The PI3K pathway regulates cell metabolism, proliferation, and migration, and its dysregulation is common in cancer. We now show that both physiologic and oncogenic activation of PI3K signaling ...increase the expression of its negative regulator PTEN. This limits the duration of the signal and output of the pathway. Physiologic and pharmacologic inhibition of the pathway reduces PTEN and contributes to the rebound in pathway activity in tumors treated with PI3K inhibitors and limits their efficacy. Regulation of PTEN is due to mTOR/4E-BP1-dependent control of its translation and is lost when 4E-BP1 is deleted. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the pathway activation by oncogenic PIK3CA mutants and the antitumor activity of PI3K pathway inhibitors. However, pathway output is hyperactivated in tumor cells with coexistent PI3K mutation and loss of PTEN function.
RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a ...kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.
Summary Mucin 16 (cancer antigen 125) is a cell surface glycoprotein that plays a role in promoting cancer cell growth in ovarian cancer. The aims of this study were to examine mucin 16 expression in ...a large number of digestive tract adenocarcinomas and precursors and to determine whether mucin 16 up-regulation is correlated with patient outcome. Tissue microarrays were constructed using surgical resection tissues and included pancreatic (115 normal, 29 precursors, 200 pancreatic ductal adenocarcinomas), esophageal (86 normal, 104 precursors, 95 esophageal adenocarcinomas, 35 lymph node metastases), gastric (211 normal, 8 precursors, 119 gastric adenocarcinomas, 62 lymph node metastases), and colorectal (34 normal, 17 precursors, 39 colorectal adenocarcinomas) tissues. Mucin 16 was detected in 81.5%, 69.9%, 41.2%, and 64.1% of the pancreatic ductal adenocarcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, and colorectal adenocarcinomas, respectively. Mucin 16 was seen in a subset of the precursors. On multivariate analysis, moderate/diffuse mucin 16 in pancreatic ductal adenocarcinomas was strongly associated with poor survival ( P < .001), independent of other prognosis predictors. A similar trend was observed for esophageal adenocarcinomas ( P = .160) and gastric adenocarcinomas ( P = .080). Focal mucin 16 in colorectal adenocarcinomas was significantly correlated ( P = .044) with a better patient outcome, when compared with mucin 16–negative cases. Using Western blot analysis, we found mucin 16 expression in 3 of 6 pancreatic ductal adenocarcinoma and 1 of 2 esophageal adenocarcinoma cell lines. We conclude that most of the digestive tract adenocarcinomas and a subset of their precursors express mucin 16. Mucin 16 expression is an independent predictor of poor outcome in pancreatic ductal adenocarcinomas and potentially in esophageal adenocarcinomas and gastric adenocarcinomas. We propose that mucin 16 may function as a prognostic marker and therapeutic target in the future.
To identify a predictive molecular "signature" for sensitivity to retinoic acid in pancreatic cancer.
Fourteen patient-derived, low-passage pancreatic ductal adenocarcinoma (PDAC) lines with varied ...expression of fatty acid-binding protein 5 (FABP5) and cellular retinoic acid-binding protein 2 (CRABP2) were used to evaluate the response to all-trans retinoic acid (ATRA). Cell proliferation, apoptosis, and migration/invasion assays were used to measure the in vitro response. Tumor growth was monitored in subcutaneous xenografts in athymic nude mice for 4 weeks.
Response to ATRA was observed to be dependent upon differential expression of FABP5 versus CRABP2. Thus, elevated FABP5 expression was associated with minimal cytotoxicity and tumor growth inhibition and a paradoxical increase in migration and invasion. Conversely, CRABP2 expression in the absence of FABP5 was associated with significant tumor growth inhibition with ATRA, even in gemcitabine-resistant tumors. The ATRA-resistant phenotype of FABP5(high)CRABP2(null) cells could be circumvented by ectopic expression of CRABP2. Alternatively, reexpression of endogenous CRABP2 could be enabled in FABP5(high)CRABP2(null) PDAC lines by exposure to decitabine and trichostatin A, thereby relieving epigenetic silencing of the CRABP2 gene promoter. Immunohistochemical staining for FABP5 in archival human tissue microarrays identifies a subset of cases (13 of 63, ~20%) which are negative for FABP5 expression and might be candidates for ATRA therapy.
The widely used agent ATRA deserves a "second look" in PDAC, but needs to be targeted to patient subsets with biopsy-proven FABP5-negative tumors, or be combined with a chromatin-modifying agent to reexpress endogenous CRABP2.
The PI3K pathway is a key regulator of metabolism, of cell proliferation and migration and some of its components (Eg. PIK3CA and PTEN) are frequently altered in cancer by genetic events that ...deregulate its output. However, PI3K signaling is not usually the primary driver of these tumors and inhibitors of components of the pathway have only modest antitumor effects owing to drug acquired resistance, improper scheduling and dosage of drugs etc. Negative feedbacks are the major regulators of homeostasis in signaling networks and are relieved on inhibiting the PI3K pathway, contributing to the adaptive resistance. We found that continuous long-term treatment with PI3K inhibitors mounts an adaptive response that becomes more stable as a function of duration of inhibition upon drug removal and is associated with increased growth rate and decreased sensitivity to PI3K inhibitors on re-treatment, supporting the rationale of an intermittent as opposed to continuous treatment regimen involving PI3K inhibitors. Several feedback loops exist within the PI3K pathway but none have been associated with its primary negative regulator PTEN. We now show that both physiologic and oncogenic activation of the PI3K signaling cause an increase in the expression of the lipid phosphatase PTEN, thus limiting the duration of the signal and the output of the pathway in tumors. Pharmacologic and physiologic inhibitions of the pathway reduce PTEN, thus buffering the effects of inhibition and contributing to the rebound in pathway activity that occurs in tumors treated with PI3K pathway inhibitors. Regulation of expression is due to mTOR/4EBP1 dependent control of PTEN translation and is lost when 4EBP1 is knocked out. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in 1) reducing the output of oncogenic mutants that dysregulate the pathway, 2) reducing the duration of PI3K signaling on growth factor stimulation, 3) reducing the antitumor activity of PI3K pathway inhibitors, and 3) perhaps, in mediating insulin resistance.
The set of permissions required by any Android app during installation time is considered as the feature set which are used in permission based detection of Android malwares. Those high dimensional ...feature set should be reduced to minimize computational overhead by choosing an optimal sub set of features. In recent times, selection of meaningful attributes is an inevitable step for mining of large dimensional data and the application of heuristic feature selection algorithms are the main research directions in this field. “Quality of classification” measure is inspired by rough set theory and can be combined with bio inspired heuristic search techniques (Particle swarm optimization, Genetic Algorithm etc.) in selecting optimal or near optimal subsets of features. In this work, a feature selection technique based on rough set and improvised particle swarm optimization (PSO) algorithm is proposed for selection of features in the permission based detection of Android malwares. The main contribution of this work is to recommend a new random key encoding method which is used in the proposed work (PSORS-FS) to convert classical PSO algorithm in discrete domain. It also reduces the issues related to maximum velocity of particles as well as sigmoid function which is related with binary PSO. PSORS-FS ensures diversity in the search process and it also reduces the tendency of premature convergence. Datasets of UCI, KEEL machine learning repository and two Android permission datasets have been used to evaluate the performance of the proposed method. Better classification performance has been yielded by proposed method over conventional filters and wrapper methods for most of the machine learning classifiers.
The response surface methodology has been extended to study the adsorption of malachite green dye (MG) on Indian Neem leaf powder (NLP),
Azadirachta indica
. The study was experimented by varying the ...solution concentration from 10 to 100 mg/l. The removal percentage of MG was determined by spectrophotometer at wavelength of 618 nm. Design Expert 11.0 was used as a tool to study the optimal conditions of MG adsorption (applying 2-factorial interaction model of central composite design) and evaluation of interaction effects of different operating parameters including pH, time, solute concentration, temperature and adsorbent dosage. Numerical optimization helped to identify the optimal conditions for achieving the targeted dye removal of 95.493% when the pH, time, solute concentration, temperature and adsorbent amount were set at the range of 6.868, 36.4 min, 27.899 mg/l, 308.477 K, and 4.3475 g/l respectively. The experimental results indicate that the maximum adsorption capacity of NLP depends on various operating parameter like, pH, dye concentration, particle size of adsorbents and it’s activation. It was noted that adsorption capacity of the NLP increases from 33.33 to 66.72 mg/g when it was activated with dilute HCl. The higher correlation coefficient value (
R
2
) of Langmuir isotherm 0.996 and lower
p
value (0.01203) indicate the fitness of the response surface 2FI model developed. Kinetic studies displayed the suitability of pseudo second order reaction for this adsorption process. The thermodynamic study show that the sorption process is exothermic and spontaneous in nature. It was observed that the adsorbent NLP in the form of fine powder are very effective for the removal of MG from its aqueous solution. The satisfactory values of regression coefficients at different temperature, and fittings of adsorption isotherms indicate that Indian NLP is a promising adsorbent for treatment of textile dyes.
Lyme disease in the United States is most often caused by Borrelia burgdorferi sensu stricto. After a tick bite, the patient may develop erythema migrans at that site. If hematogenous dissemination ...occurs, the patient may then develop neurologic manifestations, carditis, or arthritis. Host-pathogen interactions include factors that contribute to hematogenous dissemination to other body sites. Outer surface protein C (OspC), a surface-exposed lipoprotein of B. burgdorferi, is essential during the early stages of mammalian infection. There is a high degree of genetic variation at the
locus, and certain
types are more frequently associated with hematogenous dissemination in patients, suggesting that OspC may be a major contributing factor to the clinical outcome of B. burgdorferi infection. In order to evaluate the role of OspC in B. burgdorferi dissemination,
was exchanged between B. burgdorferi isolates with different capacities to disseminate in laboratory mice, and these strains were then tested for their ability to disseminate in mice. The results indicated that the ability of B. burgdorferi to disseminate in mammalian hosts does not depend on OspC alone. The complete genome sequences of two closely related strains of B. burgdorferi with differing dissemination phenotypes were determined, but a specific genetic locus that could explain the differences in the phenotypes could not be definitively identified. The animal studies performed clearly demonstrated that OspC is not the sole determinant of dissemination. Future studies of the type described here with additional borrelial strains will hopefully clarify the genetic elements associated with hematogenous dissemination.
Neutrophil elastase, a powerful physiological defence tool, may serve as drug target for diverse diseases due to its bystander effect on host cells like chronic obstructive pulmonary disease (COPD). ...Here, we synthesised seven novel benzoxazinone derivatives and identified that these synthetic compounds are human neutrophil elastase inhibitor that was demonstrated by enzyme substrate kinetic assay. One such compound, PD05, emerged as the most potent inhibitor with lower IC50 as compared to control drug sivelestat. While this inhibition is competitive based on substrate dilution assay, PD05 showed a high binding affinity for human neutrophil elastase (Kd = 1.63 nM) with faster association and dissociation rate compared to notable elastase inhibitors like ONO 6818 and AZD9668, and its interaction with human neutrophil elastase was fully reversible.Preclinical pharmacokinetic studies were performed in vitro where protein binding was found to be 72% with a high recovery rate, aqueous solubility of 194.7 μM, low permeability along with a favourable hERG. Experiments with cell line revealed that the molecule successfully prevented elastase induced rounding and retracted cell morphology and cell cytotoxicity. In mouse model PD05 is able to reduce the alveolar collapse induced by neutrophil elastase. In summary, we demonstrate the in situ, in vitro and in vivo anti-elastase potential of the newly synthesised benzoxazinone derivative PD05 and thus this could be promising candidate for further investigation as a drug for the treatment of COPD.
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