Collagen α1(XI) in Normal and Malignant Breast Tissue

Little is known about collagen XI expression in normal and malignant breast tissue. Tissue microarrays, constructed from 72 patients with breast carcinoma and matched normal tissue, were immunohistochemically stained with five antisera against isoform-specific regions of collagen α1(XI) N-terminal domain. Staining intensity was graded on a 0–3 scale in epithelial cytoplasm, stroma, and endothelial staining of the vasculature of each tissue core. The staining was compared to known pathologic parameters: age, tumor size, overall tumor grade, nuclear grade, tubule formation, mitotic counts, angiolymphatic invasion, node status, estrogen receptor status, progesterone receptor status, and HER-2/neu status. Estrogen and progesterone receptor status were used as a control for comparison. With antisera V1a and amino propeptide (Npp), stroma surrounding cancerous cells was found to have decreased collagen α1(XI) staining compared to stroma adjacent to normal epithelium (P=0.0006, P\u3c 0.0001). Collagen α1(XI) staining with V1a antiserum in cytoplasm of cancer cells demonstrated decreased intensity in metastasized primary tumors when compared to nonmetastasized primary tumors (P=0.009). Cytoplasmic staining with Npp antiserum in cancer demonstrated an inverse relationship to positive estrogen receptor status in cancer (P=0.012) and to progesterone receptor status (P=0.044). Stromal staining for Npp in cancerous tissue demonstrated an inverse relationship with tubule formation score (P=0.015). This is the first study to localize collagen XI within normal and malignant breast tissue. Collagen α1(XI) appears to be downregulated in stroma surrounding breast cancer. Detection of collagen XI in breast tissue may help predict women who have lymph node metastases

Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients

<br>Background:Prostate cancer cell growth is dependent upon androgen receptor (AR) activation, which is regulated by specific kinases. The aim of the current study is to establish if AR phosphorylation by Cdk1 or ERK1/2 is of prognostic significance.</br> <br>Methods: Scansite 2.0 was utilised to predict which AR sites are phosphorylated by Cdk1 and ERK1/2. Immunohistochemistry for these sites was then performed on 90 hormone-naive prostate cancer specimens. The interaction between Cdk1/ERK1/2 and AR phosphorylation was investigated in vitro using LNCaP cells.</br><br>Results:Phosphorylation of AR at serine 515 (pAR(S515)) and PSA at diagnosis were independently associated with decreased time to biochemical relapse. Cdk1 and pCdk1(161), but not ERK1/2, correlated with pAR(S515). High expression of pAR(S515) in patients with a PSA at diagnosis of ≤20 ng ml(-1) was associated with shorter time to biochemical relapse (P=0.019). This translated into a reduction in disease-specific survival (10-year survival, 38.1% vs 100%, P<0.001). In vitro studies demonstrated that treatment with Roscovitine (a Cdk inhibitor) caused a reduction in pCdk1(161) expression, pAR(S515)expression and cellular proliferation.</br> <br>Conclusion: In prostate cancer patients with PSA at diagnosis of ≤20 ng ml(-1), phosphorylation of AR at serine 515 by Cdk1 may be an independent prognostic marker.</br&gt

Enabling nursing students to focus on the Ottawa Charter and the nurses role in tackling inequalities in health through international exchange

Student nurses in a transatlantic exchange program explored the role of registered nurses in five countries’ public health systems. The Ottawa Charter provided a framework for students to examine the nurse’s responsibilities in public health. Students took practice placements in geographically rural areas on another continent and explored inequalities in health care. If nurses are to understand their role in the health care system then they must be taught the scope of their practice including their role in health promotion, public health practice and community development. For this project nursing instructors developed an assignment relevant to the aims and suitable for students in all five nursing programs. Only three of 48 students offered an assignment which focused on building healthy public policy. Nurse educators need to explore this further to ensure nurses of the future are aware of their role and responsibilities in this area and have skills to work effectively to influence and build healthy policy. The international student exchange supported the students’ developing understanding of the breadth of initiatives around the globe where nurses are actively engaged in addressing inequalities of health. Findings from an analysis of their assignments are presented in this evaluative report

Copper deficiency and effects of copper supplementation in a herd of red deer (Cervus elaphus)

