Total loss of MHC class I is an independent indicator of good prognosis in breast cancer

Tumours can be recognised by CTL and NK cells. CTL recognition depends on expression of MHC Class I loaded with peptides from tumour antigens. In contrast, loss of MHC Class I results in NK activation. In our study a large set of samples from patients with primary operable invasive breast cancer was evaluated for the expression of MHC Class I heavy and light by immunohistochemical staining of 439 breast carcinomas in a tissue microarray. Forty-seven percent (206 of 439) of breast carcinomas were considered negative for HLA Class I heavy chain (HC10), whereas lack of anti-β2m-antibody staining was observed in 39% (167 of 424) of tumours, with only 3% of the β2m-negative tumours expressing detectable HLA Class I heavy chain. Correlation with patient outcome showed direct relationship between patient survival and HLA-negative phenotype (log rank = 0.004). A positive relationship was found between the intensity of expression of MHC Class I light and heavy chains expression and histological grade of invasive tumour (p < 0.001) and Nottingham Prognostic Index (p < 0.001). To investigate whether HLA Class I heavy and light chains expression had independent prognostic significance, Cox multivariate regression analysis, including the parameters of tumour size, lymph node stage, grade and intensity of HC10 and anti-β2m staining, was carried out. In our analysis, lymph node stage (p < 0.001), tumour grade (p = 0.005) and intensity of MHC Class I light and heavy chains expression were shown to be independent prognostic factors predictive of overall survival (p-values HC10 = 0.047 and β2m = 0.018)

Racial Mislabeling in Multiracial Individuals: Implications for Professional Counseling and Education

With the extreme growth of people who identify as Biracial or Multiracial, it is evident that their unique racial experiences need to be better understood, especially within the field of professional counseling to underscore competent practice (Charmaraman, Woo, Quach, & Erkut, 2014; Jackson, Yoo, Guevarra & Harrington, 2012; Tran, Miyake, Martinez-Morales, & Csizmadia, 2016). As a result, the researchers in this study investigated the lived experiences of racial mislabeling for Multiracial individuals. The participants of this study were fourteen (n=14) individuals who identified as Multiracial and endorsed experiencing the specific form of racial invalidation entitled racial mislabeling. Data were collected through individual, semi-structured interviews. The data was analyzed using phenomenological methods within Moustakas’ (1994) transcendental approach, which led to themes that described the essence of the participants’ experience. These themes are discussed in detail and recommendations for researchers and counselor educators to improve training and education are provided

Evidence that the p53 negative / Bcl-2 positive phenotype is an independent indicator of good prognosis in colorectal cancer: A tissue microarray study of 460 patients

BACKGROUND: Advances in our understanding of the molecular biology of colorectal cancer have fuelled the search for novel molecular prognostic markers to complement existing staging systems. Markers assessed in combination may perform better than those considered individually. Using high-throughput tissue microarray technology, we describe the prognostic value of combined p53 / Bcl-2 status in colorectal cancer. PATIENTS AND METHODS: Tumour samples from 462 patients who underwent elective surgery to resect a primary colorectal cancer between 1994 and 2000 (mean follow-up of 75 months) were assembled in tissue microarray format. Clinico-pathological data including tumour grade, stage, vascular invasion status along with disease specific survival data has been collected prospectively. Immunohistochemical analysis of p53 and Bcl-2 expression was performed using antibodies DO-7 (p53) and 124 (Bcl-2), and results correlated with known clinico-pathological variables and outcomes. RESULTS: Abnormal nuclear p53 accumulation and Bcl-2 overexpression were detected in 221/445 (49.6%) and199/437 (45.5%) tumours respectively, with a significant inverse correlation between the two markers (p = 0.023). On univariate analysis no correlations were found between either marker and standard clinico-pathological variables, however nuclear p53 expression was associated with a significantly reduced survival (p = 0.024). Combined analysis of the two markers indicated that 112/432 (24.2%) cases displayed a p53(-)/Bcl-2(+) phenotype, this occurring more frequently in earlier stage tumours. Kaplan-Meier analysis revealed a significant survival advantage in these p53(-)/Bcl-2(+) tumours compared with the remaining cases (p = 0.0032). On multivariate analysis using the Cox proportional hazards model, neither p53 expression nor Bcl-2 expression alone were of independent prognostic significance, however the combined p53(-)/Bcl-2(+) phenotype was significantly associated with a good prognosis in this series (HR 0.659, 95%CI 0.452–0.959, p = 0.029). CONCLUSION: Patient stratification by combined p53 / Bcl-2 phenotype provides stage-independent prognostic information in colorectal cancer. Specifically, that up to a quarter of patients display a good prognosis p53(-)/Bcl-2(+) phenotype. This may indicate a more clinically indolent phenotype and a subset of patients for whom less aggressive adjuvant treatment appropriate

Effect of occupational therapy home visit discharge planning on participation after stroke: Protocol for the HOME Rehab trial

Introduction: After first stroke, the transition from rehabilitation to home can be confronting and fraught with challenges. Although stroke clinical practice guidelines recommend predischarge occupational therapy home visits to ensure safe discharge and provision of appropriate equipment, there is currently limited evidence to support this recommendation. Methods and analysis: The HOME Rehab trial is a national, multicentre, phase III randomised controlled trial with concealed allocation, blinded assessment and intention-to-treat analysis being conducted in Australia. The trial aim is to determine the effect and potential cost-effectiveness of an enhanced occupational therapy discharge planning intervention that involves pre and postdischarge home visits, goal setting and occupational therapy in the home (the HOME programme) in comparison to an in-hospital predischarge planning intervention. Stroke survivors aged ≥ 45 years, admitted to a rehabilitation ward, expected to return to a community (private) dwelling after discharge, with no significant prestroke disability will be randomly allocated 1:1 to receive a standardised discharge planning intervention and the HOME programme or the standardised discharge planning intervention alone. The primary outcome is participation measured using the Nottingham Extended Activities of Daily Living. Secondary outcome areas include hospital readmission, disability, performance of instrumental activities of daily living, health-related quality of life, quality of care transition and carer burden. Resources used/costs will be collected for the cost-effectiveness analysis and hospital readmission. Recruitment commenced in 2019. Allowing for potential attrition, 360 participants will be recruited to detect a clinically important treatment difference with 80% power at a two-tailed significance level of 0.05. Ethics and dissemination: This study is approved by the Alfred Health Human Research Ethics Committee and site-specific ethics approval has been obtained at all participating sites. Results of the main trial and the secondary endpoint of cost-effectiveness will be submitted for publication in peer-reviewed journals Trial registration number: ACTRN1261800136020

Enhancing caregivers’ understanding of dementia and tailoring activities in frontotemporal dementia:two case studies

PURPOSE: To describe the intervention process and results of the Tailored Activities Program (TAP) in two people diagnosed with Frontotemporal Dementia (FTD). METHOD: TAP is an occupational therapy (OT) community-based intervention program that prescribes personalised activities to reduce difficult behaviours of dementia. The OT works with carers over a 4-month period (assessment, activity prescription, and generalisation of strategies). Study measures were collected (blind researcher) pre- and post- intervention: cognition, functional disability, behavioural symptoms, and Caregiver Confidence and Vigilance. RESULTS: A 51-year-old woman with behavioural-variant FTD could consistently engage in more activities post-intervention, with scores indicating improvements to behaviour, function, and caregiver confidence. A 63-year-old man with semantic variant FTD engaged well in the prescribed activities, with scores reflecting reduced carer distress regarding challenging behaviours and improved caregiver vigilance. CONCLUSIONS: TAP is efficacious in FTD, allowing for differences in approach for FTD subtype, where behavioural symptoms are very severe and pervasive

A role for the collagen I/III and MMP-1/-13 genes in primary inguinal hernia?

BACKGROUND: Abnormal collagen metabolism is thought to play an important role in the development of primary inguinal hernia. This is underlined by detection of altered collagen metabolism and structural changes of the tissue in patients with primary inguinal hernia. However, it is still unknown whether these alterations reflect a basic dysfunction of the collagen synthesis, or of collagen degradation. METHODS: In the present study, we analysed type I and type III procollagen messenger ribonucleic acid (mRNA) and MMP-1 and MMP-13 mRNA in cultured fibroblasts from the skin of patients with primary inguinal hernia, and from patients without hernia (controls) by reverse transcription polymerase chain reaction (RT-PCR) and Northern Blot. RESULTS: The results indicated that the ratio of type I to type III procollagen mRNA was decreased in patients with primary hernia, showing significant differences as compared to controls (p = 0.01). This decrease was mainly due to the increase of type III procollagen mRNA. Furthermore, RT-PCR analysis revealed that the expression of MMP-1 mRNA in patients with primary hernia is equivalent to that of controls (p > 0.05). In addition, MMP-13 mRNA is expressed neither in patients with primary hernia nor in controls. CONCLUSION: We concluded that abnormal change of type I and type III collagen mRNAs contribute to the development of primary inguinal hernia, whereas the expressions of MMP-1 and MMP-13 mRNA appears not to be involved in the development of primary inguinal hernia. Thus, the knowledge on the transcriptional regulation of collagen in patients with primary inguinal hernia may help to understand the pathogenesis of primary inguinal hernia, and implies new therapeutic strategies for this disease

Increased Ret signalling and impact of vandetanib in acquired tamoxifen resistant breast cancer

Deregulation of the tyrosine kinase Ret and its coreceptors (GFRα) has been implicated in neoplasia, and Ret is of interest as a therapeutic target in endocrine-treated breast cancer. This study evaluated in vitro impact of vandetanib, a tyrosine kinase inhibitor able to target Ret in addition to EGFR and VEGFR2, in ER+ breast cancer cells that have acquired resistance to tamoxifen treatment. Tamoxifen resistant TAMR and endocrine responsive MCF7 cells were grown in vitro for 7 days +/- vandetanib (0.5-5μM) +/- exogenous growth factors (10-50ng/ml), and also in continuous culture with vandetanib (1μM), to monitor growth impact and emergence of vandetanib resistance. For Western blotting or immunoprecipitation, log phase cells were transferred for 24hr to serum-free medium and pre-treated for 1hr +/- vandetanib followed by Ret ligands GDNF or artemin for 5mins. Immunohistochemistry for Ret activity was performed on an ER+ tamoxifen-treated clinical breast cancer TMA sample series using Y1062 Ret phospho-antibody with HScore staining assessment. Growth of TAMR cells was substantially inhibited by vandetanib (p<0.001, IC50 0.6μM) with complete cell loss by 17weeks, contrasting rapid emergence of resistance in endocrine responsive MCF7 cells. TAMR cells were more sensitive to vandetanib vs. gefitinib (p<0.001; 1μM each agent), indicating mitogenic signalling in addition to EGFR contributed to TAMR growth. TAMR cells had elevated basal Ret expression, activity and interaction with elevated GFRα3 coreceptor expression; mature VEGFR2 was not detected in TAMR cells. Exogenous GFRα3 ligands artemin or GDNF modestly stimulated TAMR cell growth and hyperactivated Ret, downstream kinases (including MAPK, AKT) and ER Ser167, confirming functional GFRα/Ret signalling and its cross-talk with ER. Increased phospho-Ret immunostaining was also associated with shortened DFI (p=0.036) and survival (p=0.011) in tamoxifen-treated clinical ER+ breast cancers. Vandetanib (0.5-1μM) depleted GFRα3/Ret activity and decreased phospho-EGFR in TAMR cells under basal and Ret ligand-stimulated conditions, inhibited MAPK, p70S6K and S6RP phosphorylation, and partially-reduced levels of phospho-AKT and phospho-ER. However, vandetanib failed to consistently impact on HER2, 3 or 4 activity; moreover, hyperactivation of all erbB receptors by exogenous heregulin B1 (10ng/ml) recovered AKT, MAPK, p70S6K and ER AF-1 phosphorylation in the presence of vandetanib and was able to overcome the basal growth-inhibitory impact of this agent in TAMR cells. These findings demonstrate a central importance for increased Ret signalling and its cross-talk with ER in tamoxifen resistant breast cancer that can be targeted in vitro by vandetanib. Further studies are required to determine optimal combination treatments with vandetanib to circumvent potential intrinsic resistance in clinical breast cancers that exhibit heregulin B1 enrichment

Millicurrent stimulation of human articular chondrocytes cultivated in a collagen type-I gel and of human osteochondral explants

<p>Abstract</p> <p>Background</p> <p>Here we investigate the effect of millicurrent treatment on human chondrocytes cultivated in a collagen gel matrix and on human osteochondral explants.</p> <p>Methods</p> <p>Human chondrocytes from osteoarthritic knee joints were enzymatically released and transferred into a collagen type-I gel. Osteochondral explants and cell-seeded gel samples were cultivated in-vitro for three weeks. Samples of the verum groups were stimulated every two days by millicurrent treatment (3 mA, sinusoidal signal of 312 Hz amplitude modulated by two super-imposed signals of 0.28 Hz), while control samples remained unaffected. After recovery, collagen type-I, type-II, aggrecan, interleukin-1β, IL-6, TNFα and MMP13 were examined by immunohistochemistry and by real time PCR.</p> <p>Results</p> <p>With regard to the immunostainings 3 D gel samples and osteochondral explants did not show any differences between treatment and control group. The expression of all investigated genes of the 3 D gel samples was elevated following millicurrent treatment. While osteochondral explant gene expression of col-I, col-II and Il-1β was nearly unaffected, aggrecan gene expression was elevated. Following millicurrent treatment, IL-6, TNFα, and MMP13 gene expression decreased. In general, the standard deviations of the gene expression data were high, resulting in rarely significant results.</p> <p>Conclusions</p> <p>We conclude that millicurrent stimulation of human osteoarthritic chondrocytes cultivated in a 3 D collagen gel and of osteochondral explants directly influences cell metabolism.</p