Combating Resistance To Epidermal Growth Factor Recpetor Inhibitors In Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive cancer that lacks an effective targeted therapeutic. Although many TNBCs, both in vitro and in vivo, have increased expression of epidermal growth factor receptor (EGFR), EGFR targeted inhibitors, such as gefitinib (GEF), have yet to demonstrate efficacy. Using mass spectrometry to identify pathways that remain activated in the presence of GEF, we found that components of the mTOR signaling pathway remain phosphorylated. While inhibiting mTOR with temsirolimus (TEM) decreased mTOR signaling, EGFR signaling pathways remained activated and the TNBC cell lines continued to proliferate. However, dual treatment with TEM and GEF synergistically decreased cell viability in TNBC cells. Interestingly, abrogation of both EGFR and mTOR signaling did not alter the phosphorylation of key growth signaling molecules including MAPK and AKT. Instead, our data have identified the translational control pathway, specifically, eIF4B as a potentially key regulatory point in EGFR and mTOR inhibitor synergy. Further, we have also identified the transcription factor, STAT3 as another regulatory point in the EGFR and mTOR inhibitor synergy. Therefore, in this study we hypothesized that mTOR inhibition can sensitize TNBC cells to EGFR TKIs through the inhibition of eIF4B and STAT3 phosphorylation. eIF4B enhances the helicase activity of eIF4A during translation initiation. As expected, knockdown of eIF4B expression decreased cell viability comparable to the decrease observed with the combination treatment. Importantly, we have identified p70S6K and p90RSK as kinases directly responsible for eIF4B phosphorylation, such that both molecules need to be inactivated in order for eIF4B phosphorylation to be abrogated. This inactivation correlated with a loss of cell growth and viability and a decrease in clonogenic cell survival, potentially through alterations in the cell cycle. Furthermore, cap-dependent translation was inhibited to a greater extent in the combination treatment than GEF or TEM alone. Taken together these data suggest that EGFR and mTOR inhibitor combination abrogates cell growth, viability, and survival via disruption of translational control mechanisms through eIF4B. STAT3 is a widely considered oncogenic transcription factor that has been implicated in a variety of cancer types. We found a decrease in phospho-STAT3 with the GEF+TEM combination. Further DNA binding ELISAs found STAT3 activity was also significantly decreased with the combination. Overexpression of a constitutively active STAT3 plasmid found that STAT3 activation negates the GEF+TEM synergetic effect on cell viability. Together, these studies suggest a role for STAT3 in EGFR and mTOR inhibitor synergy. Taken together these data suggest that in the presence of activated MAPK and AKT, EGFR and mTOR inhibitors abrogate growth, viability, and survival via disruption of eIF4B and STAT3 phosphorylation leading to decreased translation and transcription factor DNA binding, respectively, in TNBC cell lines. The effect translation has on cancer cells in regard to the mTOR and EGFR pathways is largely unexplored in TNBC and further implicates eIF4B as a protein of interest in understanding the gefitinib and temsirolimus synergy. TNBC patients currently have limited treatment options and our data suggest that including an mTOR inhibitor along with an EGFR inhibitor in TNBC with increased EGFR expression should be further explored

Chalcogenide Glass Optical Waveguides for Infrared Biosensing

Due to the remarkable properties of chalcogenide (Chg) glasses, Chg optical waveguides should play a significant role in the development of optical biosensors. This paper describes the fabrication and properties of chalcogenide fibres and planar waveguides. Using optical fibre transparent in the mid-infrared spectral range we have developed a biosensor that can collect information on whole metabolism alterations, rapidly and in situ. Thanks to this sensor it is possible to collect infrared spectra by remote spectroscopy, by simple contact with the sample. In this way, we tried to determine spectral modifications due, on the one hand, to cerebral metabolism alterations caused by a transient focal ischemia in the rat brain and, in the other hand, starvation in the mouse liver. We also applied a microdialysis method, a well known technique for in vivo brain metabolism studies, as reference. In the field of integrated microsensors, reactive ion etching was used to pattern rib waveguides between 2 and 300 μm wide. This technique was used to fabricate Y optical junctions for optical interconnections on chalcogenide amorphous films, which can potentially increase the sensitivity and stability of an optical micro-sensor. The first tests were also carried out to functionalise the Chg planar waveguides with the aim of using them as (bio)sensors

A pre-registered, multi-lab non-replication of the Action-sentence Compatibility Effect (ACE)

The Action-sentence Compatibility Effect (ACE) is a well-known demonstration of the role of motor activity in the comprehension of language. Participants are asked to make sensibility judgments on sentences by producing movements toward the body or away from the body. The ACE is the finding that movements are faster when the direction of the movement (e.g., toward) matches the direction of the action in the to-be-judged sentence (e.g., Art gave you the pen describes action toward you). We report on a pre-registered, multi-lab replication of one version of the ACE. The results show that none of the 18 labs involved in the study observed a reliable ACE, and that the meta-analytic estimate of the size of the ACE was essentially zero.Fil: Morey, Richard. Cardiff University; Reino UnidoFil: Kaschak, Michael. Florida State University; Estados UnidosFil: Díez Álamo, Antonio. Universidad de Salamanca; España. Arizona State University; Estados UnidosFil: Glenberg, Arthur. Arizona State University; Estados Unidos. Universidad de Salamanca; EspañaFil: Zwaan, Rolf A.. Erasmus University Rotterdam; Países BajosFil: Lakens, Daniël. Eindhoven University of Technology; Países BajosFil: Ibáñez, Santiago Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de San Andrés; Argentina. University of San Francisco; Estados Unidos. Universidad Adolfo Ibañez; Chile. Trinity College Dublin; IrlandaFil: García, Adolfo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de San Andrés; Argentina. University of San Francisco; Estados Unidos. Universidad Nacional de Cuyo. Facultad de Educación Elemental y Especial; Argentina. Universidad de Santiago de Chile; ChileFil: Gianelli, Claudia. Universitat Potsdam; Alemania. Scuola Universitaria Superiore; ItaliaFil: Jones, John L.. Florida State University; Estados UnidosFil: Madden, Julie. University of Tennessee; Estados UnidosFil: Alifano Ferrero, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bergen, Benjamin. University of California at San Diego; Estados UnidosFil: Bloxsom, Nicholas G.. Ashland University; Estados UnidosFil: Bub, Daniel N.. University of Victoria; CanadáFil: Cai, Zhenguang G.. The Chinese University; Hong KongFil: Chartier, Christopher R.. Ashland University; Estados UnidosFil: Chatterjee, Anjan. University of Pennsylvania; Estados UnidosFil: Conwell, Erin. North Dakota State University; Estados UnidosFil: Wagner Cook, Susan. University of Iowa; Estados UnidosFil: Davis, Joshua D.. University of California at San Diego; Estados UnidosFil: Evers, Ellen R. K.. University of California at Berkeley; Estados UnidosFil: Girard, Sandrine. University of Carnegie Mellon; Estados UnidosFil: Harter, Derek. Texas A&m University Commerce; Estados UnidosFil: Hartung, Franziska. University of Pennsylvania; Estados UnidosFil: Herrera, Eduar. Universidad ICESI; ColombiaFil: Huettig, Falk. Max Planck Institute for Psycholinguistics; Países BajosFil: Humphries, Stacey. University of Pennsylvania; Estados UnidosFil: Juanchich, Marie. University of Essex; Reino UnidoFil: Kühne, Katharina. Universitat Potsdam; AlemaniaFil: Lu, Shulan. Texas A&m University Commerce; Estados UnidosFil: Lynes, Tom. University of East Anglia; Reino UnidoFil: Masson, Michael E. J.. University of Victoria; CanadáFil: Ostarek, Markus. Max Planck Institute for Psycholinguistics; Países BajosFil: Pessers, Sebastiaan. Katholikie Universiteit Leuven; BélgicaFil: Reglin, Rebecca. Universitat Potsdam; AlemaniaFil: Steegen, Sara. Katholikie Universiteit Leuven; BélgicaFil: Thiessen, Erik D.. University of Carnegie Mellon; Estados UnidosFil: Thomas, Laura E.. North Dakota State University; Estados UnidosFil: Trott, Sean. University of California at San Diego; Estados UnidosFil: Vandekerckhove, Joachim. University of California at Irvine; Estados UnidosFil: Vanpaeme, Wolf. Katholikie Universiteit Leuven; BélgicaFil: Vlachou, Maria. Katholikie Universiteit Leuven; BélgicaFil: Williams, Kristina. Texas A&m University Commerce; Estados UnidosFil: Ziv Crispel, Noam. BehavioralSight; Estados Unido

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

Background: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. Methods: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. Findings: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Interpretation: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

BackgroundThe safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population.MethodsPANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031.FindingsBetween Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir.InterpretationMolnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community

Models of classroom assessment for course-based research experiences

Course-based research pedagogy involves positioning students as contributors to authentic research projects as part of an engaging educational experience that promotes their learning and persistence in science. To develop a model for assessing and grading students engaged in this type of learning experience, the assessment aims and practices of a community of experienced course-based research instructors were collected and analyzed. This approach defines four aims of course-based research assessment—(1) Assessing Laboratory Work and Scientific Thinking; (2) Evaluating Mastery of Concepts, Quantitative Thinking and Skills; (3) Appraising Forms of Scientific Communication; and (4) Metacognition of Learning—along with a set of practices for each aim. These aims and practices of assessment were then integrated with previously developed models of course-based research instruction to reveal an assessment program in which instructors provide extensive feedback to support productive student engagement in research while grading those aspects of research that are necessary for the student to succeed. Assessment conducted in this way delicately balances the need to facilitate students’ ongoing research with the requirement of a final grade without undercutting the important aims of a CRE education