Intratumor heterogeneity of biomarker expression in breast carcinomas

Small biopsy samples are used increasingly to assess the biomarker expression for prognostic information and for monitoring therapeutic responses prior to and during neoadjuvant therapy. The issue of intratumor heterogeneity of expression of biomarkers, however, has raised questions about the validity of the assessment of biomarker expression based on limited tissue samples. We examined immunohistochemically the expression of HER-2neu (p185^erbB-2), epidermal growth factor receptor (EGFR), Bcl-2, p53, and proliferating cell nuclear antigen (PCNA) in 30 breast carcinomas using archived, paraffin embedded tissue and determined the extent of intratumor heterogeneity. Each section was divided into four randomly oriented discrete regions, each containing a portion of the infiltrating carcinoma. For each tumor, the entire lesion and four regions were analyzed for the expression of these markers. Scores of both membrane and cytoplasmic staining of HER-2neu and EGFR, scores of cytoplasmic staining of Bcl-2, and scores of nuclear staining of both p53 and PCNA were recorded. The intensity of staining and the proportion of immunostained cells were determined. A semiquantitative immunoscore was calculated by determining the sum of the products of the intensity and corresponding proportion of stained tumor cells. We analyzed both invasive (IDC) and in situ (DCIS) carcinomas. The Wilcoxon signed-rank test was used for paired comparisons between overall and regional immunoscores and between overall and regional percentages of stained cells. Spearman's correlation coefficients were used to assess the level of agreement of overall biomarker expression with each of the regions. Generalized linear models were used to assess overall and pair-wise differences in the absolute values of percent changes between overall and regional expression of biomarkers. For IDCs, there were no statistically significant differences in the expression of the biomarkers in terms of either the percentage of cells staining or the immunoscores when comparing the entire tumor with each region except for the lower EGFR expression of arbitrarily selected region 1 and lower p53 expression of region 1 compared to that of the entire tumor section. For DCIS, there were no statistically significant differences in the expression of the biomarkers between the entire tumor and each region except in PCNA of region 2 compared to that of entire tumor section. Positive correlation of immunoscores was observed between the entire tumor and each region as well as across all four regions for IDC. Similar observations were noted with DCIS except for HER-2neu and PCNA. No statistically significant differences were observed in the absolute values of percent changes of biomarker expression between overall and the four regions for both DCIS and IDC. Therefore, no significant intratumor heterogeneity in the expression of HER-2neu, Bcl-2, and PCNA was observed in IDC. Minor regional variations were observed for EGFR and p53 in IDC. Similarly, no significant regional variation in the expression of markers was observed in DCIS except for PCNA.     

<Emphasis Type="Italic">Candida albicans</Emphasis>genome sequence: a platform for genomics in the absence of genetics

Publication of the complete diploid genome sequence of the yeast Candida albicans will accelerate research into the pathogenesis of Candida infections. Comparative genomic analysis highlights genes that may contribute to C. albicans survival and its fitness as a human commensal and pathogen.     

Towards Harmonisation of Critical Laboratory Result Management - Review of the Literature and Survey of Australasian Practices

Timely release and communication of critical test results may have significant impact on medical decisions and subsequent patient outcomes. Laboratories therefore have an important responsibility and contribution to patient safety. Certification, accreditation and regulatory bodies also require that laboratories follow procedures to ensure patient safety, but there is limited guidance on best practices. In Australasia, no specific requirements exist in this area and critical result reporting practices have been demonstrated to be heterogeneous worldwide.Recognising the need for agreed standards and critical limits, the AACB started a quality initiative to harmonise critical result management throughout Australasia. The first step toward harmonisation is to understand current laboratory practices. Fifty eight Australasian laboratories responded to a survey and 36 laboratories shared their critical limits. Findings from this survey are compared to international practices reviewed in various surveys conducted elsewhere. For the successful operation of a critical result management system, critical tests and critical limits must be defined in collaboration with clinicians. Reporting procedures must include how critical results are identified; who can report and who can receive critical results; what is an acceptable timeframe within which results must be delivered or, if reporting fails, what escalation procedures should follow; what communication channels or systems should be used; what should be recorded and how; and how critical result procedures should be maintained and evaluated to assess impact on outcomes.In this paper we review the literature of current standards and recommendations for critical result management. Key elements of critical result reporting are discussed in view of the findings of various national surveys on existing laboratory practices, including data from our own survey in Australasia. Best practice recommendations are made that laboratories are expected to follow in order to provide high quality and safe service to patients.     

Differential cadmium and zinc distribution in relation to their physiological impact in the leaves of the accumulating Zygophyllum fabago L.

Cadmium and zinc share many similar physiochemical properties, but their compartmentation, complexation and impact on other mineral element distribution in plant tissues may drastically differ. In this study, we address the impact of 10 μm Cd or 50 μm Zn treatments on ion distribution in leaves of a metallicolous population of the non‐hyperaccumulating species Zygophyllum fabago at tissue and cell level, and the consequences on the plant response through a combined physiological, proteomic and metabolite approach. Micro‐proton‐induced X‐ray emission and laser ablation inductively coupled mass spectrometry analyses indicated hot spots of Cd concentrations in the vicinity of vascular bundles in response to Cd treatment, essentially bound to S‐containing compounds as revealed by extended X‐ray absorption fine structure and non‐protein thiol compounds analyses. A preferential accumulation of Zn occurred in vascular bundle and spongy mesophyll in response to Zn treatment, and was mainly bound to O/N‐ligands. Leaf proteomics and physiological status evidenced a protection of photosynthetically active tissues and the maintenance of cell turgor through specific distribution and complexation of toxic ions, reallocation of some essential elements, synthesis of proteins involved in photosynthetic apparatus or C‐metabolism, and metabolite synthesis with some specificities regarding the considered heavy metal treatment.     

Granular cell tumour of the soft tissues: a case report and literature review

Granular cell tumours (GCT) of the soft tissues are rare benign tumours but some time may be difficult to distinguish from malignant neoplasms. It is important that clinicians are aware of their existence. We present a new case of GCT of the soft tissues followed by a brief review of literature.     

Drug‐microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL

The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll‐like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL‐infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell‐extrinsic mechanisms of drug resistance and disease progression.     

Feeding Competition and Group Size in Alouatta pigra

Researchers consider group size in primates to be determined by complex relationships among numerous ecological forces. Antipredator benefits and better resource defense are the primary pressures for large groups. Conversely, intragroup limited food availability, can result in greater intragroup feeding competition and individual energy expenditure in larger groups, creating energetic advantages for individuals in small groups and placing an upper limit group size. However, the extent to which food availability constrains group size remains unclear for many species, including black howlers (Alouatta pigra), which ubiquitously live in small social groups (≤10 individuals). We studied the relationship between group size and 2 key indices of feeding competition—day journey length and activity budgets—in 3 groups of wild Alouatta pigra at a hurricane-damaged site in Belize, Central America. We controlled for differences in food availability between home ranges (food tree density) and compared both indicators of feeding competition directly with temporal variation in food availability for each group. Our results show no consistent association between resource availability, group size, and either index of competition, indicating that feeding competition does not limit group size at the site—i.e., that larger groups can form without increased costs of feeding competition. The results support the search for other explanations, possibly social ones, for small group size in the primates, and we conclude with suggestions and evidence for such alternative explanations.