EGFRvIV: a previously uncharacterized oncogenic mutant reveals a kinase autoinhibitory mechanism

Tumor cells often subvert normal regulatory mechanisms of signal transduction. This study shows this principle by studying yet uncharacterized mutants of the epidermal growth factor receptor (EGFR) previously identified in glioblastoma multiforme, which is the most aggressive brain tumor in adults. Unlike the well-characterized EGFRvIII mutant form, which lacks a portion of the ligand-binding cleft within the extracellular domain, EGFRvIVa and EGFRvIVb lack internal segments distal to the intracellular tyrosine kinase domain. By constructing the mutants and by ectopic expression in naive cells, we show that both mutants confer an oncogenic potential in vitro, as well as tumorigenic growth in animals. The underlying mechanisms entail constitutive receptor dimerization and basal activation of the kinase domain, likely through a mechanism that relieves a restraining molecular fold, along with stabilization due to association with HSP90. Phosphoproteomic analyses delineated the signaling pathways preferentially engaged by EGFRvIVb-identified unique substrates. This information, along with remarkable sensitivities to tyrosine kinase blockers and to a chaperone inhibitor, proposes strategies for pharmacological interception in brain tumors harboring EGFRvIV mutations.Goldhirsh FoundationNational Cancer Institute (U.S.) (CA118705)National Cancer Institute (U.S.) (CA141556)National Cancer Institute (U.S.) (U54-CA112967

An internal ribosome entry site in the 5′ untranslated region of epidermal growth factor receptor allows hypoxic expression

The expression of epidermal growth factor receptor (EGFR/ERBB1/HER1) is implicated in the progress of numerous cancers, a feature that has been exploited in the development of EGFR antibodies and EGFR tyrosine kinase inhibitors as anti-cancer drugs. However, EGFR also has important normal cellular functions, leading to serious side effects when EGFR is inhibited. One damaging characteristic of many oncogenes is the ability to be expressed in the hypoxic conditions associated with the tumour interior. It has previously been demonstrated that expression of EGFR is maintained in hypoxic conditions via an unknown mechanism of translational control, despite global translation rates generally being attenuated under hypoxic conditions. In this report, we demonstrate that the human EGFR 5′ untranslated region (UTR) sequence can initiate the expression of a downstream open reading frame via an internal ribosome entry site (IRES). We show that this effect is not due to either cryptic promoter activity or splicing events. We have investigated the requirement of the EGFR IRES for eukaryotic initiation factor 4A (eIF4A), which is an RNA helicase responsible for processing RNA secondary structure as part of translation initiation. Treatment with hippuristanol (a potent inhibitor of eIF4A) caused a decrease in EGFR 5′ UTR-driven reporter activity and also a reduction in EGFR protein level. Importantly, we show that expression of a reporter gene under the control of the EGFR IRES is maintained under hypoxic conditions despite a fall in global translation rates

HIV infection and sexual risk among men who have sex with men and women (MSMW): A systematic review and meta-analysis

Objectives: To estimate the number of men who have sex with men and women who are HIV-positive in the United States, and to compare HIV prevalence rates between men who have sex with men and women, men who have sex with men only, and men who have sex with women exclusively. Methods: Following PRISMA guidelines, we conducted a systematic review and meta-analysis of reports referencing HIV prevalence and men who have sex with men and women. We searched PubMed and Ovid PsycINFO for peer-reviewed, U.S.-based articles reporting on HIV prevalence among men who have sex with men and women. We conducted event rate, effect size, moderation and sensitivity analyses. Results: We estimate that 1.0% of U.S. males are bisexually-behaving, and that 121,800 bisexually-behaving men are HIV-positive. Men who have sex with men and women are less than half as likely to be HIV-positive as men who have sex with men only (16.9% vs. 33.3%; OR = 0.41, 95% CI: 0.31, 0.54), but more than five times as likely to be HIV-positive as men who have sex with women exclusively (18.3% vs. 3.5%; OR = 5.71, 95% CI: 3.47, 9.39). They are less likely to engage in unprotected receptive anal intercourse than men who have sex with men only (15.9% vs. 35.0%; OR = 0.36, 95% CI: 0.28, 0.46). Men who have sex with men and women in samples with high racial/ethnic minority proportions had significantly higher HIV prevalence than their counterparts in low racial/ethnic minority samples. Conclusions: This represents the first meta-analysis of HIV prevalence in the U.S. between men who have sex with men and women and men who have sex with men only. Data collection, research, and HIV prevention and care delivery specifically tailored to men who have sex with men and women are necessary to better quantify and ameliorate this population's HIV burden. © 2014 Friedman et al

Wear and corrosion interactions on titanium in oral environment : literature review

The oral cavity is a complex environment where corrosive substances from dietary, human saliva, and oral biofilms may accumulate in retentive areas of dental implant systems and prostheses promoting corrosion at their surfaces. Additionally, during mastication, micromovements may occur between prosthetic joints causing a relative motion between contacting surfaces, leading to wear. Both processes (wear and corrosion) result in a bio-tribocorrosion system once that occurs in contact with biological tissues and fluids. This review paper is focused on the aspects related to the corrosion and wear behavior of titanium-based structures in the oral environment. Furthermore, the clinical relevance of the oral environment is focused on the harmful effect that acidic substances and biofilms, formed in human saliva, may have on titanium surfaces. In fact, a progressive degradation of titanium by wear and corrosion (tribocorrosion) mechanisms can take place affecting the performance of titanium-based implant and prostheses. Also, the formation of wear debris and metallic ions due to the tribocorrosion phenomena can become toxic for human tissues. This review gathers knowledge from areas like materials sciences, microbiology, and dentistry contributing to a better understanding of bio-tribocorrosion processes in the oral environment.(undefined

Acquired resistance to anti-EGFR mAb ICR62 in cancer cells is accompanied by an increased EGFR expression, HER-2/HER-3 signalling and sensitivity to pan HER blockers

Our results provide a novel mechanistic insight into the development of acquired resistance to EGFR antibody-based therapy in colorectal cancer cells and justify further investigations on the therapeutic benefits of pan-HER family inhibitors in the treatment of colorectal cancer patients once acquired resistance to EGFR antibody-based therapy is developed

Half-Time Strategies to Enhance Second-Half Performance in Team-Sports Players: A Review and Recommendations

The competitive demands of numerous intermittent team sports require that two consecutive periods of play are separated by a half-time break. Typically, half-time allows players to: return to the changing rooms, temporarily relax from the cognitive demands of the first half of match-play, rehydrate, re-fuel, attend to injury or equipment concerns, and to receive tactical instruction and coach feedback in preparation for the second half. These passive practices have been associated with physiological changes which impair physical and cognitive performance in the initial stages of the second half. An increased risk of injury has also been observed following half-time. On the day of competition, modification of half-time practices may therefore provide Sports Scientists and Strength and Conditioning Coaches with an opportunity to optimise second half performance. An overview of strategies that may benefit team sports athletes is presented; specifically, the efficacy of: heat maintenance strategies (including passive and active methods), hormonal priming (through video feedback), post-activation potentiation, and modified hydro-nutritional practices are discussed. A theoretical model of applying these strategies in a manner that compliments current practice is also presented

Effect of exercise on fluoride metabolism in adult humans: a pilot study

An understanding of all aspects of fluoride metabolism is critical to identify its biological effects and avoid fluoride toxicity in humans. Fluoride metabolism and subsequently its body retention may be affected by physiological responses to acute exercise. This pilot study investigated the effect of exercise on plasma fluoride concentration, urinary fluoride excretion and fluoride renal clearance following no exercise and three exercise intensity conditions in nine healthy adults after taking a 1-mg Fluoride tablet. After no, light, moderate and vigorous exercise, respectively, the mean (SD) baseline-adjusted i) plasma fluoride concentration was 9.6(6.3), 11.4(6.3), 15.6(7.7) and 14.9(10.0) ng/ml; ii) rate of urinary fluoride excretion over 0–8 h was 46(15), 44(22), 34(17) and 36(17) μg/h; and iii) rate of fluoride renal clearance was 26.5(9.0), 27.2(30.4), 13.1(20.4) and 18.3(34.9) ml/min. The observed trend of a rise in plasma fluoride concentration and decline in rate of fluoride renal clearance with increasing exercise intensity needs to be investigated in a larger trial. This study, which provides the first data on the effect of exercise with different intensities on fluoride metabolism in humans, informs sample size planning for any subsequent definitive trial, by providing a robust estimate of the variability of the effect

EGFR and EGFRvIII Expression in Primary Breast Cancer and Cell Lines

EGFRvIII is a constitutively activated truncated variant of the epidermal growth factor receptor (EGFR) which has been shown to increase tumorgenicity. There are conflicting reports on the extent of EGFRvIII expression in tissues which may in part stem from the use of different assay methodologies. We investigated the expression of both EGFRvIII and wild-type EGFR (EGFRwt) in cell lines and primary breast cancers. First, we used a RT-PCR assay that can simultaneously measure EGFRwt and EGFRvIII mRNA to screen 55 tumor cell lines. We show that except for EGFRvIII transfected cells, only EGFRwt was detected. We then validated a real-time PCR assay and used this to screen 170 formalin fixed paraffin-embedded primary breast cancers for evidence of EGFRwt and EGFRvIII expression. No samples were positive for EGFRvIII expression except for control transfectants and glioblastomas. In contrast, EGFRwt was expressed at varying levels in the majority of samples tested. We conclude that the expression of EGFRvIII is extremely rare in breast cancer and therefore it does not contribute to the malignant phenotype.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44224/1/10549_2004_Article_5274918.pd