Blind Philhellenes vs. Selective Consumers of Foreign Cultures: A Reassessment of the Ancient Greco-Roman Literary Record’s Portrayal of the Gauls in Light of New Archaeological Evidence

The issue of perspective is intrinsic to historiography. This is evident in the ancient Greco-Roman literary record, specifically the limits placed on its value to modern academics by the ethnographic biases of its authors. However, with the rise of the post-processual approach to archaeology over the past thirty years, modern historians have begun to address this issue. By utilizing the impartial records offered by excavation, these scholars have increasingly managed to circumvent ancient authorial subjectivity and reevaluate the modern preconceptions it created of the world of antiquity. An example of the archaeological record\u27s value in reassessing the inherent prejudices of the ancient literary record can be seen in the instance of the archaic-era Ionian Greek colony of Massalia. While the ancient writings on Massalia have provided modern historians with a limited overview of this Greek polis, their potential for offering genuine insight is denigrated by the cultural bias evident in their overly positive portrayal of Massalia and their pejorative treatment of the native Gauls. However, by examining archaeological excavations of Massalia and surrounding Gallic sites, modern historians have begun to sidestep this Hellenic literary bias and its associated cultural stereotypes, and gain valuable insight into the much more complex reality of relations and interactions that existed between the Massaliotes and their Gallic neighbors. Overall, although ancient historians portray Massalia as a powerful bastion of civilizing Hellenism amongst the barbarian tribes of Gaul, the modern archaeological record indicates that this characterization is largely false, and that in reality Massalia\u27s Gallic trading partners were not Philhellenes who attempted to imitate Greek culture, but selective consumers who incorporated a limited range of Greek goods into their own existing cultural systems

We Will Never Speak of It: Evidence of Hitler\u27s Direct Responsibility for the Premeditation and Implementation of the Nazi Final Solution

The “Intentionalist vs. Functionalist” debate has raged amongst academic historians for decades, centered on the question of whether Adolf Hitler personally premeditated and instigated the Final Solution, or whether the idea and its implementation developed more gradually out of a collaborative effort within the ranks of the Nazi bureaucracy. This paper seeks, through careful analysis of Nazi primary source materials, to establish an “Intentionalist” argument in favor of Hitler being directly responsible for the premeditation and implementation of the infamous Nazi attempt to systematically annihilate the entirety of Europe’s Jewish population

Variation in the flowering time orthologs BrFLC and BrSOC1 in a natural population of Brassica rapa.

Understanding the genetic basis of natural phenotypic variation is of great importance, particularly since selection can act on this variation to cause evolution. We examined expression and allelic variation in candidate flowering time loci in Brassica rapa plants derived from a natural population and showing a broad range in the timing of first flowering. The loci of interest were orthologs of the Arabidopsis genes FLC and SOC1 (BrFLC and BrSOC1, respectively), which in Arabidopsis play a central role in the flowering time regulatory network, with FLC repressing and SOC1 promoting flowering. In B. rapa, there are four copies of FLC and three of SOC1. Plants were grown in controlled conditions in the lab. Comparisons were made between plants that flowered the earliest and latest, with the difference in average flowering time between these groups ∼30 days. As expected, we found that total expression of BrSOC1 paralogs was significantly greater in early than in late flowering plants. Paralog-specific primers showed that expression was greater in early flowering plants in the BrSOC1 paralogs Br004928, Br00393 and Br009324, although the difference was not significant in Br009324. Thus expression of at least 2 of the 3 BrSOC1 orthologs is consistent with their predicted role in flowering time in this natural population. Sequences of the promoter regions of the BrSOC1 orthologs were variable, but there was no association between allelic variation at these loci and flowering time variation. For the BrFLC orthologs, expression varied over time, but did not differ between the early and late flowering plants. The coding regions, promoter regions and introns of these genes were generally invariant. Thus the BrFLC orthologs do not appear to influence flowering time in this population. Overall, the results suggest that even for a trait like flowering time that is controlled by a very well described genetic regulatory network, understanding the underlying genetic basis of natural variation in such a quantitative trait is challenging

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient\u27s progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. ©2017 AACR

Feasibility of low-dose CT with model-based iterative image reconstruction in follow-up of patients with testicular cancer.

Purpose: We examine the performance of pure model-based iterative reconstruction with reduced-dose CT in follow-up of patients with early-stage testicular cancer. Methods: Sixteen patients (mean age 35.6 ± 7.4 years) with stage I or II testicular cancer underwent conventional dose (CD) and low-dose (LD) CT acquisition during CT surveillance. LD data was reconstructed with model-based iterative reconstruction (LD–MBIR). Datasets were objectively and subjectively analysed at 8 anatomical levels. Two blinded clinical reads were compared to gold-standard assessment for diagnostic accuracy. Results: Mean radiation dose reduction of 67.1% was recorded. Mean dose measurements for LD–MBIR were: thorax – 66 ± 11 mGy cm (DLP), 1.0 ± 0.2 mSv (ED), 2.0 ± 0.4 mGy (SSDE); abdominopelvic – 128 ± 38 mGy cm (DLP), 1.9 ± 0.6 mSv (ED), 3.0 ± 0.6 mGy (SSDE). Objective noise and signal-to-noise ratio values were comparable between the CD and LD–MBIR images. LD–MBIR images were superior (p < 0.001) with regard to subjective noise, streak artefact, 2-plane contrast resolution, 2-plane spatial resolution and diagnostic acceptability. All patients were correctly categorised as positive, indeterminate or negative for metastatic disease by 2 readers on LD–MBIR and CD datasets. Conclusions: MBIR facilitated a 67% reduction in radiation dose whilst producing images that were comparable or superior to conventional dose studies without loss of diagnostic utility

A multi-decade record of high quality fCO2 data in version 3 of the Surface Ocean CO2 Atlas (SOCAT)

The Surface Ocean CO2 Atlas (SOCAT) is a synthesis of quality-controlled fCO2 (fugacity of carbon dioxide) values for the global surface oceans and coastal seas with regular updates. Version 3 of SOCAT has 14.7 million fCO2 values from 3646 data sets covering the years 1957 to 2014. This latest version has an additional 4.6 million fCO2 values relative to version 2 and extends the record from 2011 to 2014. Version 3 also significantly increases the data availability for 2005 to 2013. SOCAT has an average of approximately 1.2 million surface water fCO2 values per year for the years 2006 to 2012. Quality and documentation of the data has improved. A new feature is the data set quality control (QC) flag of E for data from alternative sensors and platforms. The accuracy of surface water fCO2 has been defined for all data set QC flags. Automated range checking has been carried out for all data sets during their upload into SOCAT. The upgrade of the interactive Data Set Viewer (previously known as the Cruise Data Viewer) allows better interrogation of the SOCAT data collection and rapid creation of high-quality figures for scientific presentations. Automated data upload has been launched for version 4 and will enable more frequent SOCAT releases in the future. High-profile scientific applications of SOCAT include quantification of the ocean sink for atmospheric carbon dioxide and its long-term variation, detection of ocean acidification, as well as evaluation of coupled-climate and ocean-only biogeochemical models. Users of SOCAT data products are urged to acknowledge the contribution of data providers, as stated in the SOCAT Fair Data Use Statement. This ESSD (Earth System Science Data) “living data” publication documents the methods and data sets used for the assembly of this new version of the SOCAT data collection and compares these with those used for earlier versions of the data collection (Pfeil et al., 2013; Sabine et al., 2013; Bakker et al., 2014). Individual data set files, included in the synthesis product, can be downloaded here: doi:10.1594/PANGAEA.849770. The gridded products are available here: doi:10.3334/CDIAC/OTG.SOCAT_V3_GRID

Breast-Cancer-Specific Mortality in Patients Treated Based on the 21-Gene Assay: A SEER Population-Based Study

The 21-gene Recurrence Score assay is validated to predict recurrence risk and chemotherapy benefit in hormone-receptor-positive (HR+) invasive breast cancer. To determine prospective breast-cancer-specific mortality (BCSM) outcomes by baseline Recurrence Score results and clinical covariates, the National Cancer Institute collaborated with Genomic Health and 14 population-based registries in the the Surveillance, Epidemiology, and End Results (SEER) Program to electronically supplement cancer surveillance data with Recurrence Score results. The prespecified primary analysis cohort was 40–84 years of age, and had node-negative, HR+, HER2-negative, nonmetastatic disease diagnosed between January 2004 and December 2011 in the entire SEER population, and Recurrence Score results (N = 38,568). Unadjusted 5-year BCSM were 0.4% (n = 21,023; 95% confidence interval (CI), 0.3–0.6%), 1.4% (n = 14,494; 95% CI, 1.1–1.7%), and 4.4% (n = 3,051; 95% CI, 3.4–5.6%) for Recurrence Score \u3c 18, 18–30, and ≥ 31 groups, respectively (P \u3c 0.001). In multivariable analysis adjusted for age, tumor size, grade, and race, the Recurrence Score result predicted BCSM (P \u3c 0.001). Among patients with node-positive disease (micrometastases and up to three positive nodes; N = 4,691), 5-year BCSM (unadjusted) was 1.0% (n = 2,694; 95% CI, 0.5–2.0%), 2.3% (n = 1,669; 95% CI, 1.3–4.1%), and 14.3% (n = 328; 95% CI, 8.4–23.8%) for Recurrence Score \u3c 18, 18–30, ≥ 31 groups, respectively (P \u3c 0.001). Five-year BCSM by Recurrence Score group are reported for important patient subgroups, including age, race, tumor size, grade, and socioeconomic status. This SEER study represents the largest report of prospective BCSM outcomes based on Recurrence Score results for patients with HR+, HER2-negative, node-negative, or node-positive breast cancer, including subgroups often under-represented in clinical trials

Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study

Background Patients with diabetes and acute coronary syndrome (ACS) are at high risk for subsequent heart failure. Apabetalone is a selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. Preclinical data suggest that apabetalone exerts favorable effects on pathways related to myocardial structure and function and therefore could impact subsequent heart failure events. The effect of apabetalone on heart failure events after an ACS is not currently known. Methods The phase 3 BETonMACE trial was a double-blind, randomized comparison of apabetalone versus placebo on the incidence of major adverse cardiovascular events (MACE) in 2425 patients with a recent ACS and diabetes. This prespecified secondary analysis investigated the impact of apabetalone on hospitalization for congestive heart failure, not previously studied. Results Patients (age 62 years, 74.4% males, 90% high-intensity statin use, LDL-C 70.3 mg/dL, HDL-C 33.3 mg/dL and HbA1c 7.3%) were followed for an average 26 months. Apabetalone treated patients experienced the nominal finding of a lower rate of first hospitalization for heart failure (2.4% vs. 4.0%, HR 0.59 [95%CI 0.38–0.94], P = 0.03), total number of hospitalizations for heart failure (35 vs. 70, HR 0.47 [95%CI 0.27–0.83], P = 0.01) and the combination of cardiovascular death or hospitalization for heart failure (5.7% vs. 7.8%, HR 0.72 [95%CI 0.53–0.98], P = 0.04). Conclusion Apabetalone treatment was associated with fewer hospitalizations for heart failure in patients with type 2 diabetes and recent ACS. Future studies are warranted to define the potential for BET inhibition with apabetalone to prevent heart failure in patients with diabetes and ACS

Chronic Losartan Administration Reduces Mortality and Preserves Cardiac but Not Skeletal Muscle Function in Dystrophic Mice

Duchenne muscular dystrophy (DMD) is a degenerative disorder affecting skeletal and cardiac muscle for which there is no effective therapy. Angiotension receptor blockade (ARB) has excellent therapeutic potential in DMD based on recent data demonstrating attenuation of skeletal muscle disease progression during 6–9 months of therapy in the mdx mouse model of DMD. Since cardiac-related death is major cause of mortality in DMD, it is important to evaluate the effect of any novel treatment on the heart. Therefore, we evaluated the long-term impact of ARB on both the skeletal muscle and cardiac phenotype of the mdx mouse. Mdx mice received either losartan (0.6 g/L) (n = 8) or standard drinking water (n = 9) for two years, after which echocardiography was performed to assess cardiac function. Skeletal muscle weight, morphology, and function were assessed. Fibrosis was evaluated in the diaphragm and heart by Trichrome stain and by determination of tissue hydroxyproline content. By the study endpoint, 88% of treated mice were alive compared to only 44% of untreated (p = 0.05). No difference in skeletal muscle morphology, function, or fibrosis was noted in losartan-treated animals. Cardiac function was significantly preserved with losartan treatment, with a trend towards reduction in cardiac fibrosis. We saw no impact on the skeletal muscle disease progression, suggesting that other pathways that trigger fibrosis dominate over angiotensin II in skeletal muscle long term, unlike the situation in the heart. Our study suggests that ARB may be an important prophylactic treatment for DMD-associated cardiomyopathy, but will not impact skeletal muscle disease

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH