Overexpression of endoplasmic reticulum protein 29 regulates mesenchymal-epithelial transition and suppresses xenograft tumor growth of invasive breast cancer cells

Endoplasmic reticulum protein 29 (ERp29) is a novel endoplasmic reticulum ( ER) secretion factor that facilitates the transport of secretory proteins in the early secretory pathway. Recently, it was found to be overexpressed in several cancers; however, little is known regarding its function in breast cancer progression. In this study, we show that the expression of ERp29 was reduced with tumor progression in clinical specimens of breast cancer, and that overexpression of ERp29 resulted in G(0)/G(1) arrest and inhibited cell proliferation in MDA-MB-231 cells. Importantly, overexpression of ERp29 in MDA-MB-231 cells led to a phenotypic change and mesenchymal-epithelial transition (MET) characterized by cytoskeletal reorganization with loss of stress fibers, reduction of fibronectin (FN), reactivation of epithelial cell marker E-cadherin and loss of mesenchymal cell marker vimentin. Knockdown of ERp29 by shRNA in MCF-7 cells reduced E-cadherin, but increased vimentin expression. Furthermore, ERp29 overexpression in MDA-MB-231 and SKBr3 cells decreased cell migration/invasion and reduced cell transformation, whereas silencing of ERp29 in MCF-7 cells enhanced cell aggressive behavior. Significantly, expression of ERp29 in MDA-MB-231 cells suppressed tumor formation in nude mice by repressing the cell proliferative index (Ki-67 positivity). Transcriptional profiling analysis showed that ERp29 acts as a central regulator by upregulating a group of genes with tumor suppressive function, for example, E-cadherin (CDH1), cyclin-dependent kinase inhibitor (CDKN2B) and spleen tyrosine kinase (SYK), and by downregulating a group of genes that regulate cell proliferation (eg, FN, epidermal growth factor receptor ( EGFR) and plasminogen activator receptor ( uPAR)). It is noteworthy that ERp29 significantly attenuated the overall ERK cascade, whereas the ratio of p-ERK1 to p-ERK2 was highly increased. Taken together, our results showed that ERp29 is a novel regulator leading to cell growth arrest and cell transition from a proliferative to a quiescent state, and reprogramming molecular portraits to suppress the tumor growth of MDA-MB-231 breast cancer cells. Laboratory Investigation (2009) 89, 1229-1242; doi: 10.1038/labinvest.2009.87; published online 21 September 2009

Potential roles for the PIM1 kinase in human cancer - A molecular and therapeutic appraisal

In vitro experiments have shown the PIM1 kinase to have diverse biological roles in cell survival, proliferation and differentiation. In humans, PIM1 is often expressed in both normal and transformed cells. The PIM1 kinase is a true oncogene implicated in early transformation and tumour progression in haematopoietic malignancies and prostate carcinomas. it is associated with aggressive subgroups of lymphoma, is a marker of poor prognosis in prostate carcinomas and has been suggested to have a role in hormone insensitivity of prostate malignancies. PIM1 has a possible role in other carcinomas with 6p21 genomic alterations. On one hand, PIM1 (due to its role in malignancy) appears to be a promising target for drug development programmes but, on the other hand, the complexity of its molecular structure has posed challenges in the development of PIM1 inhibitors. In this review we discuss PIM1 expression in human tissues (including some new data from our laboratory), its role in human malignancies, as well as the possibilities and challenges in the development of target therapy for PIM1. (c) 2008 Elsevier Ltd. All rights reserved.

T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

T-box 2 (TBX2) is a transcription factor involved in mammary development and is known to be overexpressed in a subset of aggressive breast cancers. TBX2 has previously been shown to repress growth control genes such as p14(ARF) and p21(WAF1/cip1). In this study we show that TBX2 drives proliferation in breast cancer cells and this is abrogated after TBX2 small interfering RNA (siRNA) knockdown or after the expression of a dominant-negative TBX2 protein. Using microarray analysis we identified a large cohort of novel TBX2-repressed target genes including the breast tumour suppressor NDRG1 (N-myc downregulated gene 1). We show that TBX2 targets NDRG1 through a previously undescribed mechanism involving the recruitment of early growth response 1 (EGR1). We show EGR1 is required for the ability of TBX2 to repress NDRG1 and drive cell proliferation. We show that TBX2 interacts with EGR1 and that TBX2 requires EGR1 to target the NDRG1 proximal promoter. Abrogation of either TBX2 or EGR1 expression is accompanied by the upregulation of cell senescence and apoptotic markers. NDRG1 can recapitulate these effects when transfected into TBX2-expressing cells. Together, these data identify a novel mechanism for TBX2-driven oncogenesis and highlight the importance of NDRG1 as a growth control gene in breast tissue. Oncogene (2010) 29, 3252-3262; doi: 10.1038/onc.2010.84; published online 29 March 2010

The effect of priming on perceptions of dog breed traits

This study examined whether priming cues embedded in mediastyle presentations shaped people's perceptions of specific dog breeds, and in particular, the German shepherd dog (GSD). Two hundred and four adult females were exposed to one of two types of media-style presentation (stories or pictures). Half of the participants in each condition were exposed to versions designed to portray the GSD in a positive light; the remainder to stimuli developed to present the same breed in a negative light. Participants subsequently rated six individual breeds of dog, including the target breed, on a number of traits (e.g., “friendliness,“ “aggression“). Analysis revealed a significant effect of priming on people's perceptions of the GSD. Participants exposed to the negative stimuli perceived this breed as significantly less approachable, and more dangerous and aggressive, than those exposed to the positive stimuli. Priming did not influence the participants' perceptions of other breeds, even those often regarded in a negative light, although there was some evidence of breed-related category-based stereotyping. Overall, results suggest that people's perceptions of dog breeds can be influenced by verbal and visual representations. The results have implications for how dogs are portrayed in the media and other publically available sources of information.

Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis

Papillon-Lefevre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients(1,2). Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset(3-6). The PLS locus has been mapped to chromosome 11q14-q21 (refs 7-9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.

Trauma typology as a risk factor for aggression and self-harm in a complex PTSD population: The mediating role of alterations in self-perception

This study examined the role of prolonged, repeated traumatic experiences such as childhood and sectarian trauma in the development of posttraumatic aggression and self-harm. Forty-four adult participants attending therapy for complex trauma in Northern Ireland were obtained via convenience sampling. When social desirability was controlled, childhood emotional and physical neglect were significant correlates of posttraumatic hostility and history of self-harm. These relationships were mediated by alterations in self-perception (e.g., shame, guilt). Severity of sectarian-related experiences was not related to self-destructive behaviors. Moreover, none of the trauma factors were related to overt aggressive behavior. The findings have implications for understanding risk factors for posttraumatic aggression and self-harm, as well as their treatment. © 2013 Copyright Taylor & Francis Group, LLC.

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs. Oncogene (2012) 31, 3667-3678; doi:10.1038/onc.2011.531; published online 28 November 2011

The effect of increasing dietary fibre and the provision of straw racks on the welfare of sows housed in small static groups

This study assessed the effects of increasing dietary fibre levels in concentrate rations and providing access to straw in racks on the welfare of pregnant sows housed in small static groups. In a 2 x 2 factorial design experiment, 128 Large White x Landrace pregnant sows were offered one of two diets: (i) High fibre diet with 9% crude fibre, or (ii) Control diet with 4.5% CF, and one of two levels of access to a foraging substrate: (i) access to straw in racks or (ii) no straw. The study was replicated eight times using groups of four sows, and treatment periods lasted four weeks. Sows were housed in pens with voluntary cubicles and a slatted exercise area and were offered a wet diet twice a day. Back-fat levels were measured before sows were mixed into groups at 28 days post partum, and four weeks later. Aggressive interactions were recorded on the day of mixing, and injury scores were recorded one week post mixing. Scan sampling was used to collect data on general activity, posture and location of the sows, and on sham-chewing and bar-biting behaviours across the treatment period. In addition, detailed focal observations were carried out on all sows across the treatment period. Straw usage was also recorded. There were no treatment effects on changes in back-fat levels over the treatment period. Treatments had no effect on post-mixing aggression or on injury scores. However, focal observations showed that sows with access to straw were involved in fewer bouts of head-thrusting over the treatment period. Control diet sows spent more time inactive than sows on the high fibre diet, however high fibre diet sows spent more time lying with eyes closed than sows on the control diet. Sows on the high fibre diet with access to straw showed less sham-chewing and bar-biting behaviour than sows in other treatments. These results show that although a diet containing 9% crude fibre promoted resting behaviour, it was necessary to combine it with access to straw to reduce stereotypic behaviour of sows in small static groups.

Behaviour of Brent geese Branta bernicla hrota and wigeon Anas penelope feeding on intertidal Zostera spp

Mixed flocks of pale-bellied Brent geese (Branta bernicla hrota) and wigeon (Anas penelope L.) feeding on intertidal Zostera spp were studied during October 1993 with respect to tidal position, feeding method and duration, and competitive: interactions within and between species. Owing to many disturbance incidents affecting the use of the site by wildfowl, only complete data on flow tides were presented. Brent geese fed over a greater period of the tidal cycle than wigeon. Differences in feeding methods indicated that Brent geese exploited the rhizomes, which are energetically more profitable than the shoot on which wigeon fed. Aggressive interactions were recorded within species but there were no records of aggression between species. More subtle competition for space, however, may have occurred during feeding. Brent geese could reach Zostera spp For a short period after increasing depth of water prevented access by wigeon. However, individual wigeon were observed foraging near feeding Brent geese, picking up the scraps oi material discarded by the latter, and small numbers of wigeon may benefit from the presence of the geese. These benefits for some individual wigeon are not considered to compensate for the disadvantages to the latter species population as a whole in feeding on poorer-quality food for a shorter period of the tidal cycle. This disadvantage is likely to have contributed to the decline in the wigeon population on Strangford Lough, Co. Down, while numbers of Brent geese have been maintained at a high level.

Accuracy of LightCycler® SeptiFast for the detection and identification of pathogens in the blood of patients with suspected sepsis: a systematic review protocol

Background: There is growing interest in the potential utility of molecular diagnostics in improving the detection of life-threatening infection (sepsis). LightCycler® SeptiFast is a multipathogen probebased real-time PCR system targeting DNA sequences of bacteria and fungi present in blood samples within a few hours. We report here the protocol of the first systematic review of published clinical diagnostic accuracy studies of this technology when compared with blood culture in the setting of suspected sepsis. Methods/design: Data sources: the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment Database (HTA), the NHS Economic Evaluation Database (NHSEED), The Cochrane Library, MEDLINE, EMBASE, ISI Web of Science, BIOSIS Previews, MEDION and the Aggressive Research Intelligence Facility Database (ARIF). Study selection: diagnostic accuracy studies that compare the real-time PCR technology with standard culture results performed on a patient's blood sample during the management of sepsis. Data extraction: three reviewers, working independently, will determine the level of evidence, methodological quality and a standard data set relating to demographics and diagnostic accuracy metrics for each study. Statistical analysis/data synthesis: heterogeneity of studies will be investigated using a coupled forest plot of sensitivity and specificity and a scatter plot in Receiver Operator Characteristic (ROC) space. Bivariate model method will be used to estimate summary sensitivity and specificity. The authors will investigate reporting biases using funnel plots based on effective sample size and regression tests of asymmetry. Subgroup analyses are planned for adults, children and infection setting (hospital vs community) if sufficient data are uncovered. Dissemination: Recommendations will be made to the Department of Health (as part of an open-access HTA report) as to whether the real-time PCR technology has sufficient clinical diagnostic accuracy potential to move forward to efficacy testing during the provision of routine clinical care.

Intravenous tolerance effectively overcomes enhanced pro-inflammatory responses and EAE severity in the absence of IL-12 receptor signaling

Intravenous (i.v.) administration of autoantigen effectively induces Ag-specific tolerance against experimental autoimmune encephalomyelitis (EAE). We and others have shown enhanced EAE severity in mice lacking IL-12 or its receptor, strongly suggesting an immunoregulatory effect of IL-12 signaling. To examine the role of IL-12 responsiveness in autoantigen-induced tolerance in EAE, we administered autoantigen i.v. in two distinct treatment regimes to wildtype and IL-12Rβ2(-/-) mice, immunized to develop EAE. Administration at the induction phase suppressed EAE in wildtype and IL-12Rβ2(-/-) mice however the effect was somewhat less potent in the absence of IL-12Rβ2. Expression of pro-inflammatory cytokines such as IFN-γ, IL-17 and IL-2, was inhibited in wild-type tolerized mice but less so in IL-12Rβ2(-/-) mice. I.v. antigen was also effective in suppressing disease in both genotypes when given during the clinical phase of disease with similar CNS inflammation, demyelination and peripheral inflammatory cytokine profiles observed in both genotypes. There was however a mild impact of a lack of IL-12 signaling on Treg induction during tolerance induction compared to WT mice in this treatment regime. These findings show that the enhanced severity of EAE that occurs in the absence of IL-12 signaling can be effectively overcome by i.v. autoantigen, indicating that this therapeutic effect is not primarily mediated by IL-12 and that i.v. tolerance could be a powerful approach in suppressing severe and aggressive MS.

Protective qualities of surface treatments for concrete

Surface treatments are used as part of either a maintenance programme or repair work. In both cases, they provide additional protection to the concrete by either arresting or reducing the penetration of aggressive substances from the environment, Numerous materials are available for this purpose and their inherent generic properties differ considerably. Quite often this poses difficulties to practising engineers when selecting a surface treatment for a specific situation, In this review an attempt is made to explain the protective aspects of various surface treatments so that their selection can be made easier, The basic aspects of surface treatments are discussed: function, classification and performance requirements.

Effect of increasing dietary folate on red-cell folate: Implications for prevention of neural tube defects

Background Recommendations by the UK Department of Health suggest that protection from neural tube defects (NTD) can be achieved through intakes of an extra 400 mu g daily of folate/folic acid as natural food, foods fortified with folic acid, or supplements. The assumption is that all three routes of intervention would have equal effects on folate status.

Methods We assessed the effectiveness of these suggested routes of intervention in optimising folate status. 62 women were recruited from the University staff and students to take part in a 3-month intervention study. Participants were randomly assigned to one of the following five groups: folic acid supplement (400 mu g/day; I); folic-acid-fortified foods (an additional 400 mu g/day; II); dietary folate (an additional 400 mu g/day; III); dietary advice (IV), and control (V). Responses to intervention were assessed as changes in red-cell folate between preintervention and postintervention values.

Findings 41 women completed the intervention study. Red-cell folate concentrations increased significantly over the 3 months in the groups taking folic acid supplements (group I) or food fortified with folic acid (group II) only (p<0.01 for both groups). By contrast, although aggressive intervention with dietary folate (group III) or dietary advice (group IV) significantly increased intake of food folate (p<0.001 and p<0.05, respectively), there was no significant change in folate status.

Interpretation We have shown that compared with supplements and fortified food, consumption of extra folate as natural food folate is relatively ineffective at increasing folate status. We believe that advice to women to consume folate-rich foods as a means to optimise folate status is misleading.

Right to War in the Islamic Tradition:Jihad and its Compatibility with Modern International Law (will be submitted to the publisher in April 2014)

In the last century, Islam drew the world’s attention though such phenomena as the Islamic revolution in Iran, the fierce Muslim resistance against the Soviet invasion of Afghanistan, and the assassination of Egypt’s President Sadat by a radical Islamic group. But it was when Osama Bin Laden and his organization Al Qaeda were established to have been behind the 11 September attacks in the US, the age-old images of Islam, the fanatical and belligerent religion threatening what the Western world stands for, were revitalized. The impact of 9/11 attacks was so great that even balanced portrayals of Islam were eclipsed by stereotypical images of a fundamental, anti-Western and warmongering religion that bore the hallmarks of medieval prejudices and rhetoric. The popular image tailored for the Western audience reflected Islam as monolithic, intrinsically aggressive, and determined to engage in religious wars against the interests and values of the Western civilisation.
This book intends to help reduce, at least to a reasonable degree, the impact of sweeping, and at times tendentious, generalisations about Islamic laws of warfare. The main purpose of this book is to place the legal, cultural and historical practices of Islamic wars in their broader socio-political contexts, thereby establishing that there has been no undisputed understanding of what defensive or aggressive warfare entails in Islam, whether in doctrine or in practice.

Management of Barrett's esophagus in the UK: Overtreated and underbiopsied but improved by the introduction of a national randomized trial

OBJECTIVES: To assess the variation in practice of Barrett's esophagus (BE) management in comparison with accepted international guidelines before and after the introduction of a large BE randomized controlled trial (RCT) with protocols including those of tissue sampling.
DESIGN: A validated anonymized questionnaire was sent to 401 senior attending gastroenterologists asking for details of their current management of BE, especially histological sampling. Of the 228 respondents, 57 individuals (each from a different center) were in the first group to enter the ASPirin Esomeprazole (BE) Chemoprevention Trial (AspECT), and we assessed change in practice in these centers.
RESULTS: Ninety percent of specialists did not take adequate biopsies for histological diagnosis. Furthermore, 74% would consider aggressive surgical resection for prevalent cases of high-grade dysplasia in BE as their first-line choice despite the associated perioperative mortality. Ninety-two percent claim their lack of adherence to guidelines is because there is a need for stronger evidence for surveillance and medical interventions. Effect of the AspECT trial: Those clinicians in centers where the AspECT trial has started have improved adherence to ACG guidelines compared with their previous practice (P < 0.05). BE patients now get 18.8% more biopsies compared with previous practice, and 37.7% if the patient is entered into the AspECT trial (P < 0.01).
CONCLUSIONS: This large study indicates both wide variation in practice and poor compliance with guidelines. Because optimal histology is arguably the most important facet of BE management, the improvement in practice in centers taking part in the AspECT trial indicates an additional value of large international RCTs.