Variability and changes of Arctic sea ice draft distribution - submarine sonar measurements revisited

Peer reviewe

Heterogeneity and Clonal Evolution of Acquired PARP Inhibitor Resistance in TP53- and BRCA1-Deficient Cells

Homologous recombination (HR)-deficient cancers are sensitive to poly- ADP ribose polymerase inhibitors (PARPi), which have shown clinical efficacy in the treatment of high-grade serous cancers (HGSC). However, the majority of patients will relapse, and acquired PARPi resistance is emerging as a pressing clinical problem. Here we generated seven single-cell clones with acquired PARPi resistance derived from a PARPi-sensitive TP53(-/-) and BRCA1(-/-) epithelial cell line generated using CRISPR/Cas9. These clones showed diverse resistance mechanisms, and some clones presented with multiple mechanisms of resistance at the same time. Genomic analysis of the clones revealed unique transcriptional and mutational profiles and increased genomic instability in comparison with a PARPi-sensitive cell line. Clonal evolutionary analyses suggested that acquired PARPi resistance arose via clonal selection from an intrinsically unstable and heterogenous cell population in the sensitive cell line, which contained preexisting drug-tolerant cells. Similarly, clonal and spatial heterogeneity in tumor biopsies from a clinical patient with BRCA1-mutant HGSC with acquired PARPi resistance was observed. In an imaging-based drug screening, the clones showed heterogenous responses to targeted therapeutic agents, indicating that not all PARPi-resistant clones can be targeted with just one therapy. Furthermore, PARPi-resistant clones showed mechanism-dependent vulnerabilities to the selected agents, demonstrating that a deeper understanding on the mechanisms of resistance could lead to improved targeting and biomarkers for HGSC with acquired PARPi resistance. Significance: This study shows that BRCA1-deficient cells can give rise to multiple genomically and functionally heterogenous PARPi-resistant clones, which are associated with various vulnerabilities that can be targeted in a mechanism-specific manner.Peer reviewe

Prospective Longitudinal ctDNA Workflow Reveals Clinically Actionable Alterations in Ovarian Cancer

PURPOSE Circulating tumor DNA (ctDNA) detection is a minimally invasive technique that offers dynamic molecular snapshots of genomic alterations in cancer. Although ctDNA markers can be used for early detection of cancers or for monitoring treatment efficacy, the value of ctDNA in guiding treatment decisions in solid cancers is controversial. Here, we monitored ctDNA to detect clinically actionable alterations during treatment of high-grade serous ovarian cancer, the most common and aggressive form of epithelial ovarian cancer with a 5-year survival rate of 43%.PATIENTS AND METHODS We implemented a clinical ctDNA workflow to detect clinically actionable alterations in more than 500 cancer-related genes. We applied the workflow to a prospective cohort consisting of 78 ctDNA samples from 12 patients with high-grade serous ovarian cancer before, during, and after treatment. These longitudinal data sets were analyzed using our open-access ctDNA-tailored bioinformatics analysis pipeline and in-house Translational Oncology Knowledgebase to detect clinically actionable genomic alterations. The alterations were ranked according to the European Society for Medical Oncology scale for clinical actionability of molecular targets.RESULTS Our results show good concordance of mutations and copy number alterations in ctDNA and tumor samples, and alterations associated with clinically available drugs were detected in seven patients (58%). Treatment of one chemoresistant patient was changed on the basis of detection of ERBB2amplification, and this ctDNA-guided decision was followed by significant tumor shrinkage and complete normalization of the cancer antigen 125 tumor marker.CONCLUSION Our results demonstrate a proof of concept for using ctDNA to guide clinical decisions. Furthermore, our results show that longitudinal ctDNA samples can be used to identify poor-responding patients after first cycles of chemotherapy. We provide what we believe to be the first comprehensive, open-source ctDNA workflow for detecting clinically actionable alterations in solid cancers. (C) 2019 by American Society of Clinical Oncolog

Heritability of non-speech auditory processing skills

Recent insight into the genetic bases for autism spectrum disorder, dyslexia, stuttering, and language disorders suggest that neurogenetic approaches may also reveal at least one etiology of auditory processing disorder (APD). A person with an APD typically has difficulty understanding speech in background noise despite having normal pure-tone hearing sensitivity. The estimated prevalence of APD may be as high as 10% in the pediatric population, yet the causes are unknown and have not been explored by molecular or genetic approaches. The aim of our study was to determine the heritability of frequency and temporal resolution for auditory signals and speech recognition in noise in 96 identical or fraternal twin pairs, aged 6–11 years. Measures of auditory processing (AP) of non-speech sounds included backward masking (temporal resolution), notched noise masking (spectral resolution), pure-tone frequency discrimination (temporal fine structure sensitivity), and nonsense syllable recognition in noise. We provide evidence of significant heritability, ranging from 0.32 to 0.74, for individual measures of these non-speech-based AP skills that are crucial for understanding spoken language. Identification of specific heritable AP traits such as these serve as a basis to pursue the genetic underpinnings of APD by identifying genetic variants associated with common AP disorders in children and adults

Prospects & Overviews Genomics approaches to study musical aptitude

Although music and other forms of art can develop in diverse directions, they are linked to the genetic profiles of populations. Hearing music is a strong environmental trigger that serves as an excellent model to study the crosstalk between genes and the environment. We propose that the ability to enjoy and practice music requires musical aptitude, which is a common and innate trait facilitating the enjoyment and practice of music. The innate drive for music can only have arisen by exposure to music, and it develops with motivation and training in musically rich environments. Recent genomic approaches have shown that the genes responsible for inner ear development, auditory pathways and neurocognitive processes may underlay musical aptitude. It is expected that genomic approaches can be applied to musical traits and will reveal new biological mechanisms that affect human evolution, brain function, and civilisation

Mass transport in CuInSe2 from first principles

The wide scatter in experimental results has not allowed drawing solid conclusions on self-diffusion in the chalcopyrite CuInSe2 (CIS). In this work, the defect-assisted mass transport mechanisms operating in CIS are clarified using first-principles calculations. We present how the stoichiometry of the material and temperature affect the dominant diffusion mechanisms. The most mobile species in CIS is shown to be copper, whose migration proceeds either via copper vacancies or interstitials. Both of these mass-mediating agents exist in the material abundantly and face rather low migration barriers (1.09 and 0.20 eV, respectively). Depending on chemical conditions, selenium mass transport relies either solely on selenium dumbbells, which diffuse with a barrier of 0.24 eV, or also on selenium vacancies whose diffusion is hindered by a migration barrier of 2.19 eV. Surprisingly, indium plays no role in long-range mass transport in CIS; instead, indium vacancies and interstitials participate in mechanisms that promote the formation of antisites on the cation sublattice. Our results help to understand how compositional inhomogeneities arise in CIS