Authenticity in a modern music industry : a qualitative exploration into \u27selling out\u27

This paper looks at the impact of authenticity in the modern music industry. With a focus on the influence of an artist&rsquo;s life cycle and the evolution of the music industry, this paper explores the relationship between authenticity, the concept of selling out and social perception. A conceptual model is presented depicting the above relationships derived from the relevant literature. The paper concludes with a discussion of the method that will be used to undertake this research.<br /

CDK4/6 inhibitor PD0332991 in glioblastoma treatment: Does it have a future?

Glioblastoma is aggressive, highly infiltrating, and the most frequent malignant form of brain cancer. With a median survival time of only 14.6 months, when treated with the standard of care, it is essential to find new therapeutic options. A specific CDK4/6 inhibitor, PD0332991, obtained accelerated approval from the Food and Drug Administration for the treatment of patients with advanced estrogen receptor-positive and HER2-negative breast cancer. Common alterations in the cyclin D1-cyclin-dependent kinase 4/6-retinoblastoma 1 pathway in glioblastoma make PD0332991 also an interesting drug for the treatment of glioblastoma. Promising results in in vitro studies, where patient derived glioblastoma cell lines showed sensitivity to PD0332991, gave motive to start in vivo studies. Outcomes of these studies have been contrasting in terms of PD0332991 efficacy within the brain: more research is necessary to conclude whether CDK4/6 inhibitor can be beneficial in the treatment of glioblastoma

Endometrial ablation and resection versus hysterectomy for heavy menstrual bleeding: an updated systematic review and meta-analysis of effectiveness and complications

To evaluate the clinical efficacy, safety, and cost-effectiveness of endometrial ablation or resection (E:A/R) compared to hysterectomy for the treatment of heavy menstrual bleeding. Literature search was conducted, and randomized control trials (RCTs) comparing (E:A/R) versus hysterectomy were reviewed. The search was last updated in November 2022. Twelve RCTs with 2,028 women (hysterectomy: n=977 vs. [E:A/R]: n=1,051) were included in the analyzis. The meta-analysis revealed that the hysterectomy group showed improved patient-reported and objective bleeding symptoms more than those of the (E:A/R) group, with risk ratios of (mean difference [MD], 0.75; 95% confidence intervals [CI], 0.71 to 0.79) and (MD, 44.00; 95% CI, 36.09 to 51.91), respectively. Patient satisfaction was higher post-hysterectomy than (E:A/R) at 2 years of follow-up, but this effect was absent with long-term follow-up. (E:A/R) is considered an alternative to hysterectomy as a surgical management for heavy menstrual bleeding. Although both procedures are highly effective, safe, and improve the quality of life, hysterectomy is significantly superior at improving bleeding symptoms and patient satisfaction for up to 2 years. However, it is associated with longer operating and recovery times and a higher rate of postoperative complications. The initial cost of (E:A/R) is less than the cost of hysterectomy, but further surgical requirements are common; therefore, there is no difference in the cost for long-term follow-up

Analysis of sloppiness in model simulations: unveiling parameter uncertainty when mathematical models are fitted to data

This work introduces a Bayesian approach to assess the sensitivity of model outputs to changes in parameter values, constrained by the combination of prior beliefs and data. This novel approach identifies stiff parameter combinations that strongly affect the quality of the model-data fit while simultaneously revealing which of these key parameter combinations are informed primarily from the data or are also substantively influenced by the priors. We focus on the very common context in complex systems where the amount and quality of data are low compared to the number of model parameters to be collectively estimated, and showcase the benefits of our technique for applications in biochemistry, ecology, and cardiac electrophysiology. We also show how stiff parameter combinations, once identified, uncover controlling mechanisms underlying the system being modeled and inform which of the model parameters need to be prioritized in future experiments for improved parameter inference from collective model-data fitting

Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma

BackgroundThe O 6 -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM.MethodsThe inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination with RT was tested on a panel of patient derived cell lines (PDCLs) and patient-derived xenografts (PDX) models generated from GBM patients with MGMT unmethylated tumors.ResultsThe combination of veliparib and RT inhibited colony formation in the majority of PDCLs tested. The PDCL, RN1 showed significantly reduced levels of the homologous repair protein, Mre11 and a heightened response to PARP inhibition measured by increased apoptosis and decreased colony formation. The oral administration of veliparib (12.5 mg/kg, twice daily for 5 days in a 28-day treatment cycle) in combination with whole brain RT (4 Gy) induced apoptosis (Tunel staining) and decreased cell proliferation (Ki67 staining) in a PDX of MGMT unmethylated GBM. Significantly longer survival times of the PDX treated with the combination treatment were recorded compared to RT only or veliparib only.ConclusionsOur results demonstrate preclinical efficacy of targeting PARP at multiple levels and provide a new approach for the treatment of MGMT unmethylated GBM.<br /

Human prefrontal cortex gene regulatory dynamics from gestation to adulthood at single-cell resolution.

Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions. We uncover links between expression dynamics and developmental milestones, characterize the diverse timing of when cells acquire adult-like states, and identify molecular convergence from distinct developmental origins. We further reveal cellular dynamics and their regulators implicated in neurological disorders. Finally, using this reference, we benchmark cell identities and maturation states in organoid models. Together, this captures the dynamic regulatory landscape of human cortical development.This work was supported by the following grants: R.L.—National Health and Medical Research Council (NHMRC) Project Grant 1130168, NHMRC Investigator Grant 1178460, Silvia and Charles Viertel Senior Medical Research Fellowship, Howard Hughes Medical Institute International Research Scholarship, and Australian Research Council (ARC) LE170100225; S.F.—NHMRC Ideas Grant 1184421; I.V.—ARC Future Fellowship FT170100359, UNSW Scientia Fellowship, and NHMRC Project Grant RG170137; S.B.—NHMRC-ARC Dementia Research Development Fellowship 1111206; C.P.—Raine Foundation Priming Grant RPG66-21; J.M.P.—Silvia and Charles Viertel Senior Medical Research Fellowship, ARC Future Fellowship FT180100674. This work was supported by a Cancer Research Trust grant ‘‘Enabling advanced single cell cancer genomics in WA’’ and Cancer Council WA enabling grant. Genomic data were generated at the ACRF Centre for Advanced Cancer Genomics and Genomics WA. Human brain tissue was received from the UMB Brain and Tissue Bank at the University of Maryland, part of the NIH NeuroBioBank. The glioblastoma sample was procured and provided by the AGOG biobank, funded by CINSW grant SRP-08-10. L.M. was a fellow of The Lorenzo and Pamela Galli Medical Research Trust. We thank Ankur Sharma and Greg Neely for valuable feedback. The graphical abstract and elements of Figure 1A were created with BioRender.S

A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence

Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression