p120 catenin induces opposing effects on tumor cell growth depending on E-cadherin expression

p120 catenin regulates the activity of the Rho family guanosine triphosphatases (including RhoA and Rac1) in an adhesion-dependent manner. Through this action, p120 promotes a sessile cellular phenotype when associated with epithelial cadherin (E-cadherin) or a motile phenotype when associated with mesenchymal cadherins. In this study, we show that p120 also exerts significant and diametrically opposing effects on tumor cell growth depending on E-cadherin expression. Endogenous p120 acts to stabilize E-cadherin complexes and to actively promote the tumor-suppressive function of E-cadherin, potently inhibiting Ras activation. Upon E-cadherin loss during tumor progression, the negative regulation of Ras is relieved; under these conditions, endogenous p120 promotes transformed cell growth both in vitro and in vivo by activating a Rac1–mitogen-activated protein kinase signaling pathway normally activated by the adhesion of cells to the extracellular matrix. These data indicate that both E-cadherin and p120 are important regulators of tumor cell growth and imply roles for both proteins in chemoresistance and targeted therapeutics

Facilitators and barriers to help-seeking for breast and cervical cancer symptoms: a qualitative study with an ethnically diverse sample in London

Objective Earlier diagnosis of cancer has become a policy priority. There is evidence that minority ethnic groups are more likely to delay help‐seeking for cancer symptoms, but few studies have explored reasons for delay in these groups. The present study explored facilitators and barriers to help‐seeking for breast and cervical cancer in an ethnically diverse sample of women. Methods Semi‐structured interviews were carried out with 54 healthy women from a range of ethnic backgrounds; Indian, Pakistani, Bangladeshi, Caribbean, African, Black British, Black other, White British and White other. Framework analysis was used to identify themes. Results Appraising a symptom as possibly due to cancer was an important facilitator of help‐seeking, although for some the prospect of a cancer diagnosis was a deterrent. Women believed that earlier diagnosis improved the chance of survival, and this facilitated prompt help‐seeking. A sympathetic GP facilitated help‐seeking, and an unsympathetic GP was a deterrent. Some ethnic minority women described the use of alternative medicine and prayer as a first‐line strategy that might delay help‐seeking. Language barriers, racism and a tendency to ‘soldier on’ were also mentioned by these women. Conclusions Models of delay in presentation for early cancer symptoms are likely to transfer across different ethnic groups. Encouraging open discussion about cancer among minority communities could help raise awareness about the importance of early detection and promote help‐seeking as a priority response to a possible cancer symptom

Pathway Signature and Cellular Differentiation in Clear Cell Renal Cell Carcinoma

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. The purpose of this study is to define a biological pathway signature and a cellular differentiation program in ccRCC. METHODOLOGY: We performed gene expression profiling of early-stage ccRCC and patient-matched normal renal tissue using Affymetrix HG-U133a and HG-U133b GeneChips combined with a comprehensive bioinformatic analyses, including pathway analysis. The results were validated by real time PCR and IHC on two independent sample sets. Cellular differentiation experiments were performed on ccRCC cell lines and their matched normal renal epithelial cells, in differentiation media, to determine their mesenchymal differentiation potential. PRINCIPAL FINDINGS: We identified a unique pathway signature with three major biological alterations-loss of normal renal function, down-regulated metabolism, and immune activation-which revealed an adipogenic gene expression signature linked to the hallmark lipid-laden clear cell morphology of ccRCC. Culturing normal renal and ccRCC cells in differentiation media showed that only ccRCC cells were induced to undergo adipogenic and, surprisingly, osteogenic differentiation. A gene expression signature consistent with epithelial mesenchymal transition (EMT) was identified for ccRCC. We revealed significant down-regulation of four developmental transcription factors (GATA3, TFCP2L1, TFAP2B, DMRT2) that are important for normal renal development. CONCLUSIONS: ccRCC is characterized by a lack of epithelial differentiation, mesenchymal/adipogenic transdifferentiation, and pluripotent mesenchymal stem cell-like differentiation capacity in vitro. We suggest that down-regulation of developmental transcription factors may mediate the aberrant differentiation in ccRCC. We propose a model in which normal renal epithelial cells undergo dedifferentiation, EMT, and adipogenic transdifferentiation, resulting in ccRCC. Because ccRCC cells grown in adipogenic media regain the characteristic ccRCC phenotype, we have identified a new in vitro ccRCC cell model more resembling ccRCC tumor morphology

