Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways

<p>Abstract</p> <p>Background</p> <p>Osteosarcoma (OS) is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory.</p> <p>Results</p> <p>We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM) as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006) in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice.</p> <p>Conclusion</p> <p>In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both <it>in vitro </it>and <it>in vivo</it>, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.</p

Grit-related profiles predict polysubstance use in youth with a history of childhood maltreatment

Childhood maltreatment (CM) is a significant impediment to normative developmental trajectories and consistently predicts increased risk for a range of adverse outcomes, including substance misuse and polysubstance use (polySU). Yet, a subset of individuals who experience CM exhibit successful adaptations across the lifespan. Though there is an expansive literature on social, emotional, and cognitive protective factors that mitigate impacts of CM, less is known about non-social and non-cognitive protective factors such as ‘grit’ (i.e., determination to achieve long-term goals). Grit has been shown to predict adaptive functioning in a variety of domains. Using a person-centered statistical approach (i.e., latent profile analysis), we examined heterogeneity in grit in maltreated youth from the LONGSCAN sample as it related to maltreatment characteristics and substance use (SU) patterns during adolescence. We uncovered 3 latent profiles based on participants’ grit-related traits (i.e., Low Grit, Average Grit, and High Grit). Those in the High Grit profile were least likely to engage in polySU during adolescence. These findings highlight the promise of grit as a protective factor against polySU following CM and one that is not necessarily contingent upon environmental supports and/or cognitive ability. As such, this work represents a promising avenue for future preventative intervention efforts

The moderating role of socioeconomic status on level of responsibility, executive functioning, and cortical thinning during adolescence

Brain development is exquisitely sensitive to psychosocial experiences, with implications for neurodevelopmental trajectories, for better or worse. The premise of this investigation was that the level of responsibility in adolescence may relate to brain structure and higher-order cognitive functions. In a sample of 108 adolescents, we focused on cortical thickness (using FreeSurfer) as an indicator of neurodevelopment in regions previously implicated in executive functioning (EF) and examined performance on an EF task outside of the scanner, in the context of level of responsibility. We further investigated whether socioeconomic status (SES) and family stress moderated the relationship between responsibility and brain structure or EF. Findings revealed that greater responsibility was related to thinner left precuneus and right middle frontal cortex. In lower SES adolescents, greater responsibility predicted thinner left precuneus and right middle frontal cortex, which have been consistently implicated in EF. Higher SES adolescents did not show structural differences related to responsibility, however, they did exhibit better EF performance. It may be that circumstances surrounding the need for greater responsibility in lower SES households are detrimental to neurodevelopment compared to higher SES households. Alternatively, responsibility may act as a protective factor that bolsters cortical thinning in regions related to EF

Perpetuating Racism in the Ivory: Well-Meaning Whiteness in Social and Behavioral Sciences

Although there has been a recent increased awareness of the lack of support to Black scholars in academia, initiatives and action plans to address such inequity are severely lacking. Lack of support from individuals and institutions contributes to such disparities for Black scholars, stifling growth and discovery in social and behavioral research. This flaw is due to the lack of diverse representation in the research and the academic workforce. We must acknowledge the role of anti-Black racism in science and how our fellow Black scientists are negatively affected, including the impact on their careers, work-life harmony, and overall mental wellness. We address the multifaceted effects of anti-Black racism throughout the Ivory on Black scholars, academic spaces, and the field of social and behavioral sciences in general. Finally, we offer concrete recommendations to be implemented immediately and, over time, by individual White scholars and academic institutions at large

Better with age: Developmental changes in oscillatory activity during verbal working memory encoding and maintenance

