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Colin Cooper and colleagues report genome-wide sequences of multiple samples of multifocal cancer and morphologically normal tissue from the prostates of three men. They found high levels of mutations in morphologically normal tissue distant from the cancer, consistent with field effects. Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.

Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1–100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential. Ionizing radiation may induce irreparable DNA damage leading to cancer. Here, the authors identify a specific signature of mutations arising in patients exposed to ionizing radiation and suggest that radiation-induced tumorigenesis is associated with higher rates of genome-wide deletions and balanced inversions.

Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be ‘passengers’ that do not contribute to oncogenesis. However, there was evidence for ‘driver’ mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated. Cancer gene haul Over 350 cancer-causing genes have been identified by established techniques such as mapping, bioassay and by identifying plausible biological candidates. The availability of the human genome sequence now means that large-scale sequencing studies can uncover many more candidate cancer genes. Protein kinase enzymes are key to many regulatory processes and their dysfunction is a common trigger for tumours. So a sample of 518 kinases associated with more than 200 different cancers was chosen for a major sequencing effort. The study reveals more than 1, 000 previously unknown mutations linked to tumour formation — some as 'passengers' that don't contribute to cancer formation, but over 100 of them as 'driver' mutations that do contribute to disease development. As well as revealing cancer-causing defects, gene family studies like this can uncover new targets for molecular diagnostics and therapeutics. 518 protein kinase genes in the human genome have been sequenced in a large sample of tumours, providing a global view of the patterns of mutations found and the variations in the number and type of mutations between individual tumours.

Background Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue ( n  = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. Results Single nucleotide variants ( P  = 7.0 × 10 –03 , Wilcoxon rank sum test) and small insertions and deletions (indels, P  = 8.7 × 10 –06 ) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer ( P  = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial ( P  = 5.94 × 10 –05 , paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants ( P  = 3.72 × 10 –09 , paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. Conclusions Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches.

Nat. Genet. 47, 367–372 (2015); published online 2 March 2015; corrected after print 5 May 2015 In the version of this article initially published, author Manasa Ramakrishna was omitted from the author list. The error has been corrected in the PDF and HTML versions of this article.

Genet. 47, 367-372 (2015); published online 2 March 2015; corrected after print 5 May 2015 In the version of this article initially published, author Manasa Ramakrishna was omitted from the author list.

The purpose of this study was to create a sequential, pedagogical art criticism model. Current criticism strategies place emphasis on rational-cognitive approaches; some pay heed to affective objectives while still retaining a rational orientation. The transpersonal art criticism strategy developed in this thesis places equal emphasis on both cognitive and affective modes of responding to works of art. This new strategy metaphorically parallels a transpersonal model of development with content in works of art. For this purpose the transpersonal development model of Ken Wilber was used. Wilber describes development as teleologically tending towards the realization of Spirit. To establish a background and context, several structural hierarchies of knowledge are considered. Bloom's Taxonomy (affective and cognitive) has recently been used by Karen Hamblen to establish an art criticism questioning strategy. Hamblen has also identified the relationship between art criticism sequenced strategies and developmental models. Harry S. Broudy, a philosopher of education, describes both a simple developmental model as well as a method for art criticism. Recently, two studies (Housen and Parsons) have explored aesthetic development. Several art criticism sequenced strategies are then reviewed. The derivation of Ken Wilber's theory is discussed as it relates to the fields of psychoanalysis, perennial philosophy and humanistic psychology. Wilber's fifteen-stage-structure model is reviewed. It describes development from infancy to Spirit. Wilber's model embraces psychological and philosophical traditions from both Eastern and Western cultures. The transpersonal art criticism model consists of four structures: the physical, emotional, intellectual, and spiritual. The model is designed to be transactional. Viewers utilizing the model engage those aspects of themselves with corresponding aspects in the work of art. Each of the four structures builds on the succeeding structures. This criticism model is designed to transform viewers. Instead of having viewers simply assimilating new knowledge from the experience of viewing through their normal mode of responding, viewers using this model will be encouraged to explore the unconscious and conscious aspects of their lower and higher selves as well as a work of art's full potential for meaning.

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.This Consensus Statement, which is endorsed by the Pituitary Society, offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas.

ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2-knockout (Mdr2-/-) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis.