The evolution of the terrestrial-terminating Irish Sea glacier during the last glaciation

Here we reconstruct the last advance to maximum limits and retreat of the Irish Sea Glacier (ISG), the only land‐terminating ice lobe of the western British Irish Ice Sheet. A series of reverse bedrock slopes rendered proglacial lakes endemic, forming time‐transgressive moraine‐ and bedrock‐dammed basins that evolved with ice marginal retreat. Combining, for the first time on glacial sediments, optically stimulated luminescence (OSL) bleaching profiles for cobbles with single grain and small aliquot OSL measurements on sands, has produced a coherent chronology from these heterogeneously bleached samples. This chronology constrains what is globally an early build‐up of ice during late Marine Isotope Stage 3 and Greenland Stadial (GS) 5, with ice margins reaching south Lancashire by 30 ± 1.2 ka, followed by a 120‐km advance at 28.3 ± 1.4 ka reaching its 26.5 ± 1.1 ka maximum extent during GS‐3. Early retreat during GS‐3 reflects piracy of ice sources shared with the Irish‐Sea Ice Stream (ISIS), starving the ISG. With ISG retreat, an opportunistic readvance of Welsh ice during GS‐2 rode over the ISG moraines occupying the space vacated, with ice margins oscillating within a substantial glacial over‐deepening. Our geomorphological chronosequence shows a glacial system forced by climate but mediated by piracy of ice sources shared with the ISIS, changing flow regimes and fronting environments

Biologic markers of risk in nipple aspirate fluid are associated with residual cancer and tumour size

We previously demonstrated that nipple aspirate fluid (NAF) can be obtained from virtually all non-Asian women between the ages of 30 and 72. The focus of this report is to (1) determine the association of candidate markers of breast cancer risk in NAF obtained from fresh mastectomy specimens with residual breast carcinoma, and (2) evaluate the association of the markers with breast tumour progression. Nipple aspiration was performed on 97 specimens. Cytology, DNA index (including % hypertetraploid cells), cell cycle parameters (S phase fraction, % cells in G2/M), prostate-specific antigen (PSA), epidermal growth factor (EGF), testosterone, carcinoembryonic antigen (CEA) and prostaglandin D synthase (PGDS) were evaluated in NAF for their association with (1) residual ductal carcinoma in situ (DCIS) or invasive cancer, and (2) pathologic tumour size. NAF was obtained from 99% (96/97) of specimens. Atypical and malignant NAF cytology were significantly associated with residual DCIS or invasive cancer (P = 0.001) and with larger tumours (P = 0.004). One hundred per cent and 88% of subjects with malignant and atypical NAF cytology, respectively, had residual carcinoma. The percentage of cells in G2/M and DNA index were associated both with risk of residual carcinoma (P = 0.01 for each) and larger tumour size (DNA index, P = 0.03; G2/M, P = 0.05), although neither biomarker improved the ability of NAF cytology, to predict residual breast cancer. Higher DNA index was associated with atypical cytology (P = 0.0001). In summary, atypical and malignant NAF cytology are associated with larger tumour size, and are highly predictive of residual carcinoma after needle or excisional biopsy of the breast. © 1999 Cancer Research Campaig

Alternative HER/PTEN/Akt Pathway Activation in HPV Positive and Negative Penile Carcinomas

Copyright: 2011 Stankiewicz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: The pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood, though risk factors include human papillomavirus (HPV). Disruption of HER/PTEN/Akt pathway is present in many cancers; however there is little information on its function in PSCC. We investigated HER family receptors and phosphatase and tension homolog (PTEN) in HPV-positive and negative PSCC and its impact on Akt activation using immunohistochemistry and fluorescent in situ hybridisation (FISH). Methodology/Principal Findings: 148 PSCCs were microarrayed and immunostained for phosphorylated EGFR (pEGFR), HER2, HER3, HER4, phosphorylated Akt (pAkt), Akt1 and PTEN proteins. EGFR and PTEN gene status were also evaluated using FISH. HPV presence was assessed by PCR. pEGFR expression was detected significantly less frequently in HPV-positive than HPV-negative tumours (p = 0.0143). Conversely, HER3 expression was significantly more common in HPV-positive cases (p = 0.0128). HER4, pAkt, Akt and PTEN protein expression were not related to HPV. HER3 (p = 0.0054) and HER4 (p = 0.0002) receptors significantly correlated with cytoplasmic Akt1 immunostaining. All three proteins positively correlated with tumour grade (HER3, p = 0.0029; HER4, p = 0.0118; Akt1, p = 0.0001). pEGFR expression correlated with pAkt but not with tumour grade or stage. There was no EGFR gene amplification. HER2 was not detected. PTEN protein expression was reduced or absent in 62% of tumours but PTEN gene copy loss was present only in 4% of PSCCs. Conclusions/Significance: EGFR, HER3 and HER4 but not HER2 are associated with penile carcinogenesis. HPV-negative tumours tend to express significantly more pEGFR than HPV-positive cancers and this expression correlates with pAkt protein, indicating EGFR as an upstream regulator of Akt signalling in PSCC. Conversely, HER3 expression is significantly more common in HPV-positive cases and positively correlates with cytoplasmic Akt1 expression. HER4 and PTEN protein expression are not related to HPV infection. Our results suggest that PSCC patients could benefit from therapies developed to target HER receptors.Peer reviewedFinal Published versio

