Human epidermal growth factor receptor 2 (HER2) plays an important role in breast cancer progression and provides predictive information for response to targeted therapy including trastuzumab ...although this is limited. Downstream pathways, such as PI3K/Akt, are associated with HER2/HER3 heterodimerization promoting survival and proliferation amongst cancer cells. Thus, patient outcome and trastuzumab therapy effectiveness might be further characterised by HER2/HER3 dimerisation and its signalling pathways. HER2/HER3 dimerisation status was assessed, using chromogenic in situ Proximity Ligation Assay, in two breast cancer series: early stage primary breast cancer, including 224 HER2+ patients that were not submitted to trastuzumab, and HER2+ breast cancer where patients were treated with adjuvant trastuzumab (
n
= 143). Levels of biomarkers including PI3K, pAKT, ER, PgR, HER3, BCL2, p53, PTEN and p21 were measured using immunohistochemistry. Levels of HER2/HER3 heterodimers were compared with biomarker expression and patient outcome. An association between high levels of HER2/HER3 dimerisation and absence of hormone receptors, ER and PgR, was observed. We further show for the first time the presence of HER2/HER3 heterodimers and the loss of p21 expression in HER2+ breast cancer predicts a significantly poorer outcome when submitted to adjuvant trastuzumab. Breast cancer patients that reveal high levels of HER2/HER3 dimerisation and loss of p21 are associated with poor survival prognosis in patients with HER2+ breast cancer treated with adjuvant trastuzumab. Further quantification analysis of HER dimer/ligand complexes and downstream signalling pathways will begin to unravel the complex associations with patient outcome and its relationship with sensitivity to targeted treatment.
HER2 plays an important role in breast cancer progression and provides predictive and prognostic information. HER2 receptor family members function through dimerisation, which can lead to impact on ...cell function, growth and differentiation; however, their value in breast cancer development remains to be defined. This study aims to examine the relationships of HER2 heterodimers to breast cancer characteristics in trastuzumab naïve and treated cases. HER2 protein (IHC), HER2 gene (chromogenic ISH) and HER2 heterodimerisation status chromogenic in situ proximity ligation assay (PLA) were assessed in two breast cancer series prepared in tissue microarray (TMA) format. A range of signals/cell for each HER2 heterodimer was detected (0–34.6 signals/cell). The vast majority of cases with HER2 heterodimers showed HER2 gene amplification and/or protein expression. There was an association between HER2 dimerisation with HER3 and HER4 and their protein expression level but no such association was found in with HER1 (EGFR). Of the HER2+ cases, 74, 66, and 58 % showed heterodimers with EGFR, HER3 and HER4, respectively. 51 % of HER2+ tumours expressed all three heterodimers whereas 23 % of the cases did not show expression of any of the three heterodimers. There was an inverse association between the presence and levels of HER2 heterodimers and hormone receptor expression in HER2+ tumours. Tumours exhibiting high levels of HER2 heterodimers demonstrated aggressive clinicopathological features and poor outcome. In the HER2+ cases, dimerisation with EGFR and HER3 but not with HER4 showed an association with aggressive features. There was no association between HER2 heterodimers with patient breast cancer-specific survival or recurrence in HER2+ breast cancer in those patients receiving trastuzumab or not. Our results demonstrate that HER2 dimerisation is a complex process that may underlie the biological heterogeneity of HER2 positive tumours and may identify patients suitable for a specific targeted therapy but does not predict patient outcome for those receiving trastuzumab. PLA proved to be a useful tool for detecting, visualising and quantifying the frequency of protein–protein interactions in archival formalin-fixed paraffin-embedded tissue samples.
Barros F F T, Powe D G, Ellis I O & Green A R (2010) Histopathology56, 560–572
Understanding the HER family in breast cancer: interaction with ligands, dimerization and treatments
Breast carcinoma is ...the most frequent type of cancer affecting women. Among the recently described molecular and phenotypic classes of breast cancer, human epidermal growth factor receptor 2 (HER2)‐positive tumours are associated with a poor prognosis. HER2 plays an important role in cancer progression being targeted to provide predictive and prognostic information. Moreover, HER2 is related to cancer resistance against a variety of therapies; however, trastuzumab (herceptin) has proved successful in treatment of this subgroup. Nevertheless, resistance to this drug may be acquired by patients after a period of treatment, which indicates that other molecular mechanisms might influence success of this therapy. Dimerization between members of the HER family may contribute to resistance against treatments due to different combinations that trigger different downstream pathways. This is promoted by ligands, which are expressed as transmembrane precursor protein molecules and have a conserved epidermal growth factor‐like domain. Through resistance to trastuzumab, other drugs are being developed to interact in different domains of HER2 protein. It might be a good strategy to apply new drugs simultaneously to trastuzumab due to act in different domains of HER2. The study of interaction between receptors/ligands will characterize specifically their signalling pathway and understand which strategy to acquire.
The calpain family, and their endogenous inhibitor calpastatin, has been implicated in cancer progression, and recent in vitro data have indicated a role in trastuzumab resistance. The aims of our ...study were to examine expression levels of calpastatin, calpain‐1 and calpain‐2 in breast tumours from patients treated with trastuzumab following adjuvant chemotherapy to determine their potential as biomarkers to predict therapeutic response. The expression of calpastatin, calpain‐1 and calpain‐2 was determined, using immunohistochemistry (IHC), in tumours from a series of 93 patients with primary breast cancer treated with surgery and adjuvant chemotherapy with or without trastuzumab followed by trastuzumab to complete 1 year of therapy. IHC was performed using tissue microarrays constructed from cores taken from intratumour and peripheral tumour areas. Expression was correlated with clinicopathologic variables and patient outcome. Calpastatin expression was correlated with Nottingham prognostic index (p = 0.003) and lymph node status (p = 0.007). Trastuzumab resistance was defined as disease relapse during therapy. Calpain‐1 expression is associated with relapse‐free survival (p = 0.001) and remained significant in multivariate analysis accounting for confounding pathological and treatment variables (hazard ratio 4.60, 95% confidence interval 1.05–20.25; p = 0.043). Calpain‐1 may be a useful biomarker to predict relapse‐free survival in breast cancer patients treated with adjuvant trastuzumab and chemotherapy. A larger verification study is warranted.
The objective of this work was to evaluate ovicidal and larvicidal effects of Eucalyptus globulus essential oil (EGEO) on Haemonchus contortus. The chemical composition determination of EGEO was ...through gas chromatography and mass spectrometry. Egg hatch test (EHT) was performed in concentrations 21.75; 17.4; 8.7; 5.43 e 2.71 mg x mL(-1). In larval development test (LDT) were used the concentrations 43.5; 21.75; 10.87; 5.43 e 2.71 mg x mL(-1). Each trial was conducted by negative control with Tween 80 (3%) and positive control, 0.02 mg x mL(-1) of thiabendazole in EHT and 0.008 mg x mL(-1) of ivermectin in LDT. The maximum effectiveness of EGEO on eggs was 99.3% in concentration of 21.75 mg x mL(-1) and on larvae was 98.7% in concentration 43.5 mg x mL(-1). The concentration of EGEO that inhibits 50% of the eggs and larvae was 8.3 and 6.92 mg x mL(-1), respectively. The oil chemical analysis identified as main component the monoterpen 1,8-cineol. EGEO presented ovicidal and larvicidal activities in vitro, revealing a good potential for use in the control of sheep and goat gastrointestinal nematodes.
In this study, a methodology for automatic recognition of multiple simultaneous types of partial discharges (PDs) in hydro-generator stator windings was proposed. All the seven PD sources typical in ...rotating machines were considered, and up to three simultaneous sources could be identified. The functionality of identifying samples with no valid PDs was also incorporated using a new technique. The data set was composed of phase-resolved partial discharge (PRPD) patterns obtained from on-line measurements of hydro-generators. From an input PRPD, noise and interference were removed with an improved version of an image-based denoising algorithm previously proposed by the authors. Then, a novel image-based algorithm that separates partially superposed PD clouds was proposed, by decomposing the input pattern into two sub-PRPDs containing discharges of different natures. From the sub-PRPDs, one extracts features quantifying the PD distribution over amplitudes and the contour of PD clouds. Those features are fed as inputs to several artificial neural networks (ANNs), each of which solves a part of the classification problem and acts as a block of a larger system. Once trained, ANNs work collaboratively to identify an unknown sample. Good results were obtained, with overall accuracies ranging from 88% to 94.8% for all the considered PD sources.
In this paper, a novel image denoising algorithm and novel input features are proposed. The algorithm is applied to phase-resolved partial discharge (PRPD) diagrams with a single dominant partial ...discharge (PD) source, preparing them for automatic artificial-intelligence-based classification. It was designed to mitigate several sources of distortions often observed in PRPDs obtained from fully operational hydroelectric generators. The capabilities of the denoising algorithm are the automatic removal of sparse noise and the suppression of non-dominant discharges, including those due to crosstalk. The input features are functions of PD distributions along amplitude and phase, which are calculated in a novel way to mitigate random effects inherent to PD measurements. The impact of the proposed contributions was statistically evaluated and compared to classification performance obtained using formerly published approaches. Higher recognition rates and reduced variances were obtained using the proposed methods, statistically outperforming autonomous classification techniques seen in earlier works. The values of the algorithm’s internal parameters are also validated by comparing the recognition performance obtained with different parameter combinations. All typical PD sources described in hydro-generators PD standards are considered and can be automatically detected.
Arboviral diseases are disseminated all over the world. In Brazil, they remain neglected, alerting public authorities to possible outbreaks. Over here, we report the epidemiological indicators of ...Dengue from 2010 to 2015, Zika between 2015 and 2016, and Chikungunya from 2014 to 2016, within 19 municipalities of Southwestern Region of Bahia, Brazil. The data were collected from Brazilian national public information systems (SISFAD, SINAN, and IBGE) and by Endemic Control Agents. The analysis consisted of a description of vector characteristics, Home Infestation Index and characterization of human reported cases. The years 2011 and 2013 were recorded as having the highest frequencies of positive properties for the presence of the arboviruse vectors. Most municipalities presented high annual values of Home Infestation Index indicating an alert situation (62.28%). In the evaluated period, there were (i) 9,196 cases of Dengue, (ii) 636 cases of Zika and (iii) 224 cases of Chikungunya reported. This is the first report of the epidemiological characteristics of these arboviruses in the 19 municipalities of Bahia. It is believed that the data collected may contribute to public health policies aimed at controlling future epidemics of these arboviruses.
Although the prognostic significance of proliferation in early invasive breast cancer has been recognized for a long time, recent gene-expression profiling studies have reemphasized its biologic and ...prognostic value and the potential application of its assessment in routine practice, particularly to define prognostic subgroups of luminal/hormone receptor-positive (HR+) tumors. This study aimed to assess the prognostic value of a proliferation assay by using Ki-67 immunohistochemistry as compared with mitotic count scores.
Proliferation was assessed by using Ki-67 labeling index (Ki-67LI) and mitotic scores in a large (n = 1,550) and well-characterized series of clinically annotated primary operable invasive breast cancer with long-term follow-up. Tumors were phenotyped based on their IHC profiles into luminal/HR+, HER2+, and triple-negative (TN) classes. We used a split-sample development and validation approach to determine the optimal Ki-67LI cut-offs.
The optimal cut-points of Ki-67LI were 10% and 50% for the luminal class. Both Ki7LI and MS were able to split luminal tumors into subgroups with significantly variable outcomes, independent of other variables. Neither mitotic count scores nor Ki-67LI was associated with outcome in the HER2+ or the TN classes.
Assessment of proliferation by using Ki-67LI and MS can distinguish subgroups of patients within luminal/hormone receptor-positive breast cancer significantly different in clinical outcomes. Overall, both Ki-67 LI and mitotic-count scores showed comparable results. The method described could provide a cost-effective method for prognostic subclassification of luminal/hormone receptor-positive breast cancer in routine clinical practice.
Abstract Partial discharge (PD) monitoring is widely used in rotating machines to evaluate the condition of stator winding insulation, but its practice on a large scale requires the development of ...intelligent systems that automatically process these measurement data. In this paper, it is proposed a methodology of automatic PD classification in hydro-generator stator windings using neural networks. The database is formed from online PD measurements in hydro-generators in a real setting. Noise filtering techniques are applied to these data. Then, based on the concept of image projection, novel features are extracted from the filtered samples. These features are used as inputs for training several neural networks. The best performance network, obtained using statistical procedures, presents a recognition rate of 98%.
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