Copper (Cu) deficiency was diagnosed in a Norwegian red deer (Cervus elaphus) herd subsequent to deaths due to emaciation in late autumn 1999. The animals had free access to salt licks containing 3000 mg Cu/kg. An evaluation of the herd revealed poor calf growth rate, low weights of adult hinds, dull and light-coloured hair coats and cases of diarrhoea. The herd was subsequently monitored throughout a three-year period of Cu-supplementation. The monitoring regimen included clinical observation, copper serum examination, weighing, faecal parasitological examination, and reproduction control by ultrasound. During the period January 2000 to May 2001, the animals were treated with Cu oxid capsules (1 g CuO/10 kg liveweight) at 2–4 months intervals, with the exception of March to September 2000. The animals were fed continuously with Cu-enriched concentrates containing 300 mg Cu/kg, at a rate of 1/2 kg per head and day, from May 2001 to January 2003. Following both copper supplementation regimens adequate serum Cu concentrations were measured, and markedly improved body weights, coat quality and reproductive results were observed, except for the period from March to September 2000 when no treatment was given. The results showed that in a deer herd, with a diet low in Cu, supplementation with CuO capsules had to be given at intervals of a few months to maintain adequate serum Cu levels. Free access to Cu-containing salt licks did not meet the animals' Cu demand. Good and stable results were achieved by the daily feeding of Cu-enriched concentrates

Geomorphological evolution of a debris‐covered glacier surface

There exists a need to advance our understanding of debris‐covered glacier surfaces over relatively short timescales due to rapid, climatically induced areal expansion of debris cover at the global scale, and the impact debris has on mass balance. We applied unpiloted aerial vehicle structure‐from‐motion (UAV‐SfM) and digital elevation model (DEM) differencing with debris thickness and debris stability modelling to unravel the evolution of a 0.15 km2 region of the debris‐covered Miage Glacier, Italy, between June 2015 and July 2018. DEM differencing revealed widespread surface lowering (mean 4.1 ± 1.0 m a‐1; maximum 13.3 m a‐1). We combined elevation change data with local meteorological data and a sub‐debris melt model, and used these relationships to produce high resolution, spatially distributed maps of debris thickness. These maps were differenced to explore patterns and mechanisms of debris redistribution. Median debris thicknesses ranged from 0.12 to 0.17 m and were spatially variable. We observed localized debris thinning across ice cliff faces, except those which were decaying, where debris thickened. We observed pervasive debris thinning across larger, backwasting slopes, including those bordered by supraglacial streams, as well as ingestion of debris by a newly exposed englacial conduit. Debris stability mapping showed that 18.2–26.4% of the survey area was theoretically subject to debris remobilization. By linking changes in stability to changes in debris thickness, we observed that slopes that remain stable, stabilize, or remain unstable between periods almost exclusively show net debris thickening (mean 0.07 m a‐1) whilst those which become newly unstable exhibit both debris thinning and thickening. We observe a systematic downslope increase in the rate at which debris cover thickens which can be described as a function of the topographic position index and slope gradient. Our data provide quantifiable insights into mechanisms of debris remobilization on glacier surfaces over sub‐decadal timescales, and open avenues for future research to explore glacier‐scale spatiotemporal patterns of debris remobilization

Gravitational Waves From Known Pulsars: Results From The Initial Detector Era

We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom

A Small Molecule Inhibitor of PDK1/PLC gamma 1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion

Strong evidence suggests that phospholipase Cγ1 (PLCγ1) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLCγ1 activation which involves formation of a protein complex with 3-phosphoinositide-dependent protein kinase 1 (PDK1). In an effort to define novel strategies to inhibit PLCγ1-dependent signals we tested here whether a newly identified and highly specific PDK1 inhibitor, 2-O-benzyl-myo-inositol 1,3,4,5,6-pentakisphosphate (2-O-Bn-InsP5), could affect PDK1/PLCγ1 interaction and impair PLCγ1-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP5 interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLCγ1 complex. 2-O-Bn-InsP5 is able to inhibit the epidermal growth factor-induced PLCγ1 phosphorylation and activity, ultimately resulting in impaired cancer cell migration and invasion. Importantly, we report that 2-O-Bn-InsP5 inhibits cancer cell dissemination in zebrafish xenotransplants. This work demonstrates that the PDK1/PLCγ1 complex is a potential therapeutic target to prevent metastasis and it identifies 2-O-Bn-InsP5 as a leading compound for development of anti-metastatic drugs