Numerous investigations have characterized the oscillatory dynamics serving working memory in adults, but few have probed its relationship with chronological age in developing youth. We recorded magnetoencephalography during a modified Sternberg verbal working memory task in 82 youth participants aged 6–14 years old. Significant oscillatory responses were identified and imaged using a beamforming approach and the resulting whole-brain maps were probed for developmental effects during the encoding and maintenance phases. Our results indicated robust oscillatory responses in the theta (4–7 Hz) and alpha (8–14 Hz) range, with older participants exhibiting stronger alpha oscillations in left-hemispheric language regions. Older participants also had greater occipital theta power during encoding. Interestingly, there were sex-by-age interaction effects in cerebellar cortices during encoding and in the right superior temporal region during maintenance. These results extend the existing literature on working memory development by showing strong associations between age and oscillatory dynamics across a distributed network. To our knowledge, these findings are the first to link chronological age to alpha and theta oscillatory responses serving working memory encoding and maintenance, both across and between male and female youth; they reveal robust developmental effects in crucial brain regions serving higher order functions

Developmental alterations in the neural oscillatory dynamics underlying attentional reorienting

The neural and cognitive processes underlying the flexible allocation of attention undergo a protracted developmental course with changes occurring throughout adolescence. Despite documented age-related improvements in attentional reorienting throughout childhood and adolescence, the neural correlates underlying such changes in reorienting remain unclear. Herein, we used magnetoencephalography (MEG) to examine neural dynamics during a Posner attention-reorienting task in 80 healthy youth (6–14 years old). The MEG data were examined in the time-frequency domain and significant oscillatory responses were imaged in anatomical space. During the reorienting of attention, youth recruited a distributed network of regions in the fronto-parietal network, along with higher-order visual regions within the theta (3–7 Hz) and alpha-beta (10–24 Hz) spectral windows. Beyond the expected developmental improvements in behavioral performance, we found stronger theta oscillatory activity as a function of age across a network of prefrontal brain regions irrespective of condition, as well as more limited age- and validity-related effects for alpha-beta responses. Distinct brain-behavior associations between theta oscillations and attention-related symptomology were also uncovered across a network of brain regions. Taken together, these data are the first to demonstrate developmental effects in the spectrally-specific neural oscillations serving the flexible allocation of attention

COVID-19 as a Paradigmatic Model of the Heterogeneous Disease Presentation in Older People: Data from the GeroCovid Observational Study

COVID-19 may have a heterogeneous onset, especially in older age. However, whether and how COVID-19 signs and symptoms may present and aggregate together according to sociodemographic and health factors is unclear, as well as their prognostic value. This study included 981 COVID-19 inpatients who participated in the GeroCovid Observational study. Signs/symptoms at disease onset, sociodemographic, health, cognitive status, and mobility were systematically recorded. Clusters of signs/symptoms were identified through agglomerative hierarchical clustering. The associations of single signs/symptoms and symptom clusters with longer hospitalization (&gt;= 16 days) and in-hospital mortality were explored through logistic and Cox regressions. The signs/symptoms most reported in our sample (age 78.3 +/- 9.39 years; 49.4% women) were fever (62.5%), cough (45.5%), and dyspnea (62.7%). Atypical symptoms were reported by up to one-third of patients, and delirium by 9.1%. Atypical symptoms were more frequent with advancing age and with lower pre-COVID-19 cognitive and mobility levels. Older men more likely reported respiratory symptoms than women. Dyspnea (hazard ratio [HR] = 1.47, 95% confidence interval [CI]: 1.02-2.12), tachypnea (HR = 1.53, 95% CI: 1.14-2.07), low oxygen saturation (HR = 1.95, 95% CI: 1.32-2.88) and delirium (HR = 1.60, 95% CI: 1.13-2.28) were associated with higher in-hospital mortality. Four symptom clusters were identified. Compared with the mild respiratory symptoms cluster, the severe clinical impairment cluster was associated with higher mortality (HR = 2.57, 95% CI: 1.58-4.18). The severe clinical impairment and aspecific symptoms clusters were associated with longer hospitalization (odds ratio [OR] = 2.38, 95% CI: 1.56-3.63, and OR = 1.75, 95% CI: 1.08-2.83, respectively). Multiple health aspects influence COVID-19 clinical presentation. A symptom clusters approach may help predict adverse health outcomes in older patients. In addition to respiratory symptoms, delirium is independently associated with mortality risk.ClinicalTrials.gov (NCT04379440)