miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer

Background: While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. Methods: We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630’s regulation of mRNA, proteins and their phosphorylated forms. Results: We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630’s regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype. Conclusions: Taken together, our findings suggest miR-630 as a key regulator of cancer cell progression in HER2 over-expressing breast cancer, through targeting of IGF1R. This study supports miR-630 as a diagnostic and a predictive biomarker for response to HER-targeted drugs and indicates that the therapeutic addition of miR-630 may enhance and improve patients’ response to HER-targeting drugs

Adapting to Climate Change: The urgency and some challenges to begin

Our response to the challenge of climate change will shape our future in many different and crucial ways. Adaptation is about realizing the impacts of climate change and acting in such a way to limit negative impacts and embrace positive outcomes in order to reduce our vulnerability from the effects of climate change

Early human impacts and ecosystem reorganization in southern-central Africa

Modern Homo sapiens engage in substantial ecosystem modification, but it is difficult to detect the origins or early consequences of these behaviors. Archaeological, geochronological, geomorphological, and paleoenvironmental data from northern Malawi document a changing relationship between forager presence, ecosystem organization, and alluvial fan formation in the Late Pleistocene. Dense concentrations of Middle Stone Age artifacts and alluvial fan systems formed after ca. 92 thousand years ago, within a paleoecological context with no analog in the preceding half-million-year record. Archaeological data and principal coordinates analysis indicate that early anthropogenic fire relaxed seasonal constraints on ignitions, influencing vegetation composition and erosion. This operated in tandem with climate-driven changes in precipitation to culminate in an ecological transition to an early, pre-agricultural anthropogenic landscape.info:eu-repo/semantics/publishedVersio

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Photoreducible Mercury Loss from Arctic Snow Is Influenced by Temperature and Snow Age

Mercury (Hg) is an important environmental contaminant, due to its neurotoxicity and ability to bioaccumulate. The Arctic is a mercury-sensitive region, where organisms can accumulate high Hg concentrations. Snowpack mercury photoredox reactions may control how much Hg is transported with melting Arctic snow. This work aimed to (1) determine the significance of temperature combined with UV irradiation intensity and snow age on Hg(0) flux from Arctic snow and (2) elucidate the effect of temperature on snowpack Hg photoreduction kinetics. Using a Teflon flux chamber, snow temperature, UV irradiation, and snow age were found to significantly influence Hg(0) flux from Arctic snow. Cross-correlation analysis results suggest that UV radiation has a direct effect on Hg(0)­flux, while temperature may indirectly influence flux. Laboratory experiments determined that temperature influenced Hg photoreduction kinetics when snow approached the melting point (>−2 °C), where the pseudo-first-order reduction rate constant, <i>k</i>, decreased twofold, and the photoreduced Hg amount, Hg­(II)_red, increased 10-fold. This suggests that temperature influences Hg photoreduction kinetics indirectly, likely by altering the solid:liquid water ratio. These results imply that large mass transfers of Hg from snow to air may take place during the Arctic snowmelt period, altering photoreducible Hg retention and transport with snow meltwater

Examination of the validity of the Injury-Psychological Readiness to Return to Sport (I-PRRS) scale in male professional football players: A worldwide study of 29 professional teams

Perceived confidence is an important dimension of an athlete’s psychological readiness to return-to-play. However, there is no established and validated tool to evaluate confidence in professional football. This study aimed to provide preliminary evaluation of the internal structure of the Injury-Psychological Readiness to Return-to-Sport scale (I-PRRS) in a cohort of injured male professional footballers. Over an 18-month period, 29 teams from 17 leagues participated. Players sustaining injuries eliciting ≥ 3 weeks’ time-loss were recruited. Cross culturally adapted to 4 further languages, the I-PRRS was administered on two occasions: 1) day before returning-to-training and 2) day before returning-to-match-play. In total, 113 injuries were recorded with 96 completed I-PRRS data sets collected. Confirmatory factor analysis indicated the I-PRRS was a unidimensional scale, with all items measuring the same construct. The scale demonstrated good internal consistency (ω = .88). When examining longitudinal invariance of the I-PRRS across administration time-points, indices of model fit supported scalar invariance. There was preliminary evidence of good internal structure for the I-PRRS in professional male footballers. However, before further research involving the I-PRRS can be endorsed, efforts to confirm or refute empirical developments pertaining to psychological readiness are necessary

iTV in Industry 5: Are Smartphone TV Apps Easier to Use than Remote Controls to Control TV?

This paper addresses the question: are smartphone TV apps as easy to use as remote controls for controlling TV. Although smartphone apps make it easier to navigate lists of items, such as TV shows, access to other often-used functions may be less efficient because assess requires extra navigation. Also, additional steps required to access the TV app on the smartphone may offset any inherent advantage to using it. Smartphone app designs could reduce or eliminate this extra navigation and make smartphone TV apps more efficient and thus preferred over remote controls

Adapting to Climate Change: The urgency and some challenges to begin

Our response to the challenge of climate change will shape our future in many different and crucial ways. Adaptation is about realizing the impacts of climate change and acting in such a way to limit negative impacts and embrace positive outcomes in order to reduce our vulnerability from the effects of climate change