Genomic amplifications identified by circulating tumor DNA analysis guide prognosis in metastatic castration-resistant prostate cancer

PurposeAnalysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient’s treatment course. We evaluated whether the presence of specific gene amplifications (GAs) and plasma copy number (PCN) alterations are associated with disease features.MethodsThis is a single-institution retrospective study of patients with mPC who underwent ctDNA profiling using Guardant360® (Guardant Health Inc.). This test identifies single nucleotide variants (SNVs) and GAs of select genes by next-generation sequencing. A total of 155 men with mPC were studied. Patients were stratified by GA status. The Kaplan-Meier method and multivariate cox regression models were used to estimate overall survival (OS) or failure-free survival (FFS) from either the date of GA detection or the initiation of systemic therapy. The chi-square test was used to evaluate associations between clinical factors and GAs. ResultsThe presence of liver and/or lung metastases was associated with GAs of BRAF, CDK6, PI3KCA, and FGFR1. Survival analyses were completed on a subset of 83 patients with metastatic castration-resistant prostate cancer (mCRPC). Median OS was improved in patients with 1 GA compared to patients with ≥2 GAs, whether determined from the date of initial GA(s) detection (14.9 mo vs. 8.9 mo) or date of therapy initiation nearest to GA detection (16.7 mo vs. 9.0 mo). Patients without GAs had not reached median OS. Patients with androgen receptor (AR) GA only were also found to have better median OS compared to patients with AR GA plus at least one other additional GA (19.3 mo vs. 8.9 mo). Patients with PIK3CA GA had significantly lower median OS compared to patients with GAs that did not have a PIK3CA GA (5.9 mo vs. 16.0 mo). In patients with AR and/or MYC GA(s), median OS improved in those with reduced AR or MYC PCN during therapy compared to those without such a reduction (25.1 mo vs. 15.9 mo). ConclusionsThe association of select GAs with survival provides an additional tool for assessing mCRPC prognosis and informing management. Serial monitoring of ctDNA GAs is also useful to guide prognosis and therapeutic response

Reclaiming the political : emancipation and critique in security studies

The critical security studies literature has been marked by a shared commitment towards the politicization of security – that is, the analysis of its assumptions, implications and the practices through which it is (re)produced. In recent years, however, politicization has been accompanied by a tendency to conceive security as connected with a logic of exclusion, totalization and even violence. This has resulted in an imbalanced politicization that weakens critique. Seeking to tackle this situation, the present article engages with contributions that have advanced emancipatory versions of security. Starting with, but going beyond, the so-called Aberystwyth School of security studies, the argument reconsiders the meaning of security as emancipation by making the case for a systematic engagement with the notions of reality and power. This revised version of security as emancipation strengthens critique by addressing political dimensions that have been underplayed in the critical security literature

Steinert's syndrome presenting as anal incontinence: a case report

<p>Abstract</p> <p>Introduction</p> <p>Myotonic dystrophy (MD) or Steinert's syndrome is a rare cause of chronic diarrhea and anal incontinence. In the presence of chronic diarrhea and fecal incontinence with muscle weakness, neuromuscular disorders such as myotonic dystrophy should be considered in the differential diagnosis.</p> <p>Case Presentation</p> <p>We present the case of a 45-year-old Turkish man with Steinert's syndrome, who was not diagnosed until the age of 45.</p> <p>Conclusions</p> <p>In clinical practice, the persistence of diarrhea and fecal incontinence with muscle weakness should suggest that the physician perform an anal manometric study and electromyography. Neuromuscular disorders such as myotonic dystrophy should be considered in the differential diagnosis.</p

Interpretation, judgement and dialogue: a hermeneutical recollection of causal analysis in critical terrorism studies

This article problematises Critical Terrorism Studies’s (CTS) seem- ing reluctance to engage in causal explanation. An analysis of the meta-theoretical assumptions on causation in both orthodox and critical terrorism studies reveals that the latter’s refusal to incor- porate causal analysis in its broader research agenda reproduces – despite its commitment to epistemological pluralism – the for- mer’s understanding of causation as the only sustainable one. Elemental to this understanding is the idea that causation refers to the regular observation of constant conjunction. Due to the positivist leanings of such a conception, CTS is quick to dismiss it as consolidating Orthodox Terrorism Studies’s lack of critical self- reflexivity, responsibility of the researcher, and dedication towards informing state-led policies of counterterrorism. Drawing on recent work in the philosophy of science and International Relations, this article advances an alternative understanding of causation that emphasises its interpretative, normative and dialo- gical fabric. It is therefore argued that CTS should reclaim causal analysis as an essential element of its research agenda. This not only facilitates a more robust challenge against Orthodox Terrorism Studies’ conventional understanding of causation but also consolidates CTS’s endeavour of deepening and broadening our understanding that (re)embeds terrorist violence in its histor- ical and social context

Numerical modeling of the thermal contact in metal forming processes

Heat flow across the interface of solid bodies in contact is an important aspect in several engineering applications. This work presents a finite element model for the analysis of thermal contact, which takes into account the effect of contact pressure and gap dimension in the heat flow across the interface between two bodies. Additionally, the frictional heat generation is also addressed, which is dictated by the contact forces predicted by the mechanical problem. The frictional contact problem and thermal problem are formulated in the frame of the finite element method. A new law is proposed to define the interfacial heat transfer coefficient (IHTC) as a function of the contact pressure and gap distance, enabling a smooth transition between two contact status (gap and contact). The staggered scheme used as coupling strategy to solve the thermomechanical problem is briefly presented. Four numerical examples are presented to validate the finite element model and highlight the importance of the proposed law on the predicted temperature.The authors gratefully acknowledge the financial support of the Portuguese Foundation for Science and Technology (FCT) under the project PTDC/EMS-TEC/1805/2012 and by FEDER funds through the program COMPETE Programa Operacional Factores de Competitividade, under the project CENTRO-07-0224- FEDER-002001 (MT4MOBI). The second author is also grateful to the FCT for the postdoctoral grant SFRH/BPD/101334/2014. The authors would like to thank Prof. A. Andrade-Campos for helpful contributions on the development of the finite element code presented in this work.info:eu-repo/semantics/publishedVersio

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams