Search

Background: Small bowel carcinoid tumor is a rare neoplasm and increasing in incidence. Patients with small bowel carcinoid tumors often experience long delays in diagnosis due to the vague symptoms, slow growth of tumors, and lack of clinician awareness. Computed tomography (CT) is the most common imaging study for diagnosis of small bowel carcinoid tumor. It is often used with positron emission tomography (PET) to capture anatomical and functional aspects of carcinoid tumors and thus to increase the sensitivity. Purpose: We compared three different kinds of methods for the automatic detection of small bowel carcinoid tumors on CT scans, which is the first to the best of our knowledge. Methods: Thirty‐three preoperative CT scans of 33 unique patients with surgically‐proven carcinoid tumors within the small bowel were collected. Ground‐truth segmentation of tumors was drawn on CT scans by referring to available 18F‐DOPA PET scans and the corresponding radiology report. These scans were split into the trainval set (n = 24) and the test positive set (n= 9). Additionally, 22 CT scans of 22 unique patients who had no evidence of the tumor were collected to comprise the test negative set. We compared three different kinds of detection methods, which are detection network, patch‐based classification, and segmentation‐based methods. We also investigated the usefulness of small bowel segmentation for reduction of false positives (FPs) for each method. Free‐response receiver operating characteristic (FROC) curves and receiver operating characteristic (ROC) curves were used for lesion‐ and patient‐level evaluations, respectively. Statistical analyses comparing the FROC and ROC curves were also performed. Results: The detection network method performed the best among the compared methods. For lesion‐level detection, the detection network method, without the small bowel segmentation‐based filtering, achieved sensitivity values of (60.8%, 81.1%, 82.4%, 86.5%) at per‐scan FP rates of (1, 2, 4 ,8), respectively. The use of the small bowel segmentation did not improve the performance (p=0.742$p=0.742$). For patient‐level detection, again the detection network method, but with the small bowel segmentation‐based filtering, achieved the highest AUC of 0.86 with a sensitivity of 78% and specificity of 82% at the Youden point. Conclusions: The carcinoid tumors in this patient population were very small and potentially difficult to diagnose. The presented method showed reasonable sensitivity at small numbers of FPs for lesion‐level detection. It also achieved a promising AUC for patient‐level detection. The method may have clinical application in patients with this rare and difficult to detect disease. [ABSTRACT FROM AUTHOR]

Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Here, we examined whether the gain of Myc and the loss of RB1 and Trp53 function in EC cells result in SI-NET using tryptophan hydroxylase 1 (TPH1) Cre-ERT2-driven RB1fl Trp53fl MycLSL (RPM) mice. TPH1-Cre-induced gain of Myc and loss of RB1 and Trp53 function resulted in endocrine or neuronal tumors in pancreas, lung, enteric neurons, and brain. Lineage tracing indicated that the cellular origin for these tumors was TPH1-expressing neuroendocrine, neuronal, or their precursor cells in these organs. However, despite that TPH1 is most highly expressed in EC cells of the small intestine, we observed no incidence of EC cell tumors. Instead, the tumor of epithelial cell origin in the intestine was exclusively nonendocrine adenocarcinoma, suggesting dedifferentiation of EC cells into intestinal stem cells (ISCs) as a cellular mechanism. Furthermore, ex vivo organoid studies indicated that loss of functions of Rb1 and Trp53 accelerated dedifferentiation of EC cells that were susceptible to apoptosis with expression of activated MycT58A, suggesting that the rare dedifferentiating cells escaping cell death went on to develop adenocarcinomas. Lineage tracing demonstrated that EC cells in the small intestine were short-lived compared with neuroendocrine or neuronal cells in other organs. In contrast, EC cell-derived ISCs were long-lasting and actively cycling and thus susceptible to transformation. These results suggest that tissue- and cell-specific properties of EC cells such as rapid cell turnover and homeostatic dedifferentiation, affect the fate and rate of tumorigenesis induced by genetic alterations and provide important insights into EC cell-derived tumorigenesis. [ABSTRACT FROM AUTHOR]

The cholecystokinin (CCK) receptors are divided into two types, CCK-AR and CCK-BR. These receptors mediate the actions of CCK-A and CCK-B, respectively. CCK-AR and CCK-BR are coupled with G protein and guanine nucleotides serve as secondary receptors for them. The DNA coding for these receptors has been cloned and the predicted polypeptide product is a heptahelical structure. The activities of these receptors in the gastrointestinal system are discussed.

Cholecystokinins (CKK) are peptides similar to gastrin in structure and function, both as hormones and neuropeptides. CKK and its receptors are found in the central nervous system, which release them in response to a meal. The primary structure of CKK receptors have only been recently elucidated from their cloned cDNAs by molecular techniques. Studies showed that CKK receptors have many subtypes. Their biological activity is determined by the nature of residues in the COOH-terminal tetrapeptide where they are located.

Pharmacological and biochemical analyses of the structure of cholecystokinin (CCK) receptors from pancreas and gallbladder implied the presence of different subtypes of CCK-A receptors. A cloned rat pancreatic CCK-A receptor cDNA provided the sequence required for cloning and functional expression of the CCK-A receptor contained in the pancreas and gall bladder of a guinea pig. Polymerase chain reaction facilitated the cloning of guinea pig CCK-A receptor cDNA using primer sequences from gall bladder CCK-A receptor 5- and 31-noncoding regions.

G-protein-coupled receptor 40 (GPR40) is highly expressed in pancreatic islets, and its activation increases glucose-stimulated insulin secretion from pancreas. Therefore, GPR40 is considered as a target for type 2 diabetes mellitus (T2DM). Since nonalcoholic fatty liver disease (NAFLD) is associated with T2DM and GPR40 is also expressed by hepatocytes and macrophages, it is important to understand the role of GPR40 in NAFLD. However, the role of GPR40 in NAFLD in animal models has not been well defined. In this study, we fed wild-type or GPR40 knockout C57BL/6 mice a high-fat diet (HFD) for 20 wk and then assessed the effect of GPR40 deficiency on HFD-induced NAFLD. Assays on metabolic parameters showed that an HFD increased body weight, glucose, insulin, insulin resistance, cholesterol, and alanine aminotransferase (ALT), and GPR40 deficiency did not mitigate the HFD-induced metabolic abnormalities. In contrast, we found that GPR40 deficiency was associated with increased body weight, insulin, insulin resistance, cholesterol, and ALT in control mice fed a low-fat diet (LFD). Surprisingly, histology and Oil Red O staining showed that GPR40 deficiency in LFD-fed mice was associated with steatosis. Immunohistochemical analysis showed that GPR40 deficiency also increased F4/80, a macrophage biomarker, in LFD-fed mice. Furthermore, results showed that GPR40 deficiency led to a robust upregulation of hepatic fatty acid translocase (FAT)/CD36 expression. Finally, our in vitro studies showed that GPR40 knockdown by siRNA or a GPR40 antagonist increased palmitic acid-induced FAT/CD36 mRNA in hepatocytes. Taken together, this study indicates that GPR40 plays an important role in homeostasis of hepatic metabolism and inflammation and inhibits nonalcoholic steatohepatitis by possible modulation of FAT/CD36 expression. [ABSTRACT FROM AUTHOR]

Small intestinal neuroendocrine tumors (SI-NET) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. Recent studies recognize a subset of EC cells that is label-retaining at the 4 position in the crypt and functions as a reserve intestinal stem cell. Importantly, this 4 reserve EC cell subset not only contributes to regeneration of the intestinal epithelium during injury and inflammation but also to basal crypt homeostasis at a constant rate. The latter function suggests that the 4 EC cell subset serves as an active reserve stem cell via a constant rate of dedifferentiation. Characterization of early tumor formation of SI-NET, observed as crypt-based EC cell clusters in many cases of familial SI-NETs, suggests that the 4 active reserve EC cell subset is the cell of origin. This newly discovered active reserve stem cell property of EC cells can account for unique biological mechanisms and processes associated with the genesis and development of SI-NETs. The recognition of this property of the 4 active reserve EC cell subset may provide novel opportunities to explore NETs in the gastrointestinal tract and other organs. [ABSTRACT FROM AUTHOR]