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Newly diagnosed prostate cancers differ dramatically in mutational composition and lethality. The most accurate clinical predictor of lethality is tumor tissue architecture, quantified as tumor grade. To interrogate the evolutionary origins of prostate cancer heterogeneity, we analyzed 666 prostate tumor whole genomes. We identified a compendium of 223 recurrently mutated driver regions, most influencing downstream mutational processes and gene expression. We identified and validated individual germline variants that predispose tumors to acquire specific somatic driver mutations: these explain heterogeneity in disease presentation and ancestry differences. High-grade tumors have a superset of the drivers in lower-grade tumors, including increased frequency of BRCA2 and MYC mutations. Grade-associated driver mutations occur early in tumor evolution, and their earlier occurrence strongly predicts cancer relapse and metastasis. Our data suggest high- and low-grade prostate tumors both emerge from a common pre-malignant field, influenced by germline genomic context and stochastic mutation-timing.

Objective: This study investigated if human glioblastoma cancer cells (U87MG cell line) cultured in intentionally treated water could reduce cell migration, a prerequisite for metastasis, as compared to the same cells cultured in untreated (control) water., Design: Three Buddhist monks entered a meditative state and directed their awareness to bottles of ultrapure water while holding the intention that the water would cause beneficial changes in U87MG. The study was conducted double-blind whereby all aspects of the study involving cell growth and migration measures, as well as all subsequent statistical evaluations, were performed without knowledge of the type of water being used. Cell cultures were incubated in growth mediums prepared with treated and untreated water, and a wound healing assay was employed to measure cell migration., Results: U87MG cells incubated with treated water migrated less efficiently than the same cells in untreated water. A repeated measures ANOVA, spanning four time periods (0, 3, 6, and 9 h), determined that the time × water condition interaction was associated with p < 0.005., Conclusion: Intentioned awareness appeared to change as-yet unknown properties of ultrapure water, resulting in a reduction of U87MG cells migration activity. Further research is warranted to replicate these results and to investigate the underlying protein expression mechanisms in influencing cell migration., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Shared-death-experiences (SDEs) and after-death-communication-experiences (ADCEs) are non-ordinary mental experiences related to the death of a known or unknown person., Methods: These experiences were investigated by surveying four samples with different cultural backgrounds: Italian, Mexican, Brazilian and Taiwanese people. One-hundred-twenty-one participants reported 146 experiences of this type., Results: Among the main characteristics of these experiences, visual, visual-auditory and feeling experiences, which comprised 74% of all experiences, were experienced both in the dream state and a normal state of consciousness. Furthermore, most of these experiences were lived before (47.3%) or after (39%) the death of the person in relationship with the participants. More importantly, these experiences influenced the participants' death interpretation favoring the belief that death affects only the body, but the consciousness of the deceased persons survives in another reality and sometimes can communicate with relatives and friends still alive in this reality. No substantial differences were observed among the different subsamples., Conclusion: As to the origin of SDEs/ADCEs, we discuss that whereas for most of them, in particular those lived after the death of a relative or a friend, we can assume hallucinatory characteristics triggered by emotional needs, for others, for example those related to unknown individuals and/or those experienced before the death of the person still in good health, it is not possible to exclude their anomalous connections and a real encounter with a deceased person.

Objective: This study explored if human primary mesenchymal stem cells (MSCs), derived from two donors and cultivated in a medium made with intentionally treated water, would exhibit more growth and pluripotency than MSCs from the same source but grown in untreated (control) water., Design: To create the treated water, three Buddhist monks directed their attention toward commercially bottled water while holding the intention that the water would enhance the growth of MSCs. Under double-blind conditions, cell culture growth mediums were prepared with the treated and untreated water, which was in turn used to grow the primary MSCs. Primary cells obtained from two donors were designated as Cells #1 and Cells #2. The prediction was that treated water would result in increased cell proliferation, that more cells would enter the cell cycle growth phase, and that there would be increased expression of genes (NANOG, OCT4 and SOX2) associated with improved cell growth and decreased expression of genes (p16, p21, and p53) associated with a decline in cell growth. The improved growth hypothesis was directional, thus one-tailed p-values were used to evaluate the results., Results: Proliferation averaged across Cells #1 and #2 showed overall increased growth in treated as compared to control water (p = 0.0008). Cells #1 and #2 considered separately had differences in the same direction but only Cells #2 showed a significant difference on day 6 (p = 0.01). For cell cycle, there was a significantly greater percentage of Cells #2 in the S interphase with treated vs. control water (p = 0.04). For the gene expression analysis, when considering the average across the two donor cells, only the NANOG gene expression was in the predicted direction (p = 0.01); by contrast, the p16 gene expression was significantly opposite to the predicted direction (p = 0.005, one-tailed, post-hoc). For Cells #1 considered separately, no differences were significant except for p16, which resulted in an effect opposite to the predicted outcome (p = 0.05). For Cells #2, three genes were significantly in the predicted directions: NANOG (p = 0.0008), OCT4 (p = 0.005), and P53 (p = 0.05); p16 was significantly opposite to the prediction (p = 0.001)., Conclusion: Intentionally treated water appeared to have some biological effects on the growth, pluripotency and senescence of human MSCs. This was especially the case in one of the two donor cells tested, but the effects were not consistently in the predicted direction. As an exploratory study, caution is warranted in interpreting these outcomes, and adjustment for multiple testing would likely reduce some of the weaker effects to nonsignificant. But given the double-blind protocol, as well as several more significant outcomes in the predicted directions, further research is warranted., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests. The first author secured funding for this study and wrote the first draft, the second and fourth authors conducted the cell biology components of the experiment and contributed to writing the manuscript, and the third author double-checked the statistical analyses and contributed to writing the manuscript., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this article we describe four previous Tai-Chi models based on the I-Ching (Book of Changes) and their limitations. The I-Ching , the most important ancient source of information on traditional Chinese culture and cosmology, provides the metaphysical foundation for this culture, especially Confucian ethics and Taoist morality. To overcome the limitations of the four previous Tai-Chi models, we transform I-Ching cultural system into a psychological theory by applying the cultural system approach. Specifically, we propose the Jun-zi () Self-Cultivation Model (JSM), which argues that an individual (, xiao-ren ) can become an ideal person, or jun-zi , through the process of self-cultivation, leading to good fortune and the avoidance of disasters (, qu-ji bi-xiong ). The state of jun-zi is that of the well-functioning self, characterized by achieving one's full potential and an authentic, durable sense of wellbeing. In addition, we compare egoism ( xiao-ren ) and jun-zi as modes of psychological functioning. The JSM can be used to as a framework to explain social behavior, improve mental health, and develop culturally sensitive psychotherapies in Confucian culture. Finally, an examination of possible theoretical directions, clinical applications, and future research is provided., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Chang, Hsu and Shiah.)

In the present paper, we report two studies examining the relationships among renunciation of desires, death anxiety, and mental health. In the first study, we constructed the Desire Questionnaire (DQ), which measures success in renouncing certain desire. The DQ has satisfactory psychometric properties. In the second study, 501 adults from a Chinese society ranging in age from 17 to 84 years (M = 35.58, SD = 14.76) completed the DQ, the Death Anxiety Scale (DAS), and the Chinese Health Questionnaire (CHQ), which measures mental health and the presence of psychiatric symptoms. As predicted, DQ had significant negative correlations with both DAS (p < 0.05) and CHQ (p < 0.01). DAS had a significant positive correlation with CHQ (p < 0.01). In the linear mediation model, DAS was found to partially mediate the relationship between DQ and CHQ (β = - 0.18, p < 0.001). These results suggest that the negative effect of poor control of desires on mental health can be partially accounted for by death anxiety. These findings imply that training in eliminating desires can be a successful strategy to improve mental health. These results also support the Nonself Theory as a theory of death anxiety and show its relevance to the relationship between nonself and mental health., (© 2022. The Author(s).)

Replicative immortality is a hallmark of cancer, and can be achieved through telomere lengthening and maintenance. Although the role of telomere length in cancer has been well studied, its association to genomic features is less well known. Here, we report the telomere lengths of 392 localized prostate cancer tumours and characterize their relationship to genomic, transcriptomic and proteomic features. Shorter tumour telomere lengths are associated with elevated genomic instability, including single-nucleotide variants, indels and structural variants. Genes involved in cell proliferation and signaling are correlated with tumour telomere length at all levels of the central dogma. Telomere length is also associated with multiple clinical features of a tumour. Longer telomere lengths in non-tumour samples are associated with a lower rate of biochemical relapse. In summary, we describe the multi-level integration of telomere length, genomics, transcriptomics and proteomics in localized prostate cancer., (© 2021. The Author(s).)

Purpose: This study first assessed the occurrence of major depressive disorder (MDD), post-traumatic stress disorder (PTSD), symptoms of poor sleep quality and high levels of distress among residents, caused by reported long-term stress from environmental pollution emitted from the biggest petroleum chemistry factory (PCF) in the world., Methods: A total of 328 long-term residents (Mean age = 57.5, SD = 16.5 years, ranging from 22 to 95) were recruited randomly from a total population of 26,632 in Mailiao township in Taiwan next to the PCF. Trained assistants used the Disaster-Related Psychological Screening test, the Perception of Life Threats Caused by the SCNP questionnaire and the Sleep Quality Scale to interview the participants., Results: The results support our hypotheses that most of the residents (71%) would report life threats caused by the PCF. The residents displayed higher rates of major depressive episodes (24.1%), PTSD (24.5%) and symptoms of poor sleep quality. The more they felt threat from the PCF, the stronger the connection with MDD and PTSD symptoms., Conclusion: The results indicate an increased prevalence of MDD, PTSD and symptoms of poor sleep quality in those exposed to environmental pollution from the PCF, highlighting the need for prompt prevention, diagnostic and therapeutic attention., (Copyright © 2021. Published by Elsevier B.V.)

Objective: . A previously reported experiment indicated that Arabidopsis thaliana seeds with cryptochrome mutation His-CRY2 showed more robust photomorphogenic growth when hydrated with intentionally treated water as compared to untreated water. The present study attempted to replicate that outcome, adding a condition where the seeds were also intentionally treated. Arabidopsis seeds were used because they contain a photosensitive flavoprotein called cryptochrome (CRY). CRY has been proposed as a possible "transducer" of intention in living systems because it is thought to have quantum biological properties, and as such, it might potentially be sensitive to quantum observer effects., Design: Three Buddhist monks directed their attention toward commercially bottled water and Arabidopsis seeds while holding the intention to improve the growth of the plant. As a control condition, no attention was directed at water or seeds from the same sources. Under double-blinded conditions, treated and untreated seeds were placed in an incubator, hydrated with treated or untreated water, and exposed to either continuous blue light or blue plus far-red light. The seed germination process was repeated three times, each time using new seeds. A 2 × 2 × 2 ANOVA, with water, seeds, and light as factors, was used to analyze the results., Results: . Treated water was associated with enhanced photomorphogenic growth, as reflected by a shorter hypocotyl length (p = 0.04) and greater amounts of chlorophyll (p = 0.0005) and anthocyanin (p = 2 × 10 -6 ). Treated seeds resulted in greater amounts of chlorophyll (p = 0.04), but also a longer hypocotyl (p = 0.0004) and less anthocyanin (p = 0.01). Plants exposed to blue plus far-red light were constantly more robust than plants grown under blue light, regardless of the type of water or seed (p < 10 -10 )., Conclusion: . Intentionally treated water improved the growth of the His-CRY2 variant of Arabidopsis, confirming results of an earlier experiment. Enhanced growth associated with exposure to blue plus far-red light also confirmed to known effects. A more complex relationship was observed with treated seeds. Further research is required to understand the latter outcome, as it may provide clues about the underlying mechanisms of intentional influences., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.

DNA sequencing has identified recurrent mutations that drive the aggressiveness of prostate cancers. Surprisingly, the influence of genomic, epigenomic, and transcriptomic dysregulation on the tumor proteome remains poorly understood. We profiled the genomes, epigenomes, transcriptomes, and proteomes of 76 localized, intermediate-risk prostate cancers. We discovered that the genomic subtypes of prostate cancer converge on five proteomic subtypes, with distinct clinical trajectories. ETS fusions, the most common alteration in prostate tumors, affect different genes and pathways in the proteome and transcriptome. Globally, mRNA abundance changes explain only ∼10% of protein abundance variability. As a result, prognostic biomarkers combining genomic or epigenomic features with proteomic ones significantly outperform biomarkers comprised of a single data type., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.

Background: We introduce BPG, a framework for generating publication-quality, highly-customizable plots in the R statistical environment., Results: This open-source package includes multiple methods of displaying high-dimensional datasets and facilitates generation of complex multi-panel figures, making it suitable for complex datasets. A web-based interactive tool allows online figure customization, from which R code can be downloaded for integration with computational pipelines., Conclusion: BPG provides a new approach for linking interactive and scripted data visualization and is available at http://labs.oicr.on.ca/boutros-lab/software/bpg or via CRAN at https://cran.r-project.org/web/packages/BoutrosLab.plotting.general.

Transforming members of the MYC family (MYC, MYCL1, and MYCN) encode transcription factors containing six highly conserved regions, termed MYC homology boxes (MBs). By conducting proteomic profiling of the MB interactomes, we demonstrate that half of the MYC interactors require one or more MBs for binding. Comprehensive phenotypic analyses reveal that two MBs, MB0 and MBII, are universally required for transformation. MBII mediates interactions with acetyltransferase-containing complexes, enabling histone acetylation, and is essential for MYC-dependent tumor initiation. By contrast, MB0 mediates interactions with transcription elongation factors via direct binding to the general transcription factor TFIIF. MB0 is dispensable for tumor initiation but is a major accelerator of tumor growth. Notably, the full transforming activity of MYC can be restored by co-expression of the non-transforming MB0 and MBII deletion proteins, indicating that these two regions confer separate molecular functions, both of which are required for oncogenic MYC activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

MYC is an oncogenic driver that regulates transcriptional activation and repression. Surprisingly, mechanisms by which MYC promotes malignant transformation remain unclear. We demonstrate that MYC interacts with the G9a H3K9-methyltransferase complex to control transcriptional repression. Inhibiting G9a hinders MYC chromatin binding at MYC-repressed genes and de-represses gene expression. By identifying the MYC box II region as essential for MYC-G9a interaction, a long-standing missing link between MYC transformation and gene repression is unveiled. Across breast cancer cell lines, the anti-proliferative response to G9a pharmacological inhibition correlates with MYC sensitivity and gene signatures. Consistently, genetically depleting G9a in vivo suppresses MYC-dependent tumor growth. These findings unveil G9a as an epigenetic regulator of MYC transcriptional repression and a therapeutic vulnerability in MYC-driven cancers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cancer differs significantly between men and women; even after adjusting for known epidemiologic risk factors, the sexes differ in incidence, outcome, and response to therapy. These differences occur in many but not all tumor types, and their origins remain largely unknown. Here, we compare somatic mutation profiles between tumors arising in men and in women. We discovered large differences in mutation density and sex biases in the frequency of mutation of specific genes; these differences may be associated with sex biases in DNA mismatch repair genes or microsatellite instability. Sex-biased genes include well-known drivers of cancer such as β-catenin and BAP1 Sex influenced biomarkers of patient outcome, where different genes were associated with tumor aggression in each sex. These data call for increased study and consideration of the molecular role of sex in cancer etiology, progression, treatment, and personalized therapy. Significance: This study provides a comprehensive catalog of sex differences in somatic alterations, including in cancer driver genes, which influence prognostic biomarkers that predict patient outcome after definitive local therapy. Cancer Res; 78(19); 5527-37. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Betel quid (BQ), chewed by about 600 million people worldwide, is one of the most widely used addictive substances. Little is known about psychological factors in BQ chewers., Objectives: The present study was the first attempt to explore the relationships between BQ chewing, personality, and mood., Methods: A survey was conducted with a purposive sample to assess BQ chewing habits in four subgroups: BQ-only users, BQ users who smoke and/or drink, smokers and/or drinkers only, and substance nonusers. A total of 494 participants were recruited from the civilian, non-institutionalized population in Taiwan. Habitual consumption of BQ, smoking and drinking; socio-demographic variables; extraversion; and mood (tension, depression, anger, vigor, fatigue, confusion, and self-esteem). All BQ chewers were evaluated on BQ dependence domains using DSM IV and ICD-10 criteria., Results: The 6-month BQ dependency rate among BQ chewers, defined by either DSM-IV or ICD-10 criteria, ranged from 42.9 to 45.6%. BQ-only users had significantly lower scores on extraversion than substance nonusers. BQ-only users had statistically significant higher scores on confusion and total mood than substance nonusers. BQ-only users had significantly higher scores on fatigue, anger, tension, and depression, than substance nonusers, BQ users who smoke and/or drink, and smokers and/or drinkers only. The number of BQ dependence domains correlated significantly negatively with total mood scores. Conclusions/Importance: The results supported the two hypotheses: (a) BQ chewing is associated with low extraversion; and (b) BQ chewing is related to negative mood.

The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology., (© 2018 Casey et al.)

Objective: A previous experiment suggested that consumption of intentionally treated tea influenced subjective mood under double-blind, controlled conditions. To investigate that effect objectively, again under double-blind, controlled conditions, we studied whether Arabidopsis thaliana seeds hydrated with intentionally treated vs. untreated water would show differences in hypocotyl length, anthocyanin, and chlorophyll., Design: Three Buddhist monks focused their intention on commercially bottled water with the goal of improving the growth of seeds; bottled water from the same source served as an untreated control. Seeds with the following three variations of cryptochrome (CRY) were used: the wild type Arabidopsis (Columbia-4), a gain-of-function mutation (His-CRY2), and a loss-of function mutation (cry1/2), where "gain" and "loss" refer to enhanced and reduced sensitivity to blue light, respectively. Seeds were hydrated with treated or untreated water under blinded conditions, and then placed in random positions in an incubator. The germination process was repeated three times in each experiment, each time using new seeds, and then the entire experiment was repeated four times., Results: Data combined across the four experiments showed a significant decrease in hypocotyl length in the His-CRY2 seedlings (treated mean 1.31 ± 0.01mm, untreated mean 1.43 ± 0.01mm, P < 10 -13 ), a significant increase in anthocyanin with all three forms of cry, particularly His-CRY2 (treated mean 17.0 ± 0.31mg, untreated mean 14.5 ± 0.31mg, P < 10 -4 ), and a modest increase in chlorophyll in His-CRY2 (treated mean 247.6 ± 5.63mg, untreated mean 230.6 ± 5.63mg, P = .05). These outcomes conformed to the monks' intentions because a decrease in hypocotyl length and increase in anthocyanin and chlorophyll are associated with enhanced photomorphogenic growth. These experiments suggest that the His-CRY2 mutation of Arabidopsis may be an especially robust "detector" of intention., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Motivation: Microarrays are widely used to quantify DNA methylation because they are economical, require only small quantities of input DNA and focus on well-characterized regions of the genome. However, pre-processing of methylation microarray data is challenging because of confounding factors that include background fluorescence, dye bias and the impact of germline polymorphisms. Therefore, we present valuable insights and a framework for those seeking the most optimal pre-processing method through a data-driven approach., Results: Here, we show that Dasen is the optimal pre-processing methodology for the Infinium HumanMethylation450 BeadChip array in prostate cancer, a frequently employed platform for tumour methylome profiling in both the TCGA and ICGC consortia. We evaluated the impact of 11 pre-processing methods on batch effects, replicate variabilities, sensitivities and sample-to-sample correlations across 809 independent prostate cancer samples, including 150 reported for the first time in this study. Overall, Dasen is the most effective for removing artefacts and detecting biological differences associated with tumour aggressivity. Relative to the raw dataset, it shows a reduction in replicate variances of 67% and 76% for β- and M-values, respectively. Our study provides a unique pre-processing benchmark for the community with an emphasis on biological implications., Availability and Implementation: All software used in this study are publicly available as detailed in the article., Contact: paul.boutros@oicr.on.ca., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

TMPRSS2-ERG (T2E) structural rearrangements typify ∼50% of prostate tumors and result in overexpression of the ERG transcription factor. Using chromatin, genomic and expression data, we show distinct cis-regulatory landscapes between T2E-positive and non-T2E primary prostate tumors, which include clusters of regulatory elements (COREs). This difference is mediated by ERG co-option of HOXB13 and FOXA1, implementing a T2E-specific transcriptional profile. We also report a T2E-specific CORE on the structurally rearranged ERG locus arising from spreading of the TMPRSS2 locus pre-existing CORE, assisting in its overexpression. Finally, we show that the T2E-specific cis-regulatory landscape underlies a vulnerability against the NOTCH pathway. Indeed, NOTCH pathway inhibition antagonizes the growth and invasion of T2E-positive prostate cancer cells. Taken together, our work shows that overexpressed ERG co-opts master transcription factors to deploy a unique cis-regulatory landscape, inducing a druggable dependency on NOTCH signaling in T2E-positive prostate tumors.

The Minnesota Multiphasic Personality Inventory-2 (MMPI-2) is often used in forensic psychological/psychiatric assessment. This was a pilot study on the utility of the Chinese MMPI-2 in detecting feigned mental disorders. The sample consisted of 194 university students who were either simulators (informed or uninformed) or controls. All the participants were administered the Chinese MMPI-2 and the Structured Interview of Reported Symptoms-2 (SIRS-2). The results of the SIRS-2 were utilized to classify the participants into the feigning or control groups. The effectiveness of eight detection indices was investigated by using item analysis, multivariate analysis of covariance (MANCOVA), and receiver operating characteristic (ROC) analysis. Results indicated that informed-simulating participants with prior knowledge of mental disorders did not perform better in avoiding feigning detection than uninformed-simulating participants. In addition, the eight detection indices of the Chinese MMPI-2 were effective in discriminating participants in the feigning and control groups, and the best cut-off scores of three of the indices were higher than those obtained from the studies using the English MMPI-2. Thus, in this sample of university students, the utility of the Chinese MMPI-2 in detecting feigned mental disorders was tentatively supported, and the Chinese Infrequency Scale (ICH), a scale developed specifically for the Chinese MMPI-2, was also supported as a valid scale for validity checking., (© 2017 The Institute of Psychology, Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.)

Background: There is a need for markers that can specifically identify individuals at increased risk of harboring aggressive forms of prostate cancer (PCa)., Methods: We surveyed the Kallikrein ( KLK ) region ( KLK 1-15) for single-nucleotide polymorphisms (SNPs) associated with aggressive PCa (Gleason Score ≥ 8) in 1858 PCa patients. Discovery cohorts (Swiss arm of the European Randomized Study of Screening for PCa, n = 379; Toronto, Canada, n = 540) and a validation cohort (Prostate, Lung, Colorectal and Ovarian [PLCO] screening trial, n = 939) were analyzed. Fine-mapping within the KLK region was carried out by genotyping and imputation in the discovery cohort, whereas PLCO data were provided through database of Genotypes and Phenotypes ( dbGaP ). The influence of SNPs of interest on biochemical-free survival was evaluated in a cohort of localized PCa from the International Cancer Genome Consortium (ICGC; n = 130) analyzed with next-generation sequencing. Single- and multi-SNP association studies, as well as haplotype analyses, were performed. All statistical tests were two-sided., Results: Several SNPs in very strong linkage disequilibrium in the KLK 6 region and located within the same haplotype (rs113640578, rs79324425, rs11666929, rs28384475, rs3810287), identified individuals at increased risk of aggressive PCa in both discovery (odds ratio [OR] = 3.51-3.64, 95% confidence interval [CI] = 2.01 to 6.36, P = 1.0x10 -5 -8.4x10 -6 ) and validation (OR = 1.89-1.96, 95% CI = 0.99 to 3.71, P = .04-.05) cohorts. The overall test of haplotype association was highly statistically significant in each cohort ( P = 3.5x10 -4 and .006, respectively) and in the three data sets combined ( P = 2.3x10 -5 ). These germline SNPs independently predicted relapse in the ICGC cohort (hazard ratio = 3.15, 95% CI = 1.57 to 6.34, P = .001)., Conclusions: Our fine-mapping study has identified novel loci in the KLK 6 region strongly associated with aggressive PCa., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

To quantitate the meditation experience is a subjective and complex issue because it is confounded by many factors such as emotional state, method of meditation, and personal physical condition. In this study, we propose a strategy with a cross-sectional analysis to evaluate the meditation experience with 2 artificial intelligence techniques: artificial neural network and support vector machine. Within this analysis system, 3 features of the electroencephalography alpha spectrum and variant normalizing scaling are manipulated as the evaluating variables for the detection of accuracy. Thereafter, by modulating the sliding window (the period of the analyzed data) and shifting interval of the window (the time interval to shift the analyzed data), the effect of immediate analysis for the 2 methods is compared. This analysis system is performed on 3 meditation groups, categorizing their meditation experiences in 10-year intervals from novice to junior and to senior. After an exhausted calculation and cross-validation across all variables, the high accuracy rate >98% is achievable under the criterion of 0.5-minute sliding window and 2 seconds shifting interval for both methods. In a word, the minimum analyzable data length is 0.5 minute and the minimum recognizable temporal resolution is 2 seconds in the decision of meditative classification. Our proposed classifier of the meditation experience promotes a rapid evaluation system to distinguish meditation experience and a beneficial utilization of artificial techniques for the big-data analysis.

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment., Competing Interests: D.C. is an employee of TissuPath. The remaining authors declare no competing financial interests.

Culture can moderate which variables most influence subjective well-being (SWB). Because religion can be conceptualized as culture, religious differences can be considered cultural differences. However, there have been few studies comparing how different religious groups evaluate SWB at any given time. This study is among the first to investigate this issue. The present study compared Buddhists, Taoists, Christians, and atheists. In addition to demographic items, 451 Chinese adults completed Chinese version of the Socially Oriented Cultural Conception of SWB Scale. Religious belief was distributed as follows: 10 % Christian, 20 % Buddhist, 25 % Taoist, and 43 % atheists. As predicted, the socially oriented cultural conception of SWB was found to be highest among Buddhists, followed in order by Taoists, atheists, and Christians. It was concluded that the various religious groups achieved SWB in different ways.

The maintenance/strength of self is a very core concept in Western psychology and is particularly relevant to egoism, a process that draws on the hedonic principle in pursuit of desires. Contrary to this and based on Buddhism, a nonself-cultivating process aims to minimize or extinguish the self and avoid desires, leading to egolessness or selflessness. The purpose of this paper is to present the Nonself Theory (NT). The universal Mandala Model of Self (MMS) was developed to describe the well-functioning self in various cultures. The end goal of the self is to attain authentic and durable happiness. Given that the nonself is considered a well-functioning self, the MMS is suitable for constructing the NT. The ego and nonself aspects of psychological self-functioning and their underlying processes are compared, drawing on the four concepts of the MMS: biology, ideal person, knowledge/wisdom and action. The ego engages in psychological activities to strengthen the self, applying the hedonic principle of seeking desire-driven pleasure. In contrast, a nonself approach involves execution of the self-cultivation principle, which involves three ways: giving up desires, displaying compassion, practicing meditation and seeking understanding Buddhist wisdom. These three ways have the goal of seeing through and overcoming the illusion of the self to achieve a deep transformation integrally connected to the experience of eliminating the sense of self and its psychological structures. In addition, the NT provides a comprehensive framework to account for nonself-plus-compassion-related activities or experiences such as altruism, mindfulness, mediation, mysterious/peak experiences, elimination of death anxiety and moral conduct. The NT offers possible answers that might lead to a more comprehensive understanding of human beings and the deeper meaning of life, toward the ultimate goal of a well-functioning self. An examination of possible clinical applications and theoretical directions for future research in nonself psychology are provided.

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

Progesterone drives mammary stem and progenitor cell dynamics through paracrine mechanisms that are currently not well understood. Here, we demonstrate that CXCR4, the receptor for stromal-derived factor 1 (SDF-1; CXC12), is a crucial instructor of hormone-induced mammary stem and progenitor cell function. Progesterone elicits specific changes in the transcriptome of basal and luminal mammary epithelial populations, where CXCL12 and CXCR4 represent a putative ligand-receptor pair. In situ, CXCL12 localizes to progesterone-receptor-positive luminal cells, whereas CXCR4 is induced in both basal and luminal compartments in a progesterone-dependent manner. Pharmacological inhibition of CXCR4 signaling abrogates progesterone-directed expansion of basal (CD24 + CD49f hi ) and luminal (CD24 + CD49f lo ) subsets. This is accompanied by a marked reduction in CD49b + SCA-1 - luminal progenitors, their functional capacity, and lobuloalveologenesis. These findings uncover CXCL12 and CXCR4 as novel paracrine effectors of hormone signaling in the adult mammary gland, and present a new avenue for potentially targeting progenitor cell growth and malignant transformation in breast cancer., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

We examined the association among anxiety, religiosity, meaning of life and mental health in a nonclinical sample from a Chinese society. Four hundred fifty-one Taiwanese adults (150 males and 300 females) ranging in age from 17 to 73 years (M = 28.9, SD = 11.53) completed measures of Beck Anxiety Inventory, Medical Outcomes Study Health Survey, Perceived Stress Scale, Social Support Scale, and Personal Religiosity Scale (measuring religiosity and meaning of life). Meaning of life has a significant negative correlation with anxiety and a significant positive correlation with mental health and religiosity; however, religiosity does not correlate significantly anxiety and mental health after controlling for demographic measures, social support and physical health. Anxiety explains unique variance in mental health above meaning of life. Meaning of life was found to partially mediate the relationship between anxiety and mental health. These findings suggest that benefits of meaning of life for mental health can be at least partially accounted for by the effects of underlying anxiety.

Objective: To determine whether emotional stability distinguishes how experienced and novice meditators react to visual stimuli., Design: PARTICIPANTS practiced concentrative meditation and then responded to visual stimuli while continuing to meditate., Participants: Ten experienced and 10 novice meditators responded to sequences of visual stimuli after concentrative meditation., Results: As predicted, both groups had increased parasympathetic activities during concentrative meditation. Experienced meditators had increased low-frequency electroencephalography (EEG) rhythms in response to visual stimulation, whereas novices had increased high-frequency EEG rhythms. Correlational analyses revealed that novice meditators changed from a meditative state to a nonrelaxed state when the visual stimuli were presented, whereas experienced meditators maintained the meditative state., Conclusion: The study provides evidence that regular concentrative meditation can improve emotional stability and that recording physiologic responses to visual stimuli can be a good method for identifying the effects of long-term concentrative meditation practice.

Objective: The present study examined the relation between déjà vu experiences and paranormal beliefs in schizophrenic patients., Methods: A total of 522 participants (54.5% female; mean age=33.3, SD=16.02) were recruited, including 422 healthy adults (60.9% female; mean age=29.48, SD=15.07) and 100 medicated adult schizophrenic patients (27.3% female; mean age=48.98, SD=8.57). The Chinese version of the Inventory of Déjà-vu Experiences Assessment was created via back translation. Chinese versions of the Revised Paranormal Belief Scale (CRPB), Beck Anxiety Inventory (CBAI), and Perceived Stress Scale (CPSS) were also used., Results and Conclusion: After controlling for age, gender, education, and anxiety, the results supported the following three hypotheses. Schizophrenic persons have fewer déjà vu experiences than normal persons. These experiences are positively related to paranormal beliefs in healthy adults but not in schizophrenic patients. Schizophrenic patients have higher scores than healthy adults on the psi and superstitious subscales of the CRPB., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: This study explored whether drinking tea "treated" with good intentions would enhance mood more than drinking ordinary tea, under double-blind, randomized conditions., Design: Each evening, for seven days in a row, volunteers recorded their mood using the Profile of Mood States (POMS) questionnaire. On days three, four, and five of the test, each participant drank 600 mL of oolong tea in the morning and again in the afternoon. One randomly assigned group blindly received tea that had been intentionally treated by three Buddhist monks; the other group blindly received untreated tea from the same source. On the last day of the test, each person indicated what type of tea he/she believed he/she had been drinking., Participants: Stratified, random sampling was used to assign 189 adults into two groups matched by age, gender, the psychological trait of neuroticism, and the amount of tea consumed on average per day. All participants were Taiwanese and lived in Kaohsiung, Taiwan, and the test was conducted over the course of one week to reduce mood fluctuations due to changes in local weather and other common influences., Results: Those who drank treated tea showed a greater increase in mood than those who drank untreated tea (Cohen's d = 0.65, P = .02, two-tailed). Change in mood in those who believed that they were drinking treated tea was much better than those who did not believe (Cohen's d = 1.45, P = .00002, two-tailed)., Conclusion: Tea treated with good intentions improved mood more than ordinary tea derived from the same source. Belief that one was drinking treated tea produced a large improvement in mood, but only if one was actually drinking the treated tea, indicating that belief and intentional enhancement interact. This also suggests that the esthetic and intentional qualities associated with the traditional tea ceremony may have subtle influences that extend beyond the ritual itself., (© 2013 Elsevier Inc. All rights reserved.)

This study was designed to compare tactile sensitivity of children and adults on printed target stimuli covering a wide range of elevations and requiring different resolutions. A recognition-relief task using 9 digits at 6 levels of elevation from a surface (0.5, 0.4, 0.3, 0.2, 0.1, and 0.05 mm) was presented to 24 young adults and 24 children. As predicted, relief elevations as low as 0.05 mm were recognized above chance. As predicted, children performed significantly more poorly than the adults on recognition at all elevations, although the difference increased as elevation increased. Adults performed significantly better than children on high-resolution digit 8, but there was no reliable age difference on low-resolution digit 1. Recognition difference between the high- and low-resolution digits decreased nonlinearly as elevation increased, irrespective of age. Overall, the findings support previous research indicating greater tactile sensitivity in adults than in children, but the superiority was moderated by the elevation and resolution requirements of the stimuli.

This paper reports an initial study investigating the relations of paranormal beliefs with religiosity in a Chinese sample, as well as the development of a Chinese version of the Revised Paranormal Belief Scale and a test of its psychometric properties with 310 college students (5.5% Christians, 21.3% Buddhists, 61% believers in traditional Chinese religions, and 12% atheists). The reliability and validity of the Chinese version were satisfactory. In general, traditional Chinese religious believers had higher scores on paranormal belief than did Christians and atheists, and the mean total score of the Chinese participants was higher than previously reported in a Western sample. It was concluded that the greater involvement of practitioners of traditional Chinese religions in activities emphasizing paranormal experiences might contribute to their greater paranormal belief, especially as compared to the minority Christian group. The results are consistent with the idea that Christianity may offer the least support for paranormal belief.

The importance of the separation-individuation process in object relations theory is well known in disciplines of psychology, counseling, and human development. Based on the Separation-Individuation Inventory of Christenson and Wilson, which measures the manifestations of disturbances in this process, a Chinese version of the inventory was developed. For college students Cronbach coefficient alpha was .89, and test-retest reliability over 28 days was .77. The scores of the inventory had positive correlations with both the number of borderline personality characteristics and the Individualism-Collectivism Scale, respectively. Also, the mean score on the inventory of patients diagnosed with borderline personality disorder was significantly higher than that of the two normal control groups (ns = 564). Thus the inventory possessed satisfactory construct validity. Cultural differences regarding the separation-individuation process need to be investigated further.