Inhibition of ribonucleotide reductase subunit M2 enhances the radiosensitivity of metastatic pancreatic neuroendocrine tumor.

Ribonucleotide Reductase (RNR) is a rate-limiting enzyme in the production of deoxyribonucleoside triphosphates (dNTPs), which are essential substrates for DNA repair after radiation damage. We explored the radiosensitization property of RNR and investigated a selective RRM2 inhibitor, 3-AP, as a radiosensitizer in the treatment of metastatic pNETs. We investigated the role of RNR subunit, RRM2, in pancreatic neuroendocrine (pNET) cells and responses to radiation in vitro.

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors.

Patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor overall prognosis despite chemotherapy and radiotherapy (e.g., peptide receptor radionuclide therapy (PRRT)).

Kinase suppressor of Ras 1 and Exo70 promote fatty acid-stimulated neurotensin secretion through ERK1/2 signaling.

Neurotensin is a peptide hormone released from enteroendocrine cells in the small intestine in response to fat ingestion. Although the mechanisms regulating neurotensin secretion are still incompletely understood, our recent findings implicate a role for extracellular signal-regulated kinase 1 and 2 as positive regulators of free fatty acid-stimulated neurotensin secretion. Previous studies have shown that kinase suppressor of Ras 1 acts as a molecular scaffold of the Raf/MEK/extracellular signal-regulated kinase 1 and 2 kinase cascade and regulates intensity and duration of extracellular signal-regulated kinase 1 and 2 signaling.

FFAR4 Is Involved in Regulation of Neurotensin Release From Neuroendocrine Cells and Male C57BL/6 Mice.

Neurotensin (NT), a 13 amino-acid peptide, is predominantly released from enteroendocrine cells of the small bowel in response to fat ingestion. Free fatty acid receptors (FFARs) FFAR1 and FFAR4 regulate secretion of gut hormones and insulin. Here, we show that docosahexaenoic acid, a long-chain fatty acid, has the most dramatic effect on NT release.

Neurotensin Receptor 3/Sortilin Contributes to Tumorigenesis of Neuroendocrine Tumors Through Augmentation of Cell Adhesion and Migration.

Neurotensin (NTS), a 13-amino acid peptide which is distributed predominantly along gastrointestinal tract, has multiple physiologic and pathologic functions, and its effects are mediated by three distinct NTS receptors (NTSRs). Overexpression and activation of NTS signaling components, especially NTS and/or NTSR1, are closely linked with cancer progression and metastasis in various types of cancers including neuroendocrine tumors (NETs). Although deregulation of NTSR3/sortilin has been implicated in a variety of human diseases, the expression and role of NTSR3/sortilin in NETs have not been elucidated.

Characterization of Mentorship Programs in Departments of Surgery in the United States.

Importance: Mentorship is considered a key element for career satisfaction and retention in academic surgery. Stakeholders of an effective mentorship program should include the mentor, the mentee, the department, and the institution.

Objective: The objective of this study was to characterize the status of mentorship programs in departments of surgery in the United States, including the roles of all 4 key stakeholders, because to our knowledge, this has never been done.

Activation of AMPK Stimulates Neurotensin Secretion in Neuroendocrine Cells.

AMP-activated protein kinase (AMPK), a critical fuel-sensing enzyme, regulates the metabolic effects of various hormones. Neurotensin (NT) is a 13-amino acid peptide predominantly localized in enteroendocrine cells of the small bowel and released by fat ingestion. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with an increased risk of diabetes, cardiovascular disease, and mortality; however, the mechanisms regulating NT release are not fully defined.

Differential expression and tumorigenic function of neurotensin receptor 1 in neuroendocrine tumor cells.

Neurotensin (NTS), localized predominantly to the small bowel, stimulates the growth of a variety of cancers, including neuroendocrine tumors (NETs), mainly through its interaction with the high-affinity NTS receptor 1 (NTSR1). Here, we observed increased expression of NTSR1 in almost all tested clinical NET samples, but not in normal tissues. Through RT-PCR analysis, we found that the expression of NTSR1 and NTSR2 was either variable (NTSR1) or absent (NTSR2) in human NET cell lines.

The risk paradox: use of elective cholecystectomy in older patients is independent of their risk of developing complications.

Background: We recently developed and validated a prognostic model that accurately predicts the 2-year risk of emergent gallstone-related hospitalization in older patients presenting with symptomatic gallstones.

Study Design: We used 100% Texas Medicare data (2000 to 2011) to identify patients aged 66 years and older with an initial episode of symptomatic gallstones not requiring emergency hospitalization. At presentation, we calculated each patient's risk of 2-year gallstone-related emergent hospitalization using the previously validated model.

Neurotensin, a novel target of Wnt/β-catenin pathway, promotes growth of neuroendocrine tumor cells.

Wnt/β-catenin signaling plays a pivotal role in regulating cell growth and differentiation by activation of the β-catenin/T-cell factor (TCF) complex and subsequent regulation of a set of target genes that have one or more TCF-binding elements (TBEs). Hyperactivation of this pathway has been implicated in numerous malignancies including human neuroendocrine tumors (NETs). Neurotensin (NT), an intestinal hormone, induces proliferation of several gastrointestinal (GI) cancers including cancers of the pancreas and colon.

Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors.

Background: The precise involvement of the PI3K/mTOR and RAS/MEK pathways in carcinoid tumors is not well defined. Therefore, the purpose of our study was to evaluate the role these pathways play in carcinoid cell proliferation, apoptosis, and secretion and to determine the effects of combined treatment on carcinoid tumor inhibition.

Methods: The human neuroendocrine cell lines BON (pancreatic carcinoid), NCI-H727 (lung carcinoid), and QGP-1 (somatostatinoma) were treated with either the pan-PI3K inhibitor, BKM120, or the dual PI3K-mTOR inhibitor, BEZ235, alone or in combination with the MEK inhibitor, PD0325901; proliferation, apoptosis, and protein expression were assessed.

Dual inhibition of PI3K and mTOR signaling pathways decreases human pancreatic neuroendocrine tumor metastatic progression.

Objectives: Patients with advanced pancreatic neuroendocrine tumors have limited therapeutic options. Everolimus (RAD001), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, has been shown to increase progression-free survival, but not overall survival, indicating a need to identify additional therapeutic targets. Inhibition of mTOR complex 1 by RAD001 may induce upstream AKT upregulation.

Association between cholecystectomy with vs without intraoperative cholangiography and risk of common duct injury.

Importance: Significant controversy exists regarding routine intraoperative cholangiography in preventing common duct injury during cholecystectomy.

Objective: To investigate the association between intraoperative cholangiography use during cholecystectomy and common duct injury.

Design, Setting, And Participants: Retrospective cohort study of all Texas Medicare claims data from 2000 through 2009.

PTHrP is a novel mediator for TGF-β-induced apoptosis.

Parathyroid hormone-related protein (PTHrP) is a polyhormone secretory protein that plays fundamental roles in the development and function of various tissues. Transforming growth factor (TGF)-β is an important tumor suppressor that induces cell cycle arrest and apoptosis. Increased PTHrP expression has been implicated in TGF-β-induced growth inhibition in human hepatocellular carcinoma cells.

Time trends and geographic variation in use of minimally invasive breast biopsy.

Background: Current guidelines recommend minimally invasive breast biopsy (MIBB) as the gold standard for the diagnosis of breast lesions. The purpose of this study was to describe geographic patterns and time trends in the use of MIBB in Texas.

Methods: We used 100% Texas Medicare claims data (2000-2008) to identify women older than 66 years of age who underwent breast biopsy.

Deregulation of Wnt/β-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors.

Carcinoid tumors are rare neuroendocrine tumors (NETs) that are increasing in incidence. Mutation and altered expression of Wnt/β-catenin signaling components have been described in many tumors but have not been well-studied in NETs. Here, we observed accumulation of β-catenin in the cytoplasm and/or nucleus in 25% of clinical NET tissues.

Preoperative laboratory testing in patients undergoing elective, low-risk ambulatory surgery.

Background: Routine preoperative laboratory testing for ambulatory surgery is not recommended.

Methods: Patients who underwent elective hernia repair (N = 73,596) were identified from the National Surgical Quality Improvement Program (NSQIP) database (2005-2010). Patterns of preoperative testing were examined.

PI3K p110α/Akt signaling negatively regulates secretion of the intestinal peptide neurotensin through interference of granule transport.

Neurotensin (NT), an intestinal peptide secreted from N cells in the small bowel, regulates a variety of physiological functions of the gastrointestinal tract, including secretion, gut motility, and intestinal growth. The class IA phosphatidylinositol 3-kinase (PI3K) family, which comprised of p110 catalytic (α, β and δ) and p85 regulatory subunits, has been implicated in the regulation of hormone secretion from endocrine cells. However, the underlying mechanisms remain poorly understood.

A proposal for enhancing the general surgical workforce and access to surgical care.

Objective(s): The goals of this focused meeting were to verify and clarify the causes and extent of the general surgery (GS) workforce shortfalls. We also sought to define workable solutions within the existing framework of medical accreditation and certification.

Background: Numerous peer-reviewed and lay reports describe a current and worsening availability of GS services, affecting rural areas as well as large cities, academia, and the military.

Variation in the use of intraoperative cholangiography during cholecystectomy.

Background: The role of intraoperative cholangiography (IOC) in prevention of common bile duct (CBD) injuries and the management of CBD stones is controversial, and current variation in use of IOC has not been well described.

Study Design: Multilevel hierarchical models using data from the Texas Hospital Inpatient Discharge Public Use data files (2001 to 2008) were used to evaluate the percentage of variance in the use of IOC that was attributable to patient, surgeon, and hospital factors.

Results: A total of 176,981 cholecystectomies were performed in 212 hospitals in Texas.

Overexpression of Evi-1 oncoprotein represses TGF-β signaling in colorectal cancer.

Human colorectal cancer (CRC) cells are resistant to the anti-proliferative effect of transforming growth factor-β (TGF-β), suggesting that disruption of TGF-β signaling plays an important role in colorectal carcinogenesis. Ecotropic virus integration site-1 (Evi-1) oncoprotein represses TGF-β signaling by interacting with Smads, but its role in CRC has not been established. The purpose of this study is to determine whether Evi-1 plays role(s) in CRCs and to characterize Evi-1 transcript(s) in CRCs.

Gallstone pancreatitis in older patients: Are we operating enough?

Background: The recommended therapy for mild gallstone pancreatitis is cholecystectomy on initial hospitalization.

Methods: Using a 5% national Medicare sample (1996-2005), we evaluated adherence to current recommendations for gallstone pancreatitis (cholecystectomy rates on initial hospitalization and the use of endoscopic retrograde cholangiopancreatography [ERCP]/sphincterotomy). We evaluated predictors of cholecystectomy, gallstone-related readmissions, and 2-year mortality.

Overuse of CT in patients with complicated gallstone disease.

Background: When compared with ultrasound, CT scans are more expensive, have substantial radiation exposure and lower sensitivity, specificity, positive, and negative predictive values for patients with gallstone disease.

Study Design: We reviewed data on patients emergently admitted with complicated gallstone disease between January 2005 and May 2010. Use of CT and ultrasound imaging on admission was described.