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Understanding the crustal structure of the Anatolian Plate has important implications for its formation and evolution, including the extent to which its high elevation is maintained isostatically. However, the numerous teleseismic receiver function studies from which Anatolian Moho depths have been obtained return results that differ by 40km in the northern Kirsehir block to

As Asia’s largest and most rapidly rising powers in contemporary global politics, relations between India and China are becoming evermore intertwined with each other. Clear commonalities typify this symbiosis, including a shared civilisational basis, a mutual desire to rebecome great powers in international relations and common modernisation goals. At the same time, relations are beset by a number of issues, most notably long-standing territorial disputes, frictions over regional hegemony and wider diplomatic tensions (most prominently relating to China–Pakistan and India–United States ties). As such, India–China relations can be considered to resemble a ‘double-edged sword’, whereby elements of their interaction can be regarded as having concurrent benefits and liabilities. This article explores the historical roots and contemporary realisation of such a core dynamic over the last 75 years of relations between New Delhi and Beijing and investigates how their strategic goals are often simultaneously convergent and divergent. Publisher PDF

Central to India–ASEAN relations has been a consistent equivalence between their similar core principles and outlooks, which have served as a shared value-based footing upon which the two entities have built and enhanced their relations. These underlying sets of norms inform their diplomatic dealings with each other, and stem from principles and practices critical to their foundational identities and experiences. This article investigates and evaluates the historical roots of these norms and then utilizes them as an analytical vehicle with which to trace the growing strategic convergence typifying present-day India–ASEAN relations. Drawing upon constructivist accounts that emphasize the role played by history, culture, identity and learning, the article considers the key areas of agreement in relations, and how a value-based form of analysis provides an essential lens through which to better understand material factors structuring their relations. It also underlines the analytical value and empirical richness that a norm-based approach provides for analysing specific sets of norms in a specific state-to-multilateral interaction. Publisher PDF

Focal therapy (FT) ablates areas of prostate cancer rather than treating the whole gland. We compared oncological outcomes of FT to radical prostatectomy (RP). Using prospective multicentre databases of 761 FT and 572 RP cases (November/2005-September/2018), patients with PSA

Objectives To assess change in functional outcomes after a second focal high-intensity focused ultrasonography (HIFU) treatment compared with outcomes after one focal HIFU treatment. Patients and methods In this multicentre study (2005-2016), 821 men underwent focal HIFU for localized non-metastatic prostate cancer. The patient-reported outcome measures of International Prostate Symptom Score (IPSS), pad usage and erectile function (EF) score were prospectively collected for up to 3 years. To be included in the study, completion of at least one follow-up questionnaire was required. The primary outcome was comparison of change in functional outcomes between baseline and follow-up after one focal HIFU procedure vs after a second focal HIFU procedure, using IPSS, Expanded Prostate Cancer Index Composite (EPIC) and International Index of Erectile Function (IIEF) questionnaires. Results Of 821 men, 654 underwent one focal HIFU procedure and 167 underwent a second focal HIFU procedure. A total of 355 (54.3%) men undergoing one focal HIFU procedure and 65 (38.9%) with a second focal HIFU procedure returned follow-up questionnaires, respectively. The mean age and prostate-specific antigen level were 66.4 and 65.6 years, and 7.9 and 8.4 ng/mL, respectively. After one focal HIFU treatment, the mean change in IPSS was -0.03 (P = 0.02) and in IIEF (EF score) it was -0.4 (P = 0.02) at 1-2 years, with no subsequent decline. Absolute rates of erectile dysfunction increased from 9.9% to 20.8% (P = 0.08), leak-free continence decreased from 77.9% to 72.8% (P = 0.06) and pad-free continence from 98.6% to 94.8% (P = 0.07) at 1-2 years, respectively. IPSS prior to second focal HIFU treatment compared to baseline IPSS prior to first focal HIFU treatment was lower by -1.3 (P = 0.02), but mean IPSS change was +1.4 at 1-2 years (P = 0.03) and +1.2 at 2-3 years (P = 0.003) after the second focal HIFU treatment. The mean change in EF score after the second focal HIFU treatment was -0.2 at 1-2 years (P = 0.60) and -0.5 at 2-3 years (P = 0.10), with 17.8% and 6.2% of men with new erectile dysfunction. The rate of new pad use was 1.8% at 1-2 years and 2.6% at 2-3 years. Conclusion A second focal HIFU procedure causes minor detrimental effects on urinary function and EF. These data can be used to counsel patients with non-metastatic prostate cancer prior to considering HIFU therapy.

Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Focal therapy aims to treat areas of cancer to confer oncological control whilst reducing treatment-related functional detriment.To report oncological outcomes and adverse events following focal high-intensity focused ultrasound (HIFU) for treating nonmetastatic prostate cancer.An analysis of 1379 patients with ≥6 mo of follow-up prospectively recorded in the HIFU Evaluation and Assessment of Treatment (HEAT) registry from 13 UK centres (2005-2020) was conducted. Five or more years of follow-up was available for 325 (24%) patients. Focal HIFU therapy used a transrectal ultrasound-guided device (Sonablate; Sonacare Inc., Charlotte, NC, USA).Failure-free survival (FFS) was primarily defined as avoidance of no evidence of disease to require salvage whole-gland or systemic treatment, or metastases or prostate cancer-specific mortality. Differences in FFS between D'Amico risk groups were determined using a log-rank analysis. Adverse events were reported using Clavien-Dindo classification.The median (interquartile range) age was 66 (60-71) yr and prostate-specific antigen was 6.9 (4.9-9.4) ng/ml with D'Amico intermediate risk in 65% (896/1379) and high risk in 28% (386/1379). The overall median follow-up was 32 (17-58) mo; for those with ≥5 yr of follow-up, it was 82 (72-94). A total of 252 patients had repeat focal treatment due to residual or recurrent cancer; overall 92 patients required salvage whole-gland treatment. Kaplan-Meier 7-yr FFS was 69% (64-74%). Seven-year FFS in intermediate- and high-risk cancers was 68% (95% confidence interval [CI] 62-75%) and 65% (95% CI 56-74%; p = 0.3). Clavien-Dindo2 adverse events occurred in 0.5% (7/1379). The median 10-yr follow-up is lacking.Focal HIFU in carefully selected patients with clinically significant prostate cancer, with six and three of ten patients having, respectively, intermediate- and high-risk cancer, has good cancer control in the medium term.Focal high-intensity focused ultrasound treatment to areas of prostate with cancer can provide an alternative to treating the whole prostate. This treatment modality has good medium-term cancer control over 7 yr, although 10-yr data are not yet available.

INTRODUCTION AND OBJECTIVES:Focal therapy (FT) has a low side-effect profile but there is uncertainty about its medium-long term cancer control compared to radical approaches. Both focal HIFU and f...

Background High-intensity focused ultrasound (HIFU) is a minimally-invasive treatment for nonmetastatic prostate cancer. Objective To report medium-term outcomes in men receiving primary whole-gland HIFU from a national multi-centre registry cohort. Design, setting, and participants Five-hundred and sixty-nine patients at eight hospitals were entered into an academic registry. Intervention Whole-gland HIFU (Sonablate 500) for primary nonmetastatic prostate cancer. Redo-HIFU was permitted as part of the intervention. Outcome measurements and statistical analysis Our primary failure-free survival outcome incorporated no transition to any of the following: (1) local salvage therapy (surgery or radiotherapy), (2) systemic therapy, (3) metastases, or (4) prostate cancer-specific mortality. Secondary outcomes included adverse events and genitourinary function. Results and limitations Mean age was 65 yr (47–87 yr). Median prostate-specific antigen was 7.0 ng/ml (interquartile range 4.4–10.2). National Comprehensive Cancer Network low-, intermediate-, and high-risk disease was 161 (28%), 321 (56%), and 81 (14%), respectively. One hundred and sixty three of 569 (29%) required a total of 185 redo-HIFU procedures. Median follow-up was 46 (interquartile range 23–61) mo. Failure-free survival at 5 yr after first HIFU was 70% (95% confidence interval [CI]: 64–74). This was 87% (95% CI: 78–93), 63% (95% CI: 56–70), and 58% (95% CI: 32–77) for National Comprehensive Cancer Network low-, intermediate-, and high-risk groups, respectively. Fifty eight of 754 (7.7%) had one urinary tract infection, 22/574 (2.9%) a recurrent urinary tract infection, 22/754 (3%) epididymo-orchitis, 227/754 (30%) endoscopic interventions, 1/754 (0.13%) recto-urethral fistula, and 1/754 (0.13%) osteitis pubis. Of 206 known to be pad-free pre-HIFU, 183/206 (88%) remained pad free, and of 236 with good baseline erectile function, 91/236 (39%) maintained good function. The main limitation is lack of long-term data. Conclusions Whole-gland HIFU is a repeatable day-case treatment that confers low rates of urinary incontinence. Disease control at a median of just under 5 yr of follow-up demonstrates its potential as a treatment for nonmetastatic prostate cancer. Endoscopic interventions and erectile dysfunction rates are similar to other whole-gland treatments. Patient summary In this report we looked at the 5-yr outcomes following whole-gland high-intensity focused ultrasound treatment for prostate cancer and found that cancer control was acceptable with a low risk of urine leakage. However, risk of erectile dysfunction and further operations was similar to other whole-gland treatments like surgery and radiotherapy.

Over 230 entries This new dictionary defines critical terms relating to China’s politics since 1949. It comprises succinct definitions covering core political structures, ideologies, and practices, as well as individuals, groups, and concerns that are essential to them. Covering the full spectrum of Chinese politics, authoritative and up-to-date entries include charm offensive, cybersecurity, hukou system, Silk Road, and United Nations Peacekeeping Operations. Complete with useful weblinks, this new addition to the Oxford Quick Reference series is an indispensable companion for students studying Asian and international politics, as well as for professionals whose interests relate to China’s expanding domestic and foreign politics.

Over 280 entries This new dictionary covers India’s core political structures, ideologies, and practices, as well as individuals, groups, and concerns that are essential to them. The entries cover a diverse range of subjects, from caste, the Gujral Doctrine, and the Indian diaspora to the Partition of India and the Shah Bano controversy. The dictionary captures the richness of India’s politics, as well as its foremost ideas and principles, explaining and interrogating important historical events and social concerns. Complete with useful web links, this new addition to the Oxford Quick Reference series is an indispensable companion for students studying Asian and international politics, as well as for professionals whose interests relate to India’s expanding domestic and foreign politics.

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials. Postprint

This article highlights the dominant aims of the current BJP government concerning India’s foreign policy. Using a constructivist-centred and discourse-orientated approach, it distils the three prevailing strategic goals integral to the Narendra Modi led regime, namely; gaining great power recognition; realising a multipolar world order; and enacting the “Act East” policy.The study finds that, although proof of a prevailing “Modi Doctrine” is scarce, the presence of these three aims is notably consistent and prevalent within official discourses and scholarly accounts of the foreign policy preferences of the second NDA. Their repetition and reiteration constitutes evidence of both a significant acceleration and a noteworthy tone shift concerning how Indian foreign policy has been conceptualised and conducted since 2014. Publisher PDF

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A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses., Author summary Cancer is a genetic disease where changes in DNA cause alterations in the control of cellular systems leading to unchecked growth. Copy number changes, including duplications, amplifications, and deletions, are a common type of DNA change observed in cancer cells but it is not always clear which of the changes are important in driving cancer development. We have examined this class of genetic alteration in prostate cancer by DNA sequencing the whole genome in 103 cancers. 64 recurrent copy number changes were detected, of which 28 were new. For genetic losses our study comprehensively assessed the role of a model called the “Knudson two-hit genetic model” where alterations in both alleles of a gene is required to generate functional alterations. This model was only supported a minor proportion of recurrent deletions (15/40). This observation indicates that other mechanisms, such haploinsufficiency and epigenetic inactivation, may account for the majority of deletions. Our studies highlight several novel changes including those in non-coding lincRNA sequences, the identification ZNF292 as a target gene for a recurrent deletion on chromosome 6, and the common Knudson deletions at the NKX3.1 loci on chromosome 8.

Clinically significant nonmetastatic prostate cancer (PCa) is currently treated using whole-gland therapy. This approach is effective but can have urinary, sexual, and rectal side effects.To report on 5-yr PCa control following focal high-intensity focused ultrasound (HIFU) therapy to treat individual areas of cancer within the prostate.This was a prospective study of 625 consecutive patients with nonmetastatic clinically significant PCa undergoing focal HIFU therapy (Sonablate) in secondary care centres between January 1, 2006 and December 31, 2015. A minimum of 6-mo follow-up was available for599 patients. Intermediate- or high-risk PCa was found in 505 patients (84%).Disease was localised using multiparametric magnetic resonance imaging (mpMRI) combined with targeted and systematic biopsies, or transperineal mapping biopsies. Areas of significant disease were treated. Follow-up included prostate-specific antigen (PSA) measurement, mpMRI, and biopsies.The primary endpoint, failure-free survival (FFS), was defined as freedom from radical or systemic therapy, metastases, and cancer-specific mortality.The median follow-up was 56 mo (interquartile range [IQR] 35-70). The median age was 65 yr (IQR 61-71) and median preoperative PSA was 7.2 ng/ml (IQR 5.2-10.0). FFS was 99% (95% confidence interval [CI] 98-100%) at 1 yr, 92% (95% CI 90-95%) at 3 yr, and 88% (95% 85-91%) at 5 yr. For the whole patient cohort, metastasis-free, cancer-specific, and overall survival at 5 yr was 98% (95% CI 97-99%), 100%, and 99% (95% CI 97-100%), respectively. Among patients who returned validated questionnaires, 241/247 (98%) achieved complete pad-free urinary continence and none required more than 1 pad/d. Limitations include the lack of long-term follow-up.Focal therapy for select patients with clinically significant nonmetastatic prostate cancer is effective in the medium term and has a low probability of side effects.In this multicentre study of 625 patients undergoing focal therapy using high-intensity focused ultrasound (HIFU), failure-free survival, metastasis-free survival, cancer-specific survival, and overall survival were 88%, 98%, 100%, and 99%, respectively. Urinary incontinence (any pad use) was 2%. Focal HIFU therapy for patients with clinically significant prostate cancer that has not spread has a low probability of side effects and is effective at 5 yr.

What has structured Chinese security practice over the last 100 years since the Xinhai (1911) Revolution? Moreover, what are the ideational principles and norms that have influenced China's international relations? Employing an analytical framework concerning norm creation (“security identity”), this article details how different norms originated, became established and subsequently served to orientate Chinese foreign policy behavior. Such a process has been critically informed by China's international interaction, learning and experience across the last 100 years, revealing how past relations can inform present and future conduct. Undertaking an analysis in this fashion implies not so much how a state “should” behave but instead indicates the broad continuities structuring its security practice. From the focus upon security identity (which gives ideational rather than structural explanations of security behavior), our analysis rests upon the elucidation of three inter-related normative sources. These three sources have been tempered via the interplay between China's international interaction and internal political developments, and show the ideational precedents in China's foreign policy behavior. The three sources are: (i) the political (internal political developments); (ii) the physical (relations with neighboring/bordering states); and (iii) the perceptual (conceptions of self, the international system and their mutual relationship). Overall, the article finds a relative consistency to how security has been ideationally conceived of in China, and highlights three core norms essential to such a conception – centralized control, territorial restoration, and (re)becoming a great power.

China is undergoing a transitional period of rapid economic and social development. The way in which this period is managed will hold significant implications for the Chinese state concerning both its internal and external security. While fundamentally resting upon progressing from a developing to a developed economy, this transition highlights deep issues and tensions affecting China—ranging from rising societal inequalities to various separatism threats to mounting individualism. Regardless of internal succession struggles within the Communist Party of China (CCP), it is critical to focus upon this multitude of (mounting) social and economic issues—particularly outside of the political realm—that China's new leaders will have to face. Here, we highlight three themes central to this transition—a search for internal stability; China's multiple, interlocking internal issues; and the longevity, resilience and adaptability of the CCP—in order to assess their potential impact on China's domestic and,...

This article investigates how a Pakistan–terrorism nexus originated and then became solidified and embedded into Indian security perspectives. From the First Kashmir War in 1947–1948 to the 26 November 2008 Mumbai attacks, it has been the repeated behaviour of Pakistan towards India, and the nature of their major national and sub-national conflicts, which has led to this nexus. Central to its formation has been the repeated military strategy of initial infiltrations by irregular troops followed by the use of conventional troops—an approach employed by Pakistan in 1947, 1965 and 1999. Pakistan’s concurrent support of various insurgencies and terrorism against India has compounded this association, and entrenched the contemporary Pakistan–terrorism nexus within India’s (foreign and domestic) security perspectives. Given its persistent resonance within both Pakistani strategic behaviour and Indian elite mindsets, the article finds that the Pakistan–terrorism nexus will remain as a durable and critical lynchpin within South Asian security dynamics.

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.

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

This article investigates how the Bharatiya Janata Party (BJP)-led National Democratic Alliance (NDA) government influenced India's domestic politics from 1998 to 2004. It argues that the core norms constituting the BJP's ideological basis precipitated lasting changes in the nature and functioning of India's domestic politics. The article finds that through leading the NDA government, the BJP made trends that had been normalising prior to 1998 and mainstreamed them in Indian domestic politics. This mainstreaming created a lasting legacy comprised of two specific changes – the redefinition of Indian democracy along more multi-faceted and majoritarian lines and the entrenchment of communalism and communal politics. These changes persisted after the BJP-led NDA left power in 2004, continued into subsequent Congress-led United Progressive Alliances and produced a long-term behavioural shift in Indian politics. Such normative changes threatened the tenets of secularism and inclusiveness that had been ...

What structured the fundamental nature of Indian security for the first 50 years of the country's independence? This article draws out four normative parameters that have been tempered and normalised during this period through India's international interaction along with her internal political developments. Using notions of ‘security identity’, the article unpacks these normative parameters in order to investigate holistically the interaction between both domestic and foreign influences in India's international relations. As such, the article finds a relative consistency to how security has been conceived of in India—displaying sustained threats to its territorial integrity, a continued democratic tradition, ongoing fears of communal violence plus an engrained desire for a greater global role. In turn, it has been the interface between internal and external factors that has structured, and continues to structure, Indian security.

OBJECTIVE To integrate the mapping of ERG alterations with the collection of expression microarray (EMA) data, as previous EMA analyses have failed to consider the genetic heterogeneity and complex patterns of ERG alteration frequently found in cancerous prostates. MATERIALS AND METHODS We determined genome-wide expression levels with GeneChip Human Exon 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 35 specimens of prostate cancer from 28 prostates. RESULTS The expression profiles showed clustering, in unsupervised hierarchical analyses, into two distinct prostate cancer categories, with one group strongly associated with indicators of poor clinical outcome. The two categories are not tightly linked to ERG status. By analysis of the data we identified a subgroup of cancers lacking ERG rearrangements that showed an outlier pattern of SPINK1 mRNA expression. There was a major distinction between ERG rearranged and non-rearranged cancers that involves the levels of expression of genes linked to exposure to beta-oestradiol, and to retinoic acid. CONCLUSIONS Expression profiling of prostate cancer samples containing single patterns of ERG alterations can provide novel insights into the mechanism of prostate cancer development, and support the view that factors other than ERG status are the major determinants of poor clinical outcome.

Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).

This article explores the concept of diaspora in relation to constructivism within IR theory. It begins by investigating the origins, definition and implications of the phenomenon of diaspora, before focusing on issues concerning identity interpenetration and multiple loyalties. Consequently, the article outlines diaspora's relationship to constructivism, particularly in terms of identity formation and the self/other dyad, as well as in the analysis of culture and transnational norms, and concludes by examining the challenges and possibilities diaspora poses for constructivist IR theory. Acting as both commentary and conjecture, this article serves as a conceptual overview of diaspora, while arousing intellectual concern for what will be a dominant issue of emerging identity politics in the twenty-first century.

© 2015 Nature America, Inc. All rights reserved.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.