TGF-Beta suppresses VEGFA-mediated angiogenesis in colon cancer metastasis.

The FET cell line, derived from an early stage colon carcinoma, is non-tumorigenic in athymic nude mice. Engineered FET cells that express TGF-α (FETα) display constitutively active EGFR/ErbB signaling. These cells readily formed xenograft tumors in athymic nude mice. Importantly, FETα cells retained their response to TGF-beta-mediated growth inhibition, and, like the parental FET cells, expression of a dominant negative TGF-beta type II receptor (DNRII) in FETα cells (FETα/DNRII) abrogated responsiveness to TGF-beta-induced growth inhibition and apoptosis under stress conditions in vitro and increased metastatic potential in an orthotopic model in vivo, which indicates metastasis suppressor activity of TGF-beta signaling in this model. Cancer angiogenesis is widely regarded as a key attribute for tumor formation and progression. Here we show that TGF-beta signaling inhibits expression of vascular endothelial growth factor A (VEGFA) and that loss of autocrine TGF-beta in FETα/DNRII cells resulted in increased expression of VEGFA. Regulation of VEGFA expression by TGF-beta is not at the transcriptional level but at the post-transcriptional level. Our results indicate that TGF-beta decreases VEGFA protein stability through ubiquitination and degradation in a PKA- and Smad3-dependent and Smad2-independent pathway. Immunohistochemical (IHC) analyses of orthotopic tumors showed significantly reduced TGF-beta signaling, increased CD31 and VEGFA staining in tumors of FETα/DNRII cells as compared to those of vector control cells. These results indicate that inhibition of TGF-beta signaling increases VEGFA expression and angiogenesis, which could potentially contribute to enhanced metastasis of those cells in vivo. IHC studies performed on human colon adenocarcinoma specimens showed that TGF-beta signaling is inversely correlated with VEGFA expression, indicating that TGF-beta-mediated suppression of VEGFA expression exists in colon cancer patients

Computerized acoustic assessment of treatment efficacy of nebulized epinephrine and albuterol in RSV bronchiolitis

<p>Abstract</p> <p>Aim</p> <p>We evaluated the use of computerized quantification of wheezing and crackles compared to a clinical score in assessing the effect of inhaled albuterol or inhaled epinephrine in infants with RSV bronchiolitis.</p> <p>Methods</p> <p>Computerized lung sounds analysis with quantification of wheezing and crackles and a clinical score were used during a double blind, randomized, controlled nebulized treatment pilot study. Infants were randomized to receive a single dose of 1 mgr nebulized l-epinephrine or 2.5 mgr nebulized albuterol. Computerized quantification of wheezing and crackles (PulmoTrack^®) and a clinical score were performed prior to, 10 minutes post and 30 minutes post treatment. Results were analyzed with Student's t-test for independent samples, Mann-Whitney U test and Wilcoxon test.</p> <p>Results</p> <p>15 children received albuterol, 12 received epinephrine. The groups were identical at baseline. Satisfactory lung sounds recording and analysis was achieved in all subjects. There was no significant change in objective quantification of wheezes and crackles or in the total clinical scores either within the groups or between the groups. There was also no difference in oxygen saturation and respiratory distress.</p> <p>Conclusion</p> <p>Computerized lung sound analysis is feasible in young infants with RSV bronchiolitis and provides a non-invasive, quantitative measure of wheezing and crackles in these infants. </p> <p><b>Trial registration number</b>: ClinicalTrials.gov NCT00361452</p

A Tale of Switched Functions: From Cyclooxygenase Inhibition to M-Channel Modulation in New Diphenylamine Derivatives

Cyclooxygenase (COX) enzymes are molecular targets of nonsteroidal anti-inflammatory drugs (NSAIDs), the most used medication worldwide. However, the COX enzymes are not the sole molecular targets of NSAIDs. Recently, we showed that two NSAIDs, diclofenac and meclofenamate, also act as openers of Kv7.2/3 K+ channels underlying the neuronal M-current. Here we designed new derivatives of diphenylamine carboxylate to dissociate the M-channel opener property from COX inhibition. The carboxylate moiety was derivatized into amides or esters and linked to various alkyl and ether chains. Powerful M-channel openers were generated, provided that the diphenylamine moiety and a terminal hydroxyl group are preserved. In transfected CHO cells, they activated recombinant Kv7.2/3 K+ channels, causing a hyperpolarizing shift of current activation as measured by whole-cell patch-clamp recording. In sensory dorsal root ganglion and hippocampal neurons, the openers hyperpolarized the membrane potential and robustly depressed evoked spike discharges. They also decreased hippocampal glutamate and GABA release by reducing the frequency of spontaneous excitatory and inhibitory post-synaptic currents. In vivo, the openers exhibited anti-convulsant activity, as measured in mice by the maximal electroshock seizure model. Conversion of the carboxylate function into amide abolished COX inhibition but preserved M-channel modulation. Remarkably, the very same template let us generating potent M-channel blockers. Our results reveal a new and crucial determinant of NSAID-mediated COX inhibition. They also provide a structural framework for designing novel M-channel modulators, including openers and blockers

Thrive: Success Strategies for the Modern-Day Faculty Member

The THRIVE collection is intended to help faculty thrive in their roles as educators, scholars, researchers, and clinicians. Each section contains a variety of thought-provoking topics that are designed to be easily digested, guide personal reflection, and put into action. Please use the THRIVE collection to help: Individuals study topics on their own, whenever and wherever they want Peer-mentoring or other learning communities study topics in small groups Leaders and planners strategically insert faculty development into existing meetings Faculty identify campus experts for additional learning, grand rounds, etc. If you have questions or want additional information on a topic, simply contact the article author or email [email protected]://digitalcommons.unmc.edu/facdev_books/1000/thumbnail.jp

The Impact of eHealth on the Quality and Safety of Health Care: A Systematic Overview

Aziz Sheikh and colleagues report the findings of their systematic overview that assessed the impact of eHealth solutions on the quality and safety of health care

Medical informatics as a discipline at the beginning of the 21st century

OBJECTIVES: To analyse the present situation of the discipline medical informatics and to propose actions for change. METHODS: Evaluation of the current situation mainly based on anecdotal evidence. RESULTS: The difference between the scientific and the engineering aspects of medical informatics get blurred. Because of the requirements of European funding medical informatics focuses more on engineering than on science. Too many manuscripts are submitted that describe engineered artefacts without a scientific purpose. Some of the subjects (like security issues) that are studied in medical informatics are not considered important by medical faculties thus impeding support. CONCLUSIONS: The methodological underpinnings of our research should be strengthened, impact studies should be more frequently performed; the quality of results reporting should be increase