warming yang and invigorating qi” acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis. PMID:27127487

  14. "Warming yang and invigorating qi" acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis.

    Science.gov (United States)

    Huang, Hai-Peng; Pan, Hong; Wang, Hong-Feng

    2016-03-01

    Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. "Warming yang and invigorating qi" acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following "warming yang and invigorating qi" acupuncture therapy. Needles were inserted at acupressure points Shousanli (LI10), Zusanli (ST36), Pishu (BL20), and Shenshu (BL23) once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These findings suggest that "warming yang and invigorating qi" acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis. PMID:27127487

  15. “Warmingyang and invigoratingqi” acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis

    Institute of Scientific and Technical Information of China (English)

    Hai-peng Huang; Hong Pan; Hong-feng Wang

    2016-01-01

    Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. “Warmingyang and invigoratingqi” acupuncture treatment has been shown to reduce serum inlfammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental au-toimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following “warmingyang and invigoratingqi” acupuncture therapy. Needles were inserted at acupressure pointsShou-sanli (LI10),Zusanli(ST36),Pishu (BL20), and Shenshu (BL23) once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was signiifcantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These ifndings suggest that “warmingyangand invigoratingqi” acu-puncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis.

  16. "Warming yang and invigorating qi" acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis

    Directory of Open Access Journals (Sweden)

    Hai-peng Huang

    2016-01-01

    Full Text Available Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. "Warming yang and invigorating qi" acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following "warming yang and invigorating qi" acupuncture therapy. Needles were inserted at acupressure points Shousanli (LI10, Zusanli (ST36, Pishu (BL20, and Shenshu (BL23 once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These findings suggest that "warming yang and invigorating qi" acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis.

  17. Differential expression of pancreatic protein andchemosensing receptor mRNAs in NKCC1-null intestine

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    AIM To investigate the intestinal functions of the NKCC1Na+-K+-2Cl cotransporter (SLC12a2 gene), differentialmRNA expression changes in NKCC1-null intestine wereanalyzed.METHODS: Microarray analysis of mRNA from intestinesof adult wild-type mice and gene-targeted NKCC1-null mice (n = 6 of each genotype) was performed toidentify patterns of differential gene expression changes.Differential expression patterns were further examinedby Gene Ontology analysis using the online Gorillaprogram, and expression changes of selected genes wereverified using northern blot analysis and quantitativereal time-polymerase chain reaction. Histological stainingand immunofluorescence were performed to identify celltypes in which upregulated pancreatic digestive enzymeswere expressed.RESULTS: Genes typically associated with pancreaticfunction were upregulated. These included lipase,amylase, elastase, and serine proteases indicative ofpancreatic exocrine function, as well as insulin andregenerating islet genes, representative of endocrinefunction. Northern blot analysis and immunohistochemistryshowed that differential expression of exocrinepancreas mRNAs was specific to the duodenum andlocalized to a subset of goblet cells. In addition, a majorpattern of changes involving differential expression ofolfactory receptors that function in chemical sensing, aswell as other chemosensing G-protein coupled receptors,was observed. These changes in chemosensory receptorexpression may be related to the failure of intestinalfunction and dependency on parenteral nutritionobserved in humans with SLC12a2 mutations.CONCLUSION: The results suggest that loss of NKCC1affects not only secretion, but also goblet cell functionand chemosensing of intestinal contents via G-proteincoupled chemosensory receptors.

  18. Reduced retinoids and retinoid receptors' expression in pancreatic cancer: A link to patient survival.

    Science.gov (United States)

    Bleul, Tim; Rühl, Ralph; Bulashevska, Svetlana; Karakhanova, Svetlana; Werner, Jens; Bazhin, Alexandr V

    2015-09-01

    Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. All-trans retinoic acid (ATRA) is the major physiologically active form of vitamin A, regulating expression of many genes. Disturbances of vitamin A metabolism are prevalent in some cancer cells. The main aim of this work was to investigate deeply the components of retinoid signaling in PDAC compared to in the normal pancreas and to prove the clinical importance of retinoid receptor expression. For the study, human tumor tissues obtained from PDAC patients and murine tumors from the orthotopic Panc02 model were used for the analysis of retinoids, using high performance liquid chromatography mass spectrometry and real-time RT-PCR gene expression analysis. Survival probabilities in univariate analysis were estimated using the Kaplan-Meier method and the Cox proportional hazards model was used for the multivariate analysis. In this work, we showed for the first time that the ATRA and all-trans retinol concentration is reduced in PDAC tissue compared to their normal counterparts. The expression of RARα and β as well as RXRα and β are down-regulated in PDAC tissue. This reduced expression of retinoid receptors correlates with the expression of some markers of differentiation and epithelial-to-mesenchymal transition as well as of cancer stem cell markers. Importantly, the expression of RARα and RXRβ is associated with better overall survival of PDAC patients. Thus, reduction of retinoids and their receptors is an important feature of PDAC and is associated with worse patient survival outcomes.

  19. [Autoimmune hepatitis].

    Science.gov (United States)

    Ostojić, Rajko

    2003-01-01

    Autoimmune hepatitis is an unresolving, hepatocellular inflammation of unknown cause that is characterized by the presence of periportal hepatitis on histologic examination, tissue autoantibodies in serum, and hypergammaglobulinemia. By international consensus, the designation autoimmune hepatitis has replaced alternative terms for the condition. Three types of autoimmune hepatitis have been proposed based on immunoserologic findings. Type 1 autoimmune hepatitis is characterized by the presence of antinuclear antibodies (ANA) or smooth muscle antibodies (SMA) (or both) in serum. Seventy percent of patients with type 1 of autoimmune hepatitis are women. This type is the most common form and accounts for at least 80% of cases. Type 2 is characterized by the presence of antibodies to liver-kidney microsome type 1 (anti-LKM1) in serum. Patients with this type of autoimmune hepatitis are predominantly children. Type 3 autoimmune hepatitis is characterized by the presence of antibodies to soluble liver antigen (anti-SLA) in serum. There are no individual features that are pathognomonic of autoimmune hepatitis, and its diagnosis requires the confident exclusion of other conditions. The large majority of patients show satisfactory response to corticosteroid (usually prednisone or prednisolone) therapy. For the past 30 years it has been customary to add azathioprine as a "steroid sparing" agent to allow lower doses of steroids to be used and remission, once achieved, can be sustained in many patients with azathioprine alone after steroid withdrawal. Patients with autoimmune hepatitis who have decompensated during or after corticosteroid therapy are candidates for liver transplantation.

  20. Review of idiopathic pancreatitis

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Recent advances in understanding of pancreatitis and advances in technology have uncovered the veils of idiopathic pancreatitis to a point where a thorough history and judicious use of diagnostic techniques elucidate the cause in over 80% of cases. This review examines the multitude of etiologies of what were once labeled idiopathic pancreatitis and provides the current evidence on each. This review begins with a background review of the current epidemiology of idiopathic pancreatitis prior to discussion of various etiologies. Etiologies of medications, infections, toxins,autoimmune disorders, vascular causes, and anatomic and functional causes are explored in detail. We conclude with management of true idiopathic pancreatitis and a summary of the various etiologic agents. Throughout this review, areas of controversies are highlighted.

  1. Follicular pancreatitis: a distinct form of chronic pancreatitis-an additional mimic of pancreatic neoplasms.

    Science.gov (United States)

    Gupta, Rajib K; Xie, Bill H; Patton, Kurt T; Lisovsky, Mikhail; Burks, Eric; Behrman, Stephen W; Klimstra, David; Deshpande, Vikram

    2016-02-01

    Follicular pancreatitis is a recently described variant of chronic pancreatitis characterized clinically by the formation of a discrete pancreatic mass and histologically by the presence of florid lymphoid aggregates with reactive germinal centers. Our aim was to study the clinical and histologic features of follicular pancreatitis, as well as to critically examine potential overlap with autoimmune pancreatitis. Immunohistochemistry for Bcl-2, CD21, κ and λ light chains as well as IgG4 and IgG were performed. We found a total of 6 patients (male-female ratio, 2:1; mean age, 57 years) who fulfilled the diagnosis of follicular pancreatitis in our institutions. Four had an incidental diagnosis, while two presented with abdominal pain, fatigue, and elevated liver enzymes. On imaging, 3 patients had a discrete solid mass, whereas 2 cases showed a dilated main pancreatic duct, mimicking an intraductal pancreatic mucinous neoplasm on imaging. One patient had a lesion in the intra-pancreatic portion of the common bile duct. On histopathology, all cases showed numerous lymphoid follicles with Bcl-2-negative germinal centers either in a periductal or in a more diffuse (periductal and intra-parenchymal) fashion, but without attendant storiform fibrosis, obliterative phlebitis, or granulocytic epithelial lesions. IgG4-to-IgG ratio was <40% in 5 cases. A comparison cohort revealed germinal centers in 25% of type 1 autoimmune pancreatitis and 2% of type 2 autoimmune pancreatitis cases, but none were periductal in location. In conclusion, follicular pancreatitis, an under-recognized mimic of pancreatic neoplasms is characterized by intrapancreatic lymphoid follicles with reactive germinal centers. PMID:26563969

  2. Association of Prion Protein Expression with Pancreatic Adenocarcinoma Survival in the SEER Residual Tissue Repository

    Science.gov (United States)

    Sy, Man-Sun; Altekruse, Sean F.; Li, Chaoyang; Lynch, Charles F.; Goodman, Marc T.; Hernandez, Brenda Y.; Huang, Xiaoran; Saber, Maria Sibug; Hewitt, Stephen M.; Xin, Wei

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is an important cause of cancer death with no clear prognostic biomarker. Expression of prion (PrP) has been reported to be a marker of poor prognosis in a series of Caucasian PDAC cases. We determined the prognostic value of PrP in a racially and geographically diverse population-based series of PDAC cases. PrP expression was examined in 142 PDAC cases from three cancer registries. Cases included 71 Caucasian, 54 Asian/Pacific Islanders and 17 Blacks diagnosed from 1983–2000, and followed through 2008. Hazard ratios (HR) and 95% confidence intervals (CIs) for the association of PrP expression with survival were computed after adjustment for case attributes. The risk of death was about four times higher (HR=3.8; 95% CI: 2.2, 6.5) among 108 PDAC cases with PrP+ tumors (median survival 5 months) compared to the 34 cases with PrP− tumors (median survival 20 months). Of 51 cases with resected, localized PDAC median survival was 74 months for 17 cases with PrP− tumors versus 14 months for 34 cases with PrP+ tumors (HR=6.7; 95% CI: 2.6, 17.4). All 6 surviving cases had PrP− negative tumors (median survival, >10 years). PrP may have potential as a prognostic biomarker in PDAC patient management. PMID:22820080

  3. Thyrotropin releasing hormone (TRH) affects gene expression in pancreatic beta-cells.

    Science.gov (United States)

    Luo, LuGuang; Yano, Naohiro

    2005-01-01

    Thyrotropin-releasing hormone (TRH), originally identified as a hypothalamic hormone, is expressed in the pancreas. The peptide has been shown to control glycemia, although the role of TRH in the pancreas has not yet been clarified. In quiescent INS-1 cells (rat immortalized beta-cell line), 200 nM of TRH for 24 hours significantly increased insulin levels in the culture medium and in cell extracts. In studies with gene array technology where about 60% to 75% of the 1081 genes were detected, TRH significantly stimulated multiple groups of gene expressions, including G-protein-coupled receptor and related signaling, such as insulin secretion, endoplasmic reticulum traffic mechanisms, cell-cycle regulators, protein turnover factors, DNA recombination, and growth factors. Noticeably, TRH suppressed the genes of proapoptotic Bcl-2-associated protein X, Bcl-xL/ Bcl-2-associated death promoter, and Fas. The multiple gene expressions in response to TRH in pancreatic cells suggest that the changed microenvironment brought about by TRH may influence beta-cellfunction. PMID:16392621

  4. Down-regulation of STAT3 expression by vector-based small interfering RNA inhibits pancreatic cancer growth

    Institute of Scientific and Technical Information of China (English)

    Chen Huang; Guang Yang; Tao Jiang; Jun Cao; Ke-Jian Huang; Zheng-Jun Qiu

    2011-01-01

    AIM: To evaluate the effect of RNA interference (RNAi) mediated silence of signal transduction and activation of transcription (STAT)3 on the growth of human pancreatic cancer cells both in vitro and in vivo . METHODS: STAT3 specific shRNA was used to silence the expression of STAT3 in pancreatic cancer cell line SW1990. The anti-growth effects of RNAi against STAT3 were studied in vitro and in experimental cancer xenografts in nude mice. The potential pathways involved in STAT3 signaling were detected using reverse transcription polymerase chain reaction and western blotting. RESULTS: The expression of the STAT3 was inhibited using RNAi in SW1990 cells. RNAi against STAT3 inhibited cell proliferation, induced cell apoptosis and significantly reduced the levels of CyclinD1 and Bcl-xL when compared with parental and control vector-transfected cells. In vivo experiments showed that RNAi against STAT3 inhibited the tumorigenicity of SW1990 cells and significantly suppressed tumor growth when it was directly injected into tumors. CONCLUSION: STAT3 signaling pathway plays an important role in the progression of pancreatic cancer, and silence of STAT3 gene using RNAi technique may be a novel therapeutic option for treatment of pancreatic cancer.

  5. Dexamethasone mediates protection against acute pancreatitis via upregulation of pancreatitis-associated proteins

    OpenAIRE

    Kandil, Emad; Lin, Yin-yao; Bluth, Martin H; Zhang, Hong; Levi, Gabriel; Zenilman, Michael E

    2006-01-01

    AIM: To examine the influence of dexamethasone on pancreatitis-associated protein (PAP) gene expression using both in vitro and in vivo models of acute pancreatitis and to study how PAP gene expression correlates with severity of pancreatitis.

  6. The Influence of Differentially Expressed Tissue-Type Plasminogen Activator in Experimental Autoimmune Encephalomyelitis: Implications for Multiple Sclerosis.

    Directory of Open Access Journals (Sweden)

    Lisa Cm Dahl

    Full Text Available Tissue type plasminogen activator (t-PA has been implicated in the development of multiple sclerosis (MS and in rodent models of experimental autoimmune encephalomyelitis (EAE. We show that levels of t-PA mRNA and activity are increased ~4 fold in the spinal cords of wild-type mice that are mice subjected to EAE. This was also accompanied with a significant increase in the levels of pro-matrix metalloproteinase 9 (pro-MMP-9 and an influx of fibrinogen. We next compared EAE severity in wild-type mice, t-PA-/- mice and T4+ transgenic mice that selectively over-express (~14-fold mouse t-PA in neurons of the central nervous system. Our results confirm that t-PA deficient mice have an earlier onset and more severe form of EAE. T4+ mice, despite expressing higher levels of endogenous t-PA, manifested a similar rate of onset and neurological severity of EAE. Levels of proMMP-9, and extravasated fibrinogen in spinal cord extracts were increased in mice following EAE onset regardless of the absence or over-expression of t-PA wild-type. Interestingly, MMP-2 levels also increased in spinal cord extracts of T4+ mice following EAE, but not in the other genotypes. Hence, while the absence of t-PA confers a more deleterious form of EAE, neuronal over-expression of t-PA does not overtly protect against this condition with regards to symptom onset or severity of EAE.

  7. Correlations among PPAR, DNMT1, and DNMT3B Expression Levels and Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Valerio Pazienza

    2012-01-01

    Full Text Available Emerging evidence indicates that peroxisome proliferator-activated receptor γ (PPARγ and DNA methyltransferases (DNMTs play a role in carcinogenesis. In this study we aimed to evaluate the expression of PPARγ, DNMT1, and DNMT3B and their correlation with clinical-pathological features in patients with pancreatic cancer (PC, and to define the effect of PPARγ activation on DNMTs expression in PC cell lines. qRT-PCR analysis showed that DNMT3B expression was downregulated in tumors compared to normal tissues (=0.03, whereas PPARγ and DNMT1 levels did not show significant alterations in PC patients. Expression levels between PPARγ and DNMT1 and between DNMT1 and DNMT3B were highly correlated (=0.008 and =0.05 resp.. DNMT3B overexpression in tumor tissue was positively correlated with both lymph nodes spreading (=0.046 and resection margin status (=0.04, and a borderline association with perineural invasion (=0.06 was found. Furthermore, high levels of DNMT3B expression were significantly associated with a lower mortality in the whole population (HR=0.485; 95%CI=0.262–0.895, =0.02 and in the subgroup of patients without perineural invasion (HR=0.314; 95%CI=0.130–0.758; =0.01, while such association was not observed in patients with tumor invasion into perineural structures (=0.70. In conclusion, in vitro and in vivo PPARγ and DNMTs appear interrelated in PC, and this interaction might influence cell phenotype and disease behavior.

  8. MR imaging of pancreatic diseases

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Katsuyoshi E-mail: itokatsu@po.cc.yamaguchi-u.ac.jp; Koike, Shinji; Matsunaga, Naofumi

    2001-05-01

    This article presents current MR imaging techniques for the pancreas, and review a spectrum of MR imaging features of various pancreatic diseases. These include: 1) congenital anomalies such as anomalous union of pancreatobiliary ducts, divisum, and annular pancreas, 2) inflammatory diseases, including acute or chronic pancreatitis with complications, groove pancreatitis, and autoimmune pancreatitis, tumor-forming pancreatitis, 3) pancreatic neoplasms, including adenocarcinoma, islet cell tumors, and cystic neoplasms (microcystic adenoma, mucinous cystic neoplasms, and intraductal mucin-producing pancreatic tumor). Particular attention is paid to technical advances in MR imaging of the pancreas such as fat-suppression, MR pancreatography (single- or multi-slice HASTE), and thin-section 3D multiphasic contrast-enhanced dynamic sequences. Imaging characteristics that may lead to a specific diagnosis or narrow the differential diagnosis are also discussed.

  9. mt-Nd2a Modifies Resistance Against Autoimmune Type 1 Diabetes in NOD Mice at the Level of the Pancreatic β-Cell

    OpenAIRE

    Chen, Jing; Gusdon, Aaron M.; Piganelli, Jon; Leiter, Edward H.; Mathews, Clayton E

    2010-01-01

    OBJECTIVE To investigate whether a single nucleotide polymorphism (SNP) in the mitochondrial gene for NADH dehydrogenase 2 (mt-Nd2) can modulate susceptibility to type 1 diabetes in NOD mice. RESEARCH DESIGN AND METHODS NOD/ShiLtJ mice conplastic for the alloxan resistant (ALR)/Lt-derived mt-Nd2a allele (NOD.mtALR) were created and compared with standard NOD (carrying the mt-Nd2c allele) for susceptibility to spontaneous autoimmune diabetes, or to diabetes elicited by reciprocal adoptive sple...

  10. Low expression of nucleus accumbens-associated protein 1 predicts poor prognosis for patients with pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Nishi, Takeshi; Maruyama, Riruke; Urano, Takeshi; Nakayama, Naomi; Kawabata, Yasunari; Yano, Seiji; Yoshida, Manabu; Nakayama, Kentaro; Miyazaki, Kohji; Takenaga, Keizo; Tanaka, Tsuneo; Tajima, Yoshitsugu

    2012-12-01

    Nucleus accumbens-associated protein 1 (NAC1) is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. High expression of NAC1 is considered to have adverse effects on prognosis through negative regulation of growth arrest and DNA-damage-inducible 45-γ interacting protein 1 (GADD45GIP1) in ovarian and cervical carcinomas. In the present study, the expression of NAC1 in pancreatic ductal adenocarcinoma (PDA) was measured using immunohistochemistry and computer-assisted image analysis in order to investigate its correlation with various clinicopathological parameters and prognosis. Patients with low-NAC1 PDA had worse overall survival (P = 0.0010) and a shorter disease-free survival (P = 0.0036) than patients with high-NAC1 PDA. This was a clinical effect opposite to that reported in ovarian and cervical carcinomas. Furthermore, knockdown of NAC1 in pancreatic carcinoma cell lines did not increase expression of the GADD45GIP1 protein. These results indicate that the gene(s) regulated by NAC1 vary depending on the types of carcinoma or originating tissue, and that low expression of NAC1 predicts poor prognosis for patients with PDA.

  11. Nuclear antigen expression by ultraviolet light irradiation - a contribution to the UV-induced autoimmunity

    International Nuclear Information System (INIS)

    A review is given about nuclear antigen expression due to UVB, UVA, and PUVA. UVB alters DNA resulting in strong immunogenic UVDNA and complementary antibodies. Antibodies to UVDNA cross react with double-stranded DNA. UVDNA plays a (hypothetical) role in the induction of cutaneous lesions in lupus erythematosus (LE). Investigations about SS-A/Ro expression due to UVB seem to be more important under this view. Antibodies against SS-A/Ro are related to an increased photosensitivity in LE. PUVA and UVA are able to induce antinuclear antibodies of unknown specificity. It is likely that PUVA enhances SS-A/Ro expression in vitro. The results are discussed in sense of LE photobiology and unwanted side effects of photo(chemo)therapy in psoriasis. (author)

  12. Doublecortin-like kinase 1 is elevated serologically in pancreatic ductal adenocarcinoma and widely expressed on circulating tumor cells.

    Directory of Open Access Journals (Sweden)

    Dongfeng Qu

    Full Text Available Doublecortin-like kinase 1 (DCLK1 is a putative pancreatic stem cell marker and is upregulated in pancreatic cancer, colorectal cancer, and many other solid tumors. It marks tumor stem cells in mouse models of intestinal neoplasia. Here we sought to determine whether DCLK1 protein can be detected in the bloodstream and if its levels in archived serum samples could be quantitatively assessed in pancreatic cancer patients. DCLK1 specific ELISA, western blotting, and immunohistochemical analyses were used to determine expression levels in the serum and staining intensity in archived tumor tissues of pancreatic ductal adenocarcinoma (PDAC patients and in pancreatic cancer mouse models. DCLK1 levels in the serum were elevated in early stages of PDAC (stages I and II compared to healthy volunteers (normal controls. No differences were observed between stages III/IV and normal controls. In resected surgical tissues, DCLK1 expression intensity in the stromal cells was significantly higher than that observed in tumor epithelial cells. Circulating tumor cells were isolated from KPCY mice and approximately 52% of these cells were positive for Dclk1 staining. Dclk1 levels in the serum of KPC mice were also elevated. We have previously demonstrated that DCLK1 plays a potential role in regulating epithelial mesenchymal transition (EMT. Given the increasingly recognized role of EMT derived stem cells in cancer progression and metastasis, we hypothesize that DCLK1 may contribute to the metastatic process. Taken together, our results suggest that DCLK1 serum levels and DCLK1 positive circulating tumor cells should be further assessed for their potential diagnostic and prognostic significance.

  13. Purification and characterization of the first recombinant bird pancreatic lipase expressed in Pichia pastoris: The turkey

    Directory of Open Access Journals (Sweden)

    Fendri Ahmed

    2011-01-01

    Full Text Available Abstract Background The turkey pancreatic lipase (TPL was purified from delipidated pancreases. Some biochemical properties and kinetic studies were determined using emulsified system and monomolecular film techniques. Those studies have shown that despite the accumulation of free fatty acids at the olive oil/water interface, TPL continues to hydrolyse efficiently the olive oil and the TC4 in the absence of colipase and bile salts, contrary to most classical digestive lipases which denaturate rapidly under the same conditions. The aim of the present study was to express TPL in the methylotrophic yeast Pichia pastoris in order to get a large amount of this enzyme exhibiting interesting biochemical properties, to purify and characterize the recombinant enzyme. Results The recombinant TPL was secreted into the culture medium and the expression level reached about 15 mg/l after 4 days of culture. Using Q-PCR, the number of expression cassette integrated on Pichia genomic DNA was estimated to 5. The purified rTPL, with molecular mass of 50 kDa, has a specific activity of 5300 U/mg on emulsified olive oil and 9500 U/mg on tributyrin. The optimal temperature and pH of rTPL were 37°C and pH 8.5. The stability, reaction kinetics and effects of calcium ions and bile salts were also determined. Conclusions Our results show that the expressed TPL have the same properties as the native TPL previously purified. This result allows us the use of the recombinant enzyme to investigate the TPL structure-function relationships.

  14. Vaccines and autoimmunity.

    Science.gov (United States)

    De Martino, M; Chiappini, E; Galli, L

    2013-01-01

    Vaccines have eradicated or controlled many infectious diseases, saving each year millions of lives and quality of life of many other millions of people. In spite of the success of vaccines over the last two centuries, parents (and also some health care workers) gloss over the devastating consequences of diseases, which are now avoided thanks to vaccines, and direct their attention to possible negative effects of immunization. Three immunological objections are raised: vaccines cause antigenic overload, natural immunity is safer and better than vaccine-induced immunity, and vaccines induce autoimmunity. The last point is examined in this review. Theoretically, vaccines could trigger autoimmunity by means of cytokine production, anti-idiotypic network, expression of human histocompatibility leukocyte antigens, modification of surface antigens and induction of novel antigens, molecular mimicry, bystander activation, epitope spreading, and polyclonal activation of B cells. There is strong evidence that none of these mechanisms is really effective in causing autoimmune diseases. Vaccines are not a source of autoimmune diseases. By contrast, absolute evidence exists that infectious agents can trigger autoimmune mechanisms and that they do cause autoimmune diseases.

  15. Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis

    NARCIS (Netherlands)

    Hackeng, Wenzel M.; Brosens, Lodewijk A A; Poruk, Katherine E.; Noë, Michaël; Hosoda, Waki; Poling, Justin S.; Rizzo, Anthony; Campbell-Thompson, Martha; Atkinson, Mark A.; Konukiewitz, Björn; Klöppel, Günter; Heaphy, Christopher M.; Meeker, Alan K.; Wood, Laura D.

    2016-01-01

    Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in

  16. Effects of supraphysiologic concentration glucose on pancreatic duodenal homeobox-1 expression and insulin secretion in rats

    Institute of Scientific and Technical Information of China (English)

    XIAO Chang-qing; DENG Hong-ming; HUANG Yun

    2007-01-01

    @@ The islet transcription factor pancreatic duodenal homeobox-1 (PDX-1, also known as insulin promoter factor-1 or IPF-1) is an orphan homeodomain protein that plays an important role in the development, proliferation,differentiation and maturation of pancreatic cells.

  17. Down-regulation of survivin expression by small interfering RNA induces pancreatic cancer cell apoptosis and enhances its radiosensitivity

    Institute of Scientific and Technical Information of China (English)

    Hai-Tao Guan; Xing-Huan Xue; Zhi-Jun Dai; Xi-Jing Wang; Ang Li; Zhao-Yin Qin

    2006-01-01

    AIM: To investigate the inhibitory effect of small interfering RNA (siRNA) on the expression of survivin in pancreatic cancer cell line PC-2 and the role of siRNA in inducing PC-2 cell apoptosis and enhancing its radiosensitivity.METHODS: A siRNA plasmid expression vector against survivin was constructed and transfected into PC-2 cells with LipofectamineTM 2000. The down regulation of survivin expression was detected by semi-quantitive RT-PCR and immunohistochemical SP method and the role of siRNA in inducing PC-2 cell apoptosis and enhancing its radiosensitivity was detected by flow cytometry.RESULTS: The sequence-specific siRNA efficiently and specifically down-regulated the expression of survivin at both mRNA and protein levels. The expression inhibition ratio was 81.25% at mRNA level detected by semiquantitive RT-PCR and 74.24% at protein level detected by immunohistochemical method. Forty-eight hours after transfection,apoptosis was induced in 7.03% cells by siRNA and in 14.58% cells by siRNA combined with radiation.CONCLUSION: The siRNA plasmid expression vector against survivin can inhibit the expression of survivin in PC-2 cells efficiently and specifically. Inhibiting the expression of survivin can induce apoptosis of PC-2 cells and enhance its radiosensitivity significantly. RNAi against survivin is of potential value in gene tnerapy of pancreatic cancer.

  18. Low Expression of ARHI Is Associated with Shorter Progression-Free Survival in Pancreatic Endocrine Tumors1*

    OpenAIRE

    Irene, Dalai; Edoardo, Missiaglia; Stefano, Barbi; Giovanni, Butturini; Claudio, Doglioni; Massimo, Falconi; Aldo, Scarpa

    2007-01-01

    Little is known about the molecular anomalies involved in the development and progression of malignancy of pancreatic endocrine tumors (PETs). A recently identified member of the Ras family, Ras homologue member I (ARHI), has been shown to be involved in breast, ovary, and thyroid carcinogenesis. Unlike other members, it acts as a tumor suppressor gene that inhibits cell growth. Here we analyzed the mRNA expression of ARHI in 52 primary PETs and 16 normal pancreata using quantitative reverse ...

  19. Differentially expressed genes in pancreatic ductal adenocarcinomas identified through serial analysis of gene expression

    DEFF Research Database (Denmark)

    Hustinx, Steven R; Cao, Dengfeng; Maitra, Anirban;

    2004-01-01

    Serial analysis of gene expression (SAGE) is a powerful tool for the discovery of novel tumor markers. The publicly available online SAGE libraries of normal and neoplastic tissues (http://www.ncbi.nlm.nih.gov/SAGE/) have recently been expanded; in addition, a more complete annotation of the human...... of this program. Novel differentially expressed genes in a cancer type can be identified by revisiting updated and expanded SAGE databases. TAGmapper should prove to be a powerful tool for the discovery of novel tumor markers through assignment of uncharacterized SAGE tags....

  20. MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo.

    Science.gov (United States)

    Cavalli, Giulio; Hayashi, Masahiro; Jin, Ying; Yorgov, Daniel; Santorico, Stephanie A; Holcomb, Cherie; Rastrou, Melinda; Erlich, Henry; Tengesdal, Isak W; Dagna, Lorenzo; Neff, C Preston; Palmer, Brent E; Spritz, Richard A; Dinarello, Charles A

    2016-02-01

    Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genome-wide association study of 2,853 Caucasian vitiligo patients. The super-enhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5- and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an "adjuvant" during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.

  1. Autoimmune Diseases

    Science.gov (United States)

    ... Some examples of CAM are herbal products, chiropractic , acupuncture , and hypnosis . If you have an autoimmune disease, ... Toll-Free: 877-226-4267 National Institute of Diabetes and Digestive and Kidney Diseases, NIH, HHS Phone: ...

  2. Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis.

    Science.gov (United States)

    Fristedt, Richard; Elebro, Jacob; Gaber, Alexander; Jonsson, Liv; Heby, Margareta; Yudina, Yulyana; Nodin, Björn; Uhlén, Mathias; Eberhard, Jakob; Jirström, Karin

    2014-01-01

    The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmö and Lund University Hospitals, Sweden, between 2001-2011. Tissue microarrays were constructed from primary tumours (n = 175) and paired lymph node metastases (n = 105). A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR) for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3%) primary tumours and in 96/105 (91.4%) lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018). Low pIgR expression was significantly associated with poor differentiation grade (p time, that high tumour-specific pIgR expression signifies a more favourable tumour phenotype and that low expression independently predicts a shorter survival in patients with pancreatic and periampullary cancer. The mechanistic basis for the putative tumour suppressing properties of pIgR in these cancers merits further study. PMID:25397670

  3. Relationship between telomerase activity and its subunit expression and inhibitory effect of antisense hTR on pancreatic carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jia-Hua Zhou; Hong-Mei Zhang; Quan Chen; Dong-Dong Han; Fei Pei; Li-Shan Zhang; De-Tong Yang

    2003-01-01

    AIM: To directly investigate the relationship between telomerase activity and its subunit expression and the inhibitory effect of antisense hTR on pancreatic carcinogenesis.METHODS: We examined the telomerase activity and its subunit expression by cell culture, polymerase chain reaction (PCR), PCR-silver staining, PCR-ELISA, DNA sequencing, MTT and flow cytometry methods.RESULTS: PCR-silver staining and PCR-ELISA methods had the same specificity and sensitivity as the TRAP method.Telomerase activity was detected in the extract of the 10th,20th and 30th passages of P3 cells,while it was absent in fibroblasts. Furthermore, after the 30th generation, the proliferation period of fibroblast cells was significantly prolonged. Telomerase activity and hTERTmRNA were detected in two pancreatic carcinoma cell lines, but were found to be negative in human fibroblast cells. Telomerase activity and hTERTmRNA were tested in pancreatic carcinoma specimens of 24 cases. The telomerase activity was positive in 21 of the 24 cases (87.5 %), and the hTERTmRNA in 20 cases (83.3 %). In adjacent normal tissues positive rates were both 12.5 %. There was a significant difference between the two groups. This indicated a significant correlation between the expression level of telomerase activity and histologic differentiation,metastasis and advanced clinical stage of pancreatic carcinoma. Our findings showed that the expressions of hTR and TP1mRNA were not correlated with the activity of telomerase but the expression of hTERTmRNA was. After treatment with PS-ODNs, telomerase activity in P3 cells weakened and the inhibiting effect became stronger with an increase in PS-ODNs concentration. There was a significant difference between different PS-ODN groups (P<0.05). Inhibition of telomerase activity occurred most significant with PS-ODN1.The results of the FCM test of pancreatic cancer P3 cells showed an increase in the apoptotic rate with increasing PS-ODN1 and PS-ODN2concentrations

  4. Low-dose oral interferon modulates expression of inflammatory and autoimmune genes in cattle.

    Science.gov (United States)

    Mamber, Stephen W; Lins, Jeremy; Gurel, Volkan; Hutcheson, David P; Pinedo, Pablo; Bechtol, David; Krakowka, Steven; Fields-Henderson, Rachel; Cummins, Joseph M

    2016-04-01

    While the safety and efficacy profiles of orally administered bovine interferon (IFN) alpha have been documented, the mechanism(s) that result in clinical benefits remain elusive. One approach to delineating the molecular pathways of IFN efficacy is through the use of gene expression profiling technologies. In this proof-of-concept study, different (0, 50, 200 and 800 units) oral doses of natural bovine IFN (type I) were tested in cattle to determine if oral IFN altered the expression of genes that may be pivotal to the development of systemic resistance to viral infections such as foot-and-mouth disease (FMD). Oral IFN was administered twice: Time 0 and 8h later. Blood was collected at 0, 8 and 24h after the first IFN administration, and DNA isolated from peripheral blood mononuclear cells (PBMCs) was employed in quantitative polymerase chain reaction (qPCR) microarray assays. Within 8h, 50 and 200 units of oral IFN induced significant (PFMDV) until such a time that an effective vaccine can be produced and distributed to producers. PMID:27032505

  5. Role of endogenous cortistatin in the regulation of ghrelin system expression at pancreatic level under normal and obese conditions.

    Directory of Open Access Journals (Sweden)

    Belén Chanclón

    Full Text Available Ghrelin-system components [native ghrelin, In1-ghrelin, Ghrelin-O-acyltransferase enzyme (GOAT and receptors (GHS-Rs] are expressed in a wide variety of tissues, including the pancreas, where they exert different biological actions including regulation of neuroendocrine secretions, food intake and pancreatic function. The expression of ghrelin system is regulated by metabolic conditions (fasting/obesity and is associated with the progression of obesity and insulin resistance. Cortistatin (CORT, a neuropeptide able to activate GHS-R, has emerged as an additional link in gut-brain interplay. Indeed, we recently reported that male CORT deficient mice (cort-/- are insulin-resistant and present a clear dysregulation in the stomach ghrelin-system. The present work was focused at analyzing the expression pattern of ghrelin-system components at pancreas level in cort-/- mice and their control littermates (cort +/+ under low- or high-fat diet. Our data reveal that all the ghrelin-system components are expressed at the mouse pancreatic level, where, interestingly, In1-ghrelin was expressed at higher levels than native-ghrelin. Thus, GOAT mRNA levels were significantly lower in cort-/- mice compared with controls while native ghrelin, In1-ghrelin and GHS-R transcript levels remained unaltered under normal metabolic conditions. Moreover, under obese condition, a significant increase in pancreatic expression of native-ghrelin, In1-ghrelin and GHS-R was observed in obese cort+/+ but not in cort-/- mice. Interestingly, insulin expression and release was elevated in obese cort+/+, while these changes were not observed in obese cort-/- mice. Altogether, our results indicate that the ghrelin-system expression is clearly regulated in the pancreas of cort+/+ and cort -/- under normal and/or obesity conditions suggesting that this system may play relevant roles in the endocrine pancreas. Most importantly, our data demonstrate, for the first time, that endogenous

  6. Expression of cell cycle regulator p57kip2, cyclinE protein and proliferating cell nuclear antigen in human pancreatic cancer: An immunohistochemical study

    Institute of Scientific and Technical Information of China (English)

    Hui Yue; Hui-Yong Jiang

    2005-01-01

    AIM: To investigate the effects of p57kip2, cyclinE protein and proliferating cell nuclear antigen (PCNA) on occurrence and progression of human pancreatic cancer.METHODS: The expression of p57kip2, cyclinE protein and PCNA in tumor tissues and adjacent tissues from 32patients with pancreatic cancer was detected by SP immunohistochemical technique.RESULTS: The positive expression rate of p57kip2 protein in tumor tissues was 46.9%, which was lower than that in adjacent pancreatic tissues (x2 = 5.317, P<0.05). P57kip2protein positive expression remarkably correlated with tumor cell differentiation (P<0.05), but not with lymph node metastasis (P>0.05). The positive expression rate of cyclinE protein in tumor tissues was 68.8%, which was higher than that in adjacent pancreatic tissues (x2 = 4.063,P<0.05). CyclinE protein positive expression significantly correlated with tumor cell differentiation and lymph node metastasis (P<0.05). The positive expression rate of PCNA in the tumor tissues was 71.9%, which was higher than that in adjacent pancreatic tissues (x2 = 5.189, P<0.05).PCNA positive expression remarkably correlated with tumor cell differentiation and lymph node metastasis (P<0.05).CONCLUSION: The decreased expression of p57kip2 and/or overexpression of cyclinE protein and PCNA may contribute to the occurrence and progression of pancreatic cancer.p57kip2, cyclinE protein, and PCNA play an important role in occurrence and progression of pancreatic cancer.

  7. Low expression of aldehyde deyhdrogenase 1A1 (ALDH1A1) is a prognostic marker for poor survival in pancreatic cancer

    International Nuclear Information System (INIS)

    Aldehyde deyhdrogenase 1 (ALDH1) has been characterised as a cancer stem cell marker in different types of tumours. Additionally, it plays a pivotal role in gene regulation and endows tumour cells with augmented chemoresistance. Recently, ALDH1A1 has been described as a prognostic marker in a pancreatic cancer tissue microarray. The aim of this study was to reevaluate the expression of ALDH1A1 as a prognostic marker on whole-mount tissue sections. Real-time-quantitative-PCR (qRT-PCR) and Western blotting were used to evaluate the expression profile of ALDH1A1 in seven pancreatic cancer cell lines and one non-malignant pancreatic cell line. Immunostaining against ALDH1A1 and Ki-67 was performed on paraffin-embedded samples from 97 patients with pancreatic cancer. The immunohistochemical results were correlated to histopathological and clinical data. qRT-PCR and Western blotting revealed a different expression pattern of ALDH1A1 in different malignant and non-malignant pancreatic cell lines. Immunohistochemical analysis demonstrated that ALDH1A1 was confined to the cellular cytoplasm and occurred in 72 cases (74%), whereas it was negative in 25 cases (26%). High expression of ALDH1A1 was significantly correlated to an increased proliferation rate (Spearman correlation, p = 0.01). Univariate and multivariate analyses showed that decreased expression of ALDH1A1 is an independent adverse prognostic factor for overall survival. Immunonhistochemical analysis on whole-mount tissue slides revealed that ALDH1A1 is more abundantly expressed in pancreatic cancer than initially reported by a tissue microarray analysis. Moreover, high expression of ALDH1A1 correlated significantly with the proliferation of tumour cells. Intriguingly, this study is the first which identifies low expression of ALDH1A1 as an independent adverse prognostic marker for overall survival in pancreatic cancer

  8. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

    Science.gov (United States)

    Raj, Prithvi; Rai, Ekta; Song, Ran; Khan, Shaheen; Wakeland, Benjamin E; Viswanathan, Kasthuribai; Arana, Carlos; Liang, Chaoying; Zhang, Bo; Dozmorov, Igor; Carr-Johnson, Ferdicia; Mitrovic, Mitja; Wiley, Graham B; Kelly, Jennifer A; Lauwerys, Bernard R; Olsen, Nancy J; Cotsapas, Chris; Garcia, Christine K; Wise, Carol A; Harley, John B; Nath, Swapan K; James, Judith A; Jacob, Chaim O; Tsao, Betty P; Pasare, Chandrashekhar; Karp, David R; Li, Quan Zhen; Gaffney, Patrick M; Wakeland, Edward K

    2016-01-01

    Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes. DOI: http://dx.doi.org/10.7554/eLife.12089.001 PMID:26880555

  9. Artesunate ameliorates severe acute pancreatitis (SAP) in rats by inhibiting expression of pro-inflammatory cytokines and Toll-like receptor 4.

    Science.gov (United States)

    Cen, Yanyan; Liu, Chao; Li, Xiaoli; Yan, Zifei; Kuang, Mei; Su, Yujie; Pan, Xichun; Qin, Rongxin; Liu, Xin; Zheng, Jiang; Zhou, Hong

    2016-09-01

    Severe acute pancreatitis (SAP) is a severe clinical condition with significant morbidity and mortality. Multiple organs dysfunction (MOD) is the leading cause of SAP-related death. The over-release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α is the underlying mechanism of MOD; however, there is no effective agent against the inflammation. Herein, artesunate (AS) was found to increase the survival of SAP rats significantly when injected with 3.5% sodium taurocholate into the biliopancreatic duct in a retrograde direction, improving their pancreatic pathology and decreasing serum amylase and pancreatic lipase activities along with substantially reduced pancreatic IL-1β and IL-6 release. In vitro, AS-pretreatment strongly inhibited IL-1β and IL-6 release and their mRNA expressions in the pancreatic acinar cells treated with lipopolysaccharide (LPS) but exerted little effect on TNF-α release. Additionally, AS reduced the mRNA expressions of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) p65 as well as their protein expressions in the pancreatic acinar cells. In conclusion, our results demonstrated that AS could significantly protect SAP rats, and this protection was related to the reduction of digestive enzyme activities and pro-inflammatory cytokine expressions via inhibition of TLR4/NF-κB signaling pathway. Therefore, AS may be considered as a potential therapeutic agent against SAP.

  10. Artesunate ameliorates severe acute pancreatitis (SAP) in rats by inhibiting expression of pro-inflammatory cytokines and Toll-like receptor 4.

    Science.gov (United States)

    Cen, Yanyan; Liu, Chao; Li, Xiaoli; Yan, Zifei; Kuang, Mei; Su, Yujie; Pan, Xichun; Qin, Rongxin; Liu, Xin; Zheng, Jiang; Zhou, Hong

    2016-09-01

    Severe acute pancreatitis (SAP) is a severe clinical condition with significant morbidity and mortality. Multiple organs dysfunction (MOD) is the leading cause of SAP-related death. The over-release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α is the underlying mechanism of MOD; however, there is no effective agent against the inflammation. Herein, artesunate (AS) was found to increase the survival of SAP rats significantly when injected with 3.5% sodium taurocholate into the biliopancreatic duct in a retrograde direction, improving their pancreatic pathology and decreasing serum amylase and pancreatic lipase activities along with substantially reduced pancreatic IL-1β and IL-6 release. In vitro, AS-pretreatment strongly inhibited IL-1β and IL-6 release and their mRNA expressions in the pancreatic acinar cells treated with lipopolysaccharide (LPS) but exerted little effect on TNF-α release. Additionally, AS reduced the mRNA expressions of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) p65 as well as their protein expressions in the pancreatic acinar cells. In conclusion, our results demonstrated that AS could significantly protect SAP rats, and this protection was related to the reduction of digestive enzyme activities and pro-inflammatory cytokine expressions via inhibition of TLR4/NF-κB signaling pathway. Therefore, AS may be considered as a potential therapeutic agent against SAP. PMID:27318790

  11. Aberrant expression of nuclear HDAC3 and cytoplasmic CDH1 predict a poor prognosis for patients with pancreatic cancer.

    Science.gov (United States)

    Jiao, Feng; Hu, Hai; Han, Ting; Zhuo, Meng; Yuan, Cuncun; Yang, Haiyan; Wang, Lei; Wang, Liwei

    2016-03-29

    Previous studies showed that aberrant CDH1 or/and HDAC3 localization is essential for the progression of some human cancers. Here, we investigate the prognostic significance of aberrant CDH1 and HDAC3 localization in 84 pancreatic cancer patients. Our results show that increases in both membrane and cytoplasmic CDH1 correlate with lymph node metastasis (P = 0.026 and P 0.05). Multivariate analysis showed that nuclear HDAC3 and cytoplasmic CDH1 (P = 0.001 and P = 0.010, respectively), as well as tumor differentiation (P = 0.009) are independent prognostic factors. Most importantly, patients with high co-expression of nuclear HDAC3 and cytoplasmic CDH1 had shorter survival times (P CDH1 have independent prognostic value in pancreatic cancer and provide novel targets for prognostic therapeutics.

  12. Expression profiling of wild type and β-catenin gene disrupted human BxPC-3 pancreatic adenocarcinoma cells

    Directory of Open Access Journals (Sweden)

    Petter Angell Olsen

    2015-06-01

    Full Text Available To study the role of WNT/β-catenin signaling in pancreatic adenocarcinoma, human BxPC-3 cell lines deficient of the central canonical WNT signaling protein β-catenin were established by using zinc-finger nuclease mediated targeted genomic disruption of the β-catenin gene (CTNNB1. Comparison of the global transcription levels in wild type cells with two β-catenin gene disrupted clones identified 85 transcripts that were the most differentially regulated. Gene ontology (GO term enrichment analysis of these transcripts identified “cell adhesion” as the most significantly enriched GO term. Here we describe the data from the transcription profiling analysis published in the article “Implications of Targeted Genomic Disruption of β-Catenin in BxPC-3 Pancreatic Adenocarcinoma Cells” [1]. Data have been deposited to the Gene Expression Omnibus (GEO database repository with the dataset identifier GSE63072.

  13. Tissue expression of the tumour associated antigen CA242 in benign and malignant pancreatic lesions. A comparison with CA 50 and CA 19-9.

    OpenAIRE

    Haglund, C.; Lindgren, J.; Roberts, P. J.; Kuusela, P.; Nordling, S.

    1989-01-01

    The expression of a novel tumour associated antigen CA 242, defined by the monoclonal antibody C 242, was studied by immunoperoxidase staining in formalin-fixed, paraffin-embedded tissue sections from normal pancreata, pancreata with pancreatitis and benign and malignant pancreatic neoplasms. The antigenic determinant of the C 242 antibody is a sialylated carbohydrate structure, related but chemically different from tumour marker antigens CA 19-9 and CA 50. Thirty-eight of 41 (93%) well to mo...

  14. Major histocompatibility complex class I-related chain A/B (MICA/B) expression in tumor tissue and serum of pancreatic cancer: Role of uric acid accumulation in gemcitabine-induced MICA/B expression

    International Nuclear Information System (INIS)

    Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind the immunoreceptor NKG2D and play an important role in mediating the cyotoxicity of NK and T cells. In this study, we sought to study MICA/B expression in pancreatic cancer and to determine whether and how genotoxic drugs such as gemcitabine can affect MICA/B expression and natural killer cytotoxity. Seven pancreatic cancer cell lines were analyzed for MICA/B expression by flow cytometry and for their sensitivity to NK-92 cell killing by a 51Cr release assay. MICA/B expression in tumor tissues and sera of pancreatic cancer was analyzed by immunohistochemical staining (IHC) and ELISA, respectively. Two MICA/B-positive cell lines were sensitive to the cytotoxic activity of NK-92 cells. Other two MICA/B-positive cell lines and three MICA/B-negative cell lines were resistant to NK-92 cell killing. MICA/B expression was positive in 17 of 25 (68%) pancreatic ductal adenocarcinomas but not in normal pancreatic ductal epithelial cells. Serum MICA/B levels were significantly elevated in patients with pancreatic adenocarcinomas but did not correlate with the stage of pancreatic cancer and patient survival. Gemcitabine therapy led to increased serum MICA levels in 6 of 10 patients with detectable serum MICA. Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing toward a PANC-1 cancer cell line exposed to radiation and two genotoxic drugs, gemcitabine and 5-fluorouracil. The levels of MICA/B expression in serum and tissue of pancreatic cancer are elevated. DNA damage-induced MICA/B expression is mediated through increased uric acid production

  15. Alterations in MicroRNA Expression Contribute to Fatty Acid–Induced Pancreatic β-Cell Dysfunction

    Science.gov (United States)

    Lovis, Pascal; Roggli, Elodie; Laybutt, D. Ross; Gattesco, Sonia; Yang, Jiang-Yan; Widmann, Christian; Abderrahmani, Amar; Regazzi, Romano

    2008-01-01

    OBJECTIVE—Visceral obesity and elevated plasma free fatty acids are predisposing factors for type 2 diabetes. Chronic exposure to these lipids is detrimental for pancreatic β-cells, resulting in reduced insulin content, defective insulin secretion, and apoptosis. We investigated the involvement in this phenomenon of microRNAs (miRNAs), a class of noncoding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation. RESEARCH DESIGN AND METHODS—We analyzed miRNA expression in insulin-secreting cell lines or pancreatic islets exposed to palmitate for 3 days and in islets from diabetic db/db mice. We studied the signaling pathways triggering the changes in miRNA expression and determined the impact of the miRNAs affected by palmitate on insulin secretion and apoptosis. RESULTS—Prolonged exposure of the β-cell line MIN6B1 and pancreatic islets to palmitate causes a time- and dose-dependent increase of miR34a and miR146. Elevated levels of these miRNAs are also observed in islets of diabetic db/db mice. miR34a rise is linked to activation of p53 and results in sensitization to apoptosis and impaired nutrient-induced secretion. The latter effect is associated with inhibition of the expression of vesicle-associated membrane protein 2, a key player in β-cell exocytosis. Higher miR146 levels do not affect the capacity to release insulin but contribute to increased apoptosis. Treatment with oligonucleotides that block miR34a or miR146 activity partially protects palmitate-treated cells from apoptosis but is insufficient to restore normal secretion. CONCLUSIONS—Our findings suggest that at least part of the detrimental effects of palmitate on β-cells is caused by alterations in the level of specific miRNAs. PMID:18633110

  16. Vasohibin-1 Expression Is Regulated by Transforming Growth Factor-β/Bone Morphogenic Protein Signaling Pathway Between Tumor-Associated Macrophages and Pancreatic Cancer Cells

    Science.gov (United States)

    Seppänen, Hanna; Kauttu, Tuuli; Vainionpää, Sanna; Ye, Yingjiang; Mustonen, Harri

    2013-01-01

    Vasohibin-1 has been detected in endothelial cells as an intrinsic angiogenesis inhibitor. Both tumor-associated macrophages (TAMs) and transforming growth factor-β (TGF-β)/bone morphogenic protein (BMP) signaling have been reported to promote angiogenesis in cancer. However, whether vasohibin-1 expression is regulated by TGF-β/BMP signaling between TAMs and cancer cells remains unclear. The expression of TGF-β1, TGF-β2, BMP-4, and BMP-7 in TAMs and the expression of vasohibin-1, vascular endothelial growth factor-A (VEGF-A), and VEGF-C in two pancreatic cancer cell lines (a nonmetastatic cell line Panc-1 and a distant metastatic cell line HPAF-II) were measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). The TGF-β receptor 1 and BMP receptor 1 were inhibited by the inhibitor SB-431542 and LDN193189, respectively. Thereafter, vasohibin-1, VEGF-A, and VEGF-C expression was detected by real-time RT-PCR. We found that the expression of TGF-β1, TGF-β2, BMP-4, and BMP-7 was upregulated in TAMs cocultured with pancreatic cancer cells. Vasohibin-1, VEGF-A, and VEGF-C mRNA expression in pancreatic cancer cells was upregulated by TAMs. Vasohibin-1 expression in pancreatic cancer cells cocultured with TAMs was upregulated significantly when TGF-β receptors or BMP receptors were inhibited, but VEGF-C expression was downregulated. Therefore, Vasohibin-1 expression is regulated by the TGF-β/BMP signaling between TAMs and pancreatic cancer cells. These results might shed a new light on the antiangiogenesis therapy in the pancreatic cancer. PMID:23651239

  17. In vivo pancreatic β-cell-specific expression of antiaging gene Klotho: a novel approach for preserving β-cells in type 2 diabetes.

    Science.gov (United States)

    Lin, Yi; Sun, Zhongjie

    2015-04-01

    Protein expression of an antiaging gene, Klotho, was depleted in pancreatic islets in patients with type 2 diabetes mellitus (T2DM) and in db/db mice, an animal model of T2DM. The objective of this study was to investigate whether in vivo expression of Klotho would preserve pancreatic β-cell function in db/db mice. We report for the first time that β-cell-specific expression of Klotho attenuated the development of diabetes in db/db mice. β-Cell-specific expression of Klotho decreased hyperglycemia and enhanced glucose tolerance. The beneficial effects of Klotho were associated with significant improvements in T2DM-induced decreases in number of β-cells, insulin storage levels in pancreatic islets, and glucose-stimulated insulin secretion from pancreatic islets, which led to increased blood insulin levels in diabetic mice. In addition, β-cell-specific expression of Klotho decreased intracellular superoxide levels, oxidative damage, apoptosis, and DNAJC3 (a marker for endoplasmic reticulum stress) in pancreatic islets. Furthermore, β-cell-specific expression of Klotho increased expression levels of Pdx-1 (insulin transcription factor), PCNA (a marker of cell proliferation), and LC3 (a marker of autophagy) in pancreatic islets in db/db mice. These results reveal that β-cell-specific expression of Klotho improves β-cell function and attenuates the development of T2DM. Therefore, in vivo expression of Klotho may offer a novel strategy for protecting β-cells in T2DM. PMID:25377875

  18. Autoimmune disease

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    2005164 Optimal cut-point of glutamic acid decar-boxylase antibody (GAD-Ab) for differentiating two subtypes of latent autoimmune diabetes in adults (LADA). LI Xia(李霞), et al. Dept Endocrinol, 2nd Xiangya Hosp, Central South Univ, Changsha, 410011. Chin J Diabetes, 2005;13(1) :34-38. Objective: To investigate the optimal cut-point of glutamate decarboxylase antibody (GAD-Ab) for differentiating two subtypes of latent autoimmune diabetes in adults (I. ADA). Methods: The frequency

  19. Autoimmune synaptopathies.

    Science.gov (United States)

    Crisp, Sarah J; Kullmann, Dimitri M; Vincent, Angela

    2016-02-01

    Autoantibodies targeting proteins at the neuromuscular junction are known to cause several distinct myasthenic syndromes. Recently, autoantibodies targeting neurotransmitter receptors and associated proteins have also emerged as a cause of severe, but potentially treatable, diseases of the CNS. Here, we review the clinical evidence as well as in vitro and in vivo experimental evidence that autoantibodies account for myasthenic syndromes and autoimmune disorders of the CNS by disrupting the functional or structural integrity of synapses. Studying neurological and psychiatric diseases of autoimmune origin may provide new insights into the cellular and circuit mechanisms underlying a broad range of CNS disorders. PMID:26806629

  20. Associations between gene polymorphisms of thymidylate synthase with its protein expression and chemosensitivity to 5-fluorouracil in pancreatic carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    ZHANG Qiang; ZHAO Yu-pei; LIAO Quan; HU Ya; XU Qiang; ZHOU Li; SHU Hong

    2011-01-01

    Background Thymidylate synthase (TS) is a key regulatory enzyme for de novo DNA synthesis.TS activity is also an important determinant of the response to chemotherapy with fluoropyrimidine prodrugs,and its expression may be affected by gene polymorphisms.In this study,we investigated the associations between polymorphisms of the TS gene and its protein expression,and the implications on the efficacy of 5-fluorouracil (5-FU) in pancreatic cancer cells.Methods Genotypes based on the 28-bp TS tandem repeat for pancreatic cell lines were determined by electrophoretic analysis of PCR products.A single nucleotide polymorphism (SNP) at nucleotide 12 of the second 28-bp repeat of the 3R allele was determined by nucleotide sequencing.The chemosensitivity of pancreatic carcinoma cells to 5-FU in vitro was evaluated using Cell Counting Kit-8 (CCK-8).TS protein expression was analyzed by Western blotting.Results Seven pancreatic carcinoma cell lines had different genotypes in terms of the 28-bp TS tandem repeat,as follows:homozygous 2R/2R (T3M4 and BxPC-3 cells),heterozygous 2R/3R (AsPC-1,Capan-1,and SU86.86),and homozygous 3R/3R (PANC-1 and COLO357).The optical density ratio of genotypes 3R/3R,2R/2R and 2R/3R was 1.393±0.374,0.568±0.032 and 0.561±0.056,respectively.Cells with the 2R/3R or 3R/3R genotypes were further analyzed for the G to C SNP at nucleotide 12 of the second 28-bp repeat of the 3R allele,yielding heterozygous 2R/3Rc (AsPC-1,Capan-1,and SU86.86),homozygous 3Rg/3Rg (COLO357) and homozygous 3Rc/3Rc (PANC-1).The optical density ratio of homozygous 3Rg/3Rg cells and homozygous 3Rc/3Rc cells was 1.723±0.062 and 1.063±0.134,respectively,and this difference was statistically significant (P <0.05).Cells with the 2R/2R and 2R/3R genotypes of TS were hypersensitive to 5-FU in vitro as compared with those with the 3R/3R cells.Conclusions Polymorphisms in the TS gene influenced its protein expression and affected sensitivity of 5-FU in seven pancreatic cancer cell

  1. Expression of lysophosphatidic acid and its receptor in human pancreatic cancer and its clinical evaluation of diagnosis and therapy

    Institute of Scientific and Technical Information of China (English)

    WANG Shao-kai; TAO Chen-jie; WANG Wei-dong; L(U)Guang-mei; GONG Yong-ling

    2011-01-01

    Lysophosphatidic acid(LPA) is a naturally occurring phospholipid with diverse effects in various cells, ranging from immediate morphological alteration to long lasting cellular function changes, such as induction of stimulation of cell proliferation, survival, drug resistance and motility. Like many other biomediators, LPA interacts with cells through specific cell surface receptors(G protein-coupled receptors). LPA1/Edg-2,LPA2/Edg-4 and LPA3/Edg-7, named as Edg/LP subfamily, are the three most common lysophosphatidic acid receptors. LPA plays a critical role as a general growth, survival and pro-angiogenic factor in the regulation of pathophysiological processes in vivo and in vitro. Recent literatures suggest that abnormalities in LPA metabolism and function in pancreatic cancer patients may contribute to the initiation and progression of the disease. Thus, LPA might be a potential target for clinical pancreatic cancer diagnosis and therapy. Herein we review the expression of LPA and its receptors in the carcinogenesis of human malignancies, with focus on human pancreatic cancer, and also clinical diagnosis and treatment has been evaluated.

  2. Pancreatic lipase-related protein (PY-PLRP) highly expressed in the vitellogenic ovary of the scallop, Patinopecten yessoensis.

    Science.gov (United States)

    Kim, Kyoung Sun; Kim, Bo Kwang; Kim, Hak Jun; Yoo, Myong Suk; Mykles, Donald L; Kim, Hyun-Woo

    2008-09-01

    A cDNA (1206 bp) encoding a pancreatic lipase-related protein (PY-PLRP) was obtained from the ovary of the scallop, Patinopecten yessoensis, using a differentially expressed gene system. The open reading frame specified a protein containing 353 amino acids (~38 kDa). The N-terminal catalytic domain, which contained the catalytic triad of serine, aspartate, and histidine residues, 10 cysteine residues involved in disulfide bridges, and the conserved lid domain, indicated that the protein would be catalytically active. However, PY-PLRP lacked the C-terminal colipase-binding domain present in mammalian PLRPs. Sequence analysis of the catalytic domains of PY-PLRP with members of the pancreatic triglyceride lipase (PTL) family suggested that PY-PLRP was related to mammalian PLRP1, PLRP2, and PTL. End-point reverse transcriptase-polymerase chain reaction (RT-PCR) after 25 cycles showed that PY-PLRP was expressed at a high level in the ovary and at low levels in testis and mantle; expression was not detected in gill, digestive gland, and adductor muscle. Quantitative PCR of RNA from ovaries at different stages of development showed that PY-PLRP was expressed at a significantly higher level in the late growth stage than in the ripe and spent stages. These data suggest that PY-PLRP plays a role in lipid metabolism associated with oocyte maturation and vitellogenesis that occurs during ovarian growth. PMID:18602322

  3. E2-2 Dependent Plasmacytoid Dendritic Cells Control Autoimmune Diabetes.

    Directory of Open Access Journals (Sweden)

    Lisbeth Hansen

    Full Text Available Autoimmune diabetes is a consequence of immune-cell infiltration and destruction of pancreatic β-cells in the islets of Langerhans. We analyzed the cellular composition of the insulitic lesions in the autoimmune-prone non-obese diabetic (NOD mouse and observed a peak in recruitment of plasmacytoid dendritic cells (pDCs to NOD islets around 8-9 weeks of age. This peak coincides with increased spontaneous expression of type-1-IFN response genes and CpG1585 induced production of IFN-α from NOD islets. The transcription factor E2-2 is specifically required for the maturation of pDCs, and we show that knocking out E2-2 conditionally in CD11c+ cells leads to a reduced recruitment of pDCs to pancreatic islets and reduced CpG1585 induced production of IFN-α during insulitis. As a consequence, insulitis has a less aggressive expression profile of the Th1 cytokine IFN-γ and a markedly reduced diabetes incidence. Collectively, these observations demonstrate a disease-promoting role of E2-2 dependent pDCs in the pancreas during autoimmune diabetes in the NOD mouse.

  4. E2-2 Dependent Plasmacytoid Dendritic Cells Control Autoimmune Diabetes

    Science.gov (United States)

    Hansen, Lisbeth; Schmidt-Christensen, Anja; Gupta, Shashank; Fransén-Pettersson, Nina; Hannibal, Tine D.; Reizis, Boris; Santamaria, Pere; Holmberg, Dan

    2015-01-01

    Autoimmune diabetes is a consequence of immune-cell infiltration and destruction of pancreatic β-cells in the islets of Langerhans. We analyzed the cellular composition of the insulitic lesions in the autoimmune-prone non-obese diabetic (NOD) mouse and observed a peak in recruitment of plasmacytoid dendritic cells (pDCs) to NOD islets around 8–9 weeks of age. This peak coincides with increased spontaneous expression of type-1-IFN response genes and CpG1585 induced production of IFN-α from NOD islets. The transcription factor E2-2 is specifically required for the maturation of pDCs, and we show that knocking out E2-2 conditionally in CD11c+ cells leads to a reduced recruitment of pDCs to pancreatic islets and reduced CpG1585 induced production of IFN-α during insulitis. As a consequence, insulitis has a less aggressive expression profile of the Th1 cytokine IFN-γ and a markedly reduced diabetes incidence. Collectively, these observations demonstrate a disease-promoting role of E2-2 dependent pDCs in the pancreas during autoimmune diabetes in the NOD mouse. PMID:26624013

  5. Amyloid precursor protein and growth-associated protein 43 expression in brain white matter and spinal cord tissues in a rat model of experimental autoimmune encephalomyelitis

    Institute of Scientific and Technical Information of China (English)

    Yizhou Wang; Shuang Kou; Jingcheng Tang; Ping Zhang; Qiuxia Zhang; Yan Liu; Qi Zheng; Hui Zhao; Lei Wang

    2011-01-01

    Studies have demonstrated that amyloid precursor protein (APP) expression increases in multiple sclerosis tissues during acutely and chronically active stages.To determine the relationship between axonal injury and regeneration in multiple sclerosis, an animal model of experimental autoimmune encephalomyelitis was induced using different doses of myelin basic protein peptide.APP and growth-associated protein 43 (GAP-43), which is considered a specific marker of neural regeneration, were assessed by western blot analysis.Expression of APP and GAP-43, as well as the correlation between these two proteins, in brain white matter and spinal cord tissues of experimental autoimmune encephalomyelitis rats at different pathological stages was analyzed.Results showed that APP and GAP-43 expression increased during the acute stage and decreased during remission, with a positive correlation between APP and GAP-43 expression in brain white matter and spinal cord tissues.These results suggest that APP and GAP-43 could provide nutritional and protective effects on damaged neurons.

  6. Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, C; Penkowa, M; Demestre, M;

    2005-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS). EAE and MS are characterized by CNS inflammation, demyelination and neurodegeneration. The inflammatory response occurring within the CNS leads to glial activation, dysfunction and death, as well as...... antioxidant proteins may provide therapeutic benefits in MS....

  7. Autoimmun hypophysitis

    DEFF Research Database (Denmark)

    Krarup, Therese; Hagen, Claus

    2010-01-01

    during pregnancy or postpartum, but also occurs in males and children. AH is often associated with other autoimmune diseases, most frequently with Hashimoto's thyroiditis. The symptoms are caused by enlargement of the pituitary gland and disturbances of the hormone function. Treatment is either...

  8. Cytosolic Double-Stranded DNA as a Damage-Associated Molecular Pattern Induces the Inflammatory Response in Rat Pancreatic Stellate Cells: A Plausible Mechanism for Tissue Injury-Associated Pancreatitis

    Directory of Open Access Journals (Sweden)

    Taichi Nakamura

    2012-01-01

    Full Text Available Pancreatitis is an inflammatory disease of unknown causes. There are many triggers causing pancreatitis, such as alcohol, common bile duct stone, virus and congenital or acquired stenosis of main pancreatic duct, which often involve tissue injuries. Pancreatitis often occurs in sterile condition, where the dead/dying pancreatic parenchymal cells and the necrotic tissues derived from self-digested-pancreas were observed. However, the causal relationship between tissue injury and pancreatitis and how tissue injury could induce the inflammation of the pancreas were not elucidated fully until now. This study demonstrates that cytosolic double-stranded DNA increases the expression of several inflammatory genes (cytokines, chemokines, type I interferon, and major histocompatibility complex in rat pancreatic stellate cells. Furthermore, these increase accompanied the multiple signal molecules genes, such as interferon regulatory factors, nuclear factor-kappa B, low-molecular-weight protein 2, and transporter associated with antigen processing 1. We suggest that this phenomenon is a plausible mechanism that might explain how cell damage of the pancreas or tissue injury triggers acute, chronic, and autoimmune pancreatitis; it is potentially relevant to host immune responses induced during alcohol consumption or other causes.

  9. Expression and significance of SOCS3 in liver tissue of rats with severe acute pancreatitis complicated by liver injury

    OpenAIRE

    Wang, Bin; Zhang, Xiao-Hua; Miao-fan YANG; Xiao-wei WU; Xu, Xiao-Bing; Mei-xia GUO; Min-li LI

    2012-01-01

    Objective  To investigate the expression and mechanism of action of suppressor of cytokine signaling 3 (SOCS3) in liver tissue of rats with experimental severe acute pancreatitis (SAP) concurring with liver injury. Methods  The rat model of SAP was reproduced by retrograde injection of 4% sodium taurocholate into the biliopancreatic duct. Thirty-two male SD rats were randomly assigned into 4 groups (8 each): normal control group (NC), SAP 6h, 12h, and 18h groups. The levels of serum amylase (...

  10. Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis.

    Directory of Open Access Journals (Sweden)

    Richard Fristedt

    Full Text Available The polymeric immunoglobulin receptor (pIgR is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmö and Lund University Hospitals, Sweden, between 2001-2011. Tissue microarrays were constructed from primary tumours (n = 175 and paired lymph node metastases (n = 105. A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3% primary tumours and in 96/105 (91.4% lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018. Low pIgR expression was significantly associated with poor differentiation grade (p < 0.001, perineural growth (p = 0.027, lymphatic invasion (p = 0.016, vascular invasion (p = 0.033 and infiltration of the peripancreatic fat (p = 0.039. In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI 1.71-5.25 and early recurrence (HR = 2.89, 95% CI 1.67-4.98. This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10-3.57. These results demonstrate, for the first time, that high tumour-specific pIgR expression signifies

  11. Transgenic Expression of a Single Transcription Factor Pdx1 Induces Transdifferentiation of Pancreatic Acinar Cells to Endocrine Cells in Adult Mice.

    Science.gov (United States)

    Miyazaki, Satsuki; Tashiro, Fumi; Miyazaki, Jun-Ichi

    2016-01-01

    A promising approach to new diabetes therapies is to generate β cells from other differentiated pancreatic cells in vivo. Because the acinar cells represent the most abundant cell type in the pancreas, an attractive possibility is to reprogram acinar cells into β cells. The transcription factor Pdx1 (Pancreas/duodenum homeobox protein 1) is essential for pancreatic development and cell lineage determination. Our objective is to examine whether exogenous expression of Pdx1 in acinar cells of adult mice might induce reprogramming of acinar cells into β cells. We established a transgenic mouse line in which Pdx1 and EGFP (enhanced green fluorescent protein) could be inducibly expressed in the acinar cells. After induction of Pdx1, we followed the acinar cells for their expression of exocrine and endocrine markers using cell-lineage tracing with EGFP. The acinar cell-specific expression of Pdx1 in adult mice reprogrammed the acinar cells as endocrine precursor cells, which migrated into the pancreatic islets and differentiated into insulin-, somatostatin-, or PP (pancreatic polypeptide)-producing endocrine cells, but not into glucagon-producing cells. When the mice undergoing such pancreatic reprogramming were treated with streptozotocin (STZ), the newly generated insulin-producing cells were able to ameliorate STZ-induced diabetes. This paradigm of in vivo reprogramming indicates that acinar cells hold promise as a source for new islet cells in regenerative therapies for diabetes. PMID:27526291

  12. Transgenic Expression of a Single Transcription Factor Pdx1 Induces Transdifferentiation of Pancreatic Acinar Cells to Endocrine Cells in Adult Mice

    Science.gov (United States)

    Miyazaki, Satsuki; Tashiro, Fumi; Miyazaki, Jun-ichi

    2016-01-01

    A promising approach to new diabetes therapies is to generate β cells from other differentiated pancreatic cells in vivo. Because the acinar cells represent the most abundant cell type in the pancreas, an attractive possibility is to reprogram acinar cells into β cells. The transcription factor Pdx1 (Pancreas/duodenum homeobox protein 1) is essential for pancreatic development and cell lineage determination. Our objective is to examine whether exogenous expression of Pdx1 in acinar cells of adult mice might induce reprogramming of acinar cells into β cells. We established a transgenic mouse line in which Pdx1 and EGFP (enhanced green fluorescent protein) could be inducibly expressed in the acinar cells. After induction of Pdx1, we followed the acinar cells for their expression of exocrine and endocrine markers using cell-lineage tracing with EGFP. The acinar cell-specific expression of Pdx1 in adult mice reprogrammed the acinar cells as endocrine precursor cells, which migrated into the pancreatic islets and differentiated into insulin-, somatostatin-, or PP (pancreatic polypeptide)-producing endocrine cells, but not into glucagon-producing cells. When the mice undergoing such pancreatic reprogramming were treated with streptozotocin (STZ), the newly generated insulin-producing cells were able to ameliorate STZ-induced diabetes. This paradigm of in vivo reprogramming indicates that acinar cells hold promise as a source for new islet cells in regenerative therapies for diabetes. PMID:27526291

  13. T-bet expression by Foxp3+ T regulatory cells is not essential for their suppressive function in CNS autoimmune disease or colitis

    Directory of Open Access Journals (Sweden)

    Rhoanne C McPherson

    2015-02-01

    Full Text Available Accumulation of T regulatory (Treg cells within the central nervous system (CNS during experimental autoimmune encephalomyelitis (EAE is essential for the resolution of disease. CNS Treg cells have been shown to uniformly express the Th1-associated molecules T-bet and CXCR3. Here we report that the expression of T-bet is not required for the function of these Treg within the CNS. Using mice that lacked T-bet expression specifically within the Treg compartment, we demonstrate that there was no deficit in Treg recruitment into the CNS during EAE and no difference in the resolution of disease compared to control mice. T-bet deficiency did not impact on the in vitro suppressive capacity of Treg. Transfer of T-bet-deficient Treg was able to suppress clinical signs of either EAE, or colitis. These observations demonstrate that, although Treg can acquire characteristics associated with pathogenic Teff cells, this process is not necessarily required for their suppressive capacity and the resolution of autoimmune inflammation.

  14. Melatonin enhances interleukin-10 expression and suppresses chemotaxis to inhibit inflammation in situ and reduce the severity of experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Chen, Shyi-Jou; Huang, Shing-Hwa; Chen, Jing-Wun; Wang, Kai-Chen; Yang, Yung-Rong; Liu, Pi-Fang; Lin, Gu-Jiun; Sytwu, Huey-Kang

    2016-02-01

    Melatonin is the major product secreted by the pineal gland at night and displays multifunctional properties, including immunomodulatory functions. In this study, we investigated the therapeutic effect of melatonin in experimental autoimmune encephalomyelitis (EAE). We demonstrated that melatonin exhibits a therapeutic role by ameliorating the clinical severity and restricting the infiltration of inflammatory Th17 cells into the CNS of mice with myelin oligodendrocyte glycoprotein (MOG)-induced EAE. Furthermore, melatonin enhances splenic interleukin (IL)-10 expression in regulatory T cells by inducing IL-27 expression in the splenic DC; it also suppresses the expression of IFN-γ, IL-17, IL-6, and CCL20 in the CNS and inhibits antigen-specific T cell proliferation. However, there were no significant differences in the percentage of splenic regulatory T cells. These data provide the first evidence that the therapeutic administration of melatonin is effective in mice with EAE and modulates adaptive immunity centrally and peripherally. Thus, we suggest that melatonin could play an adjunct therapeutic role in treating human CNS autoimmune diseases such as multiple sclerosis. Melatonin merits further studies in animals and humans. PMID:26735612

  15. Dual Effects of β3 Integrin Subunit Expression on Human Pancreatic Cancer Models

    Directory of Open Access Journals (Sweden)

    S. Marchán

    2010-01-01

    Full Text Available Background: Pancreatic cancer, the fifth leading cause of adult cancer death in Western countries, lacks early detection, and displays significant dissemination ability. Accumulating evidence shows that integrin-mediated cell attachment to the extracellular matrix induces phenotypes and signaling pathways that regulate tumor cell growth and migration.

  16. CONSTRUCTION OF ACTIVE RECOMBINANT CASPASE-3 EUKARYOTIC EXPRESSION PLA SMID AND EFFECT OF r-CASPASE-3 ON APOPTOSIS OF PANCREATIC CARCINOMA CELLS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To construct active recombinant cas pa ses-3 gene(r-caspases-3)eukaryotic expression plasmid and observe the apoptos is inducing activity of r-caspase-3 in pancreatic carcinoma cells. Methods pcDNA3.1(+)/r-caspase-3 was constructed and pan creatic carcinoma cells(PC-Ⅱ)were transfected with the pcDNA3.1(+)/r-caspases -3 by liposomes(LipofectAMINE).The expression of r-Caspase-3 mRNA in pancreat ic carcinoma cells was detected by reverse transcription process of the polymera se chain reaction(RT-PCR), and the signs of apoptosis were examined in pancreat ic carcinoma cells by the methods of the DNA electrophoresis and flow cytometry analysis(FACS).Results The sequence inserted in pBlueSKM/r-Caspase-3 p lasmid was coincident with that of the r-caspases-3. The evaluation result of pcDNA3.1(+)/r-caspases-3 through enzyme cutting was correct. A 894bp strap was observed by RT-PCR after pancreatic carcinoma cells being transfected with the pcDNA3.1(+)/r-caspases-3 by liposomes. No strap was found in control groups. A characteristic DNA ladder was observed in pancreatic carcinoma cells DNA elect r ophoresis, and transparent hypodiploid karyotype peak was found by FACS. Conclusion The plasmid of pcDNA3.1(+)/r-Caspase-3 was c onstructed successfully, the expression of r-Caspase-3 mRMA in pancreatic carc inoma cells was confirmed by RT-PCR, and pcDNA3.1(+)/r-Caspase-3 can induce a poptosis in pancreatic carcinoma cells.

  17. High class I HDAC activity and expression are associated with RelA/p65 activation in pancreatic cancer in vitro and in vivo

    OpenAIRE

    A. Lehmann; Denkert, C; Budczies, J.; Buckendahl, A C; Darb-Esfahani, S; A. Noske; Müller, B M; Bahra, M.; Neuhaus, P; Dietel, M; Kristiansen, G; Weichert, W

    2009-01-01

    BACKGROUND: The strong association between aberrant HDAC activity and the occurrence of cancer has led to the development of a variety of HDAC inhibitors (HDIs), which emerge as promising new targeted anticancer therapeutics. METHODS: Due to the pivotal role of RelA/p65 in the tumorigenesis of pancreatic neoplasia we examined the expression of class I HDACs 1, 2 and 3 in a large cohort of human pancreatic carcinomas and correlated our findings with RelA/p65 expression status. Furthermore, we ...

  18. High class I HDAC activity and expression are associated with RelA/p65 activation in pancreatic cancer in vitro and in vivo

    OpenAIRE

    Neuhaus Peter; Bahra Marcus; Müller Berit; Noske Aurelia; Darb-Esfahani Silvia; Buckendahl Ann-Christin; Budczies Jan; Denkert Carsten; Lehmann Annika; Dietel Manfred; Kristiansen Glen; Weichert Wilko

    2009-01-01

    Abstract Background The strong association between aberrant HDAC activity and the occurrence of cancer has led to the development of a variety of HDAC inhibitors (HDIs), which emerge as promising new targeted anticancer therapeutics. Methods Due to the pivotal role of RelA/p65 in the tumorigenesis of pancreatic neoplasia we examined the expression of class I HDACs 1, 2 and 3 in a large cohort of human pancreatic carcinomas and correlated our findings with RelA/p65 expression status. Furthermo...

  19. VAMP-2 and cellubrevin are expressed in pancreatic beta-cells and are essential for Ca(2+)-but not for GTP gamma S-induced insulin secretion.

    Science.gov (United States)

    Regazzi, R; Wollheim, C B; Lang, J; Theler, J M; Rossetto, O; Montecucco, C; Sadoul, K; Weller, U; Palmer, M; Thorens, B

    1995-01-01

    VAMP proteins are important components of the machinery controlling docking and/or fusion of secretory vesicles with their target membrane. We investigated the expression of VAMP proteins in pancreatic beta-cells and their implication in the exocytosis of insulin. cDNA cloning revealed that VAMP-2 and cellubrevin, but not VAMP-1, are expressed in rat pancreatic islets and that their sequence is identical to that isolated from rat brain. Pancreatic beta-cells contain secretory granules that store and secrete insulin as well as synaptic-like microvesicles carrying gamma-aminobutyric acid. After subcellular fractionation on continuous sucrose gradients, VAMP-2 and cellubrevin were found to be associated with both types of secretory vesicle. The association of VAMP-2 with insulin-containing granules was confirmed by confocal microscopy of primary cultures of rat pancreatic beta-cells. Pretreatment of streptolysin-O permeabilized insulin-secreting cells with tetanus and botulinum B neurotoxins selectively cleaved VAMP-2 and cellubrevin and abolished Ca(2+)-induced insulin release (IC50 approximately 15 nM). By contrast, the pretreatment with tetanus and botulinum B neurotoxins did not prevent GTP gamma S-stimulated insulin secretion. Taken together, our results show that pancreatic beta-cells express VAMP-2 and cellubrevin and that one or both of these proteins selectively control Ca(2+)-mediated insulin secretion. Images PMID:7796801

  20. Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma.

    Science.gov (United States)

    Kokkinakis, Demetrius M; Liu, Xiaoyan; Neuner, Russell D

    2005-09-01

    The effect of methionine deprivation (methionine stress) on the proliferation, survival, resistance to chemotherapy, and regulation of gene and protein expression in pancreatic tumor lines is examined. Methionine stress prevents successful mitosis and promotes cell cycle arrest and accumulation of cells with multiple micronuclei with decondensed chromatin. Inhibition of mitosis correlates with CDK1 down-regulation and/or inhibition of its function by Tyr(15) phosphorylation or Thr(161) dephosphorylation. Inhibition of cell cycle progression correlates with loss of hyperphosphorylated Rb and up-regulation of p21 via p53 and/or transforming growth factor-beta (TGF-beta) activation depending on p53 status. Although methionine stress-induced toxicity is not solely dependent on p53, the gain in p21 and loss in CDK1 transcription are more enhanced in wild-type p53 tumors. Up-regulation of SMAD7, a TGF-beta signaling inhibitor, suggests that SMAD7 does not restrict the TGF-beta-mediated induction of p21, although it may prevent up-regulation of p27. cDNA oligoarray analysis indicated a pleiotropic response to methionine stress. Cell cycle and mitotic arrest is in agreement with up-regulation of NF2, ETS2, CLU, GADD45alpha, GADD45beta, and GADD45gamma and down-regulation of AURKB, TOP2A, CCNA, CCNB, PRC1, BUB1, NuSAP, IFI16, and BRCA1. Down-regulation of AREG, AGTR1, M-CSF, and EGF, IGF, and VEGF receptors and up-regulation of GNA11 and IGFBP4 signify loss of growth factor support. PIN1, FEN1, and cABL up-regulation and LMNB1, AREG, RhoB, CCNG, TYMS, F3, and MGMT down-regulation suggest that methionine stress sensitizes the tumor cells to DNA-alkylating drugs, 5-fluorouracil, and radiation. Increased sensitivity of pancreatic tumor cell lines to temozolomide is shown under methionine stress conditions and is attributed in part to diminished O(6)-methylguanine-DNA methyltransferase and possibly to inhibition of the cell cycle progression. PMID:16170025

  1. Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma.

