A microRNA-Dependent Circuit Controlling p63/p73 Homeostasis: p53 Family Cross-Talk Meets Therapeutic Opportunity

The p53 family transcription factors p53, p63 and p73 make diverse contributions in development and cancer. Mutation or deletion of p53 is observed in the majority of human cancers. In contrast, p63 and p73 are not lost in cancer but mediate distinct genetic roles in normal and tumor-specific contexts: p73 promotes genome stability and mediates chemosensitivity, while p63 largely lacks these p53-like functions and instead promotes proliferation and cell survival. We recently uncovered a mechanism which maintains p63/p73 homeostasis within the epithelium through direct transcriptional regulation of microRNAs (miRs). We discovered that several of the top p63-regulated miRs target p73 for inhibition, including miR-193a-5p, a direct p63/p73 transcriptional target which is repressed by p63 and activated by p73 both in vitro and in vivo. The resulting feed-forward circuit involving p63, miR-193a-5p and p73 controls p73 levels, cell viability and DNA damage susceptibility in certain cancers including squamous cell carcinoma. Here, we discuss the evolutionary implications of this regulatory circuit, which may point to a general mechanism of miR-mediated cross-talk within transcription factor gene families. Additionally, we suggest that inducible chemoresistance mediated by this miR-dependent mechanism might be an attractive target for therapeutic intervention

Early-Stage Progression of Breast Cancer

Breast cancer can be defined as a group of diseases with heterogeneous origins, molecular profiles and behaviors characterized by uncontrolled proliferation of cells within the mammary tissue. Around one in eight women in the US will develop breast cancer in their lifetime, making it the second most frequently diagnosed cancer behind skin cancer [1]. In 2015, an estimated 231,840 cases of invasive carcinoma were diagnosed, and over 40,000 deaths were caused by breast cancer which accounts for almost 7% of all cancer mortality each year. In 2015, 60,290 cases of in situ breast cancer were diagnosed, representing over 14% of all new cancer cases among women and men. The steep increase in diagnosis of early‐stage breast cancer over the past 10 years is believed to be a result of more frequent mammography. However, since over half of these in situ lesions will not progress to invasive breast cancer, controversies have arisen about approaches to treatment and prevention of progression of early‐stage in situ breast cancer. Understanding the mechanisms of transition of normal breast to in situ pre‐neoplastic lesions and invasive breast cancer is currently a major focus of breast cancer research with implications for preventive and clinical management of breast cancer. In this review, we give an overview of current knowledge on the molecular and pathological changes that occur during early‐stage progression of breast cancer and describe some of the current models that are used to study this process

Tout ce que vous avez toujours voulu savoir sur les médias sociaux sans jamais oser le demander... - Guide Social Média 2012

À travers des pistes de pratiques, des modes de communication et de traitement de l’information, le guide propose des définitions, des pistes d\u27usages simples, des définitions, des conseils et des cas concrets. Les outils sont explicités dans leurs fonctionnalités essentielles et de nombreux exemples sont fournis . Quelques plates-formes de réseaux sociaux évoquées au sein de ce guide : Twitter, Facebook, Pinterest, LinkedIn, Viadeo, Google Plus

Non-Emergency Medical Transportation Needs of Middle-Aged and Older Adults: A Rural-Urban Comparison in Delaware, USA.

Background: Older adults in rural areas have unique transportation barriers to accessing medical care, which include a lack of mass transit options and considerable distances to health-related services. This study contrasts non-emergency medical transportation (NEMT) service utilization patterns and associated costs for Medicaid middle-aged and older adults in rural versus urban areas. Methods: Data were analyzed from 39,194 NEMT users of LogistiCare-brokered services in Delaware residing in rural (68.3%) and urban (30.9%) areas. Multivariable logistic analyses compared trip characteristics by rurality designation. Results: Rural (37.2%) and urban (41.2%) participants used services more frequently for dialysis than for any other medical concern. Older age and personal accompaniment were more common and wheel chair use was less common for rural trips. The mean cost per trip was greater for rural users (difference of $2910 per trip), which was attributed to the greater distance per trip in rural areas. Conclusions: Among a sample who were eligible for subsidized NEMT and who utilized this service, rural trips tended to be longer and, therefore, higher in cost. Over 50% of trips were made for dialysis highlighting the need to address prevention and, potentially, health service improvements for rural dialysis patients

