290 results on '"Walker, Rosemary A."'
Search Results
252. Immunohistochemical detection of steroid receptors in breast cancer: a working protocol.
- Author
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Leake, Robin, Barnes, Diana, Pinder, Sarah, Ellis, Ian, Anderson, Liz, Anderson,, Tom, Adamson, Ruth, Rhodes, Tony, Miller, Keith, and Walker, Rosemary
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- 2000
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253. The Family-Gram.
- Author
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Walker, Rosemary
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PARENT-teacher relationships ,COMMUNICATION in education ,RELIGIOUS life of children ,RELIGIOUS education ,COMMUNICATION ,INFORMATION theory - Abstract
The article discusses the significance of establishing an open communication between catechists and the parents of their students in religious education. Constant communication with parents enable catechists to contact them in case of inclement weather or any other reason that might call for the session to be canceled. It is also an essential way of keeping them informed of the activities, behavior and progress of their children.
- Published
- 2008
254. The Dotted Line
- Author
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Walker, Rosemary
- Abstract
No Abstract.
- Published
- 2000
255. IDENTIFICATION OF MEDICATION NON-ADHERENCE FACTORS IN ADOLESCENT TRANSPLANT PATIENTS: THE PATIENT'S VIEWPOINT.
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Bullington, Pamela, Pawola, Lawrence, Walker, Rosemary, Valenta, Annette, Briars, Leslie, and John, Eunice
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- 2006
256. DRIVING ON INSULIN -- WHAT IS DIABETES UK'S POLICY?
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Rodgers, Jill and Walker, Rosemary
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- 2002
257. Conference has given boost to collaborative efforts.
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Walker, Rosemary
- Published
- 2000
258. Estrogen Alters the Splicing of Type 1 Corticotropin-Releasing Hormone Receptor in Breast Cancer Cells
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Lal, Suchita, Allan, Anna, Markovic, Danijela, Walker, Rosemary, Macartney, James, Europe-Finner, Nick, Tyson-Capper, Alison, and Grammatopoulos, Dimitris K.
- Abstract
Altered splicing of a stress hormone receptor correlates with estrogen receptor–positive breast cancer.
- Published
- 2013
- Full Text
- View/download PDF
259. Credibility and recognition through accreditation.
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Walker, Rosemary
- Published
- 1997
260. A call for unity among diabetes nurses.
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Walker, Rosemary
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- 1997
261. Identification of medication non-adherence factors in adolescent transplant patients: The patient's viewpoint.
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Bullington, Pamela, Pawola, Larry, Walker, Rosemary, Valenta, Annette, Briars, Leslie, and John, Eunice
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MEDICAL research , *KIDNEY transplantation , *DRUG prescribing , *TEENAGERS , *PATIENT compliance - Abstract
Studies report a clear association between medication non-adherence and an unfavorable transplant outcome. The adolescent population, in particular, has difficulty adhering to post-transplant medication regimens. The purpose of this study is to identify, categorize and understand the opinions of adolescent transplant patients regarding why they may not take their medications as prescribed. From January to August 2005, nine adolescent kidney transplant patients at an urban medical center were surveyed and asked to rank-order 33 statements regarding their opinions on why adolescents may not take their medications as prescribed. Q-methodology, a powerful tool in subjective study, was used to identify and categorize the viewpoints of adolescents on this subject. Three factors emerged and were labeled to reflect their distinct viewpoints: (1) Medication Issues (e.g. taste, size, frequency, schedule), (2) Troubled Adolescent (e.g. poor home life, depression, overwhelming situation), and (3) Deliberate Non-Adherer (e.g. attention-seeker, infallible attitude). By understanding these different viewpoints and the factors that contribute to them, it may be easier to identify which management approach to non-adherence works best in specific subgroups of patients. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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262. Religious coping, perceived discrimination, and posttraumatic growth in an international sample of forcibly displaced Muslims.
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Alsubaie, Mohammed K., Dolezal, Michael, Sheikh, Ifrah S., Rosencrans, Peter, Walker, Rosemary S., Zoellner, Lori A., and Bentley, Jacob
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ISLAM , *STATISTICS , *SURVEYS , *REFUGEES , *QUESTIONNAIRES , *PSYCHOLOGICAL adaptation , *PSYCHOLOGY & religion , *DATA analysis , *POSTTRAUMATIC growth - Abstract
Displaced persons are exposed to trauma and experience posttraumatic stress symptoms (PTS). Many displaced Muslims come from communities that rely on religious practices to cope with traumatic experiences, and religious coping has been identified as predictive of posttraumatic growth (PTG). Discrimination may contribute to increased PTS and promote in-group identification. In this study, we hypothesized that perceived discrimination would enhance the relationship between religious coping and PTG. Results indicated that religious coping predicted PTG, but the overall interaction with discrimination was not significant. However, probing moderating effects at discrete levels of discrimination yielded enhanced relationship between religious coping and PTG at its mean and above until reaching the highest values of discrimination. For individuals who experience moderate to high levels of discrimination, religious coping increased PTG. These findings highlight the essential role of religious coping in promoting growth for many Muslims exposed to forced migration and elevated levels of discrimination. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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263. Optimising the management of breast cancer in older patients
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Tahir, Mohammad, Walker, Rosemary, and Stotter, Anne
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618.97 - Abstract
This study aimed to optimise the treatment of early breast cancer in older patients. It tested the hypothesis that comprehensive geriatric assessment (CGA) could be used to predict two-year survival in older breast cancer patients. Based on the CGA scoring a treatment algorithm was devised that could help in recommending whether primary endocrine treatment (PET) or surgery plus endocrine treatment would be best indicated in individual patients. Methods: The study included women >70 years of age with early breast cancer, seen in a dedicated Leicester clinic between 01/2005 and 04/2007. All patients had comprehensive assessment including documentation of Satariano Index of Co-morbidities (SIC), Mini-Mental State Examination (MMSE), Geriatric Depression Score (GDS), Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL) and American Society of Anaesthesiologists (ASA) grade. Logistic regression analysis explored any association between these components and two-year survival. Components with positive association were formulated into a Breast Cancer in Elderly Treatment Algorithm (BCETA). Results: 123 patients were included, age range 70-94 (median-82). Twenty-two patients died within two years. Logistic regression analysis found MMSE, ADL, and ASA score to have an independent association with two-year survival. The scores of these components were formulated into a BCETA. Logistic regression revealed a statistically significant association between the BCETA score and two-year survival (p-value 0.00). Other results for the BCETA prognostic model were: sensitivity 89%, specificity 46%, positive predictive value 87%, negative predictive value 52%, odds ratio 7.1 (95% CI 2.5-20.2), and overall accuracy of 81%. C-statistic value (area under ROC curve) for the BCETA score was 0.70. Conclusion: Breast Cancer in Elderly Treatment Algorithm is a new approach to optimise the management of breast cancer in elderly patients. It can help in identifying high-risk patients with expected short-survival who may benefit from PET, if their cancer is hormone receptor positive. Patients with predicted longer life expectancy (lowrisk) may be recommended standard treatment. Further studies are needed to validate it in a larger population.
- Published
- 2014
264. Parathyroid hormone related protein and hypercalcaemia in breast cancer.
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Bundred, N.J., Ratcliffe, Wendy A., Walker, Rosemary A., Coley, S., Morrison, J.M., and Ratcliffe, J.G.
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PARATHYROID hormone , *HYPERCALCEMIA , *BREAST cancer - Abstract
Examines the role of parathyroid hormone related protein of hypercacaemia in women with breast cancer. Determination of the plasma concentrations and tumor expression of parathyroid hormone related protein; Measurement on the bone metastases and serum calcium concentration of women; Pattern of cancer relapse.
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- 1991
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265. Aberrations of DPPA3 (STELLA), EDR1 (PHC1), GDF3, and NANOG, putative stem cell-associated genes on chromosome 12, in breast carcinoma
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Ruangpratheep, Chetana, Shaw, Jacqueline., and Walker, Rosemary
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616.99449 - Abstract
Introduction: Chromosome 12p13 has been reported to show gain/amplification in some breast cancers. This region contains putative stem cell-associated genes: DPPA3, EDR1, GDF3, and NANOG, but these genes have not been investigated in breast previously. Hence, the aim of this thesis was to study their role in breast carcinomas. Materials and methods: The mRNA expression was evaluated in normal and malignant breast tissues using TaqMan® gene expression assays. Western blotting and immunohistochemistry were used for determination of protein expression. Copy number variations (CNVs) were assessed by TaqMan® copy number assays (CNAs) and Affymetrix® genome-wide human single nucleotide polymorphism (SNP) array 6.0. Results: Expression of DPPA3, EDR1, and NANOG was undetectable in normal breast tissue, but there was variable expression in breast carcinomas (BC) where expression of these genes tended to be higher in surrounding normal breast tissue. GDF3 was not expressed in BC. At the 95% confidence interval, higher expression of DPPA3 in BC was related to axillary lymph node metastasis; lower expression of DPPA3, EDR1, and NANOG correlated with high grade; and lower expression of NANOG was found in tumours of size > 2.0 cm. Both TaqMan® CNAs targeting each gene individually and SNP 6.0 genome wide array revealed complicated patterns of CNVs for these genes. The majority of BC had gain of DPPA3 but loss (deletion) of EDR1 and NANOG. However, there was no significant correlation between CNVs and either mRNA expression or protein expression. Conclusion: Variable aberrations in copy number and expression of DPPA3, EDR1, and NANOG genes in the chromosome 12p13 region are associated with aggressive characteristics of breast carcinomas.
- Published
- 2012
266. Molecular differences in sporadic breast cancer in young women (≤ 35-year old) : analysis of TGFBI, DDB2 and MCM5
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Touma, Dona, Shaw, Jacqueline, and Walker, Rosemary
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616.99 - Abstract
The aim of this study was to investigate mRNA and protein expression of three genes (Transforming Growth Factor Beta Induced (TGFBI), Damaged-Specific DNA Binding (DDB2) and Minichromosomal Maintenance-5 (MCM5)) in breast cancers. Q-RT-PCR (36 cancers, 8 normal/benign tissues and 9 organoid samples), western blotting (6 cell lines, 6 cancers and 4 normal/benign tissues) and immunohistochemistry (67 breast cancers) were performed, and for TGFBI functional assays (viability, apoptosis and invasion) were carried out in two cell lines (ZR-75-1 and MDA-MB-468) after transient transfection with recombinant TGFBI and vector controls. TGFBI showed reduced mRNA and protein expression in all cancer cell lines relative to HBL-100. The mRNA levels were also significantly lower in breast cancers compared to normal/benign tissues. Immunohistochemistry results showed that 46 / 67 breast cancers were negative or had <1% nuclear staining. There was a significant correlation between TGFBI mRNA levels and patient age; with lower levels expressed in younger women (p=0.04). Higher expression of DDB2 mRNA was observed in ER/PR positive (MCF-7, T47-D and ZR-75-1) compared to ER/PR negative (HBL-100, MDA-MB-231 and MDA-MB-468) cell lines. Higher DDB2 mRNA levels was significantly correlated with ER positive (p=0.04) and grade II (p=0.02) tumours; lower levels were associated with younger patient age (p=0.025). In addition, higher DDB2 protein expression was associated with ER (p=0.001) and PR (p=0.004). Elevated MCM5 mRNA and protein levels were observed in MCF-7 and MDA-MB-231. MCM5 immunoreactivity was significantly correlated with low grade (p=0.02) and ER/PR positive (ER p=0.04 and PR p=0.01) tumours. Transfection with TGFBI had no effect on viability, apoptosis and invasion of ZR-75-1 and MDA-MB-468 cells. In conclusion, the results fail to support the hypothesis of this study, namely that expression of TGFBI, DDB2 and MCM5 could contribute to the more aggressive features of sporadic breast cancers in younger women.
- Published
- 2011
267. Differences in Posttraumatic and Psychosocial Outcomes Among Refugees, Asylum Seekers, and Internally Displaced Persons.
- Author
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Dolezal, Michael L., Alsubaie, Mohammed K., Sheikh, Ifrah, Rosencrans, Peter, Walker, Rosemary S., Zoellner, Lori A., and Bentley, Jacob A.
