A qualitative evaluation of occupational therapy-led work rehabilitation for people with inflammatory arthritis : perspectives of therapists and their line managers

Introduction: Occupational therapy-led work rehabilitation for employed people with inflammatory arthritis and work problems was piloted in five hospitals in the United Kingdom. This qualitative study explored the views of participating occupational therapists and their line managers about the work rehabilitation training received and conducting the intervention, with particular focus on the structured interview used, the Work Experience Survey – Rheumatic Conditions. Method: Face-to-face semi-structured interviews were conducted with occupational therapists (n¼9), followed by telephone interviews with their line managers (n¼2). Interviews were audio-recorded, transcribed verbatim and thematically analysed by three researchers to maximize validity. Results: The main themes emerging from the occupational therapists’ interviews were: varying levels of prior knowledge and experience of work rehabilitation, initial concerns about the feasibility of a lengthy work assessment in practice and increased confidence in delivering work rehabilitation as the study progressed. The line managers’ interviews generated themes around the positive impact of the work rehabilitation training the occupational therapists received, and changes in their practice. Conclusion: The Work Experience Survey – Rheumatic Conditions was considered a good choice of work assessment which can be implemented in practice. Once therapists had provided the work intervention several times, their confidence and skills increase

Balancing Selection at the Tomato RCR3 Guardee Gene Family Maintains Variation in Strength of Pathogen Defense

Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in plants. In plant-pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the''Guard-Hypothesis,'' R proteins (the ``guards'') can sense modification of target molecules in the host (the ``guardees'') by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3) and its guard (Cf-2). We conclude that, in addition to coevolution at the ``guardee-effector'' interface for pathogen recognition, natural selection acts on the ``guard-guardee'' interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto-immune responses in the absence of the corresponding pathogen

ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer

PMCID: PMC3446380This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Immunohistochemistry profiles of breast ductal carcinoma: factor analysis of digital image analysis data

<p>Abstract</p> <p>Background</p> <p>Molecular studies of breast cancer revealed biological heterogeneity of the disease and opened new perspectives for personalized therapy. While multiple gene expression-based systems have been developed, current clinical practice is largely based upon conventional clinical and pathologic criteria. This gap may be filled by development of combined multi-IHC indices to characterize biological and clinical behaviour of the tumours. Digital image analysis (DA) with multivariate statistics of the data opens new opportunities in this field.</p> <p>Methods</p> <p>Tissue microarrays of 109 patients with breast ductal carcinoma were stained for a set of 10 IHC markers (ER, PR, HER2, Ki67, AR, BCL2, HIF-1α, SATB1, p53, and p16). Aperio imaging platform with the Genie, Nuclear and Membrane algorithms were used for the DA. Factor analysis of the DA data was performed in the whole group and hormone receptor (HR) positive subgroup of the patients (n = 85).</p> <p>Results</p> <p>Major factor potentially reflecting aggressive disease behaviour (i-Grade) was extracted, characterized by opposite loadings of ER/PR/AR/BCL2 and Ki67/HIF-1α. The i-Grade factor scores revealed bimodal distribution and were strongly associated with higher Nottingham histological grade (G) and more aggressive intrinsic subtypes. In HR-positive tumours, the aggressiveness of the tumour was best defined by positive Ki67 and negative ER loadings. High Ki67/ER factor scores were strongly associated with the higher G and Luminal B types, but also were detected in a set of G1 and Luminal A cases, potentially indicating high risk patients in these categories. Inverse relation between HER2 and PR expression was found in the HR-positive tumours pointing at differential information conveyed by the ER and PR expression. SATB1 along with HIF-1α reflected the second major factor of variation in our patients; in the HR-positive group they were inversely associated with the HR and BCL2 expression and represented the major factor of variation. Finally, we confirmed high expression levels of p16 in Triple-negative tumours.</p> <p>Conclusion</p> <p>Factor analysis of multiple IHC biomarkers measured by automated DA is an efficient exploratory tool clarifying complex interdependencies in the breast ductal carcinoma IHC profiles and informative value of single IHC markers. Integrated IHC indices may provide additional risk stratifications for the currently used grading systems and prove to be useful in clinical outcome studies.</p> <p>Virtual Slides</p> <p>The virtual slide(s) for this article can be found here: <url>http://www.diagnosticpathology.diagnomx.eu/vs/1512077125668949</url></p

Toward optimal implementation of cancer prevention and control programs in public health: A study protocol on mis-implementation

