Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma

The current model for breast cancer progression proposes independent “low‐grade (LG) like” and “high‐grade (HG) like” pathways but lacks a known precursor to HG cancer. We applied low coverage whole genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. 14/20 isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG‐like CNA than LG DCIS (eg. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent “low‐grade like” and “high‐grade like” pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH could be more clinically significant than LG DCIS, requiring biomarkers for personalising management

Analyzing the Impacts of Off-Road Vehicle (ORV) Trails on Watershed Processes in Wrangell-St. Elias National Park and Preserve, Alaska

Trails created by off-road vehicles (ORV) in boreal lowlands are known to cause local impacts, such as denuded vegetation, soil erosion, and permafrost thaw, but impacts on stream and watershed processes are less certain. In Wrangell-St. Elias National Park and Preserve (WRST), Alaska, ORV trails have caused local resource damage in intermountain lowlands with permafrost soils and abundant wetlands and there is a need to know whether these impacts are more extensive. Comparison of aerial photography from 1957, 1981, and 2004 coupled with ground surveys in 2009 reveal an increase in trail length and number and show an upslope expansion of a trail system around points of stream channel initiation. We hypothesized that these impacts could also cause premature initiation and headward expansion of channels because of lowered soil resistance and greater runoff accumulation as trails migrate upslope. Soil monitoring showed earlier and deeper thaw of the active layer in and adjacent to trails compared to reference sites. Several rainfall-runoff events during the summer of 2009 showed increased and sustained flow accumulation below trail crossings and channel shear forces sufficient to cause headward erosion of silt and peat soils. These observations of trail evolution relative to stream and wetland crossings together with process studies suggest that ORV trails are altering watershed processes. These changes in watershed processes appear to result in increasing drainage density and may also alter downstream flow regimes, water quality, and aquatic habitat. Addressing local land-use disturbances in boreal and arctic parklands with permafrost soils, such as WRST, where responses to climate change may be causing concurrent shifts in watershed processes, represents an important challenge facing resource managers

Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity

Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies

Recommendations for the design of therapeutic trials for neonatal seizures

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from welldesigned clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population

Social anxiety symptoms in young children:Investigating the interplay of theory of mind and expressions of shyness

Children’s early onset of social anxiety may be associated with their social understanding, and their ability to express emotions adaptively. We examined whether social anxiety in 48-month-old children (N = 110; 54 boys) was related to: a) a lower level of theory of mind (ToM); b) a lower proclivity to express shyness in a positive way (adaptive); and c) a higher tendency to express shyness in a negative way (non-adaptive). In addition, we investigated to what extent children’s level of social anxiety was predicted by the interaction between ToM and expressions of shyness. Children’s positive and negative expressions of shyness were observed during a performance task. ToM was measured with a validated battery, and social anxiety was assessed using both parents’ reports on questionnaires. Socially anxious children had a lower level of ToM, and displayed more negative and less positive shy expressions. However, children with a lower level of ToM who expressed more positive shyness were less socially anxious. Additional results show that children who displayed shyness only in a negative manner were more socially anxious than children who expressed shyness only in a positive way and children who did not display any shyness. Moreover, children who displayed both positive and negative expressions of shyness were more socially anxious than children who displayed shyness only in a positive way. These findings highlight the importance of ToM development and socio-emotional strategies, and their interaction, on the early development of social anxiety

Towards screening Barrett’s Oesophagus: current guidelines, imaging modalities and future developments

Barrett’s oesophagus is the only known precursor to oesophageal adenocarcinoma (OAC). Although guidelines on the screening and surveillance exist in Barrett’s oesophagus, the current strategies are inadequate. Oesophagogastroduodenoscopy (OGD) is the gold standard method in screening for Barrett’s oesophagus. This invasive method is expensive with associated risks negating its use as a current screening tool for Barrett’s oesophagus. This review explores current definitions, epidemiology, biomarkers, surveillance, and screening in Barrett’s oesophagus. Imaging modalities applicable to this condition are discussed, in addition to future developments. There is an urgent need for an alternative non-invasive method of screening and/or surveillance which could be highly beneficial towards reducing waiting times, alleviating patient fears and reducing future costs in current healthcare services. Vibrational spectroscopy has been shown to be promising in categorising Barrett’s oesophagus through to high-grade dysplasia (HGD) and OAC. These techniques need further validation through multicentre trials

Racial and Imperial Thinking in International Theory and Politics: Truman, Attlee and the Korean War

- Connects the background ideas of race and empire to world politics - Uses case of Truman and Attlee in the Korean War - Argues that liberal-realist internationalists’ assumptions about the US-led post-war order obscure those background ideas and fail to understand the character of the post-war order - Argues liberal-realist internationalism is akin to a legitimating ideology rather than an explanatory theory - Argues that such failings render liberal internationalism inadequate to explain or prescribe ways for the United States/West to manage the ‘rise of the rest’ today This article connects the background ideas of race and empire to world politics by looking at the world views and actions of Truman and Attlee in the Korean War. The article argues that liberal-realist internationalists’ assumptions about the US-led post-war order obscure those background ideas and fail to understand the character of the post-war order. I consider two kinds of ‘background ideas’—policy-makers’ and those embedded in liberal internationalism. Put together, these ideas render liberal-realist internationalism akin to a legitimating ideology rather than an explanatory theory. More broadly, and in the longer run, such failure to comprehend the character of the post-war order, and the roles of race, empire and periphery war in it, renders the theory inadequate to explain or prescribe ways for the United States/West to manage the ‘rise of the rest’ today