    Science.gov (United States)

    Kokkinakis, Demetrius M; Liu, Xiaoyan; Neuner, Russell D

    2005-09-01

    The effect of methionine deprivation (methionine stress) on the proliferation, survival, resistance to chemotherapy, and regulation of gene and protein expression in pancreatic tumor lines is examined. Methionine stress prevents successful mitosis and promotes cell cycle arrest and accumulation of cells with multiple micronuclei with decondensed chromatin. Inhibition of mitosis correlates with CDK1 down-regulation and/or inhibition of its function by Tyr(15) phosphorylation or Thr(161) dephosphorylation. Inhibition of cell cycle progression correlates with loss of hyperphosphorylated Rb and up-regulation of p21 via p53 and/or transforming growth factor-beta (TGF-beta) activation depending on p53 status. Although methionine stress-induced toxicity is not solely dependent on p53, the gain in p21 and loss in CDK1 transcription are more enhanced in wild-type p53 tumors. Up-regulation of SMAD7, a TGF-beta signaling inhibitor, suggests that SMAD7 does not restrict the TGF-beta-mediated induction of p21, although it may prevent up-regulation of p27. cDNA oligoarray analysis indicated a pleiotropic response to methionine stress. Cell cycle and mitotic arrest is in agreement with up-regulation of NF2, ETS2, CLU, GADD45alpha, GADD45beta, and GADD45gamma and down-regulation of AURKB, TOP2A, CCNA, CCNB, PRC1, BUB1, NuSAP, IFI16, and BRCA1. Down-regulation of AREG, AGTR1, M-CSF, and EGF, IGF, and VEGF receptors and up-regulation of GNA11 and IGFBP4 signify loss of growth factor support. PIN1, FEN1, and cABL up-regulation and LMNB1, AREG, RhoB, CCNG, TYMS, F3, and MGMT down-regulation suggest that methionine stress sensitizes the tumor cells to DNA-alkylating drugs, 5-fluorouracil, and radiation. Increased sensitivity of pancreatic tumor cell lines to temozolomide is shown under methionine stress conditions and is attributed in part to diminished O(6)-methylguanine-DNA methyltransferase and possibly to inhibition of the cell cycle progression.

  2. Characterization of the in vitro expressed autoimmune rippling muscle disease immunogenic domain of human titin encoded by TTN exons 248-249

    International Nuclear Information System (INIS)

    Highlights: → Affinity purification of the autoimmune rippling muscle disease immunogenic domain of titin. → Partial sequence analysis confirms that the peptides is in the I band region of titin. → This region of the human titin shows high degree of homology to mouse titin N2-A. -- Abstract: Autoimmune rippling muscle disease (ARMD) is an autoimmune neuromuscular disease associated with myasthenia gravis (MG). Past studies in our laboratory recognized a very high molecular weight skeletal muscle protein antigen identified by ARMD patient antisera as the titin isoform. These past studies used antisera from ARMD and MG patients as probes to screen a human skeletal muscle cDNA library and several pBluescript clones revealed supporting expression of immunoreactive peptides. This study characterizes the products of subcloning the titin immunoreactive domain into pGEX-3X and the subsequent fusion protein. Sequence analysis of the fusion gene indicates the cloned titin domain (GenBank ID: (EU428784)) is in frame and is derived from a sequence of N2-A spanning the exons 248-250 an area that encodes the fibronectin III domain. PCR and EcoR1 restriction mapping studies have demonstrated that the inserted cDNA is of a size that is predicted by bioinformatics analysis of the subclone. Expression of the fusion protein result in the isolation of a polypeptide of 52 kDa consistent with the predicted inferred amino acid sequence. Immunoblot experiments of the fusion protein, using rippling muscle/myasthenia gravis antisera, demonstrate that only the titin domain is immunoreactive.

  3. Characterization of the in vitro expressed autoimmune rippling muscle disease immunogenic domain of human titin encoded by TTN exons 248-249

    Energy Technology Data Exchange (ETDEWEB)

    Zelinka, L. [Biomedical Sciences Program, Kent State University, Kent, OH (United States); McCann, S.; Budde, J.; Sethi, S.; Guidos, M.; Giles, R. [Center for Applied Chemical Biology, Department of Biological Sciences, Youngstown State University, One University Plaza, Youngstown, OH 44555 (United States); Walker, G.R., E-mail: grwalker@ysu.edu [Center for Applied Chemical Biology, Department of Biological Sciences, Youngstown State University, One University Plaza, Youngstown, OH 44555 (United States); Biomedical Sciences Program, Kent State University, Kent, OH (United States)

    2011-08-05

    Highlights: {yields} Affinity purification of the autoimmune rippling muscle disease immunogenic domain of titin. {yields} Partial sequence analysis confirms that the peptides is in the I band region of titin. {yields} This region of the human titin shows high degree of homology to mouse titin N2-A. -- Abstract: Autoimmune rippling muscle disease (ARMD) is an autoimmune neuromuscular disease associated with myasthenia gravis (MG). Past studies in our laboratory recognized a very high molecular weight skeletal muscle protein antigen identified by ARMD patient antisera as the titin isoform. These past studies used antisera from ARMD and MG patients as probes to screen a human skeletal muscle cDNA library and several pBluescript clones revealed supporting expression of immunoreactive peptides. This study characterizes the products of subcloning the titin immunoreactive domain into pGEX-3X and the subsequent fusion protein. Sequence analysis of the fusion gene indicates the cloned titin domain (GenBank ID: (EU428784)) is in frame and is derived from a sequence of N2-A spanning the exons 248-250 an area that encodes the fibronectin III domain. PCR and EcoR1 restriction mapping studies have demonstrated that the inserted cDNA is of a size that is predicted by bioinformatics analysis of the subclone. Expression of the fusion protein result in the isolation of a polypeptide of 52 kDa consistent with the predicted inferred amino acid sequence. Immunoblot experiments of the fusion protein, using rippling muscle/myasthenia gravis antisera, demonstrate that only the titin domain is immunoreactive.

  4. Autoimmune Encephalitis

    OpenAIRE

    Leypoldt, Frank; Wandinger, Klaus-Peter; Bien, Christian G; Dalmau, Josep

    2013-01-01

    The term autoimmune encephalitis is used to describe a group of disorders characterised by symptoms of limbic and extra-limbic dysfunction occurring in association with antibodies against synaptic antigens and proteins localised on the neuronal cell surface. In recent years there has been a rapidly expanding knowledge of these syndromes resulting in a shift in clinical paradigms and new insights into pathogenic mechanisms. Since many patients respond well to immunosuppressive treatment, the r...

  5. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator.

    Science.gov (United States)

    Zhu, Meng-Lei; Bakhru, Pearl; Conley, Bridget; Nelson, Jennifer S; Free, Meghan; Martin, Aaron; Starmer, Joshua; Wilson, Elizabeth M; Su, Maureen A

    2016-01-01

    Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well understood. Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared with females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity. PMID:27072778

  6. miR-21 expression and clinical outcome in locally advanced pancreatic cancer: exploratory analysis of the pancreatic cancer Erbitux, radiotherapy and UFT (PERU) trial

    Science.gov (United States)

    Khan, Khurum; Cunningham, David; Peckitt, Clare; Barton, Sarah; Tait, Diana; Hawkins, Maria; Watkins, David; Starling, Naureen; Rao, Sheela; Begum, Ruwaida; Thomas, Janet; Oates, Jacqui; Guzzardo, Vincenza; Fassan, Matteo; Braconi, Chiara; Chau, Ian

    2016-01-01

    Background Locally advanced pancreatic cancer (LAPC) is associated with high mortality, and biomarker-driven treatment approach is currently lacking. This study evaluated safety and efficacy of a combination approach of chemotherapy followed by chemo-radiotherapy (CRT) +/− cetuximab, and the prognostic role of miR-21 in patients with LAPC treated with a multimodality approach. Patients and Methods This was a randomised phase II trial in which patients with inoperable LAPC were offered gemcitabine and capecitabine (GEM-CAP) for 16 weeks. Patients with stable disease or response after GEM-CAP were randomised to capecitabine or UFT plus radiotherapy (RT) (A), or capecitabine or UFT plus cetuximab plus RT (B). The primary outcome of the study was overall survival (OS). Clinical outcome was compared according to baseline circulating miR-21 levels. Results 17 patients were enrolled and treated with GEM-CAP, with 13 patients achieving disease control and being randomised to arms A (n:7) and B (n:6). After a median follow-up of 61.2 months, median progression free survival (PFS) was 10.4 months and 12.7 months, median OS was 15.8 months and 22.0 months in arms A and B respectively (p > 0.05). Patients with high baseline plasma miR-21 had worse PFS (3.5 vs. 12.7 months; p:0.032) and OS (5.1 vs 15.3 months; p:0.5) compared to patients with low miR-21. Circulating miR-21 levels reflected miR-21 expression within the tissues. Conclusions Addition of Cetuximab to CRT following induction chemotherapy did not improve survival. High miR-21 baseline plasma expression was associated with poor clinical outcome in LAPC patients treated with induction chemotherapy followed by chemo-radiotherapy. PMID:26862857

  7. Time-Qualified Patterns of Variation of PPARγ, DNMT1, and DNMT3B Expression in Pancreatic Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Valerio Pazienza

    2012-01-01

    Full Text Available Carcinogenesis is related to the loss of homeostatic control of cellular processes regulated by transcriptional circuits and epigenetic mechanisms. Among these, the activities of peroxisome proliferator-activated receptors (PPARs and DNA methyltransferases (DNMTs are crucial and intertwined. PPARγ is a key regulator of cell fate, linking nutrient sensing to transcription processes, and its expression oscillates with circadian rhythmicity. Aim of our study was to assess the periodicity of PPARγ and DNMTs in pancreatic cancer (PC. We investigated the time-related patterns of PPARG, DNMT1, and DNMT3B expression monitoring their mRNA levels by qRT-PCR at different time points over a 28-hour span in BxPC-3, CFPAC-1, PANC-1, and MIAPaCa-2 PC cells after synchronization with serum shock. PPARG and DNMT1 expression in PANC-1 cells and PPARG expression in MIAPaCa-2 cells were characterized by a 24 h period oscillation, and a borderline significant rhythm was observed for the PPARG, DNMT1, and DNMT3B expression profiles in the other cell lines. The time-qualified profiles of gene expression showed different shapes and phase relationships in the PC cell lines examined. In conclusion, PPARG and DNMTs expression is characterized by different time-qualified patterns in cell lines derived from human PC, and this heterogeneity could influence cell phenotype and human disease behaviour.

  8. INHIBITION OF ACTIVATED K-RAS GENE BY SIRNA EXPRESSION CASSETTES IN HUMAN PANCREATIC CARCINOMA CELL LINE MIAPACA-2

    Institute of Scientific and Technical Information of China (English)

    WANG Wei; WANG Chun-you; DONG Ji-hua; CHEN Xiong; ZHANG Min; ZHAO Gang

    2005-01-01

    Objective: To construct the small interfering RNA(siRNA) expression cassettes (SECs) targeting activated K-ras gene sequence and investigate the effects of SECs on K-ras gene in human pancreatic cancer cell line MIAPaCa-2. Methods: Three different sites of SECs were constructed by PCR. The K1/siRNA, K2/siRNA and K3/siRNA were located at the site 194, 491 and 327, respectively. They were transfected into MiaPaCa-2 cells by liposome to inhibit the expression of activated K-ras. In the interfering groups of site 194,491, we observed the cytopathic effect of confluent MiaPaCa-2 cells after they were incubated for 48 hours, and detected the apoptosis in cells by FACS, then we tested the alternation of K-ras gene in confluent MiaPaCa-2 cells by RT-PCR,immunofluorescence and western blot, respectively. Results: Introductions of the K1/siRNA and K2/siRNA against K-ras into MiaPaCa-2 cells led to cytopathic effect, slower proliferation and increased apoptosis, while the appearances of control MiaPaCa-2 cells remained well. The number of apoptotic cells increased compared with control cells. RT-PCR,immunofluorescence and western blot showed the effects of inhibited expression of activated K-ras gene by RNA interference in the K1/siRNA and K2/siRNA groups. We also found that the introduction of K3/siRNA had no effect on MiaPaCa-2 cells. Conclusion: K1/siRNA and K2/siRNA can inhibit the expression of activated K-ras and decrease the growth of MiaPaCa-2 cells, while K3/siRNA has no such effect, demonstrating that the suppression of tumor growth by siRNA is sequence-specific. We conclude that K-ras is involved in maintenance of tumor growth of human pancreatic cancer, and SECs against K-ras expression may be a powerful tool to be used therapeutically against human pancreatic cancer.

  9. Is Zinc Concentration in Pancreatic Fluid a Marker for Pancreatic Diseases?

    OpenAIRE

    Surakit Pungpapong; James S Scolapio; Timothy A. Woodward; Wallace, Michael B.; Massimo Raimondo

    2005-01-01

    Objectives An imbalance of free radicals and scavenging processes has been implicated in the pathogenesis of pancreatic tissue injury. Gradual decreases in antioxidant enzyme expression in pancreatic cells from normal pancreas to chronic pancreatitis to pancreatic cancer have been reported. Zinc is one of the components of antioxidant enzymes and may play a role in the pathogenesis of pancreatic diseases. A recent report showed a significant decrease in pancreatic zinc output in patients with...

  10. Flow Cytometric Detection of p38 MAPK Phosphorylation and Intracellular Cytokine Expression in Peripheral Blood Subpopulations from Patients with Autoimmune Rheumatic Diseases

    Directory of Open Access Journals (Sweden)

    Athanasios Mavropoulos

    2014-01-01

    Full Text Available Flow cytometric analysis of p38 mitogen-activated protein kinase (p38 MAPK signaling cascade is optimally achieved by methanol permeabilization protocols. Such protocols suffer from the difficulties to accurately detect intracellular cytokines and surface epitopes of infrequent cell subpopulations, which are removed by methanol. To overcome these limitations, we have modified methanol-based phosphoflow protocols using several commercially available antibody clones suitable for surface antigens, intracellular cytokines, and p38 MAPK. These included markers of B cells (CD19, CD20, and CD22, T cells (CD3, CD4, and CD8, NK (CD56 and CD7, and dendritic cells (CD11c. We have also tested surface markers of costimulatory molecules, such as CD27. We have successfully determined simultaneous expression of IFN-γ, as well as IL-10, and phosphorylated p38 in cell subsets. The optimized phosphoflow protocol has also been successfully applied in peripheral blood mononuclear cells or purified cell subpopulations from patients with various autoimmune diseases. In conclusion, our refined phosphoflow cytometric approach allows simultaneous detection of p38 MAPK activity and intracellular cytokine expression and could be used as an important tool to study signaling cascades in autoimmunity.

  11. Cytokine production in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis: dynamics of mRNA expression for interleukin-10, interleukin-12, cytolysin, tumor necrosis factor alpha and tumor necrosis factor beta

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Ljungdahl, A; Höjeberg, B;

    1995-01-01

    The kinetics of mRNA expression in the central nervous system (CNS) for a series of putatively disease-promoting and disease-limiting cytokines during the course of experimental autoimmune encephalomyelitis (EAE) in Lewis rats were studied. Cytokine mRNA-expressing cells were detected...

  12. Glucose-induced repression of PPARalpha gene expression in pancreatic beta-cells involves PP2A activation and AMPK inactivation

    DEFF Research Database (Denmark)

    Ravnskjaer, Kim; Boergesen, Michael; Dalgaard, Louise T;

    2006-01-01

    Tight regulation of fatty acid metabolism in pancreatic beta-cells is important for beta-cell viability and function. Chronic exposure to elevated concentrations of fatty acid is associated with beta-cell lipotoxicity. Glucose is known to repress fatty acid oxidation and hence to augment the toxi......Tight regulation of fatty acid metabolism in pancreatic beta-cells is important for beta-cell viability and function. Chronic exposure to elevated concentrations of fatty acid is associated with beta-cell lipotoxicity. Glucose is known to repress fatty acid oxidation and hence to augment...... but not AMPKalpha1 using RNAi suppressed PPARalpha expression, thereby mimicking the effect of glucose. These results indicate that activation of protein phosphatase 2A and subsequent inactivation of AMPK is necessary for glucose repression of PPARalpha expression in pancreatic beta-cells....

  13. Autoimmune diabetes is suppressed by treatment with recombinant human tissue Kallikrein-1.

    Science.gov (United States)

    Maneva-Radicheva, Lilia; Amatya, Christina; Parker, Camille; Ellefson, Jacob; Radichev, Ilian; Raghavan, Arvind; Charles, Matthew L; Williams, Mark S; Robbins, Mark S; Savinov, Alexei Y

    2014-01-01

    The kallikrein-kinin system (KKS) comprises a cascade of proteolytic enzymes and biogenic peptides that regulate several physiological processes. Over-expression of tissue kallikrein-1 and modulation of the KKS shows beneficial effects on insulin sensitivity and other parameters relevant to type 2 diabetes mellitus. However, much less is known about the role of kallikreins, in particular tissue kallikrein-1, in type 1 diabetes mellitus (T1D). We report that chronic administration of recombinant human tissue kallikrein-1 protein (DM199) to non-obese diabetic mice delayed the onset of T1D, attenuated the degree of insulitis, and improved pancreatic beta cell mass in a dose- and treatment frequency-dependent manner. Suppression of the autoimmune reaction against pancreatic beta cells was evidenced by a reduction in the relative numbers of infiltrating cytotoxic lymphocytes and an increase in the relative numbers of regulatory T cells in the pancreas and pancreatic lymph nodes. These effects may be due in part to a DM199 treatment-dependent increase in active TGF-beta1. Treatment with DM199 also resulted in elevated C-peptide levels, elevated glucagon like peptide-1 levels and a reduction in dipeptidyl peptidase-4 activity. Overall, the data suggest that DM199 may have a beneficial effect on T1D by attenuating the autoimmune reaction and improving beta cell health. PMID:25259810

  14. Autoimmune diabetes is suppressed by treatment with recombinant human tissue Kallikrein-1.

    Directory of Open Access Journals (Sweden)

    Lilia Maneva-Radicheva

    Full Text Available The kallikrein-kinin system (KKS comprises a cascade of proteolytic enzymes and biogenic peptides that regulate several physiological processes. Over-expression of tissue kallikrein-1 and modulation of the KKS shows beneficial effects on insulin sensitivity and other parameters relevant to type 2 diabetes mellitus. However, much less is known about the role of kallikreins, in particular tissue kallikrein-1, in type 1 diabetes mellitus (T1D. We report that chronic administration of recombinant human tissue kallikrein-1 protein (DM199 to non-obese diabetic mice delayed the onset of T1D, attenuated the degree of insulitis, and improved pancreatic beta cell mass in a dose- and treatment frequency-dependent manner. Suppression of the autoimmune reaction against pancreatic beta cells was evidenced by a reduction in the relative numbers of infiltrating cytotoxic lymphocytes and an increase in the relative numbers of regulatory T cells in the pancreas and pancreatic lymph nodes. These effects may be due in part to a DM199 treatment-dependent increase in active TGF-beta1. Treatment with DM199 also resulted in elevated C-peptide levels, elevated glucagon like peptide-1 levels and a reduction in dipeptidyl peptidase-4 activity. Overall, the data suggest that DM199 may have a beneficial effect on T1D by attenuating the autoimmune reaction and improving beta cell health.

  15. Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma.

    Science.gov (United States)

    Glenn, S T; Jones, C A; Sexton, S; LeVea, C M; Caraker, S M; Hajduczok, G; Gross, K W

    2014-12-11

    Efforts to model human pancreatic neuroendocrine tumors (PanNETs) in animals have been moderately successful, with minimal evidence for glucagonomas or metastatic spread. The renin gene, although classically associated with expression in the kidney, is also expressed in many other extrarenal tissues including the pancreas. To induce tumorigenesis within rennin-specific tissues, floxed alleles of p53 and Rb were selectively abrogated using Cre-recombinase driven by the renin promoter. The primary neoplasm generated is a highly metastatic islet cell carcinoma of the pancreas. Lineage tracing identifies descendants of renin-expressing cells as pancreatic alpha cells despite a lack of active renin expression in the mature pancreas. Both primary and metastatic tumors express high levels of glucagon; furthermore, an increased level of glucagon is found in the serum, identifying the pancreatic cancer as a functional glucagonoma. This new model is highly penetrant and exhibits robust frequency of metastases to the lymph nodes and the liver, mimicking human disease, and provides a useful platform for better understanding pancreatic endocrine differentiation and development, as well as islet cell carcinogenesis. The use of fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides an unique opportunity to dissect the timeline of disease, examining mechanisms of the metastatic process, as well as recovering primary and metastatic cells for identifying cooperating mutations that are necessary for progression of disease.

  16. Connexins protect mouse pancreatic β cells against apoptosis.

    Science.gov (United States)

    Klee, Philippe; Allagnat, Florent; Pontes, Helena; Cederroth, Manon; Charollais, Anne; Caille, Dorothée; Britan, Aurore; Haefliger, Jacques-Antoine; Meda, Paolo

    2011-12-01

    Type 1 diabetes develops when most insulin-producing β cells of the pancreas are killed by an autoimmune attack. The in vivo conditions modulating the sensitivity and resistance of β cells to this attack remain largely obscure. Here, we show that connexin 36 (Cx36), a trans-membrane protein that forms gap junctions between β cells in the pancreatic islets, protects mouse β cells against both cytotoxic drugs and cytokines that prevail in the islet environment at the onset of type 1 diabetes. We documented that this protection was at least partially dependent on intercellular communication, which Cx36 and other types of connexin channels establish within pancreatic islets. We further found that proinflammatory cytokines decreased expression of Cx36 and that experimental reduction or augmentation of Cx36 levels increased or decreased β cell apoptosis, respectively. Thus, we conclude that Cx36 is central to β cell protection from toxic insults. PMID:22056383

  17. Prospective Evaluation of Procalcitonin, Soluble Triggering Receptor Expressed on Myeloid Cells-1 and C-Reactive Protein in Febrile Patients with Autoimmune Diseases

    Science.gov (United States)

    Lin, Chou-Han; Hsieh, Song-Chou; Keng, Li-Ta; Lee, Ho-Sheng; Chang, Hou-Tai; Liao, Wei-Yu; Ho, Chao-Chi; Yu, Chong-Jen

    2016-01-01

    Background Both procalcitonin (PCT) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have been investigated separately as indicators of infection in patients with autoimmune diseases. Our study simultaneously evaluated both PCT and sTREM-1 along with C-reactive protein (CRP) in febrile patients with autoimmune diseases. Methods Fifty-nine patients were enrolled in the study. The patients were categorized into the infection group (n = 24) or the disease flare group (n = 35). sTREM-1, PCT and CRP concentrations at fever onset were compared between the two groups of patients. Results sTREM-1 and CRP did not differ between the two groups. PCT [median (range), ng/ml] was higher in the infection group than in the disease flare group [0.53 (0.02–12.85) vs. 0.12 (0.02–19.23), p = 0.001]. The area under the receiver-operating characteristic (ROC) for diagnosis of infection was 0.75 for PCT (p = 0.001), 0.63 for CRP (p = 0.09) and 0.52 for sTREM-1 (p = 0.79). Using 0.2 ng/ml as the cutoff value for PCT, sensitivity was 0.75 and specificity was 0.77. Negative predictive values for PCT were 92%, 87% and 82% for a prevalence of infection of 20%, 30%, and 40%, respectively. Neither immunosuppressants nor biomodulators affected the level of the three biomarkers. However, in patients treated with corticosteroids, the levels of sTREM-1 and CRP were significantly decreased compared with the untreated patients. Conclusions Setting PCT at a lower cutoff value could provide useful information on excluding infection in febrile patients with autoimmune diseases. The possible effect of corticosteroids on the level of sTREM-1 as an infection marker deserves further study. PMID:27096761

  18. Pancreatic Cancer

    Science.gov (United States)

    ... hormones that help control blood sugar levels. Pancreatic cancer usually begins in the cells that produce the juices. Some risk factors for developing pancreatic cancer include Smoking Long-term diabetes Chronic pancreatitis Certain ...

  19. Autoimmune Epilepsy

    Science.gov (United States)

    Quek, Amy M. L.; Britton, Jeffrey W.; McKeon, Andrew; So, Elson; Lennon, Vanda A.; Shin, Cheolsu; Klein, Christopher J.; Watson, Robert E.; Kotsenas, Amy L.; Lagerlund, Terrence D.; Cascino, Gregory D.; Worrell, Gregory A.; Wirrell, Elaine C.; Nickels, Katherine C.; Aksamit, Allen J.; Noe, Katherine H.; Pittock, Sean J.

    2013-01-01

    Objective To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy. Design Observational, retrospective case series. Setting Mayo Clinic Health System. Patients Thirty-two patients with an exclusive (n=11) or predominant (n = 21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more anti-epileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response-mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each. Intervention Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclo-phosphamide. Main Outcome Measure Seizure frequency. Results After a median interval of 17 months (range, 3–72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody–positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody–positive patient was seizure free after

  20. [Autoimmune epilepsy].

    Science.gov (United States)

    Seeck, M; Zacharia, A; Rossetti, A O

    2010-05-01

    There is increasing recognition of an autoimmune origin of pharmacoresistant epileptic disorders. Besides the paraneoplastic limbic encephalopathies (LE), reports of syndromes of non-paraneoplastic LE are increasingly reported in the last 5-10 years. Three antibodies are now relatively well described: Voltage-gated potassium channels (VGKC), glutamic acid decarboxylase (GAD) and N-methyl-D-aspartate receptor-(NMDA) antibodies. We review clinical syndromes, associated imaging and laboratory findings. While most reports arise from adult populations, children and adolescents are also concerned as evidenced by increasing observations. Early recognition is mandatory, since early immunomodulatory treatment appears to be related to significantly better outcome. PMID:20499581

  1. Acute pancreatitis

    OpenAIRE

    Bo-Guang Fan; Åke Andrén-Sandberg

    2010-01-01

    Background : Acute pancreatitis continues to be a serious illness, and the patients with acute pancreatitis are at risk to develop different complications from ongoing pancreatic inflammation. Aims : The present review is to highlight the classification, treatment and prognosis of acute pancreatitis. Material & Methods : We reviewed the English-language literature (Medline) addressing pancreatitis. Results : Acute pancreatitis is frequently caused by gallstone disease or excess alcohol ingest...

  2. Acute pancreatitis

    OpenAIRE

    Bo-Guang Fan; Åke Andrén-Sandberg

    2010-01-01

    Background: Acute pancreatitis continues to be a serious illness, and the patients with acute pancreatitis are at risk to develop different complications from ongoing pancreatic inflammation. Aims: The present review is to highlight the classification, treatment and prognosis of acute pancreatitis. Material & Methods: We reviewed the English-language literature (Medline) addressing pancreatitis. Results: Acute pancreatitis is frequently caused by gallstone disease or excess alcohol ingestion....

  3. Involvement of M3 Cholinergic Receptor Signal Transduction Pathway in Regulation of the Expression of Chemokine MOB-1, MCP-1 Genes in Pancreatic Acinar Cells

    Institute of Scientific and Technical Information of China (English)

    郑海; 陈道达; 张景輝; 田原

    2004-01-01

    Whether M3 cholinergic receptor signal transduction pathway is involved in regulation of the activation of NF-κB and the expression of chemokine MOB-1, MCP-1genes in pancreatic acinar cells was investigated. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, atropine and PDTC in vitro. The MOB-1 and MCP-1 mRNA expression was detected by using RT-PCR. The activation of NF-κB was monitored by using electrophoretic mobility shift assay.The results showed that as compared with control group, M3 cholinergic receptor agonist (103mol/L, 104-4ol/L carbachol) could induce a concentration-dependent and time-dependent increase in the expression of MOB-1, MCP-1 mRNA in pancreatic acinar cells. After treatment with 10 -3mol/L carbachol for 2 h, the expression of MOB-1, MCP-1 mRNA was strongest. The activity of NF-κB in pancreatic acinar cells was significantly increased (P<0.01) after treated with M3 cholinergic receptor agonist (10-3 mol/L carbachol) in vitro for 30 min. Either M3 cholinergic receptor antagonist (10-5 mol/L atropine) or NF-κB inhibitor (10-2 mol/L PDTC) could obviously inhibit the activation of NF-κB and the chemokine MOB-1, MCP-1 mRNA expression induced by carbachol (P <0.05). This inhibitory effect was significantly increased by atropine plus PDTC (P<0.01). The results of these studies indicated that M3 cholinergic receptor signal transduction pathway was likely involved in regulation of the expression of chemokine MOB-1 and MCP-1genes in pancreatic acinar cells in vitro through the activation of NF-κB.

