Citations

Although biomedical applications of nanotechnology, which typically involve functionalized nanoparticles, have taken significant strides, biological characterization of unmodified nanoparticles remains underinvestigated. Herein we demonstrate that unmodified gold nanoparticles (AuNPs) inhibit the proliferation of cancer cells in a size- and concentration-dependent manner by abrogating MAPK-signaling. In addition, these AuNPs reverse epithelial-mesenchymal transition (EMT) in cancer cells by reducing secretion of a number of proteins involved in EMT, up-regulating E-Cadherin, and down-regulating Snail, N-Cadherin, and Vimentin. Inhibition of MAPK signaling and reversal of EMT upon AuNP treatment inhibits tumor growth and metastasis in two separate orthotopic models of ovarian cancer. Western blot analyses of tumor tissues reveal up-regulation of E-Cadherin and down-regulation of Snail and phospho-MAPK, confirming the reversal of EMT and inhibition of MAPK signaling upon AuNP treatment. The ability of a single self-therapeutic nanoparticle to abrogate signaling cascades of multiple growth factors is distinctive and purports possible medical applications as potential antitumor and antimetastatic agent.

Abstract Adenosine 5′-triphosphate (ATP) is released from the cytoplasm under physiologic and pathophysiologic conditions and enters the extracellular space, where it acts on a group of recently cloned cell-surface receptors termed P2-purinoceptors (subtypes P2X and P2Y). We examined the effects of extracellular ATP, uridine triphosphate (UTP), the stable ATP analogues α,βmethylene-ATP (α,βmATP), β,γmethylene-ATP (β,γmATP), and 2-methylthio-ATP (2mSATP), and adenosine (10−6–10−3 M) on histamine release from human lung mast cells (HLMC) induced by anti-IgE and the calcium ionophore A23187. None of the nucleotides or adenosine directly induced histamine release. Adenosine exhibited a bimodal effect, enhancing histamine release at 10−6 to 10−4 M (P > 0.05, NS) and inhibiting it at 10−3 M (P < 0.05). ATP (10−4 M) enhanced anti-IgE–induced histamine release (10.9 ± 2.7% to 19.2 ± 2.9%, n = 20, P < 0.01), but not ionophore A23187-induced histamine release (n = 10). The adenine nucleotides consistently enhanced anti-IgE–induced histamine release; the rank order for this action was: ATP > 2mSATP > α,βmATP > β,γmATP, suggesting mediation by a P2Y-purinoceptor subtype. The selective P2X purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid failed to influence the effect of ATP, further supporting P2Y-purinoceptor mediation of anti-IgE–induced histamine release. UTP, an agonist at P2Y-purinoceptors, also significantly enhanced anti-IgE–induced histamine release. Application of the reverse transcription–polymerase chain reaction indicated that HLMC constitutively express the messenger RNAs encoding the P2Y1- and P2Y2-purinoceptor subtypes, and not that encoding the P2X7-purinoceptor (i.e., P2Z), a subtype implicated in ATP-induced histamine release in rodent peritoneal mast cells. The data produced in the study suggest that ATP plays an important modulatory role in histamine release from HLMC, and that it may therefore be mechanistically involved in human allergic/asthmatic reactions.

Abstract In shotgun proteomics, database search algorithms rely on fragmentation models to predict fragment ions that should be observed for a given peptide sequence. The most widely used strategy (Naive model) is oversimplified, cleaving all peptide bonds with equal probability to produce fragments of all charges below that of the precursor ion. More accurate models, based on fragmentation simulation, are too computationally intensive for on-the-fly use in database search algorithms. We have created an ordinal-regression-based model called Basophile that takes fragment size and basic residue distribution into account when determining the charge retention during CID/higher-energy collision induced dissociation (HCD) of charged peptides. This model improves the accuracy of predictions by reducing the number of unnecessary fragments that are routinely predicted for highly-charged precursors. Basophile increased the identification rates by 26% (on average) over the Naive model, when analyzing triply-charged precursors from ion trap data. Basophile achieves simplicity and speed by solving the prediction problem with an ordinal regression equation, which can be incorporated into any database search software for shotgun proteomic identification.

Abstract Barrett's esophagus is the precursor lesion of esophageal adenocarcinoma, whose progression follows sequential stages. However, the low progression rate and the inadequacy and subjective interpretation of histologic grading in predicting Barrett's esophagus progression call for more objective biomarkers that can improve risk prediction. We conducted a genome-wide profiling of 754 human microRNAs (miRNA) in 35 normal epithelium, 34 Barrett's esophagus, and 36 esophageal adenocarcinoma tissues using TaqMan real-time PCR-based profiling. Unsupervised hierarchical clustering using 294 modestly to highly expressed miRNAs showed clear clustering of two groups: normal epithelium versus Barrett's esophagus/esophageal adenocarcinoma tissues. Moreover, there was an excellent clustering of Barrett's metaplasia (without dysplasia) tissues from normal epithelium tissues. However, Barrett's esophagus tissues of different stages and esophageal adenocarcinoma tissues were interspersed. There were differentially expressed miRNAs at different stages. The majority of miRNA aberrations involved upregulation of expression in Barrett's esophagus and esophageal adenocarcinoma tissues, with the most dramatic alterations occurring at the Barrett's metaplasia stage. Known oncomiRs, such as miR-21, miR-25, and miR-223, and tumor suppressor miRNAs, including miR-205, miR-203, let-7c, and miR-133a, showed progressively altered expression from Barrett's esophagus to esophageal adenocarcinoma. We also identified a number of novel miRNAs that showed progressively altered expression, including miR-301b, miR-618, and miR-23b. The significant miRNA alterations that were exclusive to esophageal adenocarcinoma but not Barrett's esophagus included miR-375 downregulation and upregulation of five members of the miR-17-92 and its homologue clusters, which may become promising biomarkers for esophageal adenocarcinoma development. Cancer Prev Res; 6(3); 196–205. ©2013 AACR.

What's known on the subject? and What does the study add? Variations in the type of urinary diversion exist for patients undergoing radical cystectomy. Although its use has been increasing from 2001 to 2008, patients who are older, female, and primary insured by Medicaid are less likely to receive continent diversions. Furthermore, patients treated surgically at high‐volume and teaching hospitals are more likely to receive continent diversions. Objective To describe the contemporary trends in urinary diversion among patients undergoing radical cystectomy ( RC ) for bladder cancer; and elucidate whether socioeconomic disparities persist in the type of diversion performed in the USA from a population‐based cohort. Patients and Methods Using the Nationwide Inpatient Sample, we identified patients who underwent RC for bladder cancer between 2001 and 2008. Multivariable regression models were used to identify patient and hospital covariates associated with continent urinary diversion and enumerate predicted probabilities for statistically significant variables over time. Results Overall, 55 635 (92%) patients undergoing RC for bladder cancer received incontinent urinary diversion, while 4552 (8%) patients received continent diversion from 2001 to 2008. Receipt of continent urinary diversion increased from 6.6% in 2001–2002 to 9.4% in 2007–2008 ( P < 0.001 for trend). Patients who were older (odds ratio [ OR ] 0.93; P < 0.001), female ( OR 0.52; P < 0.001) and insured by Medicaid ( OR 0.54; P = 0.002) were less likely to receive continent urinary diversion. However, patients treated at teaching ( OR 2.14; P < 0.001) and high‐volume hospitals ( OR 2.39; P = 0.04) had higher odds of continent urinary diversion. Predicted probabilities of continent diversion remained lower for female patients, Medicaid insurance status, and non‐teaching and medium/low‐volume hospitals over time. Conclusions In this nationally representative sample of hospitals from 2001 to 2008, the use of continent diversion in RC gradually increased. Although variations in urinary diversion exist by hospital teaching status, case volume, patient gender and primary health insurance, increased attention in expanding the use of continent diversions may help reduce these disparities for patients undergoing RC for bladder cancer.

AbstractBackground and AimsPositron emission tomography with computed tomography (PET/CT) has been used to detect metastasis in the diagnosis of esophageal adenocarcinoma (EAC). However, the utility of PET/CT to assess primary tumor for endoscopic resectability and prognosis in early EAC remains unclear. We conducted a retrospective study to determine the association of PET/CT findings with histopathological tumor invasion depth and survival outcomes.MethodsEAC patients who underwent PET/CT followed by endoscopic mucosal resection (EMR) were included. Pathology on EMR and survival outcomes from a prospectively maintained database was retrieved. Two radiologists independently reviewed the PET/CT using the following parameters: detection of malignancy, fluorodeoxyglucose (FDG) uptake intensity, FDG focality, FDG eccentricity, esophageal thickness, maximal standard uptake value (SUVmax), and SUVmax ratio (lesion/liver).ResultsThere were 72 eligible patients: 42 (58.3%) had T1a lesions, and 30 (41.7%) had ≥ T1b. Only SUVmax ratio was associated with tumor invasion depth (odds ratio = 2.77, 95% confidence interval 1.26–7.73, P = 0.0075). Using a cut‐off of 1.48, the sensitivity and specificity of SUVmax ratio for identification of T1a lesions were 43.3% and 80.9%, respectively. Adjusting the SUVmax ratio to 2.14, 16.7% (5/30) of ≥ T1b patients were identified without any false‐positive cases. Multivariate analysis showed SUVmax ratio, Charlson comorbidity index, and esophagectomy were independent predictors for survival.ConclusionsSUVmax ratio (lesion/liver) is more accurate in predicting endoscopic resectability and mortality for EAC than other PET/CT parameters and appears promising as a useful adjunct to the current diagnostic work‐up.