Combined image and genomic analysis of high-grade serous ovarian cancer reveals PTEN loss as a common driver event and prognostic classifier.

BACKGROUND: TP53 and BRCA1/2 mutations are the main drivers in high-grade serous ovarian carcinoma (HGSOC). We hypothesise that combining tissue phenotypes from image analysis of tumour sections with genomic profiles could reveal other significant driver events. RESULTS: Automatic estimates of stromal content combined with genomic analysis of TCGA HGSOC tumours show that stroma strongly biases estimates of PTEN expression. Tumour-specific PTEN expression was tested in two independent cohorts using tissue microarrays containing 521 cases of HGSOC. PTEN loss or downregulation occurred in 77% of the first cohort by immunofluorescence and 52% of the validation group by immunohistochemistry, and is associated with worse survival in a multivariate Cox-regression model adjusted for study site, age, stage and grade. Reanalysis of TCGA data shows that hemizygous loss of PTEN is common (36%) and expression of PTEN and expression of androgen receptor are positively associated. Low androgen receptor expression was associated with reduced survival in data from TCGA and immunohistochemical analysis of the first cohort. CONCLUSION: PTEN loss is a common event in HGSOC and defines a subgroup with significantly worse prognosis, suggesting the rational use of drugs to target PI3K and androgen receptor pathways for HGSOC. This work shows that integrative approaches combining tissue phenotypes from images with genomic analysis can resolve confounding effects of tissue heterogeneity and should be used to identify new drivers in other cancers.This work was supported by Cancer Research UK [grant numbers A15601, A17197,A16561, A10124]; the University of Cambridge; National Institute for Health Research Cambridge Biomedical Research Centre and Academic Clinical Fellowship scheme (FCM); Cambridge Experimental Cancer Medicine Centre and Hutchison Whampoa Limited. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final published version. It first appeared at http://genomebiology.com/2014/15/12/526

Autosomal dominant osteopetrosis associated with renal tubular acidosis is due to a CLCN7 mutation

The aim of this study was to identify the causative mutation in a family with an unusual presentation of autosomal dominant osteopetrosis (OPT), proximal renal tubular acidosis (RTA), renal stones, epilepsy, and blindness, a combination of features not previously reported. We undertook exome sequencing of one affected and one unaffected family member, followed by targeted analysis of known candidate genes to identify the causative mutation. This identified a missense mutation (c.643G>A; p.Gly215Arg) in the gene encoding the chloride/proton antiporter 7 (gene CLCN7, protein CLC-7), which was confirmed by amplification refractory mutation system (ARMS)-PCR, and to be present in the three available patients. CLC-7 mutations are known to cause autosomal dominant OPT type 2, also called Albers-Schonberg disease, which is characterized by osteosclerosis, predominantly of the spine, pelvis and skull base, resulting in bone fragility and fractures. Albers-Schonberg disease is not reported to be associated with RTA, but autosomal recessive OPT type 3 (OPTB3) with RTA is associated with carbonic anhydrase type 2 (CA2) mutations. No mutations were detected in CA2 or any other genes known to cause proximal RTA. Neither CLCN7 nor CA2 mutations have previously been reported to be associated with renal stones or epilepsy. Thus, we identified a CLCN7 mutation in a family with autosomal dominant osteopetrosis, RTA, renal stones, epilepsy, and blindness. © 2016 Wiley Periodicals, Inc

The Low-Redshift Lyman Continuum Survey. Unveiling the ISM properties of low-zz Lyman continuum emitters

Combining 66 ultraviolet (UV) spectra and ancillary data from the Low-Redshift Lyman Continuum Survey (LzLCS) and 23 LyC observations by earlier studies, we form a statistical sample of star-forming galaxies at $z \sim 0.3$ to study the role of the cold interstellar medium (ISM) gas in the leakage of ionizing radiation. We first constrain the massive star content (ages and metallicities) and UV attenuation, by fitting the stellar continuum with a combination of simple stellar population models. The models, together with accurate LyC flux measurements, allow to determine the absolute LyC photon escape fraction for each galaxy ($f_{\rm esc}^{\rm abs}$). We measure the equivalent widths and residual fluxes of multiple HI and low-ionization state (LIS) lines, and the geometrical covering fraction adopting the picket-fence model. The $f_{\rm esc}^{\rm abs}$ spans a wide range, with a median (0.16, 0.84 quantiles) of 0.04 (0.02, 0.20), and 50 out of the 89 galaxies detected in the LyC. The HI and LIS line equivalent widths scale with the UV luminosity and attenuation, and inversely with the residual flux of the lines. The HI and LIS residual fluxes are correlated, indicating that the neutral gas is spatially traced by the LIS transitions. We find the observed trends of the absorption lines and the UV attenuation are primarily driven by the covering fraction. The non-uniform gas coverage demonstrates that LyC photons escape through low-column density channels in the ISM. The equivalent widths and residual fluxes of the UV lines strongly correlate with $f_{\rm esc}^{\rm abs}$: strong LyC leakers show weak absorption lines, low UV attenuation, and large Ly$\alpha$ equivalent widths. We finally show that simultaneous UV absorption line and dust attenuation measurements can predict, on average, the escape fraction of galaxies and the method can be applied to galaxies across a wide redshift range.Comment: 30 pages, 16 figures, 3 tables; accepted for publication in Astronomy and Astrophysics on December 16, 2021. Tables A1 to A4 are part of the LzLCS science products and will be publicly available in a dedicated websit

The Low-redshift Lyman Continuum Survey: Radio continuum properties of low-zz Lyman continuum emitters

The sources that leak Lyman-continuum (LyC) photons and lead to the reionisation of the universe are intensely studied using multiple observing facilities. Recently, the Low-redshift LyC Survey (LzLCS) has found the first large sample of LyC emitting galaxies at low redshift ($z\sim 0.3$) with the Hubble Space Telescope/Cosmic Origins Spectrograph. The LzLCS sample contains a robust estimate of the LyC escape fraction ($f_\mathrm{esc}^\mathrm{LyC}$) for 66 galaxies spanning a wide range of $f_\mathrm{esc}^\mathrm{LyC}$. Here we, for the first time, aim to study the radio continuum (RC) properties of LzLCS sources and their dependence on $f_\mathrm{esc}^\mathrm{LyC}$. We present Karl G. Jansky Very Large Array RC observations at C (4-8 GHz), S (2-4 GHz) and L (1-2 GHz) bands for a sub-sample of the LzLCS sources. The radio spectral index ($\alpha^{\mathrm{3GHz}}_\mathrm{6GHz}$) spans a wide range from being flat ( $\geq -0.1$) to very steep ($\leq -1.0$). We find that the strongest leakers in our sample show flat $\alpha^{\mathrm{3GHz}}_\mathrm{6GHz}$, weak leakers have $\alpha^{\mathrm{3GHz}}_\mathrm{6GHz}$ close to normal star-forming galaxies, and non-leakers are characterized by steep $\alpha^{\mathrm{3GHz}}_\mathrm{6GHz}$. We argue that a combination of young ages, free-free absorption, and a flat cosmic-ray energy spectrum can altogether lead to a flat $\alpha^{\mathrm{3GHz}}_\mathrm{6GHz}$ for strong leakers. Non-leakers are characterized by steep spectra which can arise due to break/cutoff at high frequencies. Such a cutoff in the spectrum can arise in a single injection model of CRs characteristic of galaxies which have recently stopped star formation. Such a relation between $\alpha^{\mathrm{3GHz}}_\mathrm{6GHz}$ and $f_\mathrm{esc}^\mathrm{LyC}$ hints at the interesting role of supernovae, CRs, and magnetic fields in facilitating the escape (and/or the lack) of LyC photons.Comment: 25 pages, 14 figures, 3 tables, Submitted to Astronomy & Astrophysic

The rationale of opportunistic bilateral salpingectomies (OBS) during benign gynaecological and obstetric surgery : a consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG)

Ovarian cancer (OC), is a disease difficult to diagnose in an early stage implicating a poor prognosis. The 5-year overall survival in Belgium has not changed in the last 18 years and remains 44 %. There is no effective screening method (secondary prevention) to detect ovarian cancer at an early stage. Primary prevention of ovarian cancer came in the picture through the paradigm shift that the fallopian tube is often the origin of ovarian cancer and not the ovary itself. Opportunistic bilateral salpingectomy (OBS) during benign gynaecological and obstetric surgery might have the potential to reduce the risk of ovarian cancer by as much as 65 %. Bilateral risk-reducing salpingectomy during a benign procedure is feasible, safe, appears to have no impact on the ovarian function and seems to be cost effective. The key question is whether we should wait for a RCT or implement OBS directly in our daily practice. Guidelines regarding OBS within our societies are therefore urgently needed. Our recommendation is to inform all women without a child wish, undergoing a benign gynaecological or obstetrical surgical procedure about the pro’s and the con’s of OBS and advise a bilateral salpingectomy. Furthermore, there is an urgent need for a prospective registry of OBS. The present article is the consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG) regarding OBS

Predictors of Breast and Cervical Cancer Screening among Chamorro Women in Southern California

This study examined the role of sociodemographic characteristics, health insurance, cancer knowledge, perceived health risk, and having a recent physicians’ visit on breast and cervical cancer screening utilization among a randomly selected group of Chamorro women (n = 250) residing in San Diego, California. Data were collected by a telephone survey and analyzed using multiple logistic regression models. After adjusting for covariates, having a recent full exam was the strongest predictor of having had a Pap exam in the past 2 years for women 21 years and older and a clinical breast exam in the past 2 years for women 40 years and over

Necdin, a p53-Target Gene, Is an Inhibitor of p53-Mediated Growth Arrest

In vitro, cellular immortalization and transformation define a model for multistep carcinogenesis and current ongoing challenges include the identification of specific molecular events associated with steps along this oncogenic pathway. Here, using NIH3T3 cells, we identified transcriptionally related events associated with the expression of Polyomavirus Large-T antigen (PyLT), a potent viral oncogene. We propose that a subset of these alterations in gene expression may be related to the early events that contribute to carcinogenesis. The proposed tumor suppressor Necdin, known to be regulated by p53, was within a group of genes that was consistently upregulated in the presence of PyLT. While Necdin is induced following p53 activation with different genotoxic stresses, Necdin induction by PyLT did not involve p53 activation or the Rb-binding site of PyLT. Necdin depletion by shRNA conferred a proliferative advantage to NIH3T3 and PyLT-expressing NIH3T3 (NIHLT) cells. In contrast, our results demonstrate that although overexpression of Necdin induced a growth arrest in NIH3T3 and NIHLT cells, a growing population rapidly emerged from these arrested cells. This population no longer showed significant proliferation defects despite high Necdin expression. Moreover, we established that Necdin is a negative regulator of p53-mediated growth arrest induced by nutlin-3, suggesting that Necdin upregulation could contribute to the bypass of a p53-response in p53 wild type tumors. To support this, we characterized Necdin expression in low malignant potential ovarian cancer (LMP) where p53 mutations rarely occur. Elevated levels of Necdin expression were observed in LMP when compared to aggressive serous ovarian cancers. We propose that in some contexts, the constitutive expression of Necdin could contribute to cancer promotion by delaying appropriate p53 responses and potentially promote genomic instability

Clinical outcomes and response to treatment of patients receiving topical treatments for pyoderma gangrenosum: a prospective cohort study

Background: pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. Objective: to estimate the effectiveness of topical therapies in the treatment of PG. Methods: prospective cohort study of UK secondary care patients with a clinical diagnosis of PG suitable for topical treatment (recruited July 2009 to June 2012). Participants received topical therapy following normal clinical practice (mainly Class I-III topical corticosteroids, tacrolimus 0.03% or 0.1%). Primary outcome: speed of healing at 6 weeks. Secondary outcomes: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality-of-life; treatment failure and recurrence. Results: Sixty-six patients (22 to 85 years) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28/66 (43.8%) of ulcers healed by 6 months. Median time-to-healing was 145 days (95% CI: 96 days, ∞). Initial ulcer size was a significant predictor of time-to-healing (hazard ratio 0.94 (0.88;80 1.00); p = 0.043). Four patients (15%) had a recurrence. Limitations: No randomised comparator Conclusion: Topical therapy is potentially an effective first-line treatment for PG that avoids possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone

Introduction: Toward an Engaged Feminist Heritage Praxis

We advocate a feminist approach to archaeological heritage work in order to transform heritage practice and the production of archaeological knowledge. We use an engaged feminist standpoint and situate intersubjectivity and intersectionality as critical components of this practice. An engaged feminist approach to heritage work allows the discipline to consider women’s, men’s, and gender non-conforming persons’ positions in the field, to reveal their contributions, to develop critical pedagogical approaches, and to rethink forms of representation. Throughout, we emphasize the intellectual labor of women of color, queer and gender non-conforming persons, and early white feminists in archaeology

Crop pests and predators exhibit inconsistent responses to surrounding landscape composition

The idea that noncrop habitat enhances pest control and represents a win–win opportunity to conserve biodiversity and bolster yields has emerged as an agroecological paradigm. However, while noncrop habitat in landscapes surrounding farms sometimes benefits pest predators, natural enemy responses remain heterogeneous across studies and effects on pests are inconclusive. The observed heterogeneity in species responses to noncrop habitat may be biological in origin or could result from variation in how habitat and biocontrol are measured. Here, we use a pest-control database encompassing 132 studies and 6,759 sites worldwide to model natural enemy and pest abundances, predation rates, and crop damage as a function of landscape composition. Our results showed that although landscape composition explained significant variation within studies, pest and enemy abundances, predation rates, crop damage, and yields each exhibited different responses across studies, sometimes increasing and sometimes decreasing in landscapes with more noncrop habitat but overall showing no consistent trend. Thus, models that used landscape-composition variables to predict pest-control dynamics demonstrated little potential to explain variation across studies, though prediction did improve when comparing studies with similar crop and landscape features. Overall, our work shows that surrounding noncrop habitat does not consistently improve pest management, meaning habitat conservation may bolster production in some systems and depress yields in others. Future efforts to develop tools that inform farmers when habitat conservation truly represents a win–win would benefit from increased understanding of how landscape effects are modulated by local farm management and the biology of pests and their enemies