  4. Influence of type-I Interferon receptor expression level on the response to type-I Interferons in human pancreatic cancer cells.

    Science.gov (United States)

    Booy, Stephanie; van Eijck, Casper H J; Dogan, Fadime; van Koetsveld, Peter M; Hofland, Leo J

    2014-03-01

    Pancreatic cancer is a highly aggressive malignancy with limited treatment options. Type-I interferons (e.g. IFN-α/-β) have several anti-tumour activities. Over the past few years, clinical studies evaluating the effect of adjuvant IFN-α therapy in pancreatic cancer yielded equivocal results. Although IFN-α and -β act via the type-I IFN receptor, the role of the number of receptors present on tumour cells is still unknown. Therefore, this study associated, for the first time, in a large panel of pancreatic cancer cell lines the effects of IFN-α/-β with the expression of type-I IFN receptors. The anti-tumour effects of IFN-α or IFN-β on cell proliferation and apoptosis were evaluated in 11 human pancreatic cell lines. Type-I IFN receptor expression was determined on both the mRNA and protein level. After 7 days of incubation, IFN-α significantly reduced cell growth in eight cell lines by 5-67%. IFN-β inhibited cell growth statistically significant in all cell lines by 43-100%. After 3 days of treatment, IFN-β induced significantly more apoptosis than IFN-α. The cell lines variably expressed the type-I IFN receptor. The maximal inhibitory effect of IFN-α was positively correlated with the IFNAR-1 mRNA (P interferon receptor expression and seems, therefore, more promising than IFN-α.

  5. Pancreatic metastasis from mycosis fungoides mimicking primary pancreatic tumor.

    Science.gov (United States)

    Ceriolo, Paola; Fausti, Valentina; Cinotti, Elisa; Bonadio, Silvia; Raffaghello, Lizzia; Bianchi, Giovanna; Orcioni, Giulio Fraternali; Fiocca, Roberto; Rongioletti, Franco; Pistoia, Vito; Borgonovo, Giacomo

    2016-03-28

    Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that can undergo local progression with possible systemic dissemination. We report a case of a patient affected by MF with a pancreatic mass that was a diagnostic challenge between primitive tumor and pancreatic metastasis from MF. Clinical setting findings and imaging studies raised the suspicion of a pancreatic primary neoplasm. A diagnostic clue was provided by the combined histomorphologic/immunohistochemical study of pancreatic and cutaneous biopsies, which revealed a pancreatic localization of MF. Considering the rarity of metastatic localization of MF to the pancreas, we next investigated whether chemokine-chemokine receptor interactions could be involved in the phenomenon to provide new insight into the possible mechanisms underlying metastatic localization of MF to the pancreas. Histological analyses of archival pancreatic tissue demonstrated that glucagon-secreting cells of the pancreatic islets expressed the CCL27 chemokine, which may have attracted in our case metastatic MF cells expressing the complementary receptor CCR10.

  6. Acute Pancreatitis and Pregnancy

    Science.gov (United States)

    ... Acute Pancreatitis > Acute Pancreatitis and Pregnancy test Acute Pancreatitis and Pregnancy Timothy Gardner, MD Acute pancreatitis is ... of acute pancreatitis in pregnancy. Reasons for Acute Pancreatitis and Pregnancy While acute pancreatitis is responsible for ...

  7. Analysis of a cDNA clone expressing a human autoimmune antigen: full-length sequence of the U2 small nuclear RNA-associated B antigen

    International Nuclear Information System (INIS)

    A U2 small nuclear RNA-associated protein, designated B'', was recently identified as the target antigen for autoimmune sera from certain patients with systemic lupus erythematosus and other rheumatic diseases. Such antibodies enabled them to isolate cDNA clone λHB''-1 from a phage λgt11 expression library. This clone appeared to code for the B'' protein as established by in vitro translation of hybrid-selected mRNA. The identity of clone λHB''-1 was further confirmed by partial peptide mapping and analysis of the reactivity of the recombinant antigen with monospecific and monoclonal antibodies. Analysis of the nucleotide sequence of the 1015-base-pair cDNA insert of clone λHB''-1 revealed a large open reading frame of 800 nucleotides containing the coding sequence for a polypeptide of 25,457 daltons. In vitro transcription of the λHB''-1 cDNA insert and subsequent translation resulted in a protein product with the molecular size of the B'' protein. These data demonstrate that clone λHB''-1 contains the complete coding sequence of this antigen. The deduced polypeptide sequence contains three very hydrophilic regions that might constitute RNA binding sites and/or antigenic determinants. These findings might have implications both for the understanding of the pathogenesis of rheumatic diseases as well as for the elucidation of the biological function of autoimmune antigens

  8. Update in Endocrine Autoimmunity

    OpenAIRE

    Anderson, Mark S.

    2008-01-01

    Context: The endocrine system is a common target in pathogenic autoimmune responses, and there has been recent progress in our understanding, diagnosis, and treatment of autoimmune endocrine diseases.

  9. Metabolic alterations and increased liver mTOR expression precede the development of autoimmune disease in a murine model of lupus erythematosus.

    Directory of Open Access Journals (Sweden)

    Laia Vilà

    Full Text Available Although metabolic syndrome (MS and systemic lupus erythematosus (SLE are often associated, a common link has not been identified. Using the BWF1 mouse, which develops MS and SLE, we sought a molecular connection to explain the prevalence of these two diseases in the same individuals. We determined SLE- markers (plasma anti-ds-DNA antibodies, splenic regulatory T cells (Tregs and cytokines, proteinuria and renal histology and MS-markers (plasma glucose, non-esterified fatty acids, triglycerides, insulin and leptin, liver triglycerides, visceral adipose tissue, liver and adipose tissue expression of 86 insulin signaling-related genes in 8-, 16-, 24-, and 36-week old BWF1 and control New-Zealand-White female mice. Up to week 16, BWF1 mice showed MS-markers (hyperleptinemia, hyperinsulinemia, fatty liver and visceral adipose tissue that disappeared at week 36, when plasma anti-dsDNA antibodies, lupus nephritis and a pro-autoimmune cytokine profile were detected. BWF1 mice had hyperleptinemia and high splenic Tregs till week 16, thereby pointing to leptin resistance, as confirmed by the lack of increased liver P-Tyr-STAT-3. Hyperinsulinemia was associated with a down-regulation of insulin related-genes only in adipose tissue, whereas expression of liver mammalian target of rapamicyn (mTOR was increased. Although leptin resistance presented early in BWF1 mice can slow-down the progression of autoimmunity, our results suggest that sustained insulin stimulation of organs, such as liver and probably kidneys, facilitates the over-expression and activity of mTOR and the development of SLE.

  10. The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1{alpha} targeted gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Miyake, Kotaro, E-mail: hif.panc@gmail.com [Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Nishioka, Masanori; Imura, Satoru; Batmunkh, Erdenebulgan [Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Uto, Yoshihiro [Department of Biological Science and Technology, Institute of Socio Technosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Nagasawa, Hideko [Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu 501-1196 (Japan); Hori, Hitoshi [Department of Biological Science and Technology, Institute of Socio Technosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Shimada, Mitsuo [Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan)

    2012-08-01

    Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1{alpha} (HIF-1{alpha}), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P < 0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P < 0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules. -- Highlights: Black-Right-Pointing-Pointer We designed and synthesized novel hypoxic cytoxin, TX-2098. Black-Right-Pointing-Pointer TX-2098 inhibited the proliferation of human pancreatic cancer cells than TPZ. Black-Right-Pointing-Pointer TX-2098 reduced VEGF protein level than TPZ. Black-Right-Pointing-Pointer TX-2098

  11. The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1α targeted gene expression

    International Nuclear Information System (INIS)

    Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1α (HIF-1α), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P < 0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P < 0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules. -- Highlights: ► We designed and synthesized novel hypoxic cytoxin, TX-2098. ► TX-2098 inhibited the proliferation of human pancreatic cancer cells than TPZ. ► TX-2098 reduced VEGF protein level than TPZ. ► TX-2098 inhibited mRNA expression of VEGF, GLUT1 and Aldolase A, not HIF-1α. ► TX-2098 improved the survival in

  12. Differentiating pancreatic lesions by Microarray and QPCR analysis of pancreatic juice RNAs

    NARCIS (Netherlands)

    C.D. Rogers; N. Fukushima; N. Sato; C. Shi; N. Prasad; S.R. Hustinx; H. Matsubayashi; M. Canto; J.R. Eshleman; R.H. Hruban; M. Goggins

    2006-01-01

    Background: The gene expression profile of pancreatic cancer is significantly different from that of normal pancreas. Differences in gene expression are detectable using microarrays, but microarrays have traditionally been applied to pancreatic cancer tissue obtained from surgical resection. We hypo

  13. High Nuclear Hypoxia-Inducible Factor 1 Alpha Expression Is a Predictor of Distant Recurrence in Patients With Resected Pancreatic Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Colbert, Lauren E. [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Fisher, Sarah B. [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia (United States); Balci, Serdar; Saka, Burcu [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Department of Pathology, Emory University, Atlanta, Georgia (United States); Chen, Zhengjia; Kim, Sungjin [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia (United States); El-Rayes, Bassel F. [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia (United States); Adsay, N. Volkan [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Department of Pathology, Emory University, Atlanta, Georgia (United States); Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia (United States); Maithel, Shishir K. [Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia (United States); Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia (United States); Landry, Jerome C. [Department of Radiation Oncology, Emory University, Atlanta, Georgia (United States); Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Biostatistics and Bioinformatics Shared Resource, Emory University, Atlanta, Georgia (United States); and others

    2015-03-01

    Purpose: To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection. Methods and Materials: Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF-1α overall expression score was defined as high percentage and intensity staining and thus score >1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. Results: Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR (P=.03), and low HIF-1α expression was significantly associated with isolated LR (P=.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P=.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR. Conclusions: High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for

  14. High Nuclear Hypoxia-Inducible Factor 1 Alpha Expression Is a Predictor of Distant Recurrence in Patients With Resected Pancreatic Adenocarcinoma

    International Nuclear Information System (INIS)

    Purpose: To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection. Methods and Materials: Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF-1α overall expression score was defined as high percentage and intensity staining and thus score >1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. Results: Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR (P=.03), and low HIF-1α expression was significantly associated with isolated LR (P=.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P=.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR. Conclusions: High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for

  15. Expressions and signification of CFTR and SPINK1 in chronic pancreatitis and chronic pancreatitis%CFTR及SPINK1蛋白在慢性胰腺炎及胰腺癌中的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    张敏; 王银萍; 倪劲松; 薛世泉; 邹亚彬; 张丽红

    2011-01-01

    目的 探讨囊性纤维化跨膜转运调节因子(cystic fibrosis transmembrane conductance regulator,CFTR)及丝氨酸蛋白酶抑制剂 Kazal 1型(Serine protease inhibitor Kazal type 1,SPINK1)在慢性胰腺炎及胰腺癌发病中的表达及其意义,为慢性胰腺炎及胰腺癌的早期诊断及预防提供实验依据,进而从基因水平上另辟新径.方法 收集吉林大学第一医院病理科及白求恩医学院病理系存档的正常胰腺组织10例,慢性胰腺炎20例,胰腺癌30例.采用免疫组织化学染色方法(SP法)分别观察了石蜡标本中CFTR及SPINK1蛋白的表达情况.结果 CFTR及SPINK1蛋白在正常胰腺组织中呈强表达,阳性表达率均为100%(10/10);在慢性胰腺炎中表达均下降,阳性表达率分别为50%(10/20)和55%(11/20),与正常胰腺组相比,具有统计学意义 (P<0.05);胰腺癌中二者的表达强度明显降低,阳性率分别为10%(3/30)和6.7%(2/30);与正常胰腺组及慢性胰腺炎组比较均具有明显差异(P<0.05).结论 CFTR及SPINK1蛋白的异常表达与慢性胰腺炎和胰腺癌的发生、发展有关,二者的表达异常可能分别或协同参与了慢性胰腺炎及胰腺癌的发病过程.%Objective  To investigate the expression and the role of cystic fibrosis transmembrane conductance regulator(CFTR ) and Serine protease inhibitor Kazal type 1( SPINK1)in chronic pancreatitis and pancreatic cancer .Provide exprerimental evidence and opened up new avenues for the prevention and treatment of pancreatitis and pancreatic cancer from gene level .Methods  Collecte paraffin specimen of normal pancreas ,chronic pancreatitis and pancreatic cancer in Department of Pathology ,First Hospital of Jilin University and Department of Anatomy ,School of Basic Medical Pathology ,Number of cases were repectively 10 cases ,20 cases ,30 cases .Observed the expression of the CFTR and SPINK 1 in paraffin protein repectively with immunochemistric staining

  16. Genetic analysis of inflammation, cytokine mRNA expression and disease course of relapsing experimental autoimmune encephalomyelitis in DA rats

    DEFF Research Database (Denmark)

    Lorentzen, J C; Andersson, M; Issazadeh-Navikas, Shohreh;

    1997-01-01

    . As a first step in this direction, we investigated the role of DA genes within and outside the major histocompatibility complex (MHC) for susceptibility to severe protracted and relapsing EAE (SPR-EAE). This form of EAE developed in DA rats but not in LEW. ACI and BN rats after immunization with syngeneic......Genetic analysis of experimental autoimmune encephalomyelitis (EAE) can provide clues to the etiology of multiple sclerosis (MS). Identifying the susceptibility genes of DA rats may be particularly rewarding since they are prone to develop a remarkably MS-like chronic and demyelinating disease...... spinal cord and complete Freund's adjuvant. Studies of crosses between DA and BN rats revealed that non-MHC genes determine susceptibility to SPR-EAE. A role for MHC-genes was also established using MHC-congenic rat strains, in which the DA MHC haplotype (av1) associated with relapsing EAE. Again, non...

  17. Expression of MUC17 is regulated by HIF1α-mediated hypoxic responses and requires a methylation-free hypoxia responsible element in pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Sho Kitamoto

    Full Text Available MUC17 is a type 1 membrane-bound glycoprotein that is mainly expressed in the digestive tract. Recent studies have demonstrated that the aberrant overexpression of MUC17 is correlated with the malignant potential of pancreatic ductal adenocarcinomas (PDACs; however, the exact regulatory mechanism of MUC17 expression has yet to be identified. Here, we provide the first report of the MUC17 regulatory mechanism under hypoxia, an essential feature of the tumor microenvironment and a driving force of cancer progression. Our data revealed that MUC17 was significantly induced by hypoxic stimulation through a hypoxia-inducible factor 1α (HIF1α-dependent pathway in some pancreatic cancer cells (e.g., AsPC1, whereas other pancreatic cancer cells (e.g., BxPC3 exhibited little response to hypoxia. Interestingly, these low-responsive cells have highly methylated CpG motifs within the hypoxia responsive element (HRE, 5'-RCGTG-3', a binding site for HIF1α. Thus, we investigated the demethylation effects of CpG at HRE on the hypoxic induction of MUC17. Treatment of low-responsive cells with 5-aza-2'-deoxycytidine followed by additional hypoxic incubation resulted in the restoration of hypoxic MUC17 induction. Furthermore, DNA methylation of HRE in pancreatic tissues from patients with PDACs showed higher hypomethylation status as compared to those from non-cancerous tissues, and hypomethylation was also correlated with MUC17 mRNA expression. Taken together, these findings suggested that the HIF1α-mediated hypoxic signal pathway contributes to MUC17 expression, and DNA methylation of HRE could be a determinant of the hypoxic inducibility of MUC17 in pancreatic cancer cells.

  18. Etiology of chronic pancreatitis: Has it changed in the last decade?

    Institute of Scientific and Technical Information of China (English)

    Raffaele Pezzilli

    2009-01-01

    The evidence from recent surveys on chronic pancreatitis carried out around the world shows that alcohol remains the main factor associated with chronic pancreatitis, even if at a frequency lower than that reported previously. It has further confirmed that heavy alcohol consumption and smoking are independent risk factors for chronic pancreatitis. Autoimmune pancreatitis accounts for 2%-4% of all forms of chronic pancreatitis, but this frequency will probably increase over the next few years. The rise in idiopathic chronic pancreatitis, especially in India, represents a black hole in recently published surveys. Despite the progress made so far regarding the possibility of establishing the hereditary forms of chronic pancreatitis and the recognition of autoimmune pancreatitis, it is possible that we are more inaccurate today than in the past in identifying the factors associated with chronic pancreatitis in our patients.

  19. [Diagnostics of autoimmune diseases].

    Science.gov (United States)

    Beleznay, Zsuzsanna; Regenass, Stephan

    2008-09-01

    Autoantibodies play a key role in diagnostic laboratories as markers of autoimmune diseases. In addition to their role as markers they mediate diverse effects in vivo. Autoantibodies with protective effect have been described. Natural protective IgM autoantibodies against tumour-antigens of malignant cells or their precursors may contribute to increased survival rates of carcinoma patients. In a mouse model of systemic lupus erythematosus it has been shown that anti-dsDNA IgM autoantibodies protect from glomerular damage. In contrast, a direct pathogenic role of autoantibodies has been well established e.g. in myasthenia gravis or in Goodpasture syndrome. Similarly autoantibodies against SSA Ro52 are detrimental in neonatal lupus erythematosus with congenital heart block. Moreover, putatively protective autoantibodies may become pathogenic during the course of the disease such as the onconeuronal autoantibodies whose pathogenicity depends on their compartmentalisation. In patients with paraneoplastic syndromes tumour cells express proteins that are also naturally present in the brain. Anti-tumour autoantibodies which temporarily suppress tumour growth can provoke an autoimmune attack on neurons once having crossed the blood-brain barrier and cause specific neurological symptoms. Only a restricted number of autoantibodies are useful follow-up markers for the effectiveness of treatment in autoimmune diseases. Certain autoantibodies hold prognostic value and appear years or even decades before the diagnosis of disease such as the antimitochondrial antibodies in primary biliary cirrhosis or anti-citrullinated protein (CCP)-antibodies in rheumatoid arthritis. It is crucial to know whether the autoantibodies in question recognise linear or conformational epitopes in order to choose the appropriate detection methods. Indirect immunofluorescence microscopy remains a very useful tool for confirmation of results of commercially available immunoassays and for detection of

  20. Acute pancreatitis

    Directory of Open Access Journals (Sweden)

    Bo-Guang Fan

    2010-01-01

    Full Text Available Background : Acute pancreatitis continues to be a serious illness, and the patients with acute pancreatitis are at risk to develop different complications from ongoing pancreatic inflammation. Aims : The present review is to highlight the classification, treatment and prognosis of acute pancreatitis. Material & Methods : We reviewed the English-language literature (Medline addressing pancreatitis. Results : Acute pancreatitis is frequently caused by gallstone disease or excess alcohol ingestion. There are a number of important issues regarding clinical highlights in the classification, treatment and prognosis of acute pancreatitis, and treatment options for complications of acute pancreatitis including pancreatic pseudocysts. Conclusions : Multidisciplinary approach should be used for the management of the patient with acute pancreatitis.

  1. Acute pancreatitis

    Directory of Open Access Journals (Sweden)

    Bo-Guang Fan

    2010-05-01

    Full Text Available Background: Acute pancreatitis continues to be a serious illness, and the patients with acute pancreatitis are at risk to develop different complications from ongoing pancreatic inflammation. Aims: The present review is to highlight the classification, treatment and prognosis of acute pancreatitis. Material & Methods: We reviewed the English-language literature (Medline addressing pancreatitis. Results: Acute pancreatitis is frequently caused by gallstone disease or excess alcohol ingestion. There are a number of important issues regarding clinical highlights in the classification, treatment and prognosis of acute pancreatitis, and treatment options for complications of acute pancreatitis including pancreatic pseudocysts. Conclusions: Multidisciplinary approach should be used for the management of the patient with acute pancreatitis.

  2. The autoimmune tautology

    OpenAIRE

    Anaya, Juan-Manuel

    2010-01-01

    Although autoimmune diseases exhibit contrasting epidemiological features, pathology, and clinical manifestations, three lines of evidence demonstrate that these diseases share similar immunogenetic mechanisms (that is, autoimmune tautology). First, clinical evidence highlights the co-occurrence of distinct autoimmune diseases within an individual (that is, polyautoimmunity) and within members of a nuclear family (that is, familial autoimmunity). Second, physiopathologic evidence indicates th...

  3. A Polyprotein-Expressing Salmonid Alphavirus Replicon Induces Modest Protection in Atlantic Salmon (Salmo Salar Against Infectious Pancreatic Necrosis

    Directory of Open Access Journals (Sweden)

    Azila Abdullah

    2015-01-01

    Full Text Available Vaccination is an important strategy for the control and prevention of infectious pancreatic necrosis (IPN in farmed Atlantic salmon (Salmo salar in the post-smolt stage in sea-water. In this study, a heterologous gene expression system, based on a replicon construct of salmonid alphavirus (SAV, was used for in vitro and in vivo expression of IPN virus proteins. The large open reading frame of segment A, encoding the polyprotein NH2-pVP2-VP4-VP3-COOH, as well as pVP2, were cloned and expressed by the SAV replicon in Chinook salmon embryo cells (CHSE-214 and epithelioma papulosum cyprini (EPC cells. The replicon constructs pSAV/polyprotein (pSAV/PP and pSAV/pVP2 were used to immunize Atlantic salmon (Salmo salar by a single intramuscular injection and tested in a subsequent IPN virus (IPNV challenge trial. A low to moderate protection against IPN was observed in fish immunized with the replicon vaccine that encoded the pSAV/PP, while the pSAV/pVP2 construct was not found to induce protection.

  4. Changes in microRNA expression contribute to pancreatic β-cell dysfunction in prediabetic NOD mice.

    Science.gov (United States)

    Roggli, Elodie; Gattesco, Sonia; Caille, Dorothée; Briet, Claire; Boitard, Christian; Meda, Paolo; Regazzi, Romano

    2012-07-01

    During the initial phases of type 1 diabetes, pancreatic islets are invaded by immune cells, exposing β-cells to proinflammatory cytokines. This unfavorable environment results in gene expression modifications leading to loss of β-cell functions. To study the contribution of microRNAs (miRNAs) in this process, we used microarray analysis to search for changes in miRNA expression in prediabetic NOD mice islets. We found that the levels of miR-29a/b/c increased in islets of NOD mice during the phases preceding diabetes manifestation and in isolated mouse and human islets exposed to proinflammatory cytokines. Overexpression of miR-29a/b/c in MIN6 and dissociated islet cells led to impairment in glucose-induced insulin secretion. Defective insulin release was associated with diminished expression of the transcription factor Onecut2, and a consequent rise of granuphilin, an inhibitor of β-cell exocytosis. Overexpression of miR-29a/b/c also promoted apoptosis by decreasing the level of the antiapoptotic protein Mcl1. Indeed, a decoy molecule selectively masking the miR-29 binding site on Mcl1 mRNA protected insulin-secreting cells from apoptosis triggered by miR-29 or cytokines. Taken together, our findings suggest that changes in the level of miR-29 family members contribute to cytokine-mediated β-cell dysfunction occurring during the initial phases of type 1 diabetes. PMID:22537941

  5. Mechanisms Regulating Acid-Base Transporter Expression in Breast- and Pancreatic Cancer

    DEFF Research Database (Denmark)

    Gorbatenko, Andrej

    Breast cancer is the most commonly diagnosed cancer in women, and the second most frequent cause of death from cancer in women. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer with only a 5% 5-year survival rate. Both types of cancer form solid tumors......, characteristics of which are a shift towards glycolytic metabolism and increased acid production. HER2 receptor overexpression in breast cancer leads to further increased glycolysis, invasion and metastasis, drug resistance and poor prognosis. Increased tumor glycolysis requires acquisition of mechanisms...... for dealing with excess acid production. In this light, evidence accumulates on the importance of pH regulatory proteins to cancer cell survival and motility. Our group previously demonstrated upregulation of the Na+/HCO3 - co-transporter NBCn1 (SLC4A7) by a constitutively active form of HER2 receptor (p95HER...

  6. Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells.

    Science.gov (United States)

    Hamano, Kunihisa; Nakagawa, Yuko; Ohtsu, Yoshiaki; Li, Longfei; Medina, Johan; Tanaka, Yuji; Masuda, Katsuyoshi; Komatsu, Mitsuhisa; Kojima, Itaru

    2015-07-01

    Glucose activates the glucose-sensing receptor T1R3 and facilitates its own metabolism in pancreatic β-cells. An inhibitor of this receptor would be helpful in elucidating the physiological function of the glucose-sensing receptor. The present study was conducted to examine whether or not lactisole can be used as an inhibitor of the glucose-sensing receptor. In MIN6 cells, in a dose-dependent manner, lactisole inhibited insulin secretion induced by sweeteners, acesulfame-K, sucralose and glycyrrhizin. The IC50 was ∼4 mmol/l. Lactisole attenuated the elevation of cytoplasmic Ca2+ concentration ([Ca2+]c) evoked by sucralose and acesulfame-K but did not affect the elevation of intracellular cAMP concentration ([cAMP]c) induced by these sweeteners. Lactisole also inhibited the action of glucose in MIN6 cells. Thus, lactisole significantly reduced elevations of intracellular [NADH] and intracellular [ATP] induced by glucose, and also inhibited glucose-induced insulin secretion. To further examine the effect of lactisole on T1R3, we prepared HEK293 cells stably expressing mouse T1R3. In these cells, sucralose elevated both [Ca2+]c and [cAMP]c. Lactisole attenuated the sucralose-induced increase in [Ca2+]c but did not affect the elevation of [cAMP]c. Finally, lactisole inhibited insulin secretion induced by a high concentration of glucose in mouse islets. These results indicate that the mouse glucose-sensing receptor was inhibited by lactisole. Lactisole may be useful in assessing the role of the glucose-sensing receptor in mouse pancreatic β-cells. PMID:25994004

  7. MicroRNA Expression in a Readily Accessible Common Hepatic Artery Lymph Node Predicts Time to Pancreatic Cancer Recurrence Postresection.

    Science.gov (United States)

    Nguyen, Hai V; Gore, Jesse; Zhong, Xin; Savant, Sudha S; Deitz-McElyea, Samantha; Schmidt, C Max; House, Michael G; Korc, Murray

    2016-10-01

    Lymph node involvement in pancreatic adenocarcinoma (PAC) predicts postresection survival, but early lymph node metastasis detection is not easily accomplished. We assessed a panel of microRNAs (miRNAs) in a common hepatic artery lymph node (station 8) that is readily accessible during pancreatoduodenectomy (PD) to determine if increased miRNA levels correlate with postresection recurrence. Station 8 lymph nodes overlying the common hepatic artery collected during PD were assayed for miRNA-10b, miRNA-30c, miRNA-21, and miRNA-155 and cytokeratin-19 (CK19), an epithelial cell marker, using quantitative PCR. Expression was correlated with disease recurrence, recurrence-free survival (RFS), and overall survival (OS). Station 8 lymph nodes from 37 patients (30 periampullary carcinomas (PCs), 2 chronic pancreatitis, 5 other cancers) exhibited increased miRNA-10b levels in 14/30 PCs, and in 10 of these 14 patients, cancer recurred during the study period (2012-2015). High miRNA-10b was also associated with shorter RFS (42.5 vs. 92.4 weeks, p < 0.05) but not OS, whereas miRNA-30c, miRNA-21, and miRNA-155 levels and CK19 mRNA levels in station 8 nodes were variable and did not correlate with RFS or OS. We conclude that elevated miRNA-10b levels in station 8 lymph nodes could be utilized to assess risk for early disease progression in patients with periampullary tumors.

  8. Loss of Periostin Results in Impaired Regeneration and Pancreatic Atrophy after Cerulein-Induced Pancreatitis.

    Science.gov (United States)

    Hausmann, Simone; Regel, Ivonne; Steiger, Katja; Wagner, Nadine; Thorwirth, Manja; Schlitter, Anna M; Esposito, Irene; Michalski, Christoph W; Friess, Helmut; Kleeff, Jörg; Erkan, Mert

    2016-01-01

    The extracellular matrix molecule periostin (POSTN, encoded by POSTN), which is secreted by activated pancreatic stellate cells, has important functions in chronic pancreatitis and pancreatic cancer. However, the role of POSTN in acute pancreatitis and subsequent regeneration processes has not been addressed so far. We analyzed the function of POSTN in pancreatic exocrine regeneration after the induction of a severe acute pancreatitis. Postn-deficient mice and wild-type control animals received repetitive cerulein injections, and a detailed histologic analysis of pancreatic tissues was performed. Although there was no difference in pancreatitis severity in the acute inflammatory phase, the recovery of the exocrine pancreas was massively impaired in Postn-deficient mice. Loss of Postn expression was accompanied by strong pancreatic atrophy and acinar-to-adipocyte differentiation, which was also reflected in gene expression patterns. Our data suggest that POSTN is a crucial factor for proper exocrine lineage-specific regeneration after severe acute pancreatitis.

  9. Loss of Periostin Results in Impaired Regeneration and Pancreatic Atrophy after Cerulein-Induced Pancreatitis.

    Science.gov (United States)

    Hausmann, Simone; Regel, Ivonne; Steiger, Katja; Wagner, Nadine; Thorwirth, Manja; Schlitter, Anna M; Esposito, Irene; Michalski, Christoph W; Friess, Helmut; Kleeff, Jörg; Erkan, Mert

    2016-01-01

    The extracellular matrix molecule periostin (POSTN, encoded by POSTN), which is secreted by activated pancreatic stellate cells, has important functions in chronic pancreatitis and pancreatic cancer. However, the role of POSTN in acute pancreatitis and subsequent regeneration processes has not been addressed so far. We analyzed the function of POSTN in pancreatic exocrine regeneration after the induction of a severe acute pancreatitis. Postn-deficient mice and wild-type control animals received repetitive cerulein injections, and a detailed histologic analysis of pancreatic tissues was performed. Although there was no difference in pancreatitis severity in the acute inflammatory phase, the recovery of the exocrine pancreas was massively impaired in Postn-deficient mice. Loss of Postn expression was accompanied by strong pancreatic atrophy and acinar-to-adipocyte differentiation, which was also reflected in gene expression patterns. Our data suggest that POSTN is a crucial factor for proper exocrine lineage-specific regeneration after severe acute pancreatitis. PMID:26632158

  10. Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy

    Directory of Open Access Journals (Sweden)

    Hayato Fujita

    2010-10-01

    Full Text Available BACKGROUND AND AIMS: The standard palliative chemotherapy for pancreatic ductal adenocarcinoma (PDAC is gemcitabine-based chemotherapy; however, PDAC still presents a major therapeutic challenge. The aims of this study were to investigate the expression pattern of genes involved in gemcitabine sensitivity in resected PDAC tissues and to determine correlations of gene expression with treatment outcome. MATERIALS AND METHODS: We obtained formalin-fixed paraffin-embedded (FFPE tissue samples from 70 patients with PDAC. Of the 70 patients, 40 received gemcitabine-based adjuvant chemotherapy (AC. We measured hENT1, dCK, CDA, RRM1, and RRM2 messenger RNA (mRNA levels by quantitative real-time reverse transcription-polymerase chain reaction and determined the combined score (GEM score, based on the expression levels of hENT1, dCK, RRM1, and RRM2, to investigate the association with survival time. By determining the expression levels of these genes in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA cytologic specimens, we investigated the feasibility of individualized chemotherapy. RESULTS: High dCK (P = .0067, low RRM2 (P = .003, and high GEM score (P = .0003 groups had a significantly longer disease-free survival in the gemcitabine-treated group. A low GEM score (<2 was an independent predictive marker for poor outcome to gemcitabine-based AC as shown by multivariate analysis (P = .0081. Altered expression levels of these genes were distinguishable in microdissected neoplastic cells from EUS-FNA cytologic specimens. CONCLUSIONS: Quantitative analyses of hENT1, dCK, RRM1, and RRM2 mRNA levels using FFPE tissue samples and microdissected neoplastic cells from EUS-FNA cytologic specimens may be useful in predicting the gemcitabine sensitivity of patients with PDAC.

  11. Identification of Achaete-scute complex-like 1 (ASCL1 target genes and evaluation of DKK1 and TPH1 expression in pancreatic endocrine tumours

    Directory of Open Access Journals (Sweden)

    Skogseid Britt

    2009-09-01

    Full Text Available Abstract Background ASCL1 role in pancreatic endocrine tumourigenesis has not been established. Recently it was suggested that ASCL1 negatively controls expression of the Wnt signalling antagonist DKK1. Notch signalling regulates expression of TPH1, the rate limiting enzyme in the biosyntesis of serotonin. Understanding the development and proliferation of pancreatic endocrine tumours (PETs is essential for the development of new therapies. Methods ASCL1 target genes in the pancreatic endocrine tumour cell line BON1 were identified by RNA interference and microarray expression analysis. Protein expressions of selected target genes in PETs were evaluated by immunohistochemistry. Results 158 annotated ASCL1 target genes were identified in BON1 cells, among them DKK1 and TPH1 that were negatively regulated by ASCL1. An inverse relation of ASCL1 to DKK1 protein expression was observed for 15 out of 22 tumours (68%. Nine tumours displayed low ASCL1/high DKK1 and six tumours high ASCL1/low DKK1 expression. Remaining PETs showed high ASCL1/high DKK1 (n = 4 or low ASCL1/low DKK1 (n = 3 expression. Nine of twelve analysed PETs (75% showed TPH1 expression with no relation to ASCL1. Conclusion A number of genes with potential importance for PET tumourigenesis have been identified. ASCL1 negatively regulated the Wnt signalling antagonist DKK1, and TPH1 expression in BON1 cells. In concordance with these findings DKK1 showed an inverse relation to ASCL1 expression in a subset of PETs, which may affect growth control by the Wnt signalling pathway.

  12. Analysis of a cDNA clone expressing a human autoimmune antigen: full-length sequence of the U2 small nuclear RNA-associated B antigen

    Energy Technology Data Exchange (ETDEWEB)

    Habets, W.J.; Sillekens, P.T.G.; Hoet, M.H.; Schalken, J.A.; Roebroek, A.J.M.; Leunissen, J.A.M.; Van de Ven, W.J.M.; Van Venrooij, W.J.

    1987-04-01

    A U2 small nuclear RNA-associated protein, designated B'', was recently identified as the target antigen for autoimmune sera from certain patients with systemic lupus erythematosus and other rheumatic diseases. Such antibodies enabled them to isolate cDNA clone lambdaHB''-1 from a phage lambdagt11 expression library. This clone appeared to code for the B'' protein as established by in vitro translation of hybrid-selected mRNA. The identity of clone lambdaHB''-1 was further confirmed by partial peptide mapping and analysis of the reactivity of the recombinant antigen with monospecific and monoclonal antibodies. Analysis of the nucleotide sequence of the 1015-base-pair cDNA insert of clone lambdaHB''-1 revealed a large open reading frame of 800 nucleotides containing the coding sequence for a polypeptide of 25,457 daltons. In vitro transcription of the lambdaHB''-1 cDNA insert and subsequent translation resulted in a protein product with the molecular size of the B'' protein. These data demonstrate that clone lambdaHB''-1 contains the complete coding sequence of this antigen. The deduced polypeptide sequence contains three very hydrophilic regions that might constitute RNA binding sites and/or antigenic determinants. These findings might have implications both for the understanding of the pathogenesis of rheumatic diseases as well as for the elucidation of the biological function of autoimmune antigens.

  13. pp32 (ANP32A expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs.

    Directory of Open Access Journals (Sweden)

    Timothy K Williams

    Full Text Available The expression of protein phosphatase 32 (PP32, ANP32A is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1, a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C, but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the mRNA encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK, causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR, while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy.

  14. Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes.

    Science.gov (United States)

    Bassi, Ênio J; Moraes-Vieira, Pedro M M; Moreira-Sá, Carla S R; Almeida, Danilo C; Vieira, Leonardo M; Cunha, Cláudia S; Hiyane, Meire I; Basso, Alexandre S; Pacheco-Silva, Alvaro; Câmara, Niels O S

    2012-10-01

    Adipose-derived mesenchymal stem cells (ADMSCs) display immunosuppressive properties, suggesting a promising therapeutic application in several autoimmune diseases, but their role in type 1 diabetes (T1D) remains largely unexplored. The aim of this study was to investigate the immune regulatory properties of allogeneic ADMSC therapy in T cell-mediated autoimmune diabetes in NOD mice. ADMSC treatment reversed the hyperglycemia of early-onset diabetes in 78% of diabetic NOD mice, and this effect was associated with higher serum insulin, amylin, and glucagon-like peptide 1 levels compared with untreated controls. This improved outcome was associated with downregulation of the CD4(+) Th1-biased immune response and expansion of regulatory T cells (Tregs) in the pancreatic lymph nodes. Within the pancreas, inflammatory cell infiltration and interferon-γ levels were reduced, while insulin, pancreatic duodenal homeobox-1, and active transforming growth factor-β1 expression were increased. In vitro, ADMSCs induced the expansion/proliferation of Tregs in a cell contact-dependent manner mediated by programmed death ligand 1. In summary, ADMSC therapy efficiently ameliorates autoimmune diabetes pathogenesis in diabetic NOD mice by attenuating the Th1 immune response concomitant with the expansion/proliferation of Tregs, thereby contributing to the maintenance of functional β-cells. Thus, this study may provide a new perspective for the development of ADMSC-based cellular therapies for T1D.

  15. Acute pancreatitis: etiology, clinical presentation, diagnosis, and therapy.

    Science.gov (United States)

    Cappell, Mitchell S

    2008-07-01

    Acute pancreatitis is a relatively common disease that affects about 300,000 patients per annum in America with a mortality of about 7%. About 75% of pancreatitis is caused by gallstones or alcohol. Other important causes include hypertriglyceridemia, medication toxicity, trauma from endoscopic retrograde cholangiopancreatography, hypercalcemia, abdominal trauma, various infections, autoimmune, ischemia, and hereditary causes. In about 15% of cases the cause remains unknown after thorough investigation. This article discusses the causes, diagnosis, imaging findings, therapy, and complications of acute pancreatitis.

  16. Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma

    NARCIS (Netherlands)

    Kuhlmann, K.F.D.; Geer, M.A. van; Bakker, C.T.; Dekker, J.E.M.; Havenga, M.J.E.; Oude Elferink, R.P.J.; Gouma, D.J.; Bosma, P.J.; Wesseling, J.G.

    2009-01-01

    Survival of patients with pancreatic cancer is poor. Adenoviral (Ad) gene therapy employing the commonly used serotype 5 reveals limited transduction efficiency due to the low amount of coxsackie-adenovirus receptor on pancreatic cancer cells. To identify fiber-chimeric adenoviruses with improved ge

  17. miR-143 decreases COX-2 mRNA stability and expression in pancreatic cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Pham, Hung [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States); Department of Medicine, Veterans Affair Greater Los Angeles Healthcare System, Los Angeles, CA 90073 (United States); Ekaterina Rodriguez, C.; Donald, Graham W.; Hertzer, Kathleen M.; Jung, Xiaoman S.; Chang, Hui-Hua; Moro, Aune; Reber, Howard A.; Hines, O. Joe [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States); Eibl, Guido, E-mail: geibl@mednet.ucla.edu [Department of Surgery, UCLA Center of Excellence in Pancreatic Diseases, UCLA David Geffen School of Medicine, University of California – Los Angeles, Los Angeles, CA 90095 (United States)

    2013-09-13

    Highlights: •Pancreatic cancer cells express low miR-143 levels and elevated p-MEK, p-MAPK and RREB1. •MEK inhibitors U0126 and PD98059 increase miR-143 expression. •miR-143 decreases COX-2 mRNA stability and expression and PGE{sub 2}. •miR-143 decreases p-p38MAPK, p-MEK, p-MAPK and RREB1 expression. -- Abstract: Small non-coding RNAs, microRNAs (miRNA), inhibit the translation or accelerate the degradation of message RNA (mRNA) by targeting the 3′-untranslated region (3′-UTR) in regulating growth and survival through gene suppression. Deregulated miRNA expression contributes to disease progression in several cancers types, including pancreatic cancers (PaCa). PaCa tissues and cells exhibit decreased miRNA, elevated cyclooxygenase (COX)-2 and increased prostaglandin E{sub 2} (PGE{sub 2}) resulting in increased cancer growth and metastases. Human PaCa cell lines were used to demonstrate that restoration of miRNA-143 (miR-143) regulates COX-2 and inhibits cell proliferation. miR-143 were detected at fold levels of 0.41 ± 0.06 in AsPC-1, 0.20 ± 0.05 in Capan-2 and 0.10 ± 0.02 in MIA PaCa-2. miR-143 was not detected in BxPC-3, HPAF-II and Panc-1 which correlated with elevated mitogen-activated kinase (MAPK) and MAPK kinase (MEK) activation. Treatment with 10 μM of MEK inhibitor U0126 or PD98059 increased miR-143, respectively, by 187 ± 18 and 152 ± 26-fold in BxPC-3 and 182 ± 7 and 136 ± 9-fold in HPAF-II. miR-143 transfection diminished COX-2 mRNA stability at 60 min by 2.6 ± 0.3-fold in BxPC-3 and 2.5 ± 0.2-fold in HPAF-II. COX-2 expression and cellular proliferation in BxPC-3 and HPAF-II inversely correlated with increasing miR-143. PGE{sub 2} levels decreased by 39.3 ± 5.0% in BxPC-3 and 48.0 ± 3.0% in HPAF-II transfected with miR-143. Restoration of miR-143 in PaCa cells suppressed of COX-2, PGE{sub 2}, cellular proliferation and MEK/MAPK activation, implicating this pathway in regulating miR-143 expression.

  18. miR-143 decreases COX-2 mRNA stability and expression in pancreatic cancer cells

    International Nuclear Information System (INIS)

    Highlights: •Pancreatic cancer cells express low miR-143 levels and elevated p-MEK, p-MAPK and RREB1. •MEK inhibitors U0126 and PD98059 increase miR-143 expression. •miR-143 decreases COX-2 mRNA stability and expression and PGE2. •miR-143 decreases p-p38MAPK, p-MEK, p-MAPK and RREB1 expression. -- Abstract: Small non-coding RNAs, microRNAs (miRNA), inhibit the translation or accelerate the degradation of message RNA (mRNA) by targeting the 3′-untranslated region (3′-UTR) in regulating growth and survival through gene suppression. Deregulated miRNA expression contributes to disease progression in several cancers types, including pancreatic cancers (PaCa). PaCa tissues and cells exhibit decreased miRNA, elevated cyclooxygenase (COX)-2 and increased prostaglandin E2 (PGE2) resulting in increased cancer growth and metastases. Human PaCa cell lines were used to demonstrate that restoration of miRNA-143 (miR-143) regulates COX-2 and inhibits cell proliferation. miR-143 were detected at fold levels of 0.41 ± 0.06 in AsPC-1, 0.20 ± 0.05 in Capan-2 and 0.10 ± 0.02 in MIA PaCa-2. miR-143 was not detected in BxPC-3, HPAF-II and Panc-1 which correlated with elevated mitogen-activated kinase (MAPK) and MAPK kinase (MEK) activation. Treatment with 10 μM of MEK inhibitor U0126 or PD98059 increased miR-143, respectively, by 187 ± 18 and 152 ± 26-fold in BxPC-3 and 182 ± 7 and 136 ± 9-fold in HPAF-II. miR-143 transfection diminished COX-2 mRNA stability at 60 min by 2.6 ± 0.3-fold in BxPC-3 and 2.5 ± 0.2-fold in HPAF-II. COX-2 expression and cellular proliferation in BxPC-3 and HPAF-II inversely correlated with increasing miR-143. PGE2 levels decreased by 39.3 ± 5.0% in BxPC-3 and 48.0 ± 3.0% in HPAF-II transfected with miR-143. Restoration of miR-143 in PaCa cells suppressed of COX-2, PGE2, cellular proliferation and MEK/MAPK activation, implicating this pathway in regulating miR-143 expression

  19. CT灌注成像在局限型自身免疫性胰腺炎诊断中的应用价值研究%The application value of the CT perfusion imaging in the diagnosis of focal-type autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    马晓璇; 时惠平; 郭薇; 于梅艳; 孟利民; 李相生; 王萍; 樊红霞

    2012-01-01

    目的 探讨胰腺全器官CT灌注成像检查在局限型自身免疫性胰腺炎(AIP)诊断中的应用价值,为该技术在AIP和胰腺癌鉴别诊断中的应用提供依据.方法 分析我院2011年2~12月7例AIP患者与8例胰腺癌患者的胰腺全器官CT灌注成像表现.对所有病例的CT征象和灌注参数进行对比分析,具体指标包括:(1)胰腺整体及病灶形态;(2)胰管的改变,如胰管狭窄、扩张及截断等;(3)邻近血管受侵情况;(4)时间-密度曲线特征;(5)灌注伪彩图特征及灌注参数指标;(6)是否合并其他自身免疫性疾病.结果 7例AIP,病变位于胰头处5例,胰体尾部2例;伴有胰管扩张5例;邻近血管均未见受侵征象;伴有肝内外胆管扩张4例;伴有溃疡性结肠炎1例.8例胰腺癌,病变位于胰头处3例,胰体尾处5例;伴有胰管扩张4例;邻近血管受侵6例;伴有肝内外胆管系统扩张2例.时间-密度曲线分析表明:AIP患者病灶强化方式与正常胰腺组织相似,但强化程度明显减低;胰腺癌患者病灶的时间-密度曲线与正常胰腺组织相比形态有较明显差别,且强化程度亦明显减低.统计学分析显示AIP与胰腺癌之间的CT灌注成像中组织血流值有明显统计学差异(P<0.05).结论 CT灌注成像可明确显示AIP血流灌注特征改变,作为常规CT检查的补充影像手段,可望在AIP的诊断和鉴别诊断中发挥重要作用.%Objective To investigate the application value of the whole pancreas CT perfusion imaging in the diagnosis of focal-type autoimmune pancreatitis (AIP) and the differential diagnosis between the AIP and pancreatic carcinoma. Methods Seven cases of focal-type AIP and 8 cases of pancreatic carcinoma underwent the whole pancreas perfusion CT imaging. The CT findings and perfusion parameters of all cases were analysed and compared , including following factors : (1) diffuse enlargement /focal lesion of pancreas ; (2) pancreatic duct changes : such as its stricture

  20. Induction of Golli-MBP Expression in CNS Macrophages During Acute LPS-Induced CNS Inflammation and Experimental Autoimmune Encephalomyelitis (EAE

    Directory of Open Access Journals (Sweden)

    Tracey L. Papenfuss

    2007-01-01

    Full Text Available Microglia are the tissue macrophages of the CNS. Microglial activation coupled with macrophage infiltration is a common feature of many classic neurodegenerative disorders. The absence of cell-type specific markers has confounded and complicated the analysis of cell-type specific contributions toward the onset, progression, and remission of neurodegeneration. Molecular screens comparing gene expression in cultured microglia and macrophages identified Golli-myelin basic protein (MBP as a candidate molecule enriched in peripheral macrophages. In situ hybridization analysis of LPS/IFNg and experimental autoimmune encephalomyelitis (EAE–induced CNS inflammation revealed that only a subset of CNS macrophages express Golli-MBP. Interestingly, the location and morphology of Golli-MBP+ CNS macrophages differs between these two models of CNS inflammation. These data demonstrate the difficulties of extending in vitro observations to in vivo biology and concretely illustrate the complex heterogeneity of macrophage activation states present in region- and stage-specific phases of CNS inflammation. Taken altogether, these are consistent with the emerging picture that the phenotype of CNS macrophages is actively defined by their molecular interactions with the CNS microenvironment.

  1. Genome-wide study reveals an important role of spontaneous autoimmunity, cardiomyocyte differentiation defect and antiangiogenic activities in gender-specific gene expression in Keshan disease

    Institute of Scientific and Technical Information of China (English)

    He Shulan; Tan Wuhong; Wang Sen; Wu Cuiyan; Wang Pan; Wang Bin; Su Xiaohui

    2014-01-01

    Background Keshan disease (KD) is an endemic cardiomyopathy in China.The etiology of KD is still under debate and there is no effective approach to preventing and curing this disease.Young women of child-bearing age are the most frequent victims in rural areas.The aim of this study was to determine the differences between molecular pathogenic mechanisms in male and female KD sufferers.Methods We extracted RNA from the peripheral blood mononuclear cells of KD patients (12 women and 4 men) and controls (12 women and 4 men).Then the isolated RNA was amplified,labeled and hybridized to Agilent human 4×44k whole genome microarrays.Gene expression was examined using oligonucleotide microarray analysis.A quantitative polymerase chain reaction assay was also performed to validate our microarray results.Results Among the genes differentially expressed in female KD patients we identified:HLA-DOA,HLA-DRA,and HLA-DQA1 associated with spontaneous autoimmunity; BMP5 and BMP7,involved in cardiomyocyte differentiation defect; and ADAMTS 8,CCL23,and TNFSF15,implicated in anti-angiogenic activities.These genes are involved in the canonical pathways and networks recognized for the female KD sufferers and might be related to the pathogenic mechanism of KD.Conclusion Our results might help to explain the higher susceptibility of women to this disease.

  2. IRE1 inhibition perturbs the unfolded protein response in a pancreatic β-cell line expressing mutant proinsulin, but does not sensitize the cells to apoptosis

    OpenAIRE

    Zhang, Liling; Nosak, Courtney; Sollazzo, Pietro; Odisho, Tanya; Volchuk, Allen

    2014-01-01

    Background The Akita mutation (C96Y) in the insulin gene results in early onset diabetes in both humans and mice. Expression of mutant proinsulin (C96Y) causes endoplasmic reticulum (ER) stress in pancreatic β-cells and consequently the cell activates the unfolded protein response (UPR). Since the proinsulin is terminally misfolded ER stress is irremediable and chronic activation of the UPR eventually activates apoptosis in some cells. Here we analyzed the IRE1-dependent activation of genes i...

  3. The autoimmune tautology.

    Science.gov (United States)

    Anaya, Juan-Manuel

    2010-01-01

    Although autoimmune diseases exhibit contrasting epidemiological features, pathology, and clinical manifestations, three lines of evidence demonstrate that these diseases share similar immunogenetic mechanisms (that is, autoimmune tautology). First, clinical evidence highlights the co-occurrence of distinct autoimmune diseases within an individual (that is, polyautoimmunity) and within members of a nuclear family (that is, familial autoimmunity). Second, physiopathologic evidence indicates that the pathologic mechanisms may be similar among autoimmune diseases. Lastly, genetic evidence shows that autoimmune phenotypes might represent pleiotropic outcomes of the interaction of non-specific disease genes.

  4. Questions and Answers on Autoimmunity and Autoimmune Diseases

    Science.gov (United States)

    ... dermatomyositis . What are some of the treatments for autoimmune diseases? Of first importance in treating any autoimmune disease ... being researched. What is the family connection in autoimmune diseases? The ability to develop an autoimmune disease is ...

  5. Clock-controlled output gene Dbp is a regulator of Arnt/Hif-1β gene expression in pancreatic islet β-cells

    Energy Technology Data Exchange (ETDEWEB)

    Nakabayashi, Hiroko; Ohta, Yasuharu, E-mail: yohta@yamaguchi-u.ac.jp; Yamamoto, Masayoshi; Susuki, Yosuke; Taguchi, Akihiko; Tanabe, Katsuya; Kondo, Manabu; Hatanaka, Masayuki; Nagao, Yuko; Tanizawa, Yukio, E-mail: tanizawa@yamaguchi-u.ac.jp

    2013-05-03

    Highlights: •Arnt mRNA expressed in a circadian manner in mouse pancreatic islets. •Expressions of Dbp and Arnt damped in the islets of a diabetic model mouse. •DBP and E4BP4 regulate Arnt promoter activity by direct binding. •Arnt may have a role in connecting circadian rhythm and metabolism. -- Abstract: Aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia inducible factor-1β (HIF-1β) has emerged as a potential determinant of pancreatic β-cell dysfunction and type 2 diabetes in humans. An 82% reduction in Arnt expression was observed in islets from type 2 diabetic donors as compared to non-diabetic donors. However, few regulators of Arnt expression have been identified. Meanwhile, disruption of the clock components CLOCK and BMAL1 is known to result in hypoinsulinemia and diabetes, but the molecular details remain unclear. In this study, we identified a novel molecular connection between Arnt and two clock-controlled output genes, albumin D-element binding protein (Dbp) and E4 binding protein 4 (E4bp4). By conducting gene expression studies using the islets of Wfs1{sup −/−} A{sup y}/a mice that develop severe diabetes due to β-cell apoptosis, we demonstrated clock-related gene expressions to be altered in the diabetic mice. Dbp mRNA decreased by 50%, E4bp4 mRNA increased by 50%, and Arnt mRNA decreased by 30% at Zeitgever Time (ZT) 12. Mouse pancreatic islets exhibited oscillations of clock gene expressions. E4BP4, a D-box negative regulator, oscillated anti-phase to DBP, a D-box positive regulator. We also found low-amplitude circadian expression of Arnt mRNA, which peaked at ZT4. Over-expression of DBP raised both mRNA and protein levels of ARNT in HEK293 and MIN6 cell lines. Arnt promoter-driven luciferase reporter assay in MIN6 cells revealed that DBP increased Arnt promoter activity by 2.5-fold and that E4BP4 competitively inhibited its activation. In addition, on ChIP assay, DBP and E4BP4 directly bound to D-box elements within the

  6. Upregulation of cathepsin W-expressing T cells is specific for autoimmune atrophic gastritis compared to other types of chronic gastritis

    Institute of Scientific and Technical Information of China (English)

    Doerthe Kuester; Michael Vieth; Ulrich Peitz; Stefan Kahl; Manfred Stolte; Albert Roessner; Ekkehard Weber; Peter Malfertheiner; Thomas Wex

    2005-01-01

    AIM: To investigate a pathophysiological role of cathepsin W (CatW), a putative thiol-dependent cysteine protease,which is specifically expressed in cytotoxic lymphocytes,in different types of chronic inflammation of the gastric mucosa.METHODS: Gastric and duodenal biopsies of patients with Helicobacter pylori ( H pylori)-associated active gastritis ( Hp,n = 19), chemically induced reactive gastritis (CG, n = 17),autoimmune atrophic gastritis (AIG, n = 20), lymphocytic corpus gastritis (LG, n = 29), celiac disease (CD, n = 10),and corresponding controls (n = 24) were analyzed by immunohistochemistry for the expression of CatW and CD45. Furthermore, immunohistochemical double staining with anti-CD3 and anti-cathepsin was performed for the samples of AIG.RESULTS: Median values of CatW-expressing cells among CD45-positive immune cells were between 2% and 6% for normal gastric mucosa, CG, and LG, whereas the corresponding value was significantly increased for AIG (24.7%, P<0.001) and significantly decreased for HP (0.7%, P<0.05). Double staining with anti-CD3 and antiCatW antibodies revealed that >90% of CatW-expressing cells in gastric mucosa of AIG were T cells. Duodenal mucosa had significantly more CatW/CD45-positive cells than normal gastric mucosa (median: 17.8% vs 2%, P<0.01).The corresponding proportion of CatW/CD45-positive cells was decreased in CD compared to duodenal mucosa (median: 2.1% vs 17.8%, P<0.05).CONCLUSION: The opposite findings regarding the presence of CatW-positive cells in AIG (increase) and CD (decrease) reflects the different cellular composition of immune cells involved in the pathogenesis of these diseases.

  7. Peroxiredoxin III protects pancreatic ß cells from apoptosis.

    Science.gov (United States)

    Wolf, Gabriele; Aumann, Nicole; Michalska, Marta; Bast, Antje; Sonnemann, Jürgen; Beck, James F; Lendeckel, Uwe; Newsholme, Philip; Walther, Reinhard

    2010-11-01

    Type 1 diabetes mellitus is characterized by a progressive autoimmune destruction of insulin-producing β cells. Macrophages and T lymphocytes release cytokines, which induce the synthesis of oxygen and nitrogen radicals in the pancreatic islets. The resulting cellular and mitochondrial damage promotes β cell death. β cells are very sensitive to the autoimmune free radical-dependent attack due to their low content of antioxidant enzymes such as glutathione peroxidase and catalase. A focal point of β cell protection should be the control of the mitochondrial redox status, which will result in the preservation of metabolic stimulus-secretion coupling. For this reason, there is a considerable interest in the mitochondrial peroxiredoxin III (PRX III), a thioredoxin-dependent peroxide reductase, which was shown to be able to protect against both oxidative and nitrosative stress. Using the Tet-On-system, we generated stably transfected rat insulinoma cells over- or under-expressing PRX III in a doxycyclin-dependent manner to analyze the effect of increased or decreased amounts of cellular PRX III, following treatment with several stressors. We provide evidence that PRX III protects pancreatic β cells from cell stress induced by accumulation of hydrogen peroxide, or the induction of inducible nitric oxide synthase or caspase-9 and -3 by pro-inflammatory cytokines or streptozotocin. Basal insulin secretion was markedly decreased in cells expressing lower levels of PRX III. We suggest PRX III may be a suitable target for promoting deceleration or even prevention of stress-associated apoptosis in pancreatic β cells and the manifestation of insulin-dependent diabetes mellitus. PMID:20807727

  8. Enriched environment inhibits mouse pancreatic cancer growth and down-regulates the expression of mitochondria-related genes in cancer cells.

    Science.gov (United States)

    Li, Guohua; Gan, Yu; Fan, Yingchao; Wu, Yufeng; Lin, Hechun; Song, Yanfang; Cai, Xiaojin; Yu, Xiang; Pan, Weihong; Yao, Ming; Gu, Jianren; Tu, Hong

    2015-01-19

    Psycho-social stress has been suggested to influence the development of cancer, but it remains poorly defined with regard to pancreatic cancer, a lethal malignancy with few effective treatment modalities. In this study, we sought to investigate the impacts of enriched environment (EE) housing, a rodent model of "eustress", on the growth of mouse pancreatic cancer, and to explore the potential underlying mechanisms through gene expression profiling. The EE mice showed significantly reduced tumor weights in both subcutaneous (53%) and orthotopic (41%) models, while each single component of EE (inanimate stimulation, social stimulation or physical exercise) was not profound enough to achieve comparative anti-tumor effects as EE. The integrative transcriptomic and proteomic analysis revealed that in response to EE, a total of 129 genes in the tumors showed differential expression at both the mRNA and protein levels. The differentially expressed genes were mostly localized to the mitochondria and enriched in the citrate cycle and oxidative phosphorylation pathways. Interestingly, nearly all of the mitochondria-related genes were down-regulated by EE. Our data have provided experimental evidence in favor of the application of positive stress or of benign environmental stimulation in pancreatic cancer therapy.

  9. Abdominal manifestations of autoimmune disorders

    International Nuclear Information System (INIS)

    Full text: Immunoglobulin G4-related disease was recognized as a systemic disease since various extrapancreatic lesions were observed in patients with autoimmune pancreatitis (AIP). The real etiology and pathogenesis of IgG4-RD is still not clearly understood. Moreover the exact role of IgG4 or IgG4-positive plasma cells in this disease has not yet been elucidated. only some inconsistent biological features such as hypergammaglobulinemia or hypocomplementemia support the autoimmune nature of the disease process. various names have been ascribed to this clinicopathological entity including IgG4-related sclerosing disease, IgG4-related systemic sclerosing disease, IgG4-related disease, IgG4-related autoimmune disease, hyper-IgG4 disease and IgG4-related systemic disease. The extrapancreatic lesions of IgG4-RD also exhibit the same characteristic histologic features including dense lymphoplasmacytic infiltrate, massive storiform fibrosis, and obliterative phlebitis as seen in IgG4-related pancreatitis. Abdominal manifestations include the following organs/systems: Bile ducts: Sclerosing cholangitis; Gallbladder and liver: Acalculous sclerosis cholecytitis with diffuse wall thickening; hepatic inflammatory pseudotumorts; Kidneys: round or wedge-shaped renal cortical nodules, peripheral cortical; lesions, mass like lesions or renal pelvic involvement; Prostate, urethra, seminal vesicle, vas deferens, uterine cervix; Autoimmune prostatitis; Retroperitoneum: Retroperitoneal fibrosis. thin or mildly thick homogeneous soft tissue lesion surrounding the abdominal aorta and its branches but also bulky masses causing hydronephroureterosis; Mesentery: Sclerosing mesenteritis usually involving the root of the mesentery; Bowel: Inflammatory bowel diseases mimicking Crohn’s disease or ulcerative colitis. various types of sclerosing nodular lesions of the bowel wall; Stomach: Gastritis, gastric ulcers and focal masses mimicking submucosal tumor; omentum: Infiltration mimicking

  10. Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity

    Institute of Scientific and Technical Information of China (English)

    Zhi-Quan Wang; Fu-Er Lu; San-Hua Leng; Xin-Sheng Fang; Guang Chen; Zeng-Si Wang; Li-Ping Dong; Zhong-Qing Yan

    2008-01-01

    AIM: To observe the effect of berberine on insulin secretion in rat pancreatic islets and to explore its possible molecular mechanism.METHODS: Primary rat islets were isolated from male Sprague-Dawley rats by collagenase digestion and treated with different concentrations (1, 3, 10 and 30 μmol/L) of berberine or 1 μmol/L Glibenclamide (GB) for 24 h. Glucose-stimulated insulin secretion (GSIS) assay was conducted and insulin was determined by radioimmunoassay. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (NTT) assay was performed to evaluate cytotoxicity. The mRNA level of hepatic nuclear factor 4 alpha (HNF4α) was determined by reverse transcription polymerase chain reaction (RT-PCR). Indirect immunofluorescence staining and Western blot analysis were employed to detect protein expression of HNF4α in the islets. Glucokinase (GK) activity was measured by spectrophotometric method.RESULTS: Berberine enhanced GSIS rather than basal insulin secretion dose-dependently in rat islets and showed no significant cytotoxicity on islet cells at the concentration of 10 μmol/L. Both mRNA and protein expressions of HNF4α were up-regulated by berberine in a dose-dependent manner, and GK activity was also increased accordingly. However, GB demonstrated no regulatory effects on HNF4α expression or GK activity.CONCLUSION: Berberine can enhance GSIS in rat islets, and probably exerts the insulinotropic effect via a pathway involving HNF4α and GK, which is distinct from sulphonylureas (SUs).

  11. Complicated Pancreatitis

    NARCIS (Netherlands)

    Bakker, O.J.

    2015-01-01

    Research questions addressed in this thesis: What is the accuracy of serum blood urea nitrogen as early predictor of complicated pancreatitis? ; What is difference in clinical outcome between patients with pancreatic parenchymal necrosis and patients with extrapancreatic necrosis without necrosis

  12. Complicated Pancreatitis

    OpenAIRE

    Bakker, O.J.

    2015-01-01

    Research questions addressed in this thesis: What is the accuracy of serum blood urea nitrogen as early predictor of complicated pancreatitis? ; What is difference in clinical outcome between patients with pancreatic parenchymal necrosis and patients with extrapancreatic necrosis without necrosis of the pancreatic parenchyma? ; What is the impact of organ failure on mortality in necrotizing pancreatitis? ; Based on individual patient data from randomized trials, does early enteral tube feedin...

  13. Childhood pancreatitis.

    Science.gov (United States)

    Uretsky, G; Goldschmiedt, M; James, K

    1999-05-01

    Acute pancreatitis is a rare finding in childhood but probably more common than is generally realized. This condition should be considered in the evaluation of children with vomiting and abdominal pain, because it can cause significant morbidity and mortality. Clinical suspicion is required to make the diagnosis, especially when the serum amylase concentration is normal. Recurrent pancreatitis may be familial as a result of inherited biochemical or anatomic abnormalities. Patients with hereditary pancreatitis are at high risk for pancreatic cancer.

  14. LOSS OF MEMBRANOUS E-CADHERIN EXPRESSION CORRELATES WITH ECTOPIC β-CATENIN ACCUMULATION AND POOR SURVIVAL IN HUMAN PANCREATIC ADENOCARCINOMA

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Objective:1.To evaluate E-cadherin expression and its clinical significance in pancreatic adenocarcinoma; 2. To further clarify if deregulation of the E-cadherin/β-catenin complex might be the cause for cytoplasmic accumulation of β-catenin. Methods:We investigated the expression pattern of E-cadherin and β-catenin on serial sections from 41 pancreatic cancers. Precipitation and Western blot analysis were performed in 12 tumors with anti-E-cadherin antibody. Results:Reduced or entirely negative expression was found in 65.9%(27 of 41) of the tumors studied; 24 of 41 tumors exhibited increased cytoplasmic immunoreactivity. Interestingly, we found a clear inverse correlation between membranous and cytoplasmic expression of E-cadherin in 43 tumors(P<0.0005).The prognosis was poor with reduced tumor E-cadherin expression (P<0.05) but not with other clinicopathological parameters (age, sex, tumor grading and TNM stage); Analysis of serial sections stained with anti-β-catenin antibody revealed a marked correlation between aberrant expression of E-cadherin and ectopic accumulation of β-catenin(P<0.01).Immunoprecipitation of lysates from pancreatic adenocarcinomas and normal pancreas revealed a clear reduced coprecipitation activity of E-cadherin and β-catenin in the carcinoma samples.Conclusions:The finding, that the loss of membranous E-cadherin correlates significantly with cytoplasmic β-catenin expression, which is a factor for poor prognosis, makes a relationship between E-cadherin dysfunction, deregulated β-catenin and activated Tcf transcription possible.

  15. RNA-binding protein HuD reduces triglyceride production in pancreatic β cells by enhancing the expression of insulin-induced gene 1.

    Science.gov (United States)

    Kim, Chongtae; Lee, Heejin; Kang, Hoin; Shin, Jung Jae; Tak, Hyosun; Kim, Wook; Gorospe, Myriam; Lee, Eun Kyung

    2016-04-01

    Although triglyceride (TG) accumulation in the pancreas leads to β-cell dysfunction and raises the chance to develop metabolic disorders such as type 2 diabetes (T2DM), the molecular mechanisms whereby intracellular TG levels are regulated in pancreatic β cells have not been fully elucidated. Here, we present evidence that the RNA-binding protein HuD regulates TG production in pancreatic β cells. Mouse insulinoma βTC6 cells stably expressing a small hairpin RNA targeting HuD (shHuD) (βTC6-shHuD) contained higher TG levels compared to control cells. Moreover, downregulation of HuD resulted in a decrease in insulin-induced gene 1 (INSIG1) levels but not in the levels of sterol regulatory element-binding protein 1c (SREBP1c), a key transcription factor for lipid production. We identified Insig1 mRNA as a direct target of HuD by using ribonucleoprotein immunoprecipitation (RIP) and biotin pulldown analyses. By associating with the 3'-untranslated region (3'UTR) of Insig1 mRNA, HuD promoted INSIG1 translation; accordingly, HuD downregulation reduced while ectopic HuD expression increased INSIG1 levels. We further observed that HuD downregulation facilitated the nuclear localization of SREBP1c, thereby increasing the transcriptional activity of SREBP1c and the expression of target genes involved in lipogenesis; likewise, we observed lower INSIG1 levels in the pancreatic islets of HuD-null mice. Taken together, our results indicate that HuD functions as a novel repressor of lipid synthesis in pancreatic β cells.

  16. Autoimmune Autonomic Ganglionopathy

    Science.gov (United States)

    ... Accessed 9/2/2015. Autoimmune Autonomic Ganglionopathy Summary. Dysautonomia International . http://www.dysautonomiainternational.org/page.php?ID= ... page Basic Information In Depth Information Basic Information Dysautonomia International offers an information page on Autoimmune autonomic ...

  17. Perspectives on autoimmunity

    Energy Technology Data Exchange (ETDEWEB)

    Cohen, I.R.

    1987-01-01

    The contents of this book are: HLA and Autoimmunity; Self-Recognition and Symmetry in the Immune System; Immunology of Insulin Dependent Diabetes Mellitus; Multiple Sclerosis; Autoimmunity and Immune Pathological Aspects of Virus Disease; Analyses of the Idiotypes and Ligand Binding Characteristics of Human Monoclonal Autoantibodies to DNA: Do We Understand Better Systemic Lupus Erythematosus. Autoimmunity and Rheumatic Fever; Autoimmune Arthritis Induced by Immunization to Mycobacterial Antigens; and The Interaction Between Genetic Factors and Micro-Organisms in Ankylosing Spondylitis: Facts and Fiction.

  18. Autoimmune vitiligo is associated with gain-of-function by a transcriptional regulator that elevates expression of HLA-A*02:01 in vivo.

    Science.gov (United States)

    Hayashi, Masahiro; Jin, Ying; Yorgov, Daniel; Santorico, Stephanie A; Hagman, James; Ferrara, Tracey M; Jones, Kenneth L; Cavalli, Giulio; Dinarello, Charles A; Spritz, Richard A

    2016-02-01

    HLA-A is a class I major histocompatibility complex receptor that presents peptide antigens on the surface of most cells. Vitiligo, an autoimmune disease in which skin melanocytes are destroyed by cognate T cells, is associated with variation in the HLA-A gene; specifically HLA-A*02:01, which presents multiple vitiligo melanocyte autoantigens. Refined genetic mapping localizes vitiligo risk in the HLA-A region to an SNP haplotype ∼20-kb downstream, spanning an ENCODE element with many characteristics of a transcriptional enhancer. Convergent CTCF insulator sites flanking the HLA-A gene promoter and the predicted transcriptional regulator, with apparent interaction between these sites, suggests this element regulates the HLA-A promoter. Peripheral blood mononuclear cells from healthy subjects homozygous for the high-risk haplotype expressed 39% more HLA-A RNA than cells from subjects carrying nonhigh-risk haplotypes (P = 0.0048). Similarly, RNAseq analysis of 1,000 Genomes Project data showed more HLA-A mRNA expressed in subjects homozygous for the high-risk allele of lead SNP rs60131261 than subjects homozygous for the low-risk allele (P = 0.006). Reporter plasmid transfection and genomic run-on sequence analyses confirm that the HLA-A transcriptional regulator contains multiple bidirectional promoters, with greatest activity on the high-risk haplotype, although it does not behave as a classic enhancer. Vitiligo risk associated with the MHC class I region thus derives from combined quantitative and qualitative phenomena: a SNP haplotype in a transcriptional regulator that induces gain-of-function, elevating expression of HLA-A RNA in vivo, in strong linkage disequilibrium with an HLA-A allele that confers *02:01 specificity.

  19. Hepatitis A vaccine associated with autoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    PA Berry; G Smith-Laing

    2007-01-01

    To describe a case of probable relapsing autoimmune hepatitis associated with vaccination against hepatitis A virus (HAV). A case report and review of literature were written concerning autoimmune hepatitis in association with hepatitis A and other hepatotropic viruses. Soon after the administration of formalin-inactivated hepatitis A vaccine, a man who had recently recovered from an uncharacterized but self-limiting hepatitic illness,experienced a severe deterioration (AST 1687 U/L, INR 1.4). Anti-nuclear antibodies were detectable, and liver biopsy was compatible with autoimmune hepatitis. The observation supports the role of HAV as a trigger of autoimmune hepatitis. Studies in helper T-cell activity and antibody expression against hepatic proteins in the context of hepatitis A infection are summarized, and the concept of molecular mimicry with regard to other forms of viral hepatitis and autoimmunity is briefly explored.

  20. Expression and significance of ICAM-1 and its counter receptors LFA-1 and Mac-1 in experimental acute pancreatitis of rats

    Institute of Scientific and Technical Information of China (English)

    Wei Sun; Yasuhiro Watanabe; Zhong-Qiu Wang

    2006-01-01

    AIM: To investigate the role of intercellular adhesion molecule-1 (ICAM-1) and its counter receptors LFA-1 and Mac-1 in acute pancreatitis (AP).METHODS: SD rats were allocated to AP group and control group randomly (25 rats each). AP was induced by infusion of 5% chenodeoxycholic acid into the pancreatic duct, followed by ligation of pancreatic duct.The rats were sacrificed at 1, 3, 6, 12 and 24 h after induction of pancreatitis. Five rats were sacrificed at one time point in the two groups before the blood and specimens from pancreas and lung were obtained. Serum amylase and ascitic fluid were measured at each time point. Expression of ICAM-1 at different time points was assessed by immunohistochemistry in pancreas and lung,and the expression of LAF-1 and Mac-1 on neutrophils at different time points was detected by flow cytometer.RESULTS: Induction of AP was confirmed by the serum levels of amylase and histological studies. The expression of ICAM-1 in pancreas increased significantly than that in the control group at all time points (P<0.05 or P<0.01),as well as the expression in lung except at 1 h. The expression of LFA-1 and Mac-1 on neutrophil in blood increased significantly in AP group than that in control group at several time points (P<0.05 or P<0.01). The amount of ascitic fluid and serum amylase level of AP group increased significantly than that of control group at all time points (P<0.05 or P<0.01). Parallel to these results, a significant neutrophil infiltration was found in pancreas and lung tissues of AP group rats.CONCLUSION: Our findings suggest the important role for ICAM-1, LFA-1 and Mac-1 in mediating the development of AP from a local disease to a systemic illness. Upregulation of ICAM-1, LFA-1, Mac-1 and subsequent leukocyte infiltration appear to be significant events of pancreatic and pulmonary injuries in AP.

  1. High Expression of HIF1a Is a Predictor of Clinical Outcome in Patients with Pancreatic Ductal Adenocarcinomas and Correlated to PDGFA, VEGF, and bFGF

    Directory of Open Access Journals (Sweden)

    Andreas-Claudius Hoffmann

    2008-07-01

    Full Text Available PURPOSE: Pancreatic cancer still has one of the worst prognoses in gastrointestinal cancers with a 5-year survival rate of 5%, making it necessary to find markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens. In this study, we investigated the prognostic values of HIF1a, bFGF, VEGF, and PDGFA gene expressions as well as their interrelationships. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded tissue samples were obtained from 41 patients with pancreatic adenocarcinoma (age, 65; range, 34–85 years. After laser capture microdissection, direct quantitative real-time reverse transcription-polymerase chain reaction assays were performed in triplicates to determine HIF1a, PDGFA, VEGF, and bFGF gene expression levels. Multivariate Cox proportional hazards regression analysis was used to assess the impact of HIF1a gene expression on prognosis. RESULTS:HIF1a was significantly correlated to every gene we tested: bFGF (P = .04, VEGF (P = .02, and PDGFA (P = .03. Tumor size, P = .04, and high HIF1a mRNA expression (cutoff, 75th percentile had a significant impact on survival, P = .009 (overall model fit, P = .02. High HIF1a expression had a sensitivity of 87.1% and a specificity of 55.6% for the diagnosis short (<6 months versus long (6–60 months survival. CONCLUSIONS: Measuring PDGFA, bFGF, and HIF1a expression may contribute to a better understanding of the prognosis of patients with pancreatic cancer and may even play a crucial role for the distribution of patients to multimodal therapeutic regimens. Larger studies including patients treated with actual chemotherapeutics seem to be warranted.

  2. Autoimmune Disease

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    2009154 Expression of cellular FLICE inhibitory proteins in peripheral blood B lymphocytes in patients with systemic lupus erythematosus.DONG Jing(董婧),et al.Dept Dermatol,Wuhan 1st Hospital,Wuhan 430030.Chin J Dermatol,2009;42(4):226-229.

  3. Understanding Autoimmune Mechanisms in Multiple Sclerosis Using Gene Expression Microarrays: Treatment Effect and Cytokine-related Pathways

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    A. Achiron

    2004-01-01

    Full Text Available Multiple sclerosis (MS is a central nervous system disease in which activated autoreactive T-cells invade the blood brain barrier and initiate an inflammatory response that leads to myelin destruction and axonal loss. The etiology of MS, as well as the mechanisms associated with its unexpected onset, the unpredictable clinical course spanning decades, and the different rates of progression leading to disability over time, remains an enigma. We have applied gene expression microarrays technology in peripheral blood mononuclear cells (PBMC to better understand MS pathogenesis and better target treatment approaches. A signature of 535 genes were found to distinguish immunomodulatory treatment effects between 13 treated and 13 untreated MS patients. In addition, the expression pattern of 1109 gene transcripts that were previously reported to significantly differentiate between MS patients and healthy subjects were further analyzed to study the effect of cytokine-related pathways on disease pathogenesis. When relative gene expression for 26 MS patients was compared to 18 healthy controls, 30 genes related to various cytokine-associated pathways were identified. These genes belong to a variety of families such as interleukins, small inducible cytokine subfamily and tumor necrosis factor ligand and receptor. Further analysis disclosed seven cytokine-associated genes within the immunomodulatory treatment signature, and two cytokine-associated genes SCYA4 (small inducible cytokine A4 and FCAR (Fc fragment of IgA, CD89 that were common to both the MS gene expression signature and the immunomodulatory treatment gene expression signature. Our results indicate that cytokine-associated genes are involved in various pathogenic pathways in MS and also related to immunomodulatory treatment effects.

  4. D-dopachrome tautomerase is over-expressed in pancreatic ductal adenocarcinoma and acts cooperatively with macrophage migration inhibitory factor to promote cancer growth.

    Science.gov (United States)

    Guo, Dawei; Guo, Jinshuai; Yao, Junchao; Jiang, Kun; Hu, Jianhua; Wang, Bo; Liu, Haiyang; Lin, Lin; Sun, Wenyu; Jiang, Xiaofeng

    2016-11-01

    Previous studies have established the important role of MIF in the development of pancreatic ductal adenocarcinoma (PDAC) for both therapeutic and diagnostic perspectives, but little is known about the expression and function of D-dopachrome tautomerase (DDT), a functional homolog of MIF, in PDAC. In the present study, we demonstrated that DDT was over-expressed in PDAC tissues in a pattern correlated with MIF. In the pancreatic cancer cell lines, PANC-1, BXPC-3 and ASPC-1, both DDT and MIF were expressed and co-localized with each other in the endosomal compartments and plasma membrane. Knockdown of DDT and MIF in PANC-1 cells cooperatively inhibited ERK1/2 and AKT phosphorylation, increased p53 expression, and reduced cell proliferation, invasion and tumor formation. These effects were rescued by the re-expression of MIF or DDT, but not by the forced expression of the tautomerase-deficient mutants of DDT and MIF, P1G-DDT and P1G-MIF. Finally, we observed that 4-iodo-6-phenylpyrimidine (4-IPP), a covalent tautomerase inhibitor of both DDT and MIF, attenuated PANC-1 cell proliferation and colony formation in vitro and tumor growth in vivo. Thus, targeting the tautomerase sites of both MIF and DDT may offer more efficient therapeutic benefits to PDAC patients. PMID:27434219

  5. Hereditary pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Richard M Charnley

    2003-01-01

    Hereditary pancreatitis is an autosomal dominant condition,which results in recurrent attacks of acute pancreatitis,progressing to chronic pancreatitis often at a young age.The majority of patients with hereditary pancreatitis expressone of two mutations (R122H or N29I) in the cationictrypsinogen gene (PRSS1 gene). It has been hypothesisedthat one of these mutations, the R122H mutation causespancreatitis by altering a trypsin recognition site sopreventing deactivation of trypsin within the pancreas andprolonging its action, resulting in autodigestion. Families withthese two mutations have been identified in many countriesand there are also other rarer mutations, which have alsobeen linked to hereditary pancreatitis.Patients with hereditary pancreatitis present in the sameway as those with sporadic pancreatitis but at an earlierage. It is common for patients to remain undiagnosed formany years, particularly ifthey present with non-specificsymptoms. Hereditary pancreatitis should always beconsidered in patients who present with recurrent pancreatitiswith a family history of pancreatic disease. If patients withthe 2 common mutations are compared, those with theR122H mutation are more likely to present at a younger ageand are more likely to require surgical intervention than thosewith N29I. Hereditary pancreatitis carries a 40 % lifetimerisk of pancreatic cancer with those patients aged between50 to 70 being most at risk in whom screening tests maybecome important.

  6. CX3CL1 (fractalkine and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin

    Directory of Open Access Journals (Sweden)

    Olsson Tomas

    2005-07-01

    Full Text Available Abstract Background Multiple sclerosis (MS is a chronic inflammatory disease of the central nervous system (CNS. It is associated with local activation of microglia and astroglia, infiltration of activated macrophages and T cells, active degradation of myelin and damage to axons and neurons. The proposed role for CX3CL1 (fractalkine in the control of microglia activation and leukocyte infiltration places this chemokine and its receptor CX3CR1 in a potentially strategic position to control key aspects in the pathological events that are associated with development of brain lesions in MS. In this study, we examine this hypothesis by analyzing the distribution, kinetics, regulation and cellular origin of CX3CL1 and CX3CR1 mRNA expression in the CNS of rats with an experimentally induced MS-like disease, myelin oligodendrocyte glycoprotein (MOG-induced autoimmune encephalomyelitis (EAE. Methods The expression of CX3CL1 and its receptor CX3CR1 was studied with in situ hybridization histochemical detection of their mRNA with radio labeled cRNA probes in combination with immunohistochemical staining of phenotypic cell markers. Both healthy rat brains and brains from rats with MOG EAE were analyzed. In defined lesional stages of MOG EAE, the number of CX3CR1 mRNA-expressing cells and the intensity of the in situ hybridization signal were determined by image analysis. Data were statistically evaluated by ANOVA, followed by Tukeyprimes multiple comparison test. Results Expression of CX3CL1 mRNA was present within neuronal-like cells located throughout the neuraxis of the healthy rat. Expression of CX3CL1 remained unaltered in the CNS of rats with MOG-induced EAE, with the exception of an induced expression in astrocytes within inflammatory lesions. Notably, the brain vasculature of healthy and encephalitic animals did not exhibit signs of CX3CL1 mRNA expression. The receptor, CX3CR1, was expressed by microglial cells in all regions of the healthy brain

  7. Expression and function of Set7/9 in pancreatic islets.

    Science.gov (United States)

    Ogihara, Takeshi; Vanderford, Nathan L; Maier, Bernhard; Stein, Roland W; Mirmira, Raghavendra G

    2009-01-01

    Histone tail acetylation and methylation are known to enhance accessibility of islet genes to transcription factors and the basal transcriptional machinery.  In this brief report, we follow up on a recent study in which we identified the islet enriched factor Set7/9 as a potentially important histone methyltransferase in β-cells (Deering, et al. Diabetes 2009; 58:185-93).  We had suggested that the methylation of H3-Lys4 by Set7/9 enhances accessibility of the insulin gene to the basal transcriptional machinery.  Consistent with this hypothesis, we show here that RNA polymerase II occupancy at the insulin and IAPP genes is considerably enhanced in β-cells compared to α cells (or NIH3T3 cells), and that the converse is true for RNA polymerase II occupancy at the glucagon gene. The enrichment of Set7/9 in β-cells appears to be dependent upon Pdx1, as knockdown of Pdx1 in INS-1 β-cells using small hairpin RNAs almost completely abolishes Set7/9 expression.  A LacZ expression vector driven by the -6.5 kilobase pair Set7/9 promoter that contains putative Pdx1 binding sites shows β-cell-line-specific expression.  Taken together, our data support further the hypothesis that Pdx1-dependent Set7/9 expression may be crucial to enhancing chromatin accessibility and transcription of β-cell genes. PMID:21099283

  8. Differential expression of neural cell adhesion molecule and cadherins in pancreatic islets, glucagonomas, and insulinomas

    DEFF Research Database (Denmark)

    Møller, C J; Christgau, S; Williamson, M R;

    1992-01-01

    The endocrine cells of the pancreas develop from the endoderm and yet display several characteristics of a neuronal phenotype. During embryonic life, ductal epithelial cells give rise to first the glugagon-producing cells (alpha-cells) and then cells that express insulin (beta-cells), somatostati...

  9. Proteins differentially expressed in human beta-cells-enriched pancreatic islet cultures and human insulinomas

    DEFF Research Database (Denmark)

    Terra, Letícia F; Teixeira, Priscila C; Wailemann, Rosangela A M;

    2013-01-01

    In view of the great demand for human beta-cells for physiological and medical studies, we generated cell lines derived from human insulinomas which secrete insulin, C-peptide and express neuroendocrine and islet markers. In this study, we set out to characterize their proteomes, comparing them t...

  10. Microarray-based gene expression profiling reveals genes and pathways involved in the oncogenic function of REG3A on pancreatic cancer cells.

    Science.gov (United States)

    Xu, Qianqian; Fu, Rong; Yin, Guoxiao; Liu, Xiulan; Liu, Yang; Xiang, Ming

    2016-03-10

    We previously reported that regenerating islet-derived protein 3 alpha (REG3A) exacerbates pancreatic malignancies. The mechanism of this effect has not been clearly elucidated. Here we first identified key differentially expressed genes (DEGs) and signal pathways in the pancreatic cancer cell line SW1990, compared to two control cell lines, by microarray analysis. We then identified key genes and pathways regulated by REG3A or the cytokine IL6 in SW1990 cells. Afterwards, these DEGs induced by REG3A or IL6 were subjected to KEGG pathway enrichment analysis and GO function analysis by the DAVID online tool. Ultimately, we constructed protein-protein interaction networks among the DEGs by Cytoscape. Among the three pancreatic cell lines, SW1990 exhibited highly deterioration with the activation of genes and pathways related to proliferation, survival, angiogenesis, and invasion. As a result, 50 DEGs enriched in 11 pathways were identified in REG3A-treated SW1990 cells, and 28 DEGs enriched in 9 pathways were detected in IL6-treated cells. Overall, results of microarray analysis followed by qRT-PCR and Western blotting suggest that REG3A regulates pancreatic cell growth by increasing the expression of at least 8 genes: JAK1, STAT3, IL10, FOXM1, KRAS, MYC, CyclinD1, and c-fos; and activation of at least 4 signal pathways: TGFβ, PDGF, angiogenesis and RAS. Similar results were obtained with IL6 treatment. Regulation network analysis confirmed the cell growth related DEGs, and further uncovered three transcription factor families with immune functions regulated by REG3A.

  11. Influence of platelet activating factor on expression of adhesion molecules in experimental pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Hua Zhao; Ji-Wei Chen; Ya-Kui Zhou; Xue-Feng Zhou; Pei-Yun Li

    2003-01-01

    AIM: To determine whether Platelet activating factor (PAF)has a regulation role in the expression of adhesion moleculesand accumulation of neutrophils in a murine model of acutepancreatitis.METHODS: One hundred twenty-eight Kunming mice weredivided into four groups. Group 1 received 0.1 mi saline s.c.every hour for three hours (sham). Group 2 received cerulein(50 μg/kg dose s.c.) every hour for three hours. Group 3received AP and additional challenge of PAF (50 rg/kg inabsolute ethanol) (AP/PAF). Group 4 received AP, plustherapeutic treatment with GAB (25 mg dose i.p.) immediatelyafter the first challenge of cerulein (AP/GAB). Animals weresacrificed at 12 h after the first challenge of saline or cerulein.Adhesion molecules of pancreas were semi-quantified bySP methods. Standard assays were performed for serumamylase and myeloperoxidase activity (MPO) of pancreas.Histology of pancreas was scored in a blind manner. Watercontent of pancreas was also measured at the same time.RESULTS: Control pancreata showed negligible adhesionmolecule expression and neutrophil accumulation. Therewere evident adhesion molecules expression and neutrophilaccumulation in AP and AP/PAF compared with sham (P<0.05).AP/GAB had a lower level of adhesion molecules, neutrophils,and water content versus AP and AP/PAF (P<0.05). Histologyshowed a trend toward improvement in AP/GAB, but didnot reach statistical significance.CONCLUSION: PAF can induce the expression of adhesionmolecules that mediate neutrophil accumulation. The PAFantagonist reduces the expression of adhesion moleculesand the severity of inflammation when given immediatelyafter the induction of mild AP in mice. These results suggestthat PAF antagonism may be useful in the treatment of mildpancreatitis after its clinical onset.

  12. Regulation of Insulin Secretion and Expression of SUR1 Gene by Chronic Exposure to Free Fatty Acids in Rat Pancreatic β Cells

    Institute of Scientific and Technical Information of China (English)

    袁莉; 邓秀玲; 陈璐璐; 周愍

    2004-01-01

    To study the effects of free fatty acids on insulin secretion and expression of SUR1 gene in rat pancreatic B cells in vitro, and to explore the molecular mechanisms in lipotoxicity inducing insulin secretion dysfunction, pancreatic islet cells were isolated and digested from male SD rats.Purified islets were incubated with either 0.25 mmol/L palmitate or 0. 125 mmol/L oleate for 48 h in vitro. Then islets were stimulated with either 5.6 mmol/L or 16.7 mmol/L glucose for 1 h. Insulin release was measured by using radioimmunoassay, and the expression of SUR1 gene mRNA was quantified by reserve transcription-polymerase chain reaction (RT-PCR). The islets exposed to both palmitate and oleate for 48 h showed an increased basal and a decreased glucose-indused insulin release as compared with control islets. Palmitate increased basal insulin secretion by 110 % (P<0.01), decreased glucose stimulated insulin secretion by 43 % (P<0.01) ; while oleate increased basal insulin secretion by 80 % (P<0.01) and decreased glucose stimulated insulin secretion by 32 % (P<0.05). RT-PCR showed that oleate significantly suppressed SUR1 gene expression by 64 % (P<0.01)as compared with the control group, while palmitate group manifested a light decrease of 15 % (P >0.05) of SUR1 gene expression. Our results suggested that chronic exposure to free fatty acids of pancreatic β cells inhibited glucose stimulated insulin secretion. Regulation of SUR1 gene expression may be involved in such effects, which may also be one of the molecular mechanisms in lipotoxocity inducing β cells secretion dysfunction.

  13. Adenoviruses Expressing PDX-1, BETA2/NeuroD and MafA Induces the Transdifferentiation of Porcine Neonatal Pancreas Cell Clusters and Adult Pig Pancreatic Cells into Beta-Cells

    Directory of Open Access Journals (Sweden)

    Young-Hye You

    2011-04-01

    Full Text Available BackgroundA limitation in the number of insulin-producing pancreatic beta-cells is a special feature of diabetes. The identification of alternative sources for the induction of insulin-producing surrogate beta-cells is a matter of profound importance. PDX-1/VP16, BETA2/NeuroD, and MafA overexpression have been shown to influence the differentiation and proliferation of pancreatic stem cells. However, few studies have been conducted using adult animal pancreatic stem cells.MethodsAdult pig pancreatic cells were prepared from the non-endocrine fraction of adult pig pancreata. Porcine neonatal pancreas cell clusters (NPCCs were prepared from neonatal pigs aged 1-2 days. The dispersed pancreatic cells were infected with PDX-1/VP16, BETA2/NeuroD, and MafA adenoviruses. After infection, these cells were transplanted under the kidney capsules of normoglycemic nude mice.ResultsThe adenovirus-mediated overexpression of PDX-1, BETA2/NeuroD and MafA induced insulin gene expression in NPCCs, but not in adult pig pancreatic cells. Immunocytochemistry revealed that the number of insulin-positive cells in NPCCs and adult pig pancreatic cells was approximately 2.6- and 1.1-fold greater than those in the green fluorescent protein control group, respectively. At four weeks after transplantation, the relative volume of insulin-positive cells in the grafts increased in the NPCCs, but not in the adult porcine pancreatic cells.ConclusionThese data indicate that PDX-1, BETA2/NeuroD, and MafA facilitate the beta-cell differentiation of NPCCs, but not adult pig pancreatic cells. Therefore PDX-1, BETA2/NeuroD, and MafA-induced NPCCs can be considered good sources for the induction of pancreatic beta-cells, and may also have some utility in the treatment of diabetes.

  14. Effects of Splenectomy on Spontaneously Chronic Pancreatitis in aly/aly Mice

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    Heng-Xiao Wang

    2010-01-01

    Full Text Available Background and Aim. Mice with alymphoplasia (aly/aly mutation characterized by a lack of lymph nodes, Peyer's patches, and well-defined lymphoid follicles in the spleen were found. In this study, we used splenectomized aly/aly mice to elucidate the effects of secondary lymphoid organs in the development of aly/aly autoimmune pancreatitis. Methods. Forty-eight 10-week-old aly/aly mice were divided into two groups for splenectomy and sham operation. Histological and immunohistochemical analyses of the pancreas were performed at the ages of 20, 30, and 40 weeks old after operation, respectively. Results. Our results showed that mononuclear cell infiltration was restricted to the interlobular connective tissues at the age of 20 weeks, and not increase obviously at the age of 30 and 40 weeks in splenectomized aly/aly mice. Furthermore, an apparent decrease in the expressions of CD4+ T, CD8+ T, and B cells was detected in the pancreatic tissues compared with sham aly/aly mice, however, no significant difference in macrophage expression between mice with and without a splenectomy. Conclusions. Inflammation infiltration and development of the pancreatitis in aly/aly mice were suppressed effectively after splenectomy, which was, at least partly, correlated to inhibition of the infiltration of T and B cells in pancreatic tissues but not to macrophages.

  15. Aetiopathogenesis of autoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    Diego Vergani; Giorgina Mieli-Vergani

    2008-01-01

    The histological hallmark of autoimmune hepatitis (AIH) is a dense portal mononuclear cell infiltrate that invades the surrounding parenchyma and comprises T and B lymphocytes,macrophages,and plasma cells.An unknown but powerful stimulus must be promoting the formation of this massive inflammatory cellular reaction that is likely to initiate and perpetuate liver damage.An autoimmune attack can follow different pathways to inflict damage on hepatocytes.Liver damage is likely to be orchestrated by CD4+T lymphocytes recognizing an autoantigenic liver peptide.To trigger an autoimmune response,the peptide must be embraced by an HLA class Ⅱ molecule and presented to naive CD4+T helper (Th0) cells by professional antigen presenting cells,with the co-stimulation of ligand-ligand fostering interaction between the two cells.Th0 cells become activated,differentiate into functional phenotypes according to the cytokines prevailing in the microenvironment and the nature of the antigen,and initiate a cascade of immune reactions determined by the cytokines produced by the activated T cells.Th1 cells,arising in the presence of the macrophage-derived interleukin (IL)-12,secrete mainly IL-2 and interferon-gamma (IFN-γ),which activate macrophages,enhance expression of HLA class Ⅰ (increasing liver cell vulnerability to a CD8+T cell cytotoxic attack),and induce expression of HLA class Ⅱ molecules on hepatocytes.Th2 cells,which differentiate from Th0 if the microenvironment is rich in IL-4,produce mainly IL-4,IL-10,and IL-13 which favour autoantibody production by B lymphocytes.Physiologically,Th1 and Th2 antagonize each other.Th17 cells,a recently described population,arise in the presence of transforming growth factor beta (TGF-β) and IL-6 and appear to have an important effector role in inflammation and autoimmunity.The process of autoantigen recognition is strictly controlled by regulatory mechanisms,such as those exerted by CD4+CD25+regulatory T cells,which derive from Th0

  16. Altered Expression of Somatostatin Receptors in Pancreatic Islets from NOD Mice Cultured at Different Glucose Concentrations In Vitro and in Islets Transplanted to Diabetic NOD Mice In Vivo

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    Eva Ludvigsen

    2011-01-01

    Full Text Available Somatostatin acts via five receptors (sst1-5. We investigated if the changes in pancreatic islet sst expression in diabetic NOD mice compared to normoglycemic mice are a consequence of hyperglycemia or the ongoing immune reaction in the pancreas. Pancreatic islets were isolated from NOD mice precultured for 5 days and further cultured for 3 days at high or low glucose before examined. Islets were also isolated from NOD mice and transplanted to normal or diabetic mice in a number not sufficient to cure hyperglycemia. After three days, the transplants were removed and stained for sst1-5 and islet hormones. Overall, changes in sst islet cell expression were more common in islets cultured in high glucose concentration in vitro as compared to the islet transplantation in vivo to diabetic mice. The beta and PP cells exhibited more frequent changes in sst expression, while the alpha and delta cells were relatively unaffected by the high glucose condition. Our findings suggest that the glucose level may alter sst expressed in islets cells; however, immune mechanisms may counteract such changes in islet sst expression.

  17. Effects of Glucagon-Like Peptide 1 on PDX-1, PAX-6 and NKx2.2 Gene Expressions in Isolated Pancreatic Islets

    Institute of Scientific and Technical Information of China (English)

    Dai Cui; Wei Tang; Cuiping Liu; Kuanfeng Xu; Chao Liu

    2006-01-01

    Objective: To observe the effect of glucagon-like peptide 1 (GLP-1) on the gene expressions of transcription factors (PDX-1, PAX-6 and NKx2.2) in freshly isolated rat pancreatic islets and investigate the associated physiological and therapeutic implication of GLP-1. Methods: The isolated rat islets were incubated with 10 nmol/L GLP-1 for 1, 3 and 5 days, respectively. Total cellular RNA was extracted and the expressions of PDX-1, PAX-6 and NKx2.2 gene were detected by semiquantity RT-PCR. Results: Compared with the control group, the PDX-1, PAX-6 and NKx2.2 gene expressions were significantly increased after co-cultured with GLP-1 for 1 day (P < 0.05). The effect was shown in a time-dependent manner. All three gene expressions reached the peak on the 5th day. Conclusion: GLP-1 can improve the function of pancreatic islet by regulating the gene expressions of transcription factors in β cells.

  18. Clinicopathological significance of Bcl-2 and Bax protein expression in human pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Ming Dong; Jian-Ping Zhou; Hao Zhang; Ke-Jian Guo; Yu-Lin Tian; Yu-Ting Dong

    2005-01-01

    AIM: To assess the clinicopathological significance of the expression of the apoptosis-inhibitory Bcl-2 protein (pBcl-2) and the apoptosis-promoting Bax protein (pBax) in human invasive ductal carcinomas (IDCs) of the pancreas. METHODS: Fifty-nine surgical specimens of IDCs of the pancreas were stained immunohistochemically to detectpBcl-2 and pBax expressions whose correlation to tumor classification, staging, and prognosis was analyzed by univariate and multivariate analyses. RESULTS: The expression of pBcl-2 and pBax was detected in 21 of 59 (35.6%) and in 29 of 59 (49.2%) patients with IDCs of the pancreas, respectively. Neither pBcl-2 nor pBax alone was correlated to TNM staging and differentiation degree of IDCs of the pancreas according to univariate analysis. By Mantel-Cox test, the median survival time after surgery for pBcl-2(+) and pBcl-2(-) groups were 14.3 and 7.3 mo, respectively (χ2= 9.357, P = 0.002) and that for pBax(+) and pBax(-) groups were 12.9 and 10.2 mo, respectively (χ2= 0.285, P>0.05).Contingency coefficient between pBd-2 and pBax expression was 0.298, indicating that there was correlation between them (χ2= 5.74, P<0.05). The median survival time after surgery for pBd-2(+)pBax(+) and pBcl-2(+)pBax(-) groups were 14.3 and 14.1 mo, respectively, and that for pBcl-2 (-)pBax(+) and pBcl-2(-)pBax(-) groups were 5.9 and 9.9 mo, respectively. There was a significant difference between pBcl-2(+)pBax(+) and pBcl-2(-)pBax(+) (χ2 = 5.06,P<0.05), such was the case for pBcl-2(+)pBax(+) andpBcl-2(-)pBax(-) (χ2= 7.18, P<0.01). Cox proportional hazards model for multivariate analysis was applied, indicating that pBcl-2, TNM staging, age and pBax were high risk factors of post-surgical survival time. CONCLUSION: Both pBcl-2 and pBax have high expression in IDCs of the pancreas, indicating that co-expression of pBcl-2 and pBax is a good indicator of favorable prognosis in IDCs of the pancreas.

  19. Endoplasmic reticulum stress response in an INS-1 pancreatic β-cell line with inducible expression of a folding-deficient proinsulin

    Directory of Open Access Journals (Sweden)

    Lai Elida

    2010-07-01

    Full Text Available Abstract Background Cells respond to endoplasmic reticulum stress (ER stress by activating the unfolded protein response. To study the ER stress response in pancreatic β-cells we developed a model system that allows for pathophysiological ER stress based on the Akita mouse. This mouse strain expresses a mutant insulin 2 gene (C96Y, which prevents normal proinsulin folding causing ER stress and eventual β-cell apoptosis. A double-stable pancreatic β-cell line (pTet-ON INS-1 with inducible expression of insulin 2 (C96Y fused to EGFP was generated to study the ER stress response. Results Expression of Ins 2 (C96Y-EGFP resulted in activation of the ER stress pathways (PERK, IRE1 and ATF6 and caused dilation of the ER. To identify gene expression changes resulting from mutant insulin expression we performed microarray expression profiling and real time PCR experiments. We observed an induction of various ER chaperone, co-chaperone and ER-associated degradation genes after 24 h and an increase in pro-apoptotic genes (Chop and Trib3 following 48 h of mutant insulin expression. The latter changes occurred at a time when general apoptosis was detected in the cell population, although the relative amount of cell death was low. Inhibiting the proteasome or depleting Herp protein expression increased mutant insulin levels and enhanced cell apoptosis, indicating that ER-associated degradation is maintaining cell survival. Conclusions The inducible mutant insulin expressing cell model has allowed for the identification of the ER stress response in β-cells and the repertoire of genes/proteins induced is unique to this cell type. ER-associated degradation is essential in maintaining cell survival in cells expressing mutant insulin. This cell model will be useful for the molecular characterization of ER stress-induced genes.

  20. Chronic Pancreatitis: Landmark Papers, Management Decisions, and Future.

    Science.gov (United States)

    DiMagno, Eugene P; DiMagno, Matthew J

    2016-01-01

    On May 16, 2015 at the invitation of the American Gastroenterological Association Institute Council E.P.D. presented a state-of-the-art lecture at Digestive Disease Week 2015. The aims were to discuss a selection of landmark papers in chronic pancreatitis (CP) that influence modern management and to conclude by suggesting some future directions. This is based on that presentation. We will specifically review the following: duct anatomy and pancreas divisum, description of chronic relapsing pancreatitis and its differentiation from recurrent acute pancreatitis and established CP (ECP), natural histories and gene discoveries of alcoholic, idiopathic and hereditary pancreatitis, development of pancreatic cancer in CP, exocrine pancreatic insufficiency and calculation of dose and delivery of enzymes, endoscopic ultrasonography, and autoimmune pancreatitis. With some exceptions, we exclude basic science and surgery.

  1. Expression of DNMT1 and DNMT3a are regulated by GLI1 in human pancreatic cancer.

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    ShanShan He

    Full Text Available BACKGROUND AND AIMS: GLI1, as an indispensable transcriptional factor of Hedgehog signaling pathway, plays an important role in the development of pancreatic cancer (PC. DNA methyltransferases (DNMTs mediate the methylation of quantity of tumor-related genes. Our study aimed to explore the relationship between GLI1 and DNMTs. METHODS: Expressions of GLI1 and DNMTs were detected in tumor and adjacent normal tissues of PC patients by immunohistochemistry (IHC. PANC-1 cells were treated by cyclopamine and GLI1-siRNA, while BxPC-3 cells were transfected with overexpression-GLI1 lentiviral vector. Then GLI1 and DNMTs expression were analyzed by qRT-PCR and western blot (WB. Then we took chromatin immunoprecipitation (ChIP to demonstrate GLI1 bind to DNMT1. Finally, nested MSP was taken to valuate the methylation levels of APC and hMLH1, when GLI1 expression altered. RESULTS: IHC result suggested the expressions of GLI1, DNMT1 and DNMT3a in PC tissues were all higher than those in adjacent normal tissues (p<0.05. After GLI1 expression repressed by cyclopamine in mRNA and protein level (down-regulation 88.1±2.2%, 86.4±2.2%, respectively, DNMT1 and DNMT3a mRNA and protein level decreased by 91.6%±2.2% and 83.8±4.8%, 87.4±2.7% and 84.4±1.3%, respectively. When further knocked down the expression of GLI1 by siRNA (mRNA decreased by 88.6±2.1%, protein decreased by 63.5±4.5%, DNMT1 and DNMT3a mRNA decreased by 80.9±2.3% and 78.6±3.8% and protein decreased by 64.8±2.8% and 67.5±5.6%, respectively. Over-expression of GLI1 by GLI1 gene transfection (mRNA increased by 655.5±85.9%, and protein increased by 272.3±14.4%., DNMT1 and DNMT3a mRNA and protein increased by 293.0±14.8% and 578.3±58.5%, 143.5±17.4% and 214.0±18.9%, respectively. ChIP assays showed GLI1 protein bound to DNMT1 but not to DNMT3a. Results of nested MSP demonstrated GLI1 expression affected the DNA methylation level of APC but not hMLH1 in PC. CONCLUSION: DNMT1 and DNMT3a

  2. Infections and autoimmune diseases.

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    Bach, Jean-François

    2005-01-01

    nature of the link. Epidemiological and clinical data support the hygiene hypothesis according to which the decrease of infections observed over the last three decades is the main cause of the incessant increase in immune disorders. The hypothesis does not exclude an etiological role for specific pathogens in a given immune disorder as might notably be the case in inflammatory bowel diseases. Even in this setting, infections could still have a non-specific protective role. Independently of the need for confirmation by epidemiological prospective studies, the hygiene hypothesis still poses numerous questions concerning the nature of protective infectious agents, the timing of their involvement with regard to the natural history of immune diseases and, most importantly, the mechanisms of protection. Four orders of mechanisms are being explored. Antigenic competition is the first hypothesis (immune responses against pathogens compete with autoimmune and allergic responses). This is probably an important mechanism but its modalities are still elusive in spite of considerable experimental data. Its discussion in the context of homeostatic regulation of lymphocyte pools has shed new light on this hypothesis with possible competition for self MHC peptide recognition and interleukin-7. Another hypothesis deals with immunoregulation. Infectious agents stimulate a large variety of regulatory cells (Th2, CD25+, Tr1, NKT, ...) whose effects extend to other specificities than those which triggered their differentiation (bystander suppression). Infectious agents may also intervene through components which are not recognized as antigens but bind to specific receptors on cells of the immune system. Major attention has recently been drawn to Toll receptors (expressed on macrophages and possibly on regulatory T cells) and TIM proteins present on Th cells, which may express the function of the virus receptor (as in the case of the Hepatitis A virus and Tim-1). Experimental data will be

  3. MCP-1 Upregulates Amylin Expression in Murine Pancreatic β Cells through ERK/JNK-AP1 and NF-κB Related Signaling Pathways Independent of CCR2

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    Cai, Kun; Qi, Dongfei; Hou, Xinwei; Wang, Oumei; Chen, Juan; Deng, Bo; Qian, Lihua; Liu, Xiaolong; Le, Yingying

    2011-01-01

    Background Amylin is the most abundant component of islet amyloid implicated in the development of type 2 diabetes. Plasma amylin levels are elevated in individuals with obesity and insulin resistance. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is involved in insulin resistance of obesity and type 2 diabetes. We investigated the effect of MCP-1 on amylin expression and the underlying mechanisms with murine pancreatic β-cell line MIN6 and pancreatic islets. Methodology/Principal Findings We found that MCP-1 induced amylin expression at transcriptional level and increased proamylin and intermediate forms of amylin at protein level in MIN6 cells and islets. However, MCP-1 had no effect on the expressions of proinsulin 1 and 2, as well as prohormone convertase (PC) 1/3 and PC2, suggesting that MCP-1 specifically induces amylin expression in β-cells. Mechanistic studies showed that although there is no detectable CCR2 mRNA in MIN6 cells and islets, pretreatment of MIN6 cells with pertussis toxin inhibited MCP-1 induced amylin expression, suggesting that alternative Gi-coupled receptor(s) mediates the inductive effect of MCP-1. MCP-1 rapidly induced ERK1/2 and JNK phosphorylation. Inhibitors for MEK1/2 (PD98059), JNK (SP600125) or AP1 (curcumin) significantly inhibited MCP-1-induced amylin mRNA expression. MCP-1 failed to induce amylin expression in pancreatic islets isolated from Fos knockout mice. EMSA showed that JNK and ERK1/2 were involved in MCP-1-induced AP1 activation. These results suggest that MCP-1 induces murine amylin expression through AP1 activation mediated by ERK1/2 or JNK. Further studies showed that treatment of MIN6 cells with NF-κB inhibitor or overexpression of IκBα dominant-negative construct in MIN6 cells significantly inhibited MCP-1-induced amylin expression, suggesting that NF-κB related signaling also participates in MCP-1-induced murine amylin expression. Conclusions/Significance MCP-1 induces amylin expression through ERK1/2/JNK

  4. MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2.

    Directory of Open Access Journals (Sweden)

    Kun Cai

    Full Text Available BACKGROUND: Amylin is the most abundant component of islet amyloid implicated in the development of type 2 diabetes. Plasma amylin levels are elevated in individuals with obesity and insulin resistance. Monocyte chemoattractant protein-1 (MCP-1, CCL2 is involved in insulin resistance of obesity and type 2 diabetes. We investigated the effect of MCP-1 on amylin expression and the underlying mechanisms with murine pancreatic β-cell line MIN6 and pancreatic islets. METHODOLOGY/PRINCIPAL FINDINGS: We found that MCP-1 induced amylin expression at transcriptional level and increased proamylin and intermediate forms of amylin at protein level in MIN6 cells and islets. However, MCP-1 had no effect on the expressions of proinsulin 1 and 2, as well as prohormone convertase (PC 1/3 and PC2, suggesting that MCP-1 specifically induces amylin expression in β-cells. Mechanistic studies showed that although there is no detectable CCR2 mRNA in MIN6 cells and islets, pretreatment of MIN6 cells with pertussis toxin inhibited MCP-1 induced amylin expression, suggesting that alternative Gi-coupled receptor(s mediates the inductive effect of MCP-1. MCP-1 rapidly induced ERK1/2 and JNK phosphorylation. Inhibitors for MEK1/2 (PD98059, JNK (SP600125 or AP1 (curcumin significantly inhibited MCP-1-induced amylin mRNA expression. MCP-1 failed to induce amylin expression in pancreatic islets isolated from Fos knockout mice. EMSA showed that JNK and ERK1/2 were involved in MCP-1-induced AP1 activation. These results suggest that MCP-1 induces murine amylin expression through AP1 activation mediated by ERK1/2 or JNK. Further studies showed that treatment of MIN6 cells with NF-κB inhibitor or overexpression of IκBα dominant-negative construct in MIN6 cells significantly inhibited MCP-1-induced amylin