Ethnicity-specific factors influencing childhood immunisation decisions among Black and Asian Minority Ethnic groups in the UK: a systematic review of qualitative research

Background: Uptake of some childhood immunisations in the UK is lower among those from some Black and Asian Minority Ethnic (BAME) backgrounds. This systematic review of qualitative research sought to understand the factors that are associated with ethnicity that influence the immunisation decisions of parents from BAME backgrounds living in the UK. Methods: Databases were searched on 2 December 2014 for studies published at any time using the terms ‘UK’ and ‘vaccination’ and ‘qualitative methods’ (and variations of these). Included articles comprised participants who were parents from BAME backgrounds. Thematic synthesis methods were used to develop descriptive and higher order themes. Themes specific to ethnicity and associated factors are reported. Results: Eight papers were included in the review. Most participants were from Black (n=62) or Asian (n=38) backgrounds. Two ethnicity-related factors affected immunisation decisions. First, factors that are related to ethnicity itself (namely religion, upbringing and migration, and language) affected parents' perceived importance of immunisations, whether immunisations were permitted or culturally acceptable and their understanding of immunisation/the immunisation schedule. Second, perceived biological differences affected decision-making and demand for information. Conclusions: Factors related to ethnicity must be considered when seeking to understand immunisation decisions among parents from BAME backgrounds. Where appropriate and feasible, vaccination information should be targeted to address beliefs about ethnic differences held by some individuals from some BAME backgrounds

Cervical screening attendance and cervical cancer risk among women who have sex with women

Objectives: To describe cervical cancer screening participation among women who have sex exclusively with women (WSEW) and women who have sex with women and men (WSWM) compared with women who have sex exclusively with men (WSEM), and women who have never had sex and compare this with bowel (colorectal) and breast screening participation. To explore whether there is evidence of differential stage 3 cervical intraepithelial neoplasia (CIN3) or cervical cancer risk. Methods: We describe cervical, bowel and breast cancer screening uptake in age groups eligible for the national screening programmes, prevalent CIN3 and cervical cancer at baseline, and incident CIN3 and cervical cancer at five years follow-up, among 218,674 women in UK Biobank, a cohort of healthy volunteers from the UK. Results: Compared with WSEM, in adjusted analysis [odds ratio (95% confidence interval)], WSEW 0.10 (0.08–0.13), WSWM 0.73 (0.58–0.91), and women who have never had sex 0.02 (0.01–0.02) were less likely to report ever having attended cervical screening. There were no differences when considering bowel cancer screening uptake (p = 0.61). For breast cancer screening, attendance was lower among WSWM 0.79 (0.68 to 0.91) and women who have never had sex 0.47 (0.29–0.58), compared with WSEM. There were incident and prevalent cases of both CIN3 and cervical cancer among WSEW and WSWM. Compared with WSEM with a single male partner, among WSEW there was a twofold increase in CIN3 1.91 (1.01 to 3.59); among WSWM with only one male partner, this was 2.25 (1.19 to 4.24). Conclusions: These findings highlight the importance of improving uptake of cervical screening among all women who have sex with women and breast screening among WSWM and women who have never had sex

Novel patient-derived xenograft mouse model for pancreatic acinar cell carcinoma demonstrates single agent activity of oxaliplatin

Additional file 4: Figure S3. Integrated genomic viewer (IGV) of BRCA2 gene. IGV displays genomic data of the PA-018 PAAC PDTX model. Chromosome 13 (Chr 13) is shown and 5bp deletions are found after position 32907365 (c.1755_1759del5), this region resides on exon 10 of BRCA2. The bottom of the image shows the nucleotides and amino acids that correspond to the reference sequence of the BRCA2 gene and protein

Whole-exome sequencing and clinical interpretation of FFPE tumor samples to guide precision cancer medicine

Translating whole exome sequencing (WES) for prospective clinical use may impact the care of cancer patients; however, multiple innovations are necessary for clinical implementation. These include: (1) rapid and robust WES from formalin-fixed paraffin embedded (FFPE) tumor tissue, (2) analytical output similar to data from frozen samples, and (3) clinical interpretation of WES data for prospective use. Here, we describe a prospective clinical WES platform for archival FFPE tumor samples. The platform employs computational methods for effective clinical analysis and interpretation of WES data. When applied retrospectively to 511 exomes, the interpretative framework revealed a “long tail” of somatic alterations in clinically important genes. Prospective application of this approach identified clinically relevant alterations in 15/16 patients. In one patient, previously undetected findings guided clinical trial enrollment leading to an objective clinical response. Overall, this methodology may inform the widespread implementation of precision cancer medicine

TIPIT: A randomised controlled trial of thyroxine in preterm infants under 28 weeks gestation: Magnetic Resonance Imaging and Magnetic Resonance Angiography protocol

<p>Abstract </p> <p>Background</p> <p>Infants born at extreme prematurity are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone described as hypothyroxinaemia, which is recognised to be a frequent phenomenon in these infants. Derangements of critical thyroid function during the sensitive window in prematurity when early development occurs, may have a range of long term effects for brain development. Further research in preterm infants using neuroimaging techniques will increase our understanding of the specificity of the effects of hypothyroxinaemia on the developing foetal brain. This is an explanatory double blinded randomised controlled trial which is aimed to assess the effect of thyroid hormone supplementation on brain size, key brain structures, extent of myelination, white matter integrity and vessel morphology, somatic growth and the hypothalamic-pituitary-adrenal axis.</p> <p>Methods</p> <p>The study is a multi-centred double blinded randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks corrected gestational age. The primary outcomes will be width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks corrected gestational age. The secondary outcomes will be thyroid hormone concentrations, the hypothalamic pituitary axis status and auxological data between birth and expected date of delivery; thyroid gland volume, brain size, volumes of key brain structures, extent of myelination and brain vessel morphology at expected date of delivery and markers of morbidity which include duration of mechanical ventilation and/or oxygen requirement and chronic lung disease.</p> <p><b>Trial registration</b></p> <p>Current Controlled Trials ISRCTN89493983</p

Perceived stress during the prenatal period: assessing measurement invariance of the Perceived Stress Scale (PSS‑10) across cultures and birth parity

Maternal prenatal stress places a substantial burden on mother’s mental health. Expectant mothers in low- and middle-income countries (LMICs) have thus far received less attention than mothers in high-income settings. This is particularly problematic, as a range of triggers, such as exposure to traumatic events (e.g. natural disasters, previous pregnancy losses) and adverse life circumstances (e.g. poverty, community violence), put mothers at increased risk of experiencing prenatal stress. The ten-item Perceived Stress Scale (PSS-10) is a widely recognised index of subjective experience of stress that is increasingly used in LMICs. However, evidence for its measurement equivalence across settings is lacking. This study aims to assess measurement invariance of the PSS-10 across eight LMICs and across birth parity. This research was carried out as part of the Evidence for Better Lives Study (EBLS, vrc.crim.cam.ac.uk/vrcresearch/EBLS). The PSS-10 was administered to N = 1,208 expectant mothers from Ghana, Jamaica, Pakistan, the Philippines, Romania, South Africa, Sri Lanka and Vietnam during the third trimester of pregnancy. Confirmatory factor analysis suggested a good model fit of a two-factor model across all sites, with items on experiences of stress loading onto a negative factor and items on perceived coping onto a positive factor. Configural and metric, but not full or partial scalar invariance, were established across all sites. Configural, metric and full scalar invariance could be established across birth parity. On average, first-time mothers reported less stress than mothers who already had children. Our findings indicate that the PSS-10 holds utility in assessing stress across a broad range of culturally diverse settings; however, caution should be taken when comparing mean stress levels across sites