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness

Background: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. Methods: Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. Results: For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. Conclusions: These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting

A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease

Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1. Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1. To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba(-/-) mice and the control littermate (gba(+/+)) by infecting differentiated primary cortical neurons in culture with an EF1 alpha-SV40T lentivirus. Immortalized gba(-/-) neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba(+/+) neurons. This null allele gba(-/-) mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies

Metabolism of Non-Enzymatically Derived Oxysterols: Clues from sterol metabolic disorders

Cholestane-3β,5α,6β-triol (3β,5α,6β-triol) is formed from cholestan-5,6-epoxide (5,6-EC) in a reaction catalysed by cholesterol epoxide hydrolase, following formation of 5,6-EC through free radical oxidation of cholesterol. 7-Oxocholesterol (7-OC) and 7β-hydroxycholesterol (7β-HC) can also be formed by free radical oxidation of cholesterol. Here we investigate how 3β,5α,6β-triol, 7-OC and 7β-HC are metabolised to bile acids. We show, by monitoring oxysterol metabolites in plasma samples rich in 3β,5α,6β-triol, 7-OC and 7β-HC, that these three oxysterols fall into novel branches of the acidic pathway of bile acid biosynthesis becoming (25R)26-hydroxylated then carboxylated, 24-hydroxylated and side-chain shortened to give the final products 3β,5α,6β-trihydroxycholanoic, 3β-hydroxy-7-oxochol-5-enoic and 3β,7β-dihydroxychol-5-enoic acids, respectively. The intermediates in these pathways may be causative of some phenotypical features of, and/or have diagnostic value for, the lysosomal storage diseases, Niemann Pick types C and B and lysosomal acid lipase deficiency. Free radical derived oxysterols are metabolised in human to unusual bile acids via novel branches of the acidic pathway, intermediates in these pathways are observed in plasma

Sarcoma treatment in the era of molecular medicine

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.Peer reviewe

Improving STEM Education: Engaged Learning in an Introductory Computer Programming Course

While the number of software engineering and computer science jobs continues to explode, academic institutions have been unable to produce enough qualified graduates to keep up with demand. An institution’s introductory computer programming course is critical to engaging, recruiting and retaining students. However, students often feel overwhelmed before they can grasp even the fundamental concepts of programming. We present novel pedagogical tools we will use in Idaho State University’s CS 1181 Introduction to Computer Programming. The tools are based on splitting concepts into two major categories: language fundamentals and problem solving. Language fundamentals are learned utilizing cued response using an online tool and is done outside of class. Problem solving is done in class using pair programming, graphical feedback and gamification. We present both the specifics of our pedagogical approach and the web-based teaching software we are developing. This research is supported by an Idaho State University Teaching Innovation Grant

MENINGKATKAN SOFTSKILL SISWA MELALUI METODE PEMBELAJARAN PROJECT BASED LEARNING PEMBUATAN MAJALAH DINDING

Penelitian terkait dengan upaya meningkatkan softskill sedang marak di kemabgnkan untuk dapat menhasilkan siswa yang mandiri dan memiliki kemampuan yang unggul. Sedangkan majalah dinding menjadi media yang tepat untuk dijadikan sebagai projek kelompok. Penelitian ini ingin melihat softskill yang akan dapat ditingkatkan oleh siswa SMAN 15 Maluku Tengah melalui projek pembuatan majalah dinding. Penelitian ini menggunakan metode kualitatif berbasis projek, secara singkat guru memberikan intruksi kepada siswa untuk membuat majalah dinding dengan tema hari guru. Selain itu penilaian perkembangan softskill siswa dilihat dari aspek keberhasilan projek dan wawancara. Berdasarkan penelitian ini dapat disimpulkan bahwa pemberian tugas projek seperti majalah dinding kepada siswa SMAN 15 Maluku Tengah dapat meningkatkan softskill siswa ekstrakulikuler karya ilmiah remaja (KIR) seperti kemampuan menulis, kemampuan jurnalistik, kreatifitas dan kemampuan bekerjasama dan pengelolaan organisasi