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Cancer immunogenomics is an emerging field that bridges genomics and immunology. The establishment of large-scale genomic collaborative efforts along with the development of new single-cell transcriptomic techniques and multi-omics approaches have enabled characterization of the mutational and transcriptional profiles of many cancer types and helped to identify clinically actionable alterations as well as predictive and prognostic biomarkers. Researchers have developed computational approaches and machine learning algorithms to accurately obtain clinically useful information from genomic and transcriptomic sequencing data from bulk tissue or single cells and explore tumours and their microenvironment. The rapid growth in sequencing and computational approaches has resulted in the unmet need to understand their true potential and limitations in enabling improvements in the management of patients with cancer who are receiving immunotherapies. In this Review, we describe the computational approaches currently available to analyse bulk tissue and single-cell sequencing data from cancer, stromal and immune cells, as well as how best to select the most appropriate tool to address various clinical questions and, ultimately, improve patient outcomes.

We derive novel algorithms for optimization problems constrained by partial differential equations describing multiscale particle dynamics, including non-local integral terms representing interactions between particles. In particular, we investigate problems where the control acts as an advection ‘flow’ vector or a source term of the partial differential equation, and the constraint is equipped with boundary conditions of Dirichlet or no-flux type. After deriving continuous first-order optimality conditions for such problems, we solve the resulting systems by developing a link with computational methods for statistical mechanics, deriving pseudospectral methods in space and time variables, and utilizing variants of existing fixed-point methods as well as a recently developed Newton–Krylov scheme. Numerical experiments indicate the effectiveness of our approach for a range of problem set-ups, boundary conditions, as well as regularization and model parameters, in both two and three dimensions. A key contribution is the provision of software which allows the discretization and solution of a range of optimization problems constrained by differential equations describing particle dynamics.

Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.

Vocal communication depends on distinguishing self-generated vocalizations from other sounds. Vocal motor corollary discharge (CD) signals are thought to support this ability by adaptively suppressing auditory cortical responses to auditory feedback. One challenge is that vocalizations, especially those produced during courtship and other social interactions, are accompanied by other movements and are emitted during a state of heightened arousal, factors that could potentially modulate auditory cortical activity. Here, we monitor auditory cortical activity, ultrasonic vocalizations (USVs), and other non-vocal courtship behaviors in a head-fixed male mouse while he interacts with a female mouse. This approach reveals a vocalization-specific signature in the auditory cortex that suppresses the activity of USV playback-excited neurons, emerges before vocal onset, and scales with USV band power. Notably, this vocal modulatory signature is also present in the auditory cortex of congenitally deaf mice, revealing an adaptive vocal CD signal that manifests independently of auditory feedback or auditory experience.

Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAFmutations in cutaneous melanoma and enrichment for CRKLamplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13genes. This positional gene programme synergized with CRKLto amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

ABSTRACTCircular RNAs (circRNAs) are an evolutionarily conserved form of noncoding RNA with covalently closed loop structures. Initial studies established a functional role for circRNAs as potent microRNA sponges and many other studies have focussed solely on this. However, the biological functions of most circRNAs are still undetermined and other functional roles are gaining traction. These include protein sponges and regulators, and coding for proteins with an alternative mechanism of translation, potentially opening up a whole new transcriptome. The first step to gaining insight into circRNA function is accurate identification and various software platforms have been developed. Specialized detection software has now evolved into whole bioinformatics pipelines that can be used for detection, de novoidentification, functional prediction, and validation of circRNAs. However, few cardiovascular circRNA studies have utilized these tools. This review summarizes current knowledge of circRNA biogenesis, bioinformatic detection tools and the emerging role of circRNAs in cardiovascular disease.

Musical and athletic skills are learned and maintained through intensive practice to enable precise and reliable performance for an audience. Consequently, understanding such complex behaviours requires insight into how the brain functions during both practice and performance. Male zebra finches learn to produce courtship songs that are more varied when alone and more stereotyped in the presence of females1. These differences are thought to reflect song practice and performance, respectively2,3, providing a useful system in which to explore how neurons encode and regulate motor variability in these two states. Here we show that calcium signals in ensembles of spiny neurons (SNs) in the basal ganglia are highly variable relative to their cortical afferents during song practice. By contrast, SN calcium signals are strongly suppressed during female-directed performance, and optogenetically suppressing SNs during practice strongly reduces vocal variability. Unsupervised learning methods4,5show that specific SN activity patterns map onto distinct song practice variants. Finally, we establish that noradrenergic signalling reduces vocal variability by directly suppressing SN activity. Thus, SN ensembles encode and drive vocal exploration during practice, and the noradrenergic suppression of SN activity promotes stereotyped and precise song performance for an audience.

The pathological mechanism of cellular dysfunction and death in Huntington’s disease (HD) is not well defined. Our transgenic HD sheep model (OVT73) was generated to investigate these mechanisms and for therapeutic testing. One particular cohort of animals has undergone focused investigation resulting in a large interrelated multi-omic dataset, with statistically significant changes observed comparing OVT73 and control ‘omic’ profiles and reported in literature. Here we make this dataset publicly available for the advancement of HD pathogenic mechanism discovery. To enable investigation in a user-friendly format, we integrated seven multi-omic datasets from a cohort of 5-year-old OVT73 (n = 6) and control (n = 6) sheep into a single database utilising the programming language R. It includes high-throughput transcriptomic, metabolomic and proteomic data from blood, brain, and other tissues. We present the ‘multi-omic’ HD sheep database as a queryable web-based platform that can be used by the wider HD research community (https://hdsheep.cer.auckland.ac.nz/). The database is supported with a suite of simple automated statistical analysis functions for rapid exploratory analyses. We present examples of its use that validates the integrity relative to results previously reported. The data may also be downloaded for user determined analysis. We propose the use of this online database as a hypothesis generator and method to confirm/refute findings made from patient samples and alternate model systems, to expand our understanding of HD pathogenesis. Importantly, additional tissue samples are available for further investigation of this cohort.

Sodium valproate (VPA) is a histone deacetylase (HDAC) inhibitor, widely prescribed in the treatment of bipolar disorder, and yet the precise modes of therapeutic action for this drug are not fully understood. After exposure of the rat serotonergic cell line RN46A to VPA, RNA-sequencing (RNA-Seq) analysis showed widespread changes in gene expression. Analysis by four bioinformatic pipelines revealed as many as 230 genes were significantly upregulated and 72 genes were significantly downregulated. A subset of 23 differentially expressed genes was selected for validation using the nCounter® platform, and of these we obtained robust validation for ADAM23, LSP1, MAOB, MMP13, PAK3, SERPINB2, SNAP91, WNT6, and ZCCHC12. We investigated the effect of lithium on this subset and found four genes, CDKN1C, LSP1, SERPINB2, and WNT6co-regulated by lithium and VPA. We also explored the effects of other HDAC inhibitors and the VPA analogue valpromide on the subset of 23 selected genes. Expression of eight of these genes, CDKN1C, MAOB, MMP13, NGFR, SHANK3, VGF, WNT6and ZCCHC12, was modified by HDAC inhibition, whereas others did not appear to respond to several HDAC inhibitors tested. These results suggest VPA may regulate genes through both HDAC-dependent and independent mechanisms. Understanding the broader gene regulatory effects of VPA in this serotonergic cell model should provide insights into how this drug works and whether other HDAC inhibitor compounds may have similar gene regulatory effects, as well as highlighting molecular processes that may underlie regulation of mood.

The ability to maximize rewards and minimize the costs of obtaining them is vital to making advantageous explore/exploit decisions. Exploratory decisions are theorized to be greater among individuals with attention-deficit/hyperactivity disorder (ADHD), potentially due to deficient catecholamine transmission. Here, we examined the effects of ADHD status and methylphenidate, a common ADHD medication, on explore/exploit decisions using a 6-armed bandit task. We hypothesized that ADHD participants would make more exploratory decisions than controls, and that MPH would reduce group differences. On separate study days, adults with (n?=?26) and without (n?=?23) ADHD completed the bandit task at baseline, and after methylphenidate or placebo in counter-balanced order. Explore/exploit decisions were modeled using reinforcement learning algorithms. ADHD participants made more exploratory decisions (i.e., chose options without the highest expected reward value) and earned fewer points than controls in all three study days, and methylphenidate did not affect these outcomes. Baseline exploratory choices were positively associated with hyperactive ADHD symptoms across all participants. These results support several theoretical models of increased exploratory choices in ADHD and suggest the unexplained variance in ADHD decisions may be due to less value tracking. The inability to suppress actions with little to no reward value may be a key feature of hyperactive ADHD symptoms.

The output of the retina is organized into many detector grids, called ‘mosaics’, that signal different features of visual scenes to the brain1–4. Each mosaic comprises a single type of retinal ganglion cell (RGC), whose receptive fields tile visual space. Many mosaics arise as pairs, signalling increments (ON) and decrements (OFF), respectively, of a particular visual feature5. Here we use a model of efficient coding6to determine how such mosaic pairs should be arranged to optimize the encoding of natural scenes. We find that information is maximized when these mosaic pairs are anti-aligned, meaning that the distances between the receptive field centres across mosaics are greater than expected by chance. We tested this prediction across multiple receptive field mosaics acquired using large-scale measurements of the light responses of rat and primate RGCs. ON and OFF RGC pairs with similar feature selectivity had anti-aligned receptive field mosaics, consistent with this prediction. ON and OFF RGC types that encode distinct features have independent mosaics. These results extend efficient coding theory beyond individual cells to predict how populations of diverse types of RGC are spatially arranged.

The ability to control the potential landscape in a medium of interacting particles could lead to intriguing collective behavior and innovative functionalities. Here, we utilize spatially reconfigurable magnetic potentials of a pinwheel artificial-spin-ice (ASI) structure to tailor the motion of superconducting vortices. The reconstituted chain structures of the magnetic charges in the pinwheel ASI and the strong interaction between magnetic charges and superconducting vortices allow significant modification of the transport properties of the underlying superconducting thin film, resulting in a reprogrammable resistance state that enables a reversible and switchable vortex Hall effect. Our results highlight an effective and simple method of using ASI as an in situ reconfigurable nanoscale energy landscape to design reprogrammable superconducting electronics, which could also be applied to the in situ control of properties and functionalities in other magnetic particle systems, such as magnetic skyrmions.

Das Wissen über die genetischen Treiber und therapeutischen Zielstrukturen von Melanomen der Schleimhäute ist bisher lückenhaft, weil nur wenig umfassende Daten zu den Mutationen bei dieser seltenen Tumorart vorliegen. Um die genomische Landschaft des mukosalen Melanoms besser zu verstehen, beschreiben wir hier die Analyse von 67 Tumoren mittels Whole-Genome-Sequenzierung nebst Validierung von Treibermutationen durch Whole-Exome-Sequenzierung von 45 Tumoren. Die Tumoren zeigten eine geringe Punktmutationslast und eine hohe Zahl von Strukturvarianten, einschließlich rekurrenter Rearrangements im Bereich von TERT, CDK4und MDM2. Signifikant mutierte Gene sind NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-Aund CHD8. SF3B1-Mutationen kamen mit erhöhter Häufigkeit in Melanomen des weiblichen Genitaltrakts und der Anorektalregion vor, und CTNNB1-Mutationen deuten auf den Beitrag einer gestörten WNT-Signaltransduktion zur Entstehung eines Teils der Schleimhautmelanome hin. TERT-Aberrationen und ATRX-Mutationen sind mit Veränderungen der Telomerlängen assoziiert. Die Mutationsprofile eines Großteils der Schleimhautmelanome deuten auf eine mögliche Empfindlichkeit gegenüber CDK4/6- und/oder MEK-Inhibitoren hin.

This paper considers the role of legal regulation in assessing the actions of firms in relation to CSR. Utilising recent legal developments surrounding the controversial practice of hydraulic fracturing ('fracking') as an illustrative example of the issue, it questions whether judging CSR is possible in a legal vacuum. Having established the linkage between CSR and the law the piece moves to illustrate that instances of legal freedom question established conceptions of CSR and warrant a greater exploration of this connection. Whilst instances of this type are conceded as rare, they do question the extent to which, without law, the responsibility for actions can be demonstrated by firms and it is this which the paper highlights.

Questions of social behavior are simultaneously among the most fundamental in neuroscience and the most challenging in artificial intelligence. Yet despite decades of work, a unified perspective from the cognitive and computational approaches to the problem has yet to emerge. Recently, however, excitement around the challenges posed to reinforcement learning by multiplayer video games, coupled with the adoption of more complex modeling strategies in social neuroscience, has broadened the interface between the two fields. Here, we review recent progress from both directions, arguing that advances in artificial intelligence provide neuroscientists with valuable tools for modeling social interactions. At the same time, the study of humans as efficient social learners can inform the design of new algorithms for multi-agent systems. We conclude by encouraging a joint approach that incorporates the best of both domains to advance a shared picture of social intelligence.

Aim:Long read sequencing offers the promise of overcoming some of the challenges in accurate genotyping of complex genes, along with the advantage of straightforward variant phasing. We have established methods for sequencing and haplotyping of the whole CYP2D6gene using nanopore sequencing. Materials and methods:32 samples covering various haplotypes including gene duplication were sequenced on the GridION platform. Results:Haplotypes of 52 alleles matched accurately to known star (*) allele subvariants, with the remaining 12 being assigned as new alleles, or new subvariants of known alleles. Duplicated alleles could be detected by analyzing the allelic balance. Conclusion:Nanopore sequencing of CYP2D6offers a high throughput method for accurate haplotyping, detection of new variants and determination of duplicated alleles.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9–4% of women and 0.3% of men2–4, with twin-based heritability estimates of 50–60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes. Genome-wide analyses identify eight independent loci associated with anorexia nervosa. Genetic correlations implicate both psychiatric and metabolic components in the etiology of this disorder, even after adjusting for the effects of common variants associated with body mass index.

The benign melanocytic nevus is the most common tumor in humans and rarely transforms into cutaneous melanoma. Elucidation of the nevus genome is required to better understand the molecular steps of progression to melanoma. We performed whole genome sequencing on a series of 14 benign melanocytic nevi consisting of both congenital and acquired types. All nevi had driver mutations in the MAPK signaling pathway, either BRAFV600E or NRASQ61R/L. No additional definite driver mutations were identified. Somatic mutations in nevi with higher mutation loads showed a predominance of mutational signatures 7a and 7b, consistent with UVR exposure, whereas nevi with lower mutation loads (including all three congenital nevi) had a predominance of the ubiquitous signatures 1 and 5. Two nevi had mutations in promoter regions predicted to bind E26 transformation-specific family transcription factors, as well as subclonal mutations in the TERTpromoter. This paper presents whole genome data from melanocytic nevi. We confirm that UVR is involved in the etiology of a subset of nevi. This study also establishes that TERTpromoter mutations are present in morphologically benign skin nevi in subclonal populations, which has implications regarding the interpretation of this emerging biomarker in sensitive assays.

BackgroundPALB2monoallelic loss-of-functiongerm-line variants confer a breast cancer risk comparable to the average BRCA2pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify loss-of-functionvariants in PALB2—without incurring overprediction—is thus of paramount clinical relevance. Towards this aim, we have performed a comprehensive characterisation of alternative splicing in PALB2, analysing its relevance for the classification of truncating and splice site variants according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.MethodsAlternative splicing was characterised in RNAs extracted from blood, breast and fimbriae/ovary-related human specimens (n=112). RNAseq, RT-PCR/CE and CloneSeq experiments were performed by five contributing laboratories. Centralised revision/curation was performed to assure high-quality annotations. Additional splicing analyses were performed in PALB2c.212–1G>A, c.1684+1G>A, c.2748+2T>G, c.3113+5G>A, c.3350+1G>A, c.3350+4A>C and c.3350+5G>A carriers. The impact of the findings on PVS1 status was evaluated for truncating and splice site variant.ResultsWe identified 88 naturally occurring alternative splicing events (81 newly described), including 4 in-frame events predicted relevant to evaluate PVS1 status of splice site variants. We did not identify tissue-specific alternate gene transcripts in breast or ovarian-related samples, supporting the clinical relevance of blood-based splicing studies.ConclusionsPVS1 is not necessarily warranted for splice site variants targeting four PALB2acceptor sites (exons 2, 5, 7 and 10). As a result, rare variants at these splice sites cannot be assumed pathogenic/likely pathogenicwithout further evidences. Our study puts a warning in up to five PALB2genetic variants that are currently reported as pathogenic/likely pathogenicin ClinVar.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case–control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n= 46,568; African, n= 6,280). Independent, genome-wide significant effects of different ADH1Bvariants were identified in European (rs1229984; P= 9.8 × 10–13) and African ancestries (rs2066702; P= 2.2 × 10–9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit–hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

The gamma function was originally discovered by Euler to solve an interpolation problem for the factorials. However, its ubiquity cannot be due to its algebraic nature alone. This article presents the close connection between the volumes of various spaces and the values of the gamma function to better understand its frequent appearance in many mathematical formulas. This connection produces a surprising similarity between Viète’s formula for πand Knar’s formula.

Geometric frustration emerges when local interaction energies in an ordered lattice structure cannot be simultaneously minimized, resulting in a large number of degenerate states. The numerous degenerate configurations may lead to practical applications in microelectronics1, such as data storage, memory and logic2. However, it is difficult to achieve very high degeneracy, especially in a two-dimensional system3,4. Here, we showcase in situ controllable geometric frustration with high degeneracy in a two-dimensional flux-quantum system. We create this in a superconducting thin film placed underneath a reconfigurable artificial-spin-ice structure5. The tunable magnetic charges in the artificial-spin-ice strongly interact with the flux quanta in the superconductor, enabling switching between frustrated and crystallized flux quanta states. The different states have measurable effects on the superconducting critical current profile, which can be reconfigured by precise selection of the spin-ice magnetic state through the application of an external magnetic field. We demonstrate the applicability of these effects by realizing a reprogrammable flux quanta diode. The tailoring of the energy landscape of interacting ‘particles’ using artificial-spin-ices provides a new paradigm for the design of geometric frustration, which could illuminate a path to control new functionalities in other material systems, such as magnetic skyrmions6, electrons and holes in two-dimensional materials7,8, and topological insulators9, as well as colloids in soft materials10–13. A superconducting thin film placed underneath a reconfigurable artificial-spin-ice structure in situ allows controllable geometric frustration with high degeneracy to be achieved.

Experimental records of single molecules or ion channels from fluorescence microscopy and patch-clamp electrophysiology often include high-frequency noise and baseline fluctuations that are not generated by the system under investigation and have to be removed. Moreover, multiple channels or conductance levels can be present at a time in the data that need to be quantified to accurately understand the behavior of the system. Manual procedures for removing these fluctuations and extracting conducting states or multiple channels are laborious, prone to subjective bias, and likely to hinder the processing of often very large data sets. We introduce a maximal likelihood formalism for separating signal from a noisy and drifting background such as fluorescence traces from imaging of elementary Ca2+release events called puffs arising from clusters of channels, and patch-clamp recordings of ion channels. Parameters such as the number of open channels or conducting states, noise level, and background signal can all be optimized using the expectation-maximization algorithm. We implement our algorithm following the Baum-Welch approach to expectation-maximization in the portable Java language with a user-friendly graphical interface and test the algorithm on both synthetic and experimental data from the patch-clamp electrophysiology of Ca2+channels and fluorescence microscopy of a cluster of Ca2+channels and Ca2+channels with multiple conductance levels. The resulting software is accurate, fast, and provides detailed information usually not available through manual analysis. Options for visual inspection of the raw and processed data with key parameters are provided, in addition to a range of statistics such as the mean open probabilities, mean open times, mean close times, dwell-time distributions for different number of channels open or conductance levels, amplitude distribution of all opening events, and number of transitions between different number of open channels or conducting levels in asci format with a single click.

The use of biochemical inducers of mesenchymal stem cell (MSC) differentiation into tenogenic lineage represents an investigated aspect of tendon disorder treatment. Bone morphogenetic protein 12 (BMP-12) is a widely studied factor, representing along with ascorbic acid (AA) and basic fibroblast growth factor (bFGF) one of the most promising stimulus in this context so far. Quantitative gene expression of specific tenogenic marker is commonly used to assess the efficacy of these supplements. Nevertheless, the reliability of these data is strongly associated with the choice of stable housekeeping genes. To date, no published studies have evaluated the stability of housekeeping genes in MSCs during tenogenic induction. Three candidate housekeeping genes (YWHAZ, RPL13A, and GAPDH) in human MSCs from bone marrow (BMSCs), adipose tissue (ASCs), and tendon cells (TCs) supplemented with BMP-12 or AA and bFGF in comparison with control untreated cells for 3 and 10 days were evaluated. GeNorm, NormFinder, and BestKeeper tools and the comparative ΔCt method were used to evaluate housekeeping gene stability and the overall ranking was determined by using by the RefFinder algorithm. In all culture conditions, YWHAZwas the most stable gene and RPL13Awas the second choice. YWHAZand RPL13Awere the two most stable genes also for ASCs and BMSCs, regardless of the time point analyzed, and for TCs at 10 days of tenogenic induction. Only for TCs at 3 days of tenogenic induction were GAPDHand YWHAZthe best performers. In conclusion, our findings will be useful for the proper selection of housekeeping genes in studies involving MSCs cultured in the presence of tenogenic factors, to obtain accurate and high-quality data from quantitative gene expression analysis.

Denosumab, an inhibitor of receptor activator of nuclear factor κ-B ligand, is an approved treatment of giant cell tumor of bone (GCTB) in adults and "skeletally mature" adolescents. Safety concerns include oversuppression of bone remodelling, with risk of osteonecrosis of the jaw (ONJ) and atypical femur fractures during treatment in adults and rebound hypercalcemia after treatment cessation in children. To date, ONJ has never been reported in children or adolescents.

ABSTRACTMale rape is a prevalent issue in society that can have a profound number of negative effects on a victim. Research into male rape is estimated to be roughly 20 years behind female rape, but has received a greater amount of academic attention in the last few decades. The aim of this research was to critically discuss male rape research, outlining the main theories, discussing gaps in the research and suggesting avenues for future investigations. The main areas in the review are the definition of rape and sexual assault in the U.K., prevalence of male rape, reasons why reports of male rape may be low, attitudes and stereotypical beliefs towards male rape victims, effects that these attitudes and male rape can have on the victim and specific characteristics of victims, offenders and the offence of male rape crimes.

•Hydraulic fracturing (fracking) is being tested in the United Kingdom as a means of accessing natural gas reserves.•The current regulatory process proposed for this industry is complex and adapted from that for existing oil and gas projects.•Local planning authorities, at present, hold considerable influence in the approval of hydraulic fracturing projects.•Concerns over the process are bifurcated between civic and scientific groups.•Future regulation might be influence by misguided concerns and as such neglect those supported by evidence.

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

The well-known Hall effect describes the transverse deflection of charged particles (electrons/holes) as a result of the Lorentz force. Similarly, it is intriguing to examine if quasi-particles without an electric charge, but with a topological charge, show related transverse motion. Magnetic skyrmions with a well-defined spin texture with a unit topological charge serve as good candidates to test this hypothesis. In spite of the recent progress made on investigating magnetic skyrmions, direct observation of the skyrmion Hall effect has remained elusive. Here, by using a current-induced spin Hall spin torque, we experimentally demonstrate the skyrmion Hall effect, and the resultant skyrmion accumulation, by driving skyrmions from the creep-motion regime (where their dynamics are influenced by pinning defects) into the steady-flow-motion regime. The experimental observation of transverse transport of skyrmions due to topological charge may potentially create many exciting opportunities, such as topological selection.

Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Whole-genome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35=8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140=2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma patients.

Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Whole-genome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35=8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140=2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma patients.

For patients with BRAF wild-type stage III and IV melanoma, there is an urgent clinical need to identify prognostic biomarkers and biomarkers predictive of treatment response. Circulating tumor DNA (ctDNA) is emerging as a blood-based biomarker and has shown promising results for many cancers, including melanoma. The purpose of this study was to identify targetable, tumor-derived mutations in patient blood that may lead to treatment alternatives and improved outcomes for patients with BRAF-negative melanoma. Using a CAPP-seq pan-cancer gene panel, ctDNA from 150 plasma samples (n = 106 patients) was assessed, including serial blood collections for a subset of patients (n = 16). ctDNA variants were detected in 85% of patients, all in targetable pathways, such as vascular endothelial growth factor receptor, epidermal growth factor receptor, phosphatidylinositol 3-kinase/AKT, Bcl2/mammalian target of rapamycin, ALK/MET, and cyclin-dependent kinase 4/6. Patients with stage IV melanoma with low ctDNA concentrations, <10 ng/mL, had significantly better disease-specific survival and progression-free survival. Patients with both a high concentration of ctDNA and any detectable ctDNA variants had the worst prognosis. In addition, these results indicated that longitudinal changes in ctDNA correlated with treatment response and disease progression determined by radiology. This study confirms that ctDNA has potential to be used as a noninvasive liquid biopsy to identify recurrent disease and detect targetable variants in patients with late-stage melanoma.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLITsignalling, G1/Stransition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53and KDM6Amutations, upregulation of the TP63∆Ntranscriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRASactivation, exocrine (NR5A2and RBPJL), and endocrine differentiation (NEUROD1and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNTsignaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3,a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNTpathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.