Butterflies are better documented and monitored worldwide than any other nonpest taxon of insects (1). In the United Kingdom alone, volunteer recorders have sampled more than 750,000 km of repeat ...transects since 1976, equivalent to walking to the Moon and back counting butterflies (2). Such programs are revealing regional extinctions and population declines that began before 1900 (3, 4). In a recent study, Habel et al. report a similar story based on inventories of butterflies and burnet moths since 1840 in a protected area in Bavaria, Germany (5). The results reveal severe species losses: Scarce, specialized butterflies have largely disappeared, leaving ecosystems dominated by common generalist ones. Similar trends are seen across Europe (6) and beyond, with protected areas failing to conserve many species for which they were once famed.
In this article, I introduce the concept of BDSM as trauma play, which is the practice of intentionally engaging in BDSM activities in order to “play” with one’s past trauma or abuse. I begin by ...offering a fuller definition of trauma play, and I then summarize some of the key scholarly discussions related to the topic, especially the themes of healing, therapy, play, and embodiment. Following this, I take an autoethnographic approach, and I investigate my own trauma play experiences, which I subsequently analyze and use to highlight the need for more systematic research into this understudied topic area that significantly impacts the lives of some BDSM practitioners.
Purpose
This study was designed to determine invasive cancer upstaging rates at surgical excision following vacuum-assisted biopsy of ductal carcinoma in situ (DCIS) among women meeting eligibility ...for active surveillance trials.
Methods
Patients with vacuum-assisted, biopsy-proven DCIS at a single center from 2008 to 2015 were retrospectively reviewed. Imaging and pathology reports were interrogated for the imaging appearance, tumor grade, hormone receptor status, and presence of comedonecrosis. Subsequent surgical reports were reviewed for upstaging to invasive disease. Cases were classified by eligibility criteria for the COMET, LORIS, and LORD DCIS active surveillance trials.
Results
Of 307 DCIS diagnoses, 15 (5%) were low, 95 (31%) intermediate, and 197 (64%) high nuclear grade. The overall upstage rate to invasive disease was 17% (53/307). Eighty-one patients were eligible for the COMET Trial, 74 for the LORIS trial, and 10 for the LORD Trial, although LORIS trial eligibility also included real-time, multiple central pathology review, including elements not routinely reported. The upstaging rates to invasive disease were 6% (5/81), 7% (5/74), and 10% (1/10) for the COMET, LORIS, and LORD trials, respectively. Among upstaged cancers (
n
= 5), four tumors were Stage IA invasive ductal carcinoma and one was Stage IIA invasive lobular carcinoma; all were node-negative.
Conclusions
DCIS upstaging rates in women eligible for active surveillance trials are low (6–10%), and in this series, all those with invasive disease were early-stage, node-negative. The careful patient selection for DCIS active surveillance trials has a low risk of missing occult invasive cancer and additional studies will determine clinical outcomes.
Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment
. The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic ...therapy
. Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded by ERBB2)-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery
were then correlated with multi-omic features in these diagnostic biopsies. Here we show that response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.
Based on content analysis of the popular evangelical magazine Christianity Today, I show that while evangelicals' outward opposition to pornography has remained steady and robust across the period ...1956 to 2010, nonetheless, during this same time, evangelicals' anti-pornography narratives have become increasingly secular. Through using and expanding Chaves's notion of internal secularization, I demonstrate how these narratives have become decreasingly legitimated through religious forms of moral authority such as scriptural prohibitions and derivative ideas about God's plan for society, and increasingly legitimated through secular forms of moral authority such as humanistic conceptions of individual rights and of psychological health. I refer to this type of internal secularization as the process of outsourcing moral authority, and I discuss the theoretical significance of this process for potential investigations of a range of other moral narratives.
Management of screen-detected ductal carcinoma in situ (DCIS) remains controversial.
A prospective cohort of patients with DCIS diagnosed through the UK National Health Service Breast Screening ...Programme (1st April 2003 to 31st March 2012) was linked to national databases and case note review to analyse patterns of care, recurrence and mortality.
Screen-detected DCIS in 9938 women, with mean age of 60 years (range 46–87), was treated by mastectomy (2931) or breast conserving surgery (BCS) (7007; 70%). At 64 months median follow-up, 697 (6.8%) had further DCIS or invasive breast cancer after BCS (7.8%) or mastectomy (4.5%) (p < 0.001). Breast radiotherapy (RT) after BCS (4363/7007; 62.3%) was associated with a 3.1% absolute reduction in ipsilateral recurrent DCIS or invasive breast cancer (no RT: 7.2% versus RT: 4.1% p < 0.001) and a 1.9% absolute reduction for ipsilateral invasive breast recurrence (no RT: 3.8% versus RT: 1.9% p < 0.001), independent of the excision margin width or size of DCIS. Women without RT after BCS had more ipsilateral breast recurrences (p < 0.001) when the radial excision margin was <2 mm. Adjuvant endocrine therapy (1208/9938; 12%) was associated with a reduction in any ipsilateral recurrence, whether RT was received (hazard ratio HR 0.57; 95% confidence interval CI 0.41–0.80) or not (HR 0.68; 95% CI 0.51–0.91) after BCS. Women who developed invasive breast recurrence had a worse survival than those with recurrent DCIS (p < 0.001). Among 321 (3.2%) who died, only 46 deaths were attributed to invasive breast cancer.
Recurrent DCIS or invasive cancer is uncommon after screen-detected DCIS. Both RT and endocrine therapy were associated with a reduction in further events but not with breast cancer mortality within 5 years of diagnosis. Further research to identify biomarkers of recurrence risk, particularly as invasive disease, is indicated.
•Adjuvant radiotherapy (RT) after wide excision is associated with a reduced risk of ipsilateral recurrence but not mortality•Survival after treatment of DCIS is excellent, with few subsequent deaths from breast cancer.•Further DCIS or invasive breast cancer is not uncommon (6.8% at 5 years)•5-year mortality was not impacted by the use of RT or endocrine therapy.
Epigenetic changes are being increasingly recognized as a prominent feature of cancer. This occurs not only at individual genes, but also over larger chromosomal domains. To investigate this, we set ...out to identify large chromosomal domains of epigenetic dysregulation in breast cancers.
We identify large regions of coordinate down-regulation of gene expression, and other regions of coordinate activation, in breast cancers and show that these regions are linked to tumor subtype. In particular we show that a group of coordinately regulated regions are expressed in luminal, estrogen-receptor positive breast tumors and cell lines. For one of these regions of coordinate gene activation, we show that regional epigenetic regulation is accompanied by visible unfolding of large-scale chromatin structure and a repositioning of the region within the nucleus. In MCF7 cells, we show that this depends on the presence of estrogen.
Our data suggest that the liganded estrogen receptor is linked to long-range changes in higher-order chromatin organization and epigenetic dysregulation in cancer. This may suggest that as well as drugs targeting histone modifications, it will be valuable to investigate the inhibition of protein complexes involved in chromatin folding in cancer cells.
While research into motivations for obtaining a genital piercing has often shown sexual pleasure to be a key reason that persons get such piercings, research has typically overlooked the diverse ways ...that sexual pleasure is conceived of amid the context of genital piercings. In this article, we use examples from a study of self-reported genital piercing stories in order to illuminate this diversity and call attention to how sex research could benefit from a more robust and inclusive understanding of sexual pleasure. In doing so, we engage with more general research on pleasure as seen in other disciplines, and we argue for both a broader understanding of sexual pleasure as well as for an accompanying methodology that focuses on individuals' own conceptions of sexual pleasure.
Aromatase inhibitors (AIs) have an established role in the treatment of breast cancer. Response rates are only 50% to 70% in the neoadjuvant setting and lower in advanced disease. Accurate biomarkers ...are urgently needed to predict response in these settings and to determine which individuals will benefit from adjuvant AI therapy.
Pretreatment and on-treatment (after 2 weeks and 3 months) biopsies were obtained from 89 postmenopausal women who had estrogen receptor-alpha positive breast cancer and were receiving neoadjuvant letrozole for transcript profiling. Dynamic clinical response was assessed with use of three-dimensional ultrasound measurements.
The molecular response to letrozole was characterized and a four-gene classifier of clinical response was established (accuracy of 96%) on the basis of the level of two genes before treatment (one gene IL6ST was associated with immune signaling, and the other NGFRAP1 was associated with apoptosis) and the level of two proliferation genes (ASPM, MCM4) after 2 weeks of therapy. The four-gene signature was found to be 91% accurate in a blinded, completely independent validation data set of patients treated with anastrozole. Matched 2-week on-treatment biopsies were associated with improved predictive power as compared with pretreatment biopsies alone. This signature also significantly predicted recurrence-free survival (P = .029) and breast cancer -specific survival (P = .009). We demonstrate that the test can also be performed with use of quantitative polymerase chain reaction or immunohistochemistry.
A four-gene predictive model of clinical response to AIs by 2 weeks has been generated and validated. Deregulated immune and apoptotic responses before treatment and cell proliferation that is not reduced 2 weeks after initiation of treatment are functional characteristics of breast tumors that do not respond to AIs.
Proteomic profiling of the estrogen/tamoxifen-sensitive MCF-7 cell line and its partially sensitive (MCF-7/LCC1) and fully resistant (MCF-7/LCC9) variants was performed to identify modifiers of ...endocrine sensitivity in breast cancer. Analysis of the expression of 120 paired phosphorylated and non-phosphorylated epitopes in key oncogenic and tumor suppressor pathways revealed that STAT1 and several phosphorylated epitopes (phospho-STAT1(Tyr701) and phospho-STAT3(Ser727)) were differentially expressed between endocrine resistant and parental controls, confirmed by qRT-PCR and western blotting. The STAT1 inhibitor EGCG was a more effective inhibitor of the endocrine resistant MCF-7/LCC1 and MCF-7/LCC9 lines than parental MCF-7 cells, while STAT3 inhibitors Stattic and WP1066 were equally effective in endocrine-resistant and parental lines. The effects of the STAT inhibitors were additive, rather than synergistic, when tested in combination with tamoxifen in vitro. Expression of STAT1 and STAT3 were measured by quantitative immunofluorescence in invasive breast cancers and matched lymph nodes. When lymph node expression was compared to its paired primary breast cancer expression, there was greater expression of cytoplasmic STAT1 (∼3.1 fold), phospho-STAT3(Ser727) (∼1.8 fold), and STAT5 (∼1.5 fold) and nuclear phospho-STAT3(Ser727) (∼1.5 fold) in the nodes. Expression levels of STAT1 and STAT3 transcript were analysed in 550 breast cancers from publicly available gene expression datasets (GSE2990, GSE12093, GSE6532). When treatment with tamoxifen was considered, STAT1 gene expression was nearly predictive of distant metastasis-free survival (DMFS, log-rank p = 0.067), while STAT3 gene expression was predictive of DMFS (log-rank p<0.0001). Analysis of STAT1 and STAT3 protein expression in a series of 546 breast cancers also indicated that high expression of STAT3 protein was associated with improved survival (DMFS, p = 0.006). These results suggest that STAT signaling is important in endocrine resistance, and that STAT inhibitors may represent potential therapies in breast cancer, even in the resistant setting.
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