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- Functionalizing liposomes with anti-CD44 aptamer for selective targeting of cancer cells. [JOURNAL ARTICLE]
- Bioconjug Chem 2014 Oct 24.
CD44 receptor protein is found to be overexpressed by many tumors and is identified as one of the most common cancer stem cell surface markers including tumors affecting colon, breast, pancreas, and head and neck making this receptor an attractive receptor for therapeutic targeting. In this study, 2'-F-pyrimidine-containing RNA aptamer (Apt1), previously selected for to CD44, was successfully conjugated to the surface of PEGylated liposomes using thiol-maleimide click reaction. The conjugation of Apt1 to the surface of liposomes was confirmed by change in size and zeta potential and by migration on agarose gel electrophoresis. The binding affinity of Apt1 was improved after conjugation compared to free-Apt. The cellular uptake for Apt1-Lip were tested by flow cytometry and confocal imaging using the two CD44+ cell lines, human lung cancer cells (A549) and human breast cancer cells (MDA-MB-231), and the CD44- cell line, mouse embryonic fibroblast cells (NIH/3T3). The results showed higher sensitivity and selectivity for Apt1-Lip compared to the blank liposomes (Mal-Lip). In conclusion we demonstrate a successful conjugation of anti-CD44 aptamer to the surface of liposome and binding preference of Apt1-Lip to CD44-expressing cancer cells and conclude to a promising potency of Apt1-Lip as a specific drug delivery system.
- A Computer-Based Automated Algorithm for Assessing Acinar Cell Loss after Experimental Pancreatitis. [JOURNAL ARTICLE]
- PLoS One 2014; 9(10):e110220.
The change in exocrine mass is an important parameter to follow in experimental models of pancreatic injury and regeneration. However, at present, the quantitative assessment of exocrine content by histology is tedious and operator-dependent, requiring manual assessment of acinar area on serial pancreatic sections. In this study, we utilized a novel computer-generated learning algorithm to construct an accurate and rapid method of quantifying acinar content. The algorithm works by learning differences in pixel characteristics from input examples provided by human experts. HE-stained pancreatic sections were obtained in mice recovering from a 2-day, hourly caerulein hyperstimulation model of experimental pancreatitis. For training data, a pathologist carefully outlined discrete regions of acinar and non-acinar tissue in 21 sections at various stages of pancreatic injury and recovery (termed the "ground truth"). After the expert defined the ground truth, the computer was able to develop a prediction rule that was then applied to a unique set of high-resolution images in order to validate the process. For baseline, non-injured pancreatic sections, the software demonstrated close agreement with the ground truth in identifying baseline acinar tissue area with only a difference of 1%±0.05% (p = 0.21). Within regions of injured tissue, the software reported a difference of 2.5%±0.04% in acinar area compared with the pathologist (p = 0.47). Surprisingly, on detailed morphological examination, the discrepancy was primarily because the software outlined acini and excluded inter-acinar and luminal white space with greater precision. The findings suggest that the software will be of great potential benefit to both clinicians and researchers in quantifying pancreatic acinar cell flux in the injured and recovering pancreas.
- Inhibition of BACE2 counteracts hIAPP-induced insulin secretory defects in pancreatic β-cells. [JOURNAL ARTICLE]
- FASEB J 2014 Oct 23.
BACE2 (β-site APP-cleaving enzyme 2) is a protease localized in the brain, where it appears to play a role in the development of Alzheimer disease (AD). It is also found in the pancreas, although its biologic function is not fully known. Amyloidogenic diseases, including AD and type 2 diabetes mellitus (T2D), share the accumulation of abnormally folded and insoluble proteins that interfere with cell function. Islet amyloid polypeptide (IAPP) deposits are a key pathogenic feature of T2D. Within this context, we found by global gene expression profiling that BACE2 was up-regulated in the rat pancreatic β-cell line INS1E stably transfected with human IAPP gene (hIAPP-INS1E). Glucose-stimulated insulin secretion (GSIS) in hIAPP-INS1E cells was 30% lower than in INS1E cells. Additionally, INS1E cells transfected with a transient overexpression of BACE2 showed a 60% decrease in proliferation, a 3-fold increase in reactive oxygen species production, and a 25% reduction in GSIS compared to control cells. Remarkably, silencing of endogenous BACE2 in hIAPP-INS1E cells resulted in a significant improvement in GSIS (3-fold increase vs. untransfected cells), revealing the significant role of BACE2 expression in β-cell function. Thus, BACE2 inhibition may be useful to recover insulin secretion in hIAPP-INS1E defective cells and may be proposed as a therapeutic target for T2D.-Alcarraz-Vizán, G., Casini, P., Cadavez, L., Visa, M., Montane, J., Servitja, J.-M., Novials, A. Inhibition of BACE2 counteracts hIAPP-induced insulin secretory defects in pancreatic β-cells.
- Solid pseudopapillary tumor of the pancreas: a rare entity. [JOURNAL ARTICLE]
- Turk J Pediatr 2014 May-June; 56(3):310-312.
Solid pseudopapillary tumor (SPT) of the pancreas is a rare neoplasm in children that mainly occurs in young females. We herein report a rare case of SPT arising from the tail of the pancreas. A 13-year-old girl was admitted to our clinic with abdominal pain and anorexia. A mass was palpated on the physical examination. A 90x72 mm, encapsulated, heterogeneous mass with solid and cystic components was defined on computerized tomography (CT). Distal pancreatectomy was performed during the operation. Histopathological examination revealed that the tumor was a SPT with negative surgical margins. A six-month follow-up after surgical resection showed no evidence of recurrent disease. SPT should always be considered in the differential diagnosis in a young female with a palpable mass.
- Updated Imaging Nomenclature for Acute Pancreatitis. [JOURNAL ARTICLE]
- AJR Am J Roentgenol 2014 Nov; 203(5):W464-W469.
KEY POINTS 1. CT is used to confirm the diagnosis of acute pancreatitis when the diagnosis is in doubt and to differentiate acute interstitial pancreatitis from necrotizing pancreatitis, which is a key element of the updated Atlanta nomenclature. The acute interstitial variety accounts for 90-95% of cases, with acute necrotizing pancreatitis accounting for the remaining cases. 2. Necrosis due to acute pancreatitis is best assessed on IV contrast-enhanced CT performed 40 seconds after injection. Peripancreatic necrosis is a subtype of necrotizing pancreatitis in which tissue death occurs in peripancreatic tissues. This is seen in isolation in 20% of patients with necrotizing pancreatitis. 3. Simple fluid collections associated with acute interstitial pancreatitis are subdivided chronologically. A collection observed within approximately 4 weeks of acute pancreatitis onset is termed an "acute peripancreatic fluid collection (APFC)." A collection older than 4 weeks should have a thin wall and is termed a "pseudocyst." Both APFCs and pseudocysts can be infected or sterile. 4. Fluid collections associated with necrotizing pancreatitis are labeled on the basis of age and the presence of a capsule. Within 4 weeks of acute pancreatitis onset, a fluid collection associated with necrotizing pancreatitis is termed an "acute necrotic collection (ANC)" whereas an older collection is termed an area of "walled-off necrosis (WON)" if it has a perceptible wall on CT. The term "pseudocyst" is not used in the setting of necrotizing pancreatitis collections. Although an ANC and a (WON can be infected or sterile, infection is far more likely compared with acute interstitial pancreatitis collections. 5. The severity of acute pancreatitis is graded on the basis of the presence of acute complications or organ failure. Mild acute pancreatitis has neither acute complications nor organ failure. Moderate-severity acute pancreatitis is associated with acute complications or organ failure lasting fewer than 48 hours. Severe acute pancreatitis is characterized by single- or multiorgan failure persisting for greater than 48 hours.
- Value of Diffusion-Weighted MRI for Differentiating Malignant From Benign Intraductal Papillary Mucinous Neoplasms of the Pancreas. [JOURNAL ARTICLE]
- AJR Am J Roentgenol 2014 Nov; 203(5):992-1000.
OBJECTIVE. The purpose of this study was to evaluate whether the use of diffusion-weighted MRI (DWI) increases diagnostic accuracy in the differentiation of malignant from benign intraductal papillary mucinous neoplasms (IPMNs) of the pancreas over the accuracy of contrast-enhanced MRI with MRCP. MATERIALS AND METHODS. A total of 61 patients with surgically resected IPMNs (19 malignant, 42 benign) who underwent gadoxetic acid-enhanced MRI, DWI, and MRCP were included. Two blinded observers evaluated two image sets, that is, conventional MRI with MRCP images versus combined conventional MRI with MRCP and DW images, and scored their confidence for malignancy of IPMNs. Qualitative analyses of the IPMNs were also conducted. Diagnostic performance (ROC curve analysis), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were evaluated. The Fisher exact test was used to compare groups. RESULTS. The diagnostic performance (area under the ROC curve [Az]) with respect to predicting malignancy of IPMNs improved significantly for both observers after additional review of DW images (p < 0.05). The diagnostic accuracy, sensitivity, specificity, PPV, and NPV of combined conventional and DW images were higher than those of conventional MR images alone. Diffusion restriction was more often present in malignant IPMNs (78.9%) than in benign IPMNs (16.7%) (p < 0.001) with excellent interobserver agreement (ĸ = 0.965). CONCLUSION. Compared with conventional MRI alone, adding DWI to conventional MRI improves diagnostic accuracy with increased specificity for differentiating malignant from benign IPMNs of the pancreas.
- Interobserver Agreement for Detection of Malignant Features of Intraductal Papillary Mucinous Neoplasms of the Pancreas on MDCT. [JOURNAL ARTICLE]
- AJR Am J Roentgenol 2014 Nov; 203(5):973-979.
OBJECTIVE. The purpose of this retrospective study was to measure interobserver agreement in the assessment of malignant imaging features of intraductal papillary mucinous neoplasms (IPMNs) on MDCT. MATERIALS AND METHODS. Pancreatic protocol CT studies were reviewed for 84 patients with resected IPMNs. Maximal diameter of the dominant cyst, presence of a mural nodule, presence of a solid component, and diameters of the main pancreatic duct (MPD) and common bile duct (CBD) were measured by four radiologists independently. In each patient, the IPMN was classified into one of three types: main duct, branch duct, or mixed IPMN. Interobserver agreement of lesion features was examined using the intraclass correlation coefficient (ICC) for continuous features and Fleiss kappa for categorical features. RESULTS. The final dataset included 55 branch duct IPMNs, nine main duct IPMNs, and 20 mixed IPMNs. Moderate agreement (ĸ = 0.458; 95% CI, 0.345-0.564) was observed in assigning branch duct, main duct, or mixed IPMN subtypes. Measurement agreement was substantial to excellent for dominant cyst (ICC = 0.852; 95% CI, 0.777-0.907), MPD (0.753, 0.655-0.837), and CBD (0.608, 0.463-0.724) but only fair to moderate for the detection of the presence of mural nodule (ĸ = 0.284, 0.125-0.432) or solid component (ĸ = 0.405, 0211-0.577). CONCLUSION. Substantial to excellent interobserver agreement in the measurement of cyst diameter, MPD, and CBD support their use for characterizing malignant features of IPMN on MDCT. However, the subjective interpretation of the presence of solid components and mural nodules by individual radiologists was more variable.
- Carrot juice fermented with Lactobacillus plantarum NCU116 ameliorates type 2 diabetes in rats. [JOURNAL ARTICLE]
- J Agric Food Chem 2014 Oct 22.
Effect of carrot juice fermented with Lactobacillus plantarum NCU116 on high fat and low-dose streptozotocin (STZ)-induced type 2 diabetes in rats was studied. Rats were randomly divided into five groups: non-diabetes mellitus (NDM), un-treated diabetes mellitus (DM), DM plus L. plantarum NCU116 (NCU), DM plus fermented carrot juice with L. plantarum NCU116 (FCJ) and DM plus non-fermented carrot juice (NFCJ). Treatment of NCU and FCJ for 5 weeks were found to favorably regulate blood glucose, hormones and lipid metabolism in the diabetic rats, accompanied by an increase in short chain fatty acids (SCFA) in colon. In addition, NCU and FCJ had restored the antioxidant capacity, morphology of pancreas and kidney, and up regulated mRNA of low-density lipoprotein (LDL) receptor, cholesterol 7α-hydroxylase (CYP7A1), glucose transporter-4 (GLUT-4), peroxisome proliferator-activated receptor-α (PPAR-α), and peroxisome proliferator-activated receptor-γ (PPAR-γ). These results have for the first time demonstrated that L. plantarum NCU116 and the fermented carrot juice had the potential ability to ameliorate type 2 diabetes in rats.
- A Tale of Two Tumors: Treating Pancreatic and Extrapancreatic Neuroendocrine Tumors. [JOURNAL ARTICLE]
- Annu Rev Med 2014 Oct 17.
Despite their perceived rarity, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rising in incidence and prevalence. The biology, natural history, and therapeutic options for GEP-NETs are heterogeneous: NETs arising in the pancreas can be distinguished from those arising elsewhere in the gastrointestinal tract, and therapy is dichotomized between these two groups. Somatostatin analogues are the mainstay of oncologic management of bowel NETs; everolimus, streptozocin, and sunitinib are approved to treat pancreatic NETs. There are significant differences in molecular genetics between pancreatic and extrapancreatic NETs, and studies are evaluating whether additional NET patients may benefit from targeted agents. We discuss the distinguishing features of these two groups of tumors, as well as the therapeutic implications of the distinction. We also [examine] the evolving therapeutic landscape and discuss the likelihood that treatment will be developed independently for pancreatic and extrapancreatic gastrointestinal NETs, with novel therapeutics effective for newly identified pathologically or molecularly defined subgroups. Expected final online publication date for the Annual Review of Medicine Volume 66 is January 14, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
- Rapamycin Protection of Livers From Ischemia and Reperfusion Injury is Dependent on Both Autophagy Induction and Mammalian Target of Rapamycin Complex 2-Akt Activation. [JOURNAL ARTICLE]
- Transplantation 2014 Oct 21.
Although rapamycin (RPM) have been studied extensively in ischemia models, its functional mechanisms remains to be defined.We determined how RPM impacted the pathogenesis of ischemia-reperfusion injury (IRI) in a murine liver partial warm ischemia model, with emphasis on its regulation of hepatocyte death.Rapamycin protected livers from IRI in the presence of fully developed liver inflammatory immune response. Rapamycin enhanced liver autophagy induction at the reperfusion stage. Dual mammalian (mechanic) target of rapamycin (mTOR)1/2 inhibitor Torin 1, despite its ability to induced autophagy, failed to protect livers from IRI. The treatment with RPM, but not Torin 1, resulted in the enhanced activation of the mTORC2-Akt signaling pathway activation in livers after reperfusion. Inactivation of Akt by Triciribine abolished the liver protective effect of RPM. The differential cytoprotective effect of RPM and Torin 1 was confirmed in vitro in hepatocyte cultures. Rapamycin, but not Trin 1, protected hepatocytes from stress and tumor necrosis factor-α induced cell death; and inhibition of autophagy by chloroquine or Akt by Triciribine abolished RPM-mediated cytoprotection.Rapamycin protected livers from IRI by both autophagy and mTORC2-Akt activation mechanisms.