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR=1.33, p=4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR=1.07, p=0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR=0.90, p=0.00033; rs927062, OR =0.94, p=0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations

The Influence of Mate Choice Motivation on Non-Financial Altruism

Several studies have found that individuals are more altruistic towards potential mates than others, suggesting altruistic behavior may be a mating signal. Much of the literature focuses on financial altruism using economic games, however altruism can also comprise of non-financial acts, which this experiment examined in an attempt to replicate and refine previous findings. A study was conducted with 199 participants, who viewed both high attractive and low attractive opposite-sex images and were asked how likely they would be to altruistically share their research credits with the person in the image, whilst controlling for self-rated attractiveness. The findings suggest that both men and women were more altruistic towards pictures of high attractive than low attractive potential mating partners (Cohen’s d = 0.37). This study therefore partially replicates previous research examining the role of mate choice effects when exploring non-financial altruism

Morphological and sedimentary responses to ice mass interaction during the last deglaciation

During decline of the last British–Irish Ice Sheet (BIIS) down‐wasting of ice meant that local sources played a larger role in regulating ice flow dynamics and driving the sediment and landform record. At the Last Glacial Maximum, glaciers in north‐western England interacted with an Irish Sea Ice Stream (ISIS) occupying the eastern Irish Sea basin (ISB) and advanced as a unified ice‐mass. During a retreat constrained to 21–17.3 ka, the sediment landform assemblages lain down reflect the progressive unzipping of the ice masses, oscillations of the ice margin during retreat, and then rapid wastage and disintegration. Evacuation of ice from the Ribble valley and Lancashire occurred first while the ISIS occupied the ISB to the west, creating ice‐dammed lakes. Deglaciation, complete after 18.6–17.3 ka, was rapid (50–25 m a−1), but slower than rates identified for the western ISIS (550–100 m a−1). The slower pace is interpreted as reflecting the lack of a calving margin and the decline of a terrestrial, grounded glacier. Ice marginal oscillations during retreat were probably forced by ice‐sheet dynamics rather than climatic variation. These data demonstrate that large grounded glaciers can display complex uncoupling and realignment during deglaciation, with asynchronous behaviour between adjacent ice lobes generating complex landform records

The p65/RelA Subunit of NF-κB Suppresses the Sustained, Antiapoptotic Activity of Jun Kinase Induced by Tumor Necrosis Factor

Tumor necrosis factor (TNF) signaling through the TNF receptors involves the recruitment of key signaling factors, leading to the activation of both the transcription factor NF-κB and the stress-activated Jun kinase (JNK). In most cells, TNF signaling leads to a rapid and transient increase in JNK activity. However, we show that TNF treatment leads to the sustained activation of JNK in cells that are null for the p65/RelA subunit of NF-κB as well as in cells expressing the super-repressor form of IκB. In addition, the data indicate that the ability of p65/RelA to regulate gene expression is required to suppress the persistent activation of JNK. Interestingly, this suppression occurs upstream of JNK, within the signal transduction cascade leading to JNK activation, without affecting the stress-activated kinase p38. Since NF-κB has previously been shown to be involved in the suppression of TNF-induced apoptosis, we were interested in determining the role of deregulated JNK activity, induced by the loss of NF-κB, in controlling the cell death response. Through the use of different approaches for inhibition of JNK, we show that the suppression of JNK activity in cells that lack active NF-κB enhances the apoptotic response to TNF. These data suggest that the activity of JNK in cells blocked for NF-κB function provides an antiapoptotic signal and explains, at least partly, why a significant number of NF-κB null cells remain viable following TNF treatment