Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer

Breast cancer metastasis remains a clinical challenge, even within a single patient across multiple sites of the disease. Genome-wide comparisons of both the DNA and gene expression of primary tumors and metastases in multiple patients could help elucidate the underlying mechanisms that cause breast cancer metastasis. To address this issue, we performed DNA exome and RNA sequencing of matched primary tumors and multiple metastases from 16 patients, totaling 83 distinct specimens. We identified tumor-specific drivers by integrating known protein-protein network information with RNA expression and somatic DNA alterations and found that genetic drivers were predominantly established in the primary tumor and maintained through metastatic spreading. In addition, our analyses revealed that most genetic drivers were DNA copy number changes, the TP53 mutation was a recurrent founding mutation regardless of subtype, and that multiclonal seeding of metastases was frequent and occurred in multiple subtypes. Genetic drivers unique to metastasis were identified as somatic mutations in the estrogen and androgen receptor genes. These results highlight the complexity of metastatic spreading, be it monoclonal or multiclonal, and suggest that most metastatic drivers are established in the primary tumor, despite the substantial heterogeneity seen in the metastases

Materializing digital collecting: an extended view of digital materiality

If digital objects are abundant and ubiquitous, why should consumers pay for, much less collect them? The qualities of digital code present numerous challenges for collecting, yet digital collecting can and does occur. We explore the role of companies in constructing digital consumption objects that encourage and support collecting behaviours, identifying material configuration techniques that materialise these objects as elusive and authentic. Such techniques, we argue, may facilitate those pleasures of collecting otherwise absent in the digital realm. We extend theories of collecting by highlighting the role of objects and the companies that construct them in materialising digital collecting. More broadly, we extend theories of digital materiality by highlighting processes of digital material configuration that occur in the pre-objectification phase of materialisation, acknowledging the role of marketing and design in shaping the qualities exhibited by digital consumption objects and consequently related consumption behaviours and experiences

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Azo Dyes, Their Environmental Effects, and Defining a Strategy for Their Biodegradation and Detoxification

Intenzivan industrijski razvoj popraćen je sve većom kompleksnošću sastava otpadnih voda, što u smislu učinkovite zaštite okoliša i održivog razvoja nalaže potrebu pospješivanja kvalitete postojećih te uvođenjem novih postupaka obrade otpadnih voda, kao iznimno važnog čimbenika u interakciji čovjeka i okoliša. Posebnu znanstveno-tehnološku pozornost zahtijevaju novosintetizirani ksenobiotici, poput azo-boja, koji su u prirodi veoma teško razgradivi. Azo-boje podložne su bioakumulaciji, a zbog alergijskih, kancerogenih, mutagenih i teratogenih svojstava nerijetko su prijetnja zdravlju ljudi i očuvanju okoliša. Primjenu fi zikalnokemijskih metoda za uklanjanje azo-boja iz otpadnih voda često ograničavaju visoke cijene, potrebe za odlaganjem nastalog štetnog mulja ili nastanak toksičnih sastojaka razgradnje. Biotehnološki postupci su, zbog mogućnosti ekonomične provedbe i postizanja potpune biorazgradnje, a time i detoksifi kacije, sve zastupljeniji u obradi svih vrsta otpadnih voda, pa tako i onih koje sadržavaju azo-boje.Intense industrial development has been accompanied by the production of wastewaters of very complex content, which pose a serious hazard to the environment, put at risk sustainable development, and call for new treatment technologies that would more effectively address the issue. One particular challenge in terms of science and technology is how to biodegrade xenobiotics such as azo dyes, which practically do not degrade under natural environmental conditions. These compounds tend to bioaccumulate in the environment, and have allergenic, carcinogenic, mutagenic, and teratogenic properties for humans. Removal of azo dyes from effl uents is mostly based on physical-chemical methods. These methods are often very costly and limited, as they accumulate concentrated sludge, which also poses a significant secondary disposal problem, or produce toxic end-products. Biotechnological approach may offer alternative, lowcost biological treatment systems that can completely biodegrade and detoxify even the hard-to-biodegrade azo dyes

Tephrostratigraphy and provenance from IODP Expedition 352, Izu-Bonin arc: tracing tephra sources and volumes from the Oligocene to the Recent

Provenance studies of widely distributed tephras, integrated within a well-defined temporal framework, are important to deduce systematic changes in the source, scale, distribution and changes in regional explosive volcanism. Here, we establish a robust tephro-chronostratigraphy for a total of 157 marine tephra layers collected during IODP Expedition 352. We infer at least three major phases of highly explosive volcanism during Oligocene to Pleistocene time. Provenance analysis based on glass composition assigns 56 of the tephras to a Japan source, including correlations with 12 major and widespread tephra layers resulting from individual eruptions in Kyushu, Central Japan and North Japan between 115 ka and 3.5 Ma. The remaining 101 tephras are assigned to four source regions along the Izu-Bonin arc. One, of exclusively Oligocene age, is proximal to the Bonin Ridge islands; two reflect eruptions within the volcanic front and back-arc of the central Izu-Bonin arc, and a fourth region corresponds to the Northern Izu-Bonin arc source. First-order volume estimates imply eruptive magnitudes ranging from 6.3 to 7.6 for Japan-related eruptions and between 5.5 and 6.5 for IBM eruptions. Our results suggest tephras between 30 and 22 Ma that show a subtly different Izu-Bonin chemical signature compared to the recent arc. After a ∼11 m.y. gap in eruption, tephra supply from the Izu-Bonin arc predominates from 15 to 5 Ma, and finally a subequal mixture of tephra sources from the (palaeo)Honshu and Izu-Bonin arcs occurs within the last ∼5 Ma