The growth of many cancers depends on self-renewing cells called cancer stem cells or tumor-propagating cells (TPCs). In human brain tumors, cells expressing the stem cell marker CD133 have been ...implicated as TPCs. Here we show that tumors from a model of medulloblastoma, the
Patched mutant mouse, are propagated not by CD133
+ cells but by cells expressing the progenitor markers Math1 and CD15/SSEA-1. These cells have a distinct expression profile that suggests increased proliferative capacity and decreased tendency to undergo apoptosis and differentiation. CD15 is also found in a subset of human medulloblastomas, and tumors expressing genes similar to those found in murine CD15
+ cells have a poorer prognosis. Thus, CD15 may represent an important marker for TPCs in medulloblastoma.
We describe the data archive and database for the SAMI Galaxy Survey, an ongoing observational program that will cover ≈3400 galaxies with integral-field (spatially-resolved) spectroscopy. Amounting ...to some three million spectra, this is the largest sample of its kind to date. The data archive and built-in query engine use the versatile Hierarchical Data Format (HDF5), which precludes the need for external metadata tables and hence the setup and maintenance overhead those carry. The code produces simple outputs that can easily be translated to plots and tables, and the combination of these tools makes for a light system that can handle heavy data. This article acts as a contextual companion to the SAMI Survey Database source code repository, samiDB, which is freely available online and written entirely in Python. We also discuss the decisions related to the selection of tools and the creation of data visualisation modules. It is our aim that the work presented in this article–descriptions, rationale, and source code–will be of use to scientists looking to set up a maintenance-light data archive for a Big Science data load.
The aim of the present study was to investigate the efficacy of infliximab for the treatment of extrapulmonary sarcoidosis. A prospective, randomised, double-blind, placebo-controlled trial was ...conducted, with infliximab at 3 and 5 mg x kg(-1) body weight administered over 24 weeks. Extrapulmonary organ severity was determined by a novel severity tool (extrapulmonary physician organ severity tool; ePOST) with an adjustment for the number of organs involved (ePOSTadj). In total, 138 patients enrolled in the trial of infliximab versus placebo for the treatment of chronic corticosteroid-dependent pulmonary sarcoidosis. The baseline severity of extrapulmonary organ involvement, as measured by ePOST, was similar across treatment groups. After 24 weeks of drug-therapy study, the change from baseline to week 24 in ePOST was greater for the combined infliximab group compared with the placebo group. After adjustment for the number of extrapulmonary organs involved, the improvement in ePOSTadj observed in the combined infliximab group was also greater than that observed in placebo-treated patients, after 24 weeks of therapy. The improvements in ePOST and ePOSTadj were not maintained during a subsequent 24-week washout period. Infliximab may be beneficial compared with placebo in the treatment of extrapulmonary sarcoidosis in patients already receiving corticosteroids, as assessed by the severity tool described in the present study.
There is accumulating evidence for decadal-scale regime shifts at the base of the food web on the Northeast US Continental Shelf. However, less evidence exists for regime shifts in fish recruitment ...success, particularly for synchronized regimes across multiple species. Here, we analyzed stock assessment output and survey data to test for regimes in the recruitment success of 18 commercially important marine species over a 29 yr timespan. We then tested whether recruitment regimes coincide with regimes in the zooplankton community, and whether the abundance of large spawners could explain the patterns in recruitment. We found evidence for 3 decadal-scale recruitment regimes: low recruitment success in the 1980s, high success in the 1990s, and a return to low recruitment success in the 2000s. This general pattern was found in all datasets of recruitment. The abundance of large spawners did not appear to be a broad-scale driver of recruitment success; however, recruitment regimes coincided with regimes in copepod abundance and size structure.
The brain is a common site of metastasis for patients with high-risk melanoma. Although surgery or stereotactic radiosurgery are highly effective local treatments for a small number of metastases, ...there is a high risk of developing additional brain metastases. The role of adjuvant whole-brain radiotherapy (WBRT) in reducing new metastases is controversial, with a lack of high-level evidence specifically for melanoma.
In this randomized phase III trial, patients who had local treatment of one to three melanoma brain metastases were randomly assigned to WBRT or observation. The primary end point was distant intracranial failure within 12 months, and secondary end points included time to intracranial failure, survival, and time to deterioration in performance status.
Between April 2009 and September 2017, 215 patients were randomly assigned from 24 centers. Median follow-up was 48.1 months (range, 39.6 to 68 months). Forty-two percent of patients in the WBRT group and 50.5% of those in the observation developed distant intracranial failure within 12 months (odds ratio, 0.71; 95% CI, 0.41 to 1.23;
= .22) and the rates over the entire follow-up period were 52.0% and 57.9%, respectively (odds ratio, 0.79; 95% CI, 0.45 to 1.36;
= .39). Local failure rate was lower after WBRT (20.0%
33.6%;
= .03). At 12 months, 41.5% of patients in the WBRT group and 51.4% of patients in the observation group had died (
= .28), with no difference in the rate of neurologic death. Median time to deterioration in performance status was 3.8 months after WBRT and 4.4 months with observation (
= .32). WBRT was associated with more grade 1 to 2 acute toxicity.
After local treatment of one to three melanoma brain metastases, adjuvant WBRT does not provide clinical benefit in terms of distant intracranial control, survival, or preservation of performance status.
The ocean plays a critical role in supporting human well-being, from providing food, livelihoods and recreational opportunities to regulating the global climate. Sustainable management aimed at ...maintaining the flow of a broad range of benefits from the ocean requires a comprehensive and quantitative method to measure and monitor the health of coupled human–ocean systems. We created an index comprising ten diverse public goals for a healthy coupled human–ocean system and calculated the index for every coastal country. Globally, the overall index score was 60 out of 100 (range 36–86), with developed countries generally performing better than developing countries, but with notable exceptions. Only 5% of countries scored higher than 70, whereas 32% scored lower than 50. The index provides a powerful tool to raise public awareness, direct resource management, improve policy and prioritize scientific research.
Extratropical transition (ET) is the process by which a tropical cyclone, upon encountering a baroclinic environment and reduced sea surface temperature at higher latitudes, transforms into an ...extratropical cyclone. This process is influenced by, and influences, phenomena from the tropics to the midlatitudes and from the meso- to the planetary scales to extents that vary between individual events. Motivated in part by recent high-impact and/or extensively observed events such as North Atlantic Hurricane Sandy in 2012 and western North Pacific Typhoon Sinlaku in 2008, this review details advances in understanding and predicting ET since the publication of an earlier review in 2003. Methods for diagnosing ET in reanalysis, observational, and model-forecast datasets are discussed. New climatologies for the eastern North Pacific and southwest Indian Oceans are presented alongside updates to western North Pacific and North Atlantic Ocean climatologies. Advances in understanding and, in some cases, modeling the direct impacts of ET-related wind, waves, and precipitation are noted. Improved understanding of structural evolution throughout the transformation stage of ET fostered in large part by novel aircraft observations collected in several recent ET events is highlighted. Predictive skill for operational and numerical model ET-related forecasts is discussed along with environmental factors influencing posttransition cyclone structure and evolution. Operational ET forecast and analysis practices and challenges are detailed. In particular, some challenges of effective hazard communication for the evolving threats posed by a tropical cyclone during and after transition are introduced. This review concludes with recommendations for future work to further improve understanding, forecasts, and hazard communication.
Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally ...evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in healthy human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing
and zebrafish hearts revealed that LDL receptor-related protein
is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to patents the proband's iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.
CCAAT enhancer–binding protein epsilon (C/EBPε) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε ...is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality.
The aim of this study was to molecularly characterize the effects of C/EBPε transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome.
Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed.
Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages.
We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBPε. Mutated C/EBPε acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPε. Similar multiomics approaches should also be used in studying other transcription factor–associated diseases.
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