FOXO transcription factor family in cancer and metastasis

Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases

Multiple Reggeon Exchange from Summing QCD Feynman Diagrams

Multiple reggeon exchange supplies subleading logs that may be used to restore unitarity to the Low-Nussinov Pomeron, provided it can be proven that the sum of Feynman diagrams to all orders gives rise to such multiple regge exchanges. This question cannot be easily tackled in the usual way except for very low-order diagrams, on account of delicate cancellations present in the sum which necessitate individual Feynman diagrams to be computed to subleading orders. Moreover, it is not clear that sums of high-order Feynman diagrams with complicated criss-crossing of lines can lead to factorization implied by the multi-regge scenario. Both of these difficulties can be overcome by using the recently developed nonabelian cut diagrams. We are then able to show that the sum of $s$-channel-ladder diagrams to all orders does lead to such multiple reggeon exchanges.Comment: uu-encoded latex file with 11 postscript figures (20 pages

Novel Bose-Einstein Interference in the Passage of a Fast Particle in a Dense Medium

When an energetic particle collides coherently with many medium particles at high energies, the Bose-Einstein symmetry with respect to the interchange of the exchanged virtual bosons leads to a destructive interference of the Feynman amplitudes in most regions of the phase space but a constructive interference in some other regions of the phase space. As a consequence, the recoiling medium particles have a tendency to come out collectively along the direction of the incident fast particle, each carrying a substantial fraction of the incident longitudinal momentum. Such an interference appearing as collective recoils of scatterers along the incident particle direction may have been observed in angular correlations of hadrons associated with a high-$p_T$ trigger in high-energy AuAu collisions at RHIC.Comment: 10 pages, 2 figures, invited talk presented at the 35th Symposium on Nuclear Physics, Cocoyoc, Mexico, January 3, 2012, to be published in IOP Conference Serie

Optical Properties of Organometallic Perovskite: An ab initio Study using Relativistic GW Correction and Bethe-Salpeter Equation

In the development of highly efficient photovoltaic cells, solid perovskite systems have demonstrated unprecedented promise, with the figure of merit exceeding nineteen percent of efficiency. In this paper, we investigate the optical and vibrational properties of organometallic cubic perovskite CH3NH3PbI3 using first-principles calculations. For accurate theoretical description, we go beyond conventional density functional theory (DFT), and calculated optical conductivity using relativist quasi-particle (GW) correction. Incorporating these many-body effects, we further solve Bethe-Salpeter equations (BSE) for excitons, and found enhanced optical conductivity near the gap edge. Due to the presence of organic methylammonium cations near the center of the perovskite cell, the system is sensitive to low energy vibrational modes. We estimate the phonon modes of CH3NH3PbI3 using small displacement approach, and further calculate the infrared absorption (IR) spectra. Qualitatively, our calculations of low-energy phonon frequencies are in good agreement with our terahertz measurements. Therefore, for both energy scales (around 2 eV and 0-20 meV), our calculations reveal the importance of many-body effects and their contributions to the desirable optical properties in the cubic organometallic perovskites system.Comment: 5 pages, 4 figure

Redesigning pictographs for patients with low health literacy and establishing preliminary steps for delivery via smart phones.

BackgroundPictographs (or pictograms) have been widely utilized to convey medication related messages and to address nonadherence among patients with low health literacy. Yet, patients do not always interpret the intended messages on commonly used pictographs correctly and there are questions how they may be delivered on mobile devices.ObjectiveOur objectives are to refine a set of pictographs to use as medication reminders and to establish preliminary steps for delivery via smart phones.MethodsCard sorting was used to identify existing pictographs that focus group members found "not easy" to understand. Participants then explored improvements to these pictographs while iterations were sketched in real-time by a graphic artist. Feedback was also solicited on how selected pictographs might be delivered via smart phones in a sequential reminder message. The study was conducted at a community learning center that provides literacy services to underserved populations in Seattle, WA. Participants aged 18 years and older who met the criteria for low health literacy using S-TOFHLA were recruited.ResultsAmong the 45 participants screened for health literacy, 29 were eligible and consented to participate. Across four focus group sessions, participants examined 91 commonly used pictographs, 20 of these were ultimately refined to improve comprehensibility using participatory design approaches. All participants in the fifth focus group owned and used cell phones and provided feedback on preferred sequencing of pictographs to represent medication messages.ConclusionLow literacy adults found a substantial number of common medication label pictographs difficult to understand. Participative design processes helped generate new pictographs, as well as feedback on the sequencing of messages on cell phones, that may be evaluated in future research

Impact of implementing a fast-track protocol and standardized guideline for the management of pediatric appendicitis

Background: In 2017, a provincial guideline was created to fast track and standardize care for pediatric appendicitis in Alberta. We conducted a study to determine the impact of implementation of the guideline at our institution on length of stay (LOS), antibiotic stewardship efforts and costs. Methods: We performed a retrospective review of the charts of all patients younger than 18 years of age who underwent appendectomy at our institution in 2 periods: before guideline implementation (Dec. 1, 2016, to May 31, 2017) and after implementation (Dec. 1, 2017, to May 31, 2018). We compared LOS, duration of antibiotic therapy, 30-day postdischarge complication rates and variable cost between the 2 cohorts. Results: Of the 276 total appendectomy procedures performed, 185 were for simple appendicitis (81 before guideline implementation and 104 after implementation), and 91 were for complicated appendicitis (44 and 47, respectively). The median LOS was shorter in the postimplementation cohort for both simple and complicated appendicitis (15.5 h [interquartile range (IQR) 12-19 h] v. 17.0 h [IQR 13-22 h], p = 0.03; and 3.0 d [IQR 2-4 d] v. 3.0 d [IQR 3-5 d], p = 0.05, respectively). Patients with complicated appendicitis had fewer antibiotic days after guideline implementation; the difference was statistically significant for patients without diffuse peritoneal contamination or abscess formation (p = 0.02). There were no differences between the cohorts with respect to 30-day rates of complications, including emergency department visits, readmission and surgical site infections. After guideline implementation, the average variable cost per patient was reduced by $230, equating to a total average annual cost savings of$75 842 for our institution. Conclusion: The implementation of a provincial guideline aimed at standardizing care in pediatric appendicitis at our institution was associated with shortened LOS, improved antibiotic stewardship efforts and reduced cost of care. Other institutions may replicate our model of a standardized pathway in the management of pediatric appendicitis in an effort to improve the quality of patient care and reduce health care costs

Predictive modeling of die filling of the pharmaceutical granules using the flexible neural tree

In this work, a computational intelligence (CI) technique named flexible neural tree (FNT) was developed to predict die filling performance of pharmaceutical granules and to identify significant die filling process variables. FNT resembles feedforward neural network, which creates a tree-like structure by using genetic programming. To improve accuracy, FNT parameters were optimized by using differential evolution algorithm. The performance of the FNT-based CI model was evaluated and compared with other CI techniques: multilayer perceptron, Gaussian process regression, and reduced error pruning tree. The accuracy of the CI model was evaluated experimentally using die filling as a case study. The die filling experiments were performed using a model shoe system and three different grades of microcrystalline cellulose (MCC) powders (MCC PH 101, MCC PH 102, and MCC DG). The feed powders were roll-compacted and milled into granules. The granules were then sieved into samples of various size classes. The mass of granules deposited into the die at different shoe speeds was measured. From these experiments, a dataset consisting true density, mean diameter (d50), granule size, and shoe speed as the inputs and the deposited mass as the output was generated. Cross-validation (CV) methods such as 10FCV and 5x2FCV were applied to develop and to validate the predictive models. It was found that the FNT-based CI model (for both CV methods) performed much better than other CI models. Additionally, it was observed that process variables such as the granule size and the shoe speed had a higher impact on the predictability than that of the powder property such as d50. Furthermore, validation of model prediction with experimental data showed that the die filling behavior of coarse granules could be better predicted than that of fine granules

Regulation of PERK expression by FOXO3: a vulnerability of drug-resistant cancer cells

The major impediment to effective cancer therapy has been the development of drug resistance. The tumour suppressive transcription factor FOXO3 promotes cell cycle arrest, senescence and cell death, and mediates the cytotoxic and cytostatic functions of cancer therapeutics. In consequence, FOXO3 is often downregulated as an adaptive response in cancer and particularly in chemotherapeutic drug-resistant cells. Consistently, we find that FOXO3 expression is attenuated in the drug-resistant MCF-7-EpiR and MCF-7-TaxR compared to the parental MCF-7 breast cancer cells. Using ChIP, short-interfering RNA (siRNA) knockdown, and overexpression assays as well as Foxo1/3/4−/− MEFs, we establish the endoplasmic reticulum (ER)-stress defence modulator PERK (eIF2AK3) as a direct downstream transcriptional target of FOXO3. In agreement, there is also a positive correlation between FOXO3 and PERK expression at the protein and RNA levels in breast cancer patient samples. We uncover that PERK expression is downregulated but its activity constitutively elevated in the drug-resistant cells. With this in mind, we exploit this adaptive response of low FOXO3 and PERK expression, and high PERK activity in drug-resistant breast cancer cells and show that these drug-resistant cells are specifically sensitive to PERK inhibition. In support of this finding, we show that ectopic overexpression of FOXO3 can reduce the sensitivity of the resistant cells to the PERK inhibitor GSK2606414, while the Foxo1/3/4−/− MEFs expressing lower levels of PERK are more sensitive to PERK inhibition compared to wild-type MEFs. PERK inhibitor-titration and -time course experiments showed that the drug-resistant cells, which express lower expression and higher activity levels of PERK, are more sensitive to the increasing concentrations of PERK inhibitor compared to parental MCF-7 cells. Our present work thus reveals a chemotherapeutic drug-resistant cancer cell vulnerability in PERK and suggests PERK as a potential target for cancer therapy, specifically in the context of drug-resistant cancers