Abstract Background Much of the cancer burden in the USA is preventable, through application of existing knowledge. State-level funders and public health practitioners are in ideal positions to affect programs and policies related to cancer control. Mis-implementation refers to ending effective programs and policies prematurely or continuing ineffective ones. Greater attention to mis-implementation should lead to use of effective interventions and more efficient expenditure of resources, which in the long term, will lead to more positive cancer outcomes. Methods This is a three-phase study that takes a comprehensive approach, leading to the elucidation of tactics for addressing mis-implementation. Phase 1: We assess the extent to which mis-implementation is occurring among state cancer control programs in public health. This initial phase will involve a survey of 800 practitioners representing all states. The programs represented will span the full continuum of cancer control, from primary prevention to survivorship. Phase 2: Using data from phase 1 to identify organizations in which mis-implementation is particularly high or low, the team will conduct eight comparative case studies to get a richer understanding of mis-implementation and to understand contextual differences. These case studies will highlight lessons learned about mis-implementation and identify hypothesized drivers. Phase 3: Agent-based modeling will be used to identify dynamic interactions between individual capacity, organizational capacity, use of evidence, funding, and external factors driving mis-implementation. The team will then translate and disseminate findings from phases 1 to 3 to practitioners and practice-related stakeholders to support the reduction of mis-implementation. Discussion This study is innovative and significant because it will (1) be the first to refine and further develop reliable and valid measures of mis-implementation of public health programs; (2) bring together a strong, transdisciplinary team with significant expertise in practice-based research; (3) use agent-based modeling to address cancer control implementation; and (4) use a participatory, evidence-based, stakeholder-driven approach that will identify key leverage points for addressing mis-implementation among state public health programs. This research is expected to provide replicable computational simulation models that can identify leverage points and public health system dynamics to reduce mis-implementation in cancer control and may be of interest to other health areas

Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation

PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models

BACKGROUND: PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models

Distinct distribution and prognostic significance of molecular subtypes of breast cancer in Chinese women: a population-based cohort study

<p>Abstract</p> <p>Background</p> <p>Molecular classification of breast cancer is an important prognostic factor. The distribution of molecular subtypes of breast cancer and their prognostic value has not been well documented in Asians.</p> <p>Methods</p> <p>A total of 2,791 breast cancer patients recruited for a population-based cohort study were evaluated for molecular subtypes of breast cancer by immunohistochemical assays. Data on clinicopathological characteristics were confirmed by centralized pathology review. The average follow-up of the patients was 53.4 months. Overall and disease-free survival by molecular subtypes of breast cancer were evaluated.</p> <p>Results</p> <p>The prevalence of the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and triple-negative subtypes were 48.6%, 16.7%, 13.7%, and 12.9%, respectively. The luminal A subtype was more likely to be diagnosed in older women (P = 0.03) and had a stronger correlation with favorable clinicopathological factors (smaller tumor size, lower histologic grade, and earlier TNM stage) than the triple-negative or HER2 subtypes. Women with triple-negative breast cancer had a higher frequency of family history of breast cancer than women with other subtypes (P = 0.048). The 5-year overall/disease-free survival percentages for the luminal A, luminal B, HER2, and triple-negative subtypes were 92.9%/88.6%, 88.6%/85.1%, 83.2%/79.1%, and 80.7%/76.0%, respectively. A similar pattern was observed in multivariate analyses. Immunotherapy was associated with improved overall and disease-free survival for luminal A breast cancer, but reduced disease-free survival (HR = 2.21, 95% CI, 1.09-4.48) for the HER2 subtype of breast cancer.</p> <p>Conclusions</p> <p>The triple-negative and HER2 subtypes were associated with poorer outcomes compared with the luminal A subtype among these Chinese women. The HER2 subtype was more prevalent in this Chinese population compared with Western populations, suggesting the importance of standardized HER2 detection and anti-HER2 therapy to potentially benefit a high proportion of breast cancer patients in China.</p

Associations between respiratory illnesses and secondhand smoke exposure in flight attendants: A cross-sectional analysis of the Flight Attendant Medical Research Institute Survey

Abstract Background Secondhand tobacco smoke (SHS) is associated with increased risk of respiratory illness, cancer, and cardiovascular disease. Prior to smoking bans on airlines in the late 1980s, flight attendants were exposed to a significant amount of SHS. In the present study, we examine associations between flight attendant SHS exposure and development of respiratory illnesses and cardiovascular disease. Methods Between December 2006 and October 2010, three hundred sixty-two flight attendants completed an online questionnaire with information regarding experience as a flight attendant, medical history, smoking history, and SHS exposure. Rates of illnesses in flight attendants were compared with an age and smoking history matched population sample from NHANES 2005-2006. Logistic regression analysis was used to examine the association of reported medical conditions and pre-ban years of exposure. Results Compared with the sample from NHANES 2005-2006, flight attendants had increased prevalence of chronic bronchitis (11.7% vs. 7.2%, p &lt; 0.05), emphysema/COPD (3.2% vs. 0.9%, p &lt; 0.03), and sinus problems (31.5% vs. 20.9%, p &lt; 0.002), despite a lower prevalence of medical illnesses including high blood pressure, diabetes, high cholesterol, heart failure, cancer, and thyroid disease. Amongst flight attendants who reported never smoking over their lifetimes, there was not a significant association between years of service as a flight attendant in the pre-smoking ban era and illnesses. However, in this same group, there was a significantly increased risk of daily symptoms (vs. no symptoms) of nasal congestion, throat, or eye irritation per 10-year increase of years of service as a flight attendant prior to the smoking ban (OR 2.14, 95% CI 1.41 - 3.24). Conclusions Flight attendants experience increased rates of respiratory illnesses compared to a population sample. The frequency of symptoms of nasal congestion, throat or eye irritation is associated with occupational SHS exposure in the pre-smoking ban era