- Abstract
Refugees, asylum seekers, and internally displaced persons differ in their experiences, potentially affecting posttraumatic outcomes such as posttraumatic stress disorder (PTSD) symptoms, posttraumatic cognitions, and posttraumatic growth (PTG), as well as psychosocial outcomes such as social connection, discrimination, and well-being. We explored these differences in a sample of N = 112 Muslim displaced persons. Results from planned contrasts indicated that refugees reported more PTSD symptoms (t[46.63] = 3.04, p = 0.004, d = 0.77) and more PTG (t[94] = 2.71, p = 0.008, d = 0.61) than asylum seekers. Higher posttraumatic cognitions predicted less social connections across displacement immigration category. The strength of this relationship was more pronounced for asylum seekers than refugees (b = -0.43, p = 0.014). Refugees may focus more on direct threats from others, resulting in more PTSD symptoms, whereas asylum seekers' uncertainty may pose a greater threat, exacerbating posttraumatic beliefs that drive social disconnection. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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268. The analysis of novel gene targets in breast cancer in women ≤35 years
- Author
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Lambe, Sinéad Marie, Walker, Rosemary, and Shaw, Jacqui
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616.99449 - Abstract
Breast cancer presenting in women aged ≤ 35 years has a more aggressive behaviour, and thus poorer prognosis, which is thought to be due to differences in the tumour biology of these tumours compared to those from older women. The aim of this study was to examine the expression of 9 novel gene targets (A-kinase anchor protein-1 (AKAP1), Acidic protein rich in leucines (APRIL), CCAAT enhancer binding protein alpha (C/EBPα), Damage-specific DNA binding protein 2 (DDB2), Granulin, Nuclear Receptor Coactivator 3 (NCOA3), Retinoic acid receptor Responder 3 (RARRES3), Retinoblastoma binding protein 4 (RBBP4), and Transforming Growth Factor beta Induced (TGFβI) identified previously by a cDNA microarray in breast cancers and female controls by RT-qPCR, western blotting, and immunohistochemistry. Six breast cell lines, 9 samples of organoids from reduction mammoplasty tissues, and 35 tumour tissues (20 cases >35 years, 15 cases ≤35 years in age) were analysed for the expression of the nine target genes using real time quantitative RT-PCR. Of the nine target genes investigated, five showed differences between normal and cancers ≤35, or between breast cancers ≤35 and those >35 years. NCOA3 and RARRES3 showed elevated levels of mRNA in breast cancers ≤35 years compared to those >35 years (p= 0.001 and p=0.002 respectively). Compared to the normal breast, TGFβI showed a reduced level of mRNA expression in both younger and older cases (p= 0.026 and p=0.001 respectively), while DDB2 and C-EBPα showed a reduced level of mRNA expression in younger group only (p=0.002 and p=0.001 respectively). NCOA3 protein expression examination using western blotting found high levels in the ER+ve cell lines MCF-7, ZR-75-1 and T47-D with a weak expression in ER−ve cell lines HBL-100 and MDA-MB-468. RARRES3 protein expression was found in 4 breast cell lines (HBL-100, MDA-MB-468, MCF-7, and ZR-75-1). IHC found expression of NCOA3 in younger and older tumours including ER+ve and ER−ve cases. This study identifies NCAO3 and RARRES3 as potential markers for breast cancers in younger women, but the data need confirmation in a larger series of cases.
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- 2009
269. Relationship between placebo response rate and clinical trial outcome in bipolar depression.
- Author
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Iovieno, Nadia, Nierenberg, Andrew A., Parkin, Susannah R., Hyung Kim, Daniel Ju, Walker, Rosemary S.W., Fava, Maurizio, and Papakostas, George I.
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DIAGNOSIS of bipolar disorder , *BIPOLAR disorder , *THERAPEUTICS , *MENTAL depression , *PLACEBOS , *CLINICAL trials , *HEALTH outcome assessment - Abstract
The aim of this work is to investigate the impact of placebo response rates on the relative risk of response to drug versus placebo in randomized, double-blind, placebo-controlled clinical trials of pharmacological therapy in Bipolar Depression (BPD). Medline/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of oral drugs used as monotherapy for the treatment of BPD. The search was limited to articles published between January 1980 and September 2015. Data extracted from 12 manuscripts and one poster with yet unpublished results, representing a total of 17 clinical trials were pooled (n = 6578). Pooled response rates for drug and placebo were 55.1% and 39.2%, corresponding to a risk ratio (RR) for responding to active treatment versus placebo of 1.29 (p < 0.001). Clinical response was defined as a 50% or greater reduction in depression scores, baseline to endpoint. A higher placebo response rate correlated with a significantly lower RR of responding to pharmacotherapy versus placebo (p = 0.002). The pooled drug and placebo response rates for studies with a placebo response rate ≤30% were 50.5% versus 26.6%, while corresponding values from studies with a placebo response rate >30 were 55.0% versus 41.6%. These results suggest that the relative efficacy of the active drug compared to placebo in clinical trials for BPD is highly heterogeneous across studies with different placebo response rates, with a worse performance in showing a superiority of the drug versus placebo for studies with placebo response rates >30%. It is important to maintain placebo response rates below this critical threshold, since this is one of the most challenging obstacles for new treatment development in BPD. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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270. A Double-Blind Placebo-Controlled Trial of Maca Root as Treatment for Antidepressant-Induced Sexual Dysfunction in Women.
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Dording, Christina M., Schettler, Pamela J., Dalton, Elizabeth D., Parkin, Susannah R., Walker, Rosemary S. W., Fehling, Kara B., Fava, Maurizio, and Mischoulon, David
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PERIMENOPAUSE , *ANTIDEPRESSANTS , *RELATIVE medical risk , *FEMALE reproductive organ diseases , *SEXUAL dysfunction , *CONFIDENCE intervals , *WOMEN , *PLACEBOS , *PSYCHOLOGICAL tests , *SURVEYS , *DESCRIPTIVE statistics , *QUESTIONNAIRES , *BLIND experiment , *ODDS ratio , *LONGITUDINAL method - Abstract
Objective. We sought to demonstrate that maca root may be an effective treatment for antidepressant-induced sexual dysfunction (AISD) in women. Method. We conducted a 12-week, double-blind, placebo-controlled trial of maca root (3.0 g/day) in 45 female outpatients (mean age of 41.5 ± 12.5 years) with SSRI/SNRI-induced sexual dysfunction whose depression remitted. Endpoints were improvement in sexual functioning as per the Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ). Results. 45 of 57 consented females were randomized, and 42 (30 premenopausal and 12 postmenopausal women) were eligible for a modified intent-to-treat analysis based on having had at least one postmedication visit. Remission rates by the end of treatment were higher for the maca than the placebo group, based on attainment of an ASEX total score ≤ 10 (9.5% for maca versus 4.8% for placebo), attaining an MGH-SFQ score ≤ 12 (30.0% for maca versus 20.0% for placebo) and reaching an MGH-SFQ score ≤ 8 (9.5% for maca versus 5.0% for placebo). Higher remission rates for the maca versus placebo group were associated with postmenopausal status. Maca was well tolerated. Conclusion. Maca root may alleviate SSRI-induced sexual dysfunction in postmenopausal women. This trial is registered with
NCT00568126 . [ABSTRACT FROM AUTHOR]- Published
- 2015
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271. Examining the Clinical Correlates of Autism Spectrum Disorder in Youth by Ascertainment Source.
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Joshi, Gagan, Faraone, Stephen, Wozniak, Janet, Petty, Carter, Fried, Ronna, Galdo, Maribel, Furtak, Stephannie, McDermott, Katie, Epstien, Cecily, Walker, Rosemary, Caron, Ashley, Feinberg, Leah, and Biederman, Joseph
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CHILDREN , *TEENAGERS , *DIAGNOSIS of autism , *MEDICAL referrals , *AFFECTIVE disorders , *AUTISM , *STATISTICAL correlation , *INTERVIEWING , *PSYCHIATRIC hospitals , *QUESTIONNAIRES , *RESEARCH funding , *STATISTICS , *T-test (Statistics) , *COMORBIDITY , *DATA analysis , *INTER-observer reliability , *DISEASE prevalence , *ADOLESCENCE - Abstract
To examine whether presentation of autism spectrum disorder (ASD) and associated patterns of psychiatric comorbidity and dysfunction vary by referral source. ASD youth referred to a specialized ambulatory program for ASD (N = 143) were compared to ASD youth referred to a general child psychiatry clinic (N = 217). More ASD clinic youth met criteria for a more robust form of ASD (autistic disorder); more youth referred to the psychiatry clinic met criteria for broader spectrum ASD (pervasive developmental disorder not otherwise specified). General psychiatry clinic youth with ASD suffered from a greater burden of psychopathologies and higher levels of dysfunction. The presentation of ASD in psychiatrically referred youth differs between general and ASD-specialized clinics, though both referral populations have high levels of comorbidity and dysfunction. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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272. Observer agreement comparing the use of virtual slides with glass slides in the pathology review component of the POSH breast cancer cohort study.
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Shaw, Emily Clare, Hanby, Andrew M., Wheeler, Kevin, Shaaban, Abeer M., Poller, David, Barton, Sheila, Treanor, Darren, Fulford, Laura, Walker, Rosemary A., Ryan, Deirdre, Lakhani, Sunil R., Wells, Clive A., Roche, Heather, Theaker, Jeffrey M., Ellis, Ian O., Jones, J. Louise, and Eccles, Diana M.
- Abstract
Aims (1) To compare the use of scanned virtual slide images (virtual microscopy) with glass slides (conventional microscopy) in the assessment of morphological characteristics of breast cancers within the setting of the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH), involving a cohort of women under 40 years of age, presenting with breast cancer. (2) To assess the acceptability to histopathologists of the use of virtual slide images. Methods 13 histopathologists from the UK and Australia participated in the POSH pathology review. The observers were asked to assess multiple morphological features such as tumour grade and type. Comparisons were made for a single observer using both virtual images and glass slides. Intra- and inter-observer variability was calculated using the &kgr; statistic and a comparison was made between the use of each image modality. Results Diagnostic performance with virtual slides was comparable to conventional microscopic assessment, with the measurement of agreement best for vascular invasion, necrosis and the presence of a central scar (&kgr;=0.37e0.78), and poor for more subjective parameters such as pleomorphism, stroma, the nature of the tumour border and the degree of lymphocytic infiltrate (&kgr;=0.1). Conclusion Virtual slides represent an acceptable methodology for central review of breast cancer histopathology and can circumvent the need for either travel to view material, or the potential problems of sending it by post. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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273. Microglandular adenosis or microglandular adenoma? A molecular genetic analysis of a case associated with atypia and invasive carcinoma.
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Geyer, Felipe C., Kushner, Yael B., Lambros, Maryou B., Natrajan, Rachael, Mackay, Alan, Tamber, Narinder, Fenwick, Kerry, Purnell, Dave, Ashworth, Alan, Walker, Rosemary A., and Reis-Filho, Jorge S.
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ADENOMA , *CANCER invasiveness , *CANCER cell growth , *FIBROCYSTIC breast disease , *PROTEIN microarrays - Abstract
Aims: Microglandular adenosis (MGA) is a rare breast lesion, which has long been considered to be hyperplastic. However, atypical forms of MGA (AMGA) and invasive carcinomas arising in the background of MGA are recorded. Recent studies have suggested that MGA may be a non-obligate precursor of invasive carcinomas that are negative for hormone receptors and lack HER-2 overexpression (triple-negative phenotype). The aim of this study was to determine whether MGA is clonal and whether it harbours chromosomal aberrations similar to those found in matched invasive ductal carcinoma of no special type (IDC-NST). Methods and results: We report on a case comprising MGA, AMGA and a high-grade IDC-NST. The three components were separately microdissected and subjected to genetic analysis with high-resolution microarray comparative genomic hybridisation. Identical genetic changes were detected in all components with subsequent acquisition of additional genetic aberrations in the invasive component, suggesting that MGA was the substrate for the development of the invasive carcinoma. Immunohistochemistry revealed concordant profiles across all components, characterized by triple-negative phenotype and variable positivity for basal markers. Conclusions: Similar to adenomas, MGA is, at least in some cases, a clonal lesion and may be a non-obligate precursor of a subgroup of high-grade triple-negative and basal-like breast carcinomas. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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274. The Importance of Careful Blood Processing in Isolation of Cell-Free DNA.
- Author
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PAGE, KAREN, POWLES, TOM, SLADE, MARTIN J., DE BELLA, MANUELA TAMBURO, WALKER, ROSEMARY A., COOMBES, R. CHARLES, and SHAW, JACQUELINE A.
- Subjects
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DNA , *CANCER patients , *POLYMERASE chain reaction , *CENTRIFUGATION , *CANCER diagnosis , *EQUIPMENT & supplies - Abstract
In healthy individuals, the source of cell-free plasma DNA is predominantly apoptotic, whereas, increased plasma DNA integrity is seen in cancer patients. Therefore, it is important to carefully isolate absolutely “cell-free” plasma DNA. Plasma DNA from 30 healthy females was analyzed using 4 PCR amplicons of increasing size, comparing standard blood processing with additional centrifugation steps prior to DNA extraction. Cellular DNA contamination, indicated by positive amplicons >300 bp was eliminated only after the extra centrifugation step. This highlights the importance of careful processing in preparation of cell-free plasma DNA as a tool for cancer detection and we recommend the use of a microcentrifuge spin, prior to DNA extraction. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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275. Tumor specific promoter region methylation of the human homologue of the Drosophila Roundabout gene DUTT1 (ROBO1) in human cancers.
- Author
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Dallol, Ashraf, Forgacs, Eva, Martinez, Alonso, Sekido, Yoshitaka, Walker, Rosemary, Kishida, Takeshi, Rabbitts, Pamela, Maher, Eamonn R., Minna, John D., and Latif, Farida
- Subjects
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GENOMES , *DROSOPHILA genetics , *CANCER genetics - Abstract
Presents a study which characterized the genomic organization of the DUTT1 (Deleted in U Twenty Twenty) human homologue of Drosophila Roundabout gene. Genomic structure of DUTT1; Mutation analysis of DUTT1 in lung and breast cancers; Methylation analysis of the promoter region of DUTT1 in primary lung and breast tumors.
- Published
- 2002
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276. Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours.
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Agathanggelou, Angelo, Honorio, Sofia, Macartney, Donia P, Martinez, Alonso, Dallol, Ashraf, Rader, Janet, Fullwood, Paul, Chauhan, Anita, Walker, Rosemary, Shaw, Jacqueline A, Hosoe, Shigeto, Lerman, Michael I, Minna, John D, Maher, Eamonn R, and Latif, Farida
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TUMORS , *LUNG tumors , *OVARIAN tumors , *BREAST tumors , *TUMOR suppressor genes - Abstract
Previously we analysed overlapping homozygous deletions in lung and breast tumours/tumour lines and defined a small region of 120 kb (part of LCTSGR1) at 3p21.3 that contained putative lung and breast cancer tumour suppressor gene(s) (TSG). Eight genes including RASSF1 were isolated from the minimal region. However, extensive mutation analysis in lung tumours and tumour lines revealed only rare inactivating mutations. Recently, de novo methylation at a CpG island associated with isoform A of RASSF1 (RASSF1A) was reported in lung tumours and tumour lines. To investigate RASSF1A as a candidate TSG for various cancers, we investigated: (a) RASSF1A methylation status in a large series of primary tumour and tumour lines; (b) chromosome 3p allele loss in lung tumours and (c) RASSF1 mutation analysis in breast tumours. RASSF1A promoter region CpG island methylation was detected in 72% of SCLC, 34% of NSCLC, 9% of breast, 10% of ovarian and 0% of primary cervical tumours and in 72% SCLC, 36% NSCLC, 80% of breast and 40% of ovarian tumour lines. In view of the lower frequency of RASSF1 methylation in primary breast cancers we proceeded to RASSF1 mutation analysis in 40 breast cancers. No mutations were detected, but six single nucleotide polymorphisms were identified. Twenty of 26 SCLC tumours with 3p21.3 allelic loss had RASSF1A methylation, while only six out of 22 NSCLC with 3p21.3 allele loss had RASSF1A methylation (P=0.0012), one out of five ovarian and none out of six cervical tumours with 3p21.3 loss had RASSF1A methylation. These results suggest that (a) RASSF1A inactivation by two hits (methylation and loss) is a critical step in SCLC tumourigenesis and (b) RASSF1A inactivation is of lesser importance in NSCLC, breast, ovarian and cervical cancers in which other genes within LCTSGR1 are likely to be implicated. Oncogene (2001) 20, 1509–1518. [ABSTRACT FROM AUTHOR]
- Published
- 2001
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277. CONTRIBUTORS
- Author
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Bury, Jonathan P., Culligan, Dominic J., Dixon, Michael F., Gallagher, P.J., Goepel, J.R., Haeney, Mansel R., Hughes, David E., Ironside, James W., MacLennan, K.A., Shortland, J.R., Slater, David N., Stephenson, T.J., van der Wal, Allard C., Walker, Rosemary A., Wallace, William A.H., Watson, Henry G., and Wells, M.
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278. Doxorubicin synergises with a TRAIL-R1-specific ligand to selectively target TRAIL-resistant breast tumour cells for apoptosis
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Naik, Shambhavi, Twiddy, Davina, Mistry, Roshna, Edwards, Jennifer M., Cohen, Gerald M., Walker, Rosemary A., and MacFarlane, Marion
- Published
- 2011
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279. Genomic analysis of circulating cell-free DNA infers breast cancer dormancy.
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Shaw, Jacqueline A., Page, Karen, Blighe, Kevin, Hava, Natasha, Guttery, David, Brown, James, Ruangpratheep, Chetana, Stebbing, Justin, Payne, Rachel, Palmieri, Carlo, Cleator, Suzy, Walker, Rosemary A., Coombes, R. Charles, and Ward, Becky
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BIOMARKERS , *BREAST cancer , *DNA , *GENOMES , *HETEROZYGOSITY , *TUMORS - Abstract
Biomarkers in breast cancer to monitor minimal residual disease have remained elusive. We hypothesized that genomic analysis of circulating free DNA (cfDNA) isolated from plasma may form the basis for a means of detecting and monitoring breast cancer. We profiled 251 genomes using Affymetrix SNP 6.0 arrays to determine copy number variations (CNVs) and loss of heterozygosity (LOH), comparing 138 cfDNA samples with matched primary tumor and normal leukocyte DNA in 65 breast cancer patients and eight healthy female controls. Concordance of SNP genotype calls in paired cfDNA and leukocyte DNA samples distinguished between breast cancer patients and healthy female controls (P < 0.0001) and between preoperative patients and patients on follow-up who had surgery and treatment (P = 0.0016). Principal component analyses of cfDNA SNP/copy number results also separated presurgical breast cancer patients from the healthy controls, suggesting specific CNVs in cfDNA have clinical significance. We identified focal high-level DNA amplification in paired tumor and cfDNA clustered in a number of chromosome arms, some of which harbor genes with oncogenic potential, including USP17L2 (DUB3), BRF1, MTA1, and JAG2. Remarkably, in 50 patients on follow-up, specific CNVs were detected in cfDNA, mirroring the primary tumor, up to 12 yr after diagnosis despite no other evidence of disease. These data demonstrate the potential of SNP/CNV analysis of cfDNA to distinguish between patients with breast cancer and healthy controls during routine follow-up. The genomic profiles of cfDNA infer dormancy/minimal residual disease in the majority of patients on followup. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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280. A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer.
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Humphries MP, Sundara Rajan S, Droop A, Suleman CAB, Carbone C, Nilsson C, Honarpisheh H, Cserni G, Dent J, Fulford L, Jordan LB, Jones JL, Kanthan R, Litwiniuk M, Di Benedetto A, Mottolese M, Provenzano E, Shousha S, Stephens M, Walker RA, Kulka J, Ellis IO, Jeffery M, Thygesen HH, Cappelletti V, Daidone MG, Hedenfalk IA, Fjällskog ML, Melisi D, Stead LF, Shaaban AM, and Speirs V
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms diagnosis, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms, Male diagnosis, Breast Neoplasms, Male drug therapy, Breast Neoplasms, Male pathology, Disease-Free Survival, Everolimus administration & dosage, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Humans, Imidazoles administration & dosage, Male, Middle Aged, Prognosis, Quinolines administration & dosage, Sex Characteristics, Transcriptome genetics, Eukaryotic Translation Initiation Factor 5A, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Breast Neoplasms, Male genetics, Eukaryotic Initiation Factor-4E genetics, Peptide Initiation Factors genetics, RNA-Binding Proteins genetics
- Abstract
Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs ( n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor. Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed ( P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival. Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. ©2016 AACR ., (©2016 American Association for Cancer Research.)
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- 2017
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281. Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer.
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Eccles SA, Aboagye EO, Ali S, Anderson AS, Armes J, Berditchevski F, Blaydes JP, Brennan K, Brown NJ, Bryant HE, Bundred NJ, Burchell JM, Campbell AM, Carroll JS, Clarke RB, Coles CE, Cook GJ, Cox A, Curtin NJ, Dekker LV, Silva Idos S, Duffy SW, Easton DF, Eccles DM, Edwards DR, Edwards J, Evans D, Fenlon DF, Flanagan JM, Foster C, Gallagher WM, Garcia-Closas M, Gee JM, Gescher AJ, Goh V, Groves AM, Harvey AJ, Harvie M, Hennessy BT, Hiscox S, Holen I, Howell SJ, Howell A, Hubbard G, Hulbert-Williams N, Hunter MS, Jasani B, Jones LJ, Key TJ, Kirwan CC, Kong A, Kunkler IH, Langdon SP, Leach MO, Mann DJ, Marshall JF, Martin L, Martin SG, Macdougall JE, Miles DW, Miller WR, Morris JR, Moss SM, Mullan P, Natrajan R, O'Connor JP, O'Connor R, Palmieri C, Pharoah PD, Rakha EA, Reed E, Robinson SP, Sahai E, Saxton JM, Schmid P, Smalley MJ, Speirs V, Stein R, Stingl J, Streuli CH, Tutt AN, Velikova G, Walker RA, Watson CJ, Williams KJ, Young LS, and Thompson AM
- Subjects
- Animals, Female, Humans, Breast Neoplasms diagnosis, Breast Neoplasms epidemiology, Breast Neoplasms etiology, Breast Neoplasms therapy, Research, Translational Research, Biomedical
- Abstract
Introduction: Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice., Methods: More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account., Results: The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working., Conclusions: With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.
- Published
- 2013
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282. Current issues in diagnostic breast pathology.
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Walker RA, Hanby A, Pinder SE, Thomas J, and Ellis IO
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- Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Biopsy, Breast chemistry, Breast Diseases classification, Breast Diseases genetics, Breast Diseases metabolism, Breast Neoplasms chemistry, Breast Neoplasms classification, Breast Neoplasms genetics, Diagnosis, Differential, Epithelial Cells pathology, Female, Genetic Markers, Humans, Immunohistochemistry, Mammary Glands, Human pathology, Molecular Diagnostic Techniques, Practice Guidelines as Topic, Predictive Value of Tests, Prognosis, Terminology as Topic, Breast pathology, Breast Diseases pathology, Breast Neoplasms pathology, Clinical Laboratory Techniques classification, Clinical Laboratory Techniques standards
- Abstract
On behalf of the NHS Breast Screening Programme Pathology Coordinating Group we present recommendations for terminology and diagnostic criteria for a number of key areas of practice in breast pathology where terminology can be confusing and where accurate communication will ensure appropriate clinical management. These recommendations cover columnar cell lesions and the spectrum of changes that can be seen in these epithelial proliferations, lobular neoplasia, micrometastases and isolated tumour cells in axillary lymph nodes, the use of basal/myoepithelial markers in diagnostic practice and oestrogen receptor testing in ductal carcinoma in situ.
- Published
- 2012
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283. A comparative biomarker study of 514 matched cases of male and female breast cancer reveals gender-specific biological differences.
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Shaaban AM, Ball GR, Brannan RA, Cserni G, Di Benedetto A, Dent J, Fulford L, Honarpisheh H, Jordan L, Jones JL, Kanthan R, Maraqa L, Litwiniuk M, Mottolese M, Pollock S, Provenzano E, Quinlan PR, Reall G, Shousha S, Stephens M, Verghese ET, Walker RA, Hanby AM, and Speirs V
- Subjects
- Adult, Aged, Aged, 80 and over, Cluster Analysis, Female, Humans, Male, Middle Aged, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Sex Factors, Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Breast Neoplasms mortality, Breast Neoplasms, Male metabolism, Breast Neoplasms, Male mortality
- Abstract
Male breast cancer remains understudied despite evidence of rising incidence. Using a co-ordinated multi-centre approach, we present the first large scale biomarker study to define and compare hormone receptor profiles and survival between male and female invasive breast cancer. We defined and compared hormone receptor profiles and survival between 251 male and 263 female breast cancers matched for grade, age, and lymph node status. Tissue microarrays were immunostained for ERα, ERβ1, -2, -5, PR, PRA, PRB and AR, augmented by HER2, CK5/6, 14, 18 and 19 to assist typing. Hierarchical clustering determined differential nature of influences between genders. Luminal A was the most common phenotype in both sexes. Luminal B and HER2 were not seen in males. Basal phenotype was infrequent in both. No differences in overall survival at 5 or 10 years were observed between genders. Notably, AR-positive luminal A male breast cancer had improved overall survival over female breast cancer at 5 (P = 0.01, HR = 0.39, 95% CI = 0.26-0.87) but not 10 years (P = 0.29, HR = 0.75, 95% CI = 0.46-1.26) and both 5 (P = 0.04, HR = 0.37, 95% CI = 0.07-0.97) and 10 years (P = 0.04, HR = 0.43, 95% CI = 0.12-0.97) in the unselected group. Hierarchical clustering revealed common clusters between genders including total PR-PRA-PRB and ERβ1/2 clusters. A striking feature was the occurrence of ERα on distinct clusters between genders. In female breast cancer, ERα clustered with PR and its isoforms; in male breast cancer, ERα clustered with ERβ isoforms and AR. Our data supports the hypothesis that breast cancer is biologically different in males and females suggesting implications for clinical management. With the incidence of male breast cancer increasing this provides impetus for further study.
- Published
- 2012
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284. Clinical and functional significance of α9β1 integrin expression in breast cancer: a novel cell-surface marker of the basal phenotype that promotes tumour cell invasion.
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Allen MD, Vaziri R, Green M, Chelala C, Brentnall AR, Dreger S, Vallath S, Nitch-Smith H, Hayward J, Carpenter R, Holliday DL, Walker RA, Hart IR, and Jones JL
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms pathology, Cell Membrane metabolism, Cell Movement physiology, Cell Proliferation, Female, Humans, Integrins physiology, Middle Aged, Neoplasm Invasiveness, Neoplasm Proteins metabolism, Neoplasm Proteins physiology, Phenotype, Prognosis, Survival Analysis, Tumor Cells, Cultured, Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Integrins metabolism
- Abstract
Integrin α9β1 is a receptor for ECM proteins, including Tenascin-C and the EDA domain of fibronectin, and has been shown to transduce TGFβ signalling. This study has examined the expression pattern of α9β1 in 141 frozen breast carcinoma samples and related expression to prognostic indices, molecular subtype and patient outcome. Effects of α9β1 on tumour cell migration and invasion were assessed using blocking antibody and gene transduction approaches. Integrin α9β1 localized to myoepithelial cells in normal ducts and acini, a pattern maintained in DCIS. A subset (17%) of invasive carcinomas exhibited tumour cell expression of α9β1, which related significantly to the basal-like phenotype, as defined by either CK5/6 or CK14 expression. Tumour expression of α9β1 showed a significant association with reduced overall patient survival (p < 0.0001; HR 5.94, 95%CI 3.26-10.82) and with reduced distant-metastasis-free survival (p < 0.0001; HR 6.37, CI 3.51-11.58). A series of breast cancer cell lines was screened for α9β1 with the highly invasive basal-like GI-101 cell line expressing significant levels. Both migration and invasion of this line were reduced significantly in the presence of α9-blocking antibody and following α9-knockdown with siRNA. Conversely, migratory and invasive behaviour of α9-negative MCF7 cells and α9-low MDA MB468 cells was enhanced significantly by over-expression of α9. Thus, α9β1 acts as a novel marker of the basal-like breast cancer subtype and expression is associated with reduced survival, while its ability to promote breast cancer cell migration and invasion suggests that it contributes to the aggressive clinical behaviour of this tumour subtype., (Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2011
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285. Expression of tenascin-C and its isoforms in the breast.
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Guttery DS, Shaw JA, Lloyd K, Pringle JH, and Walker RA
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- Animals, Breast pathology, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Female, Humans, Neoplasm Metastasis, Protein Isoforms, Tenascin genetics, Breast metabolism, Breast Neoplasms metabolism, Tenascin biosynthesis
- Abstract
Tenascin-C (TNC) is an extracellular matrix glycoprotein which is frequently up-regulated in a variety of pathological conditions including chronic inflammation and cancer. TNC has been implicated in the modulation of cell migration, proliferation, invasion and angiogenesis. Multiple isoforms of TNC can be generated through the alternative splicing of nine exons located in the fibronectin type III region of the molecule. The profile of isoforms expressed differs between cancers and normal breast, with the fully truncated TNC isoform being predominant in normal and benign tissues and higher molecular weight isoforms induced predominantly in cancer. The addition of extra domains within the fibronectin type III repeat domain greatly affects TNC function with multiple exon combinations available for splicing. Exons 14 and 16 are considered to be tumour-associated and have been shown to affect breast cell line invasion and growth in vitro to a greater extent than the full-length TNC isoform. This mini review will provide a summary of the literature to date regarding the expression of TNC isoforms in the breast and also discuss more recent developments in the field regarding exon AD1.
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- 2010
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286. Association of invasion-promoting tenascin-C additional domains with breast cancers in young women.
- Author
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Guttery DS, Hancox RA, Mulligan KT, Hughes S, Lambe SM, Pringle JH, Walker RA, Jones JL, and Shaw JA
- Subjects
- Adult, Age Factors, Binding Sites genetics, Blotting, Western, Breast metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Cell Movement, Epithelium metabolism, Female, Humans, Immunohistochemistry, In Situ Hybridization, Neoplasm Invasiveness, Protein Isoforms genetics, Protein Isoforms metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tenascin metabolism, Breast Neoplasms genetics, Cell Proliferation, Gene Expression Profiling, Tenascin genetics
- Abstract
Introduction: Tenascin-C (TNC) is a large extracellular matrix glycoprotein that shows prominent stromal expression in many solid tumours. The profile of isoforms expressed differs between cancers and normal breast, with the two additional domains AD1 and AD2 considered to be tumour associated. The aim of the present study was to investigate expression of AD1 and AD2 in normal, benign and malignant breast tissue to determine their relationship with tumour characteristics and to perform in vitro functional assays to investigate the role of AD1 in tumour cell invasion and growth., Methods: Expression of AD1 and AD2 was related to hypoxanthine phosphoribosyltransferase 1 as a housekeeping gene in breast tissue using quantitative RT-PCR, and the results were related to clinicopathological features of the tumours. Constructs overexpressing an AD1-containing isoform (TNC-14/AD1/16) were transiently transfected into breast carcinoma cell lines (MCF-7, T-47 D, ZR-75-1, MDA-MB-231 and GI-101) to assess the effect in vitro on invasion and growth. Statistical analysis was performed using a nonparametric Mann-Whitney test for comparison of clinicopathological features with levels of TNC expression and using Jonckheere-Terpstra trend analysis for association of expression with tumour grade., Results: Quantitative RT-PCR detected AD1 and AD2 mRNA expression in 34.9% and 23.1% of 134 invasive breast carcinomas, respectively. AD1 mRNA was localised by in situ hybridisation to tumour epithelial cells, and more predominantly to myoepithelium around associated normal breast ducts. Although not tumour specific, AD1 and AD2 expression was significantly more frequent in carcinomas in younger women (age ≤40 years; P < 0.001) and AD1 expression was also associated with oestrogen receptor-negative and grade 3 tumours (P < 0.05). AD1 was found to be incorporated into a tumour-specific isoform, not detected in normal tissues. Overexpression of the TNC-14/AD1/16 isoform significantly enhanced tumour cell invasion (P < 0.01) and growth (P < 0.01) over base levels., Conclusions: Together these data suggest a highly significant association between AD-containing TNC isoforms and breast cancers in younger women (age ≤40 years), which may have important functional significance in vivo.
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- 2010
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287. A multi-centre investigation towards reaching a consensus on the immunohistochemical detection of ERbeta in archival formalin-fixed paraffin embedded human breast tissue.
- Author
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Carder PJ, Murphy CE, Dervan P, Kennedy M, McCann A, Saunders PT, Shaaban AM, Foster CS, Witton CJ, Bartlett JM, Walker RA, and Speirs V
- Subjects
- Female, Histocytological Preparation Techniques standards, Humans, Immunohistochemistry standards, Interinstitutional Relations, Ireland, Laboratories standards, Pilot Projects, Reference Standards, United Kingdom, Breast Neoplasms pathology, Estrogen Receptor beta isolation & purification, Histocytological Preparation Techniques methods, Immunohistochemistry methods
- Abstract
Estrogen receptor (ER) alpha is a well-established independent prognostic factor in breast cancer whose presence determines the clinical implications of adjuvant endocrine therapy. A second receptor, ERb has been described, and a number of studies have examined its expression in breast tissue. However elucidation of the role played by ERb has been hampered by published immunohistochemical studies employing a variety of protocols and scoring systems such that inter-laboratory comparisons are difficult. Here we present a multi-centre study designed to critically evaluate inter-laboratory differences in methodology. Six UK and Irish centres participated in this study. A small series of breast cancers were stained using centre-specific laboratory protocols and scored using both centrespecific and standard scoring protocols. There was generally poor agreement as to what constituted a positive or negative case when centre-specific scoring systems were used with less than half of all cases in agreement. Concordance was improved when a standard scoring system was used but varied according to threshold for positivity employed and primary antibody. Our results emphasise the need for further studies addressing the role of ERb to be based on a wider consensus on criteria for positivity. Ideally this should be based on calibration against clinical outcome.
- Published
- 2005
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288. Cyclooxygenase-2 expression is a novel prognostic factor in malignant mesothelioma.
- Author
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Edwards JG, Faux SP, Plummer SM, Abrams KR, Walker RA, Waller DA, and O'Byrne KJ
- Subjects
- Biomarkers, Tumor metabolism, Cyclooxygenase 2, Dinoprostone metabolism, Gene Expression Regulation, Enzymologic, Humans, Isoenzymes antagonists & inhibitors, Male, Membrane Proteins, Mesothelioma pathology, Mesothelioma surgery, Peptide Fragments immunology, Peptide Fragments pharmacology, Pleural Neoplasms pathology, Pleural Neoplasms surgery, Predictive Value of Tests, Prognosis, Prospective Studies, Survival Rate, Isoenzymes metabolism, Mesothelioma enzymology, Pleural Neoplasms enzymology, Prostaglandin-Endoperoxide Synthases metabolism
- Abstract
Malignant mesothelioma (MM) is a fatal tumor of increasing incidence, which is resistant to current therapy. Cyclooxygenase-2 (COX-2) plays an important role in solid tumor growth, invasiveness, and angiogenesis, in part through the synthesis of prostaglandins such as prostaglandin E(2) (PGE(2)). In a prospective study, we evaluated COX-2 expression in snap-frozen, surgically resected MM tissue specimens using immunohistochemistry and semiquantitative Western blotting. PGE(2) was assessed by enzyme immunoassay. Thirty epithelioid, 10 biphasic, and 8 sarcomatoid tumors were evaluated. Immunohistochemistry demonstrated strong cytoplasmic tumor cell and variable stromal staining in all of the cases. COX-2 protein levels were correlated with clinicopathological prognostic factors using Kaplan-Meier and Cox proportional hazards models. High COX-2 band densitometry values correlated with poor survival (P = 0.008). In multivariate analysis, high COX-2 expression (P = 0.0005), nonepithelioid cell type (P = 0.002), and chest pain (P = 0.04) were independent predictors of poor prognosis. Furthermore, COX-2 expression contributed in multivariate analysis to both European Organization for Research and Treatment of Cancer (P = 0.001) and Cancer and Leukemia Group B (P = 0.003) prognostic scoring systems. The presence of PGE(2) was demonstrated in all of the samples. These results suggest that COX-2 expression is a prognostic factor in MM. COX-2 is a potential therapeutic target in MM, and trials are required of COX-2 inhibitors alone or in combination with existing treatment modalities.
- Published
- 2002
289. Changes in tenascin-C isoform expression in invasive and preinvasive breast disease.
- Author
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Adams M, Jones JL, Walker RA, Pringle JH, and Bell SC
- Subjects
- Alternative Splicing, Blotting, Southern, Breast Neoplasms genetics, Breast Neoplasms pathology, Carcinoma in Situ genetics, Carcinoma in Situ pathology, Carcinoma, Ductal, Breast genetics, Carcinoma, Ductal, Breast pathology, Humans, In Situ Hybridization, Neoplasm Invasiveness, Protein Isoforms, RNA, Messenger biosynthesis, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Tenascin genetics, Tumor Cells, Cultured, Breast Neoplasms metabolism, Carcinoma in Situ metabolism, Carcinoma, Ductal, Breast metabolism, Tenascin biosynthesis
- Abstract
Tenascin-C (TN) is an extracellular matrix protein that is expressed at low levels in normal adult tissue but is highly expressed around many tumors including breast carcinoma. TN exists as multiple isoforms generated through alternative splicing, and these isoforms have different effects on cell growth and migration. This study has analyzed in detail the pattern of TN isoform expression in benign, preinvasive, and invasive breast lesions using reverse transcription-PCR and Southern blotting. Significant differences in the profile of TN isoforms were identified. Although all tissues expressed the fully truncated TN, expression of two additional isoforms, one containing exon 16 (TN16) and one containing both exons 14 and 16 (TN14/16), were significantly associated with the invasive phenotype (P < 0.001). A subset of ductal carcinoma in situ (DCIS) cases were also found to express these isoforms, which may be indicative of a high risk of invasion in these lesions. Expression of these isoforms correlated with the presence of TN protein in the stroma in place of or in addition to basement membrane TN. Immunohistochemistry and in situ hybridization confirmed the production of exon 14-containing higher molecular weight isoforms by stromal fibroblasts in malignant tissue and both periductal fibroblasts and residual myoepithelial cells in DCIS. Although no evidence of tumor cell synthesis of TN was detected in the tissues, two highly invasive breast cancer cell lines (MDA-MB 231 and MDA-MB 468) were found to produce TN in contrast with tumor cells with a lower invasive capacity (MCF-7 and T47D). These results demonstrate for the first time that specific TN isoforms are expressed in invasive breast carcinomas and that these isoforms are identified in a subset of DCIS and suggest that detection of TN16 and/or TN14/16 may be used as a predictor for invasion. Functional studies are now essential to establish the effect of these isoforms on tumor behavior and evaluate whether they will provide appropriate targets for therapeutic intervention.
- Published
- 2002
290. [Immunohistochemical study of P-cadherin in breast cancer].
- Author
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Kovács A, Walker RA, Nagy A, Gomba S, Jones L, and Dearing S
- Subjects
- Carcinoma, Ductal, Breast chemistry, Carcinoma, Ductal, Breast pathology, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Receptors, Estrogen analysis, Receptors, Progesterone analysis, Breast Neoplasms chemistry, Breast Neoplasms pathology, Cadherins analysis
- Abstract
Introduction: Cell adhesion molecules play a significant role in the cellular connection of normal cells. The cadherins are believed to act as tumour suppressors, and their altered expression and function have been associated with tumour development., Aim and Methods: The authors examined the expression of a Ca++ dependent intercellular adhesion molecule, P-cadherin using an immunohistochemical method in 69 surgically resected breast carcinomas., Results: P-cadherin was detected in 30 cases (43.5%, cytoplasmic and/or membrane staining). The expression of P-cadherin was independent of tumour size and lymph node status, but correlated with a high tumour grade (grade III). In contrast, expression of E-cadherin correlated with lower tumour grade (grade I-II). P-cadherin expression was not detected in invasive lobular carcinomas., Conclusion: In general, P-cadherin was expressed at a lower frequency compared to E-cadherin, alpha-, and beta-catenin. These results suggest that an inverse relationship may exist between E- and P-cadherin in relation to grade, and that the expression of P-cadherin may be a marker of aggressiveness.
- Published
- 2002
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