Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity

We describe a bioinformatic tool, Tumor Aberration Prediction Suite (TAPS), for the identification of allele-specific copy numbers in tumor samples using data from Affymetrix SNP arrays. It includes detailed visualization of genomic segment characteristics and iterative pattern recognition for copy number identification, and does not require patient-matched normal samples. TAPS can be used to identify chromosomal aberrations with high sensitivity even when the proportion of tumor cells is as low as 30%. Analysis of cancer samples indicates that TAPS is well suited to investigate samples with aneuploidy and tumor heterogeneity, which is commonly found in many types of solid tumors

Wear Behavior of MoS2 Lubricant Layers during Sheet Metal Forming

The increased use of high and ultra-high strength steel and materials with a high adhesion tendency leads to higher demands regarding the wear resistance of forming tools. A promising approach addressing both challenges is to apply MoS2 dry film lubricant coating systems to the tool surface. These coatings reduce friction and the use of drawing oils and can also be used as an abherent. Once these coatings are exhausted, they can be chemically removed and reapplied. However, the tool life of the coatings cannot be predicted properly, due to their inhomogeneous wear behavior which depends on the forming parameters and differs locally. Moreover, there are carryover effects of MoS2-particles to already ablated areas. Given the unpredictability of the wear of dry film lubricant coatings, it is not possible to plan the recoating cycles appropriately and thus, the potential of these coatings for commercial applications is limited. In this research, the wear behavior of MoS2-layers in deep drawing processes was investigated on a test stand with DP800+Z coil material which ensures realistic load conditions at the draw ring radius. Firstly, the wear pattern was determined and locally different contact pressures were recorded and assigned to respective wear areas. Due to bending effects of the sheet material, there are two major areas of wear on the draw ring radius. During wear tests, the wear-dependent coating thickness during wear initiation was determined by using 3D laser scanning microscopy and the friction force was evaluated. © 2017 The Authors.European Research Association for Sheet Metal Working (EFB)German Federation of Industrial Research Associations (AiF)Federal Ministry of Economic Affairs and Energy (BMWi

PENGARUH LIMBAH SERBUK BESI SEBAGAI PENGGANTI SEJUMLAH AGREGAT HALUS TERHADAP CAMPURAN ASPAL

The obieaive of this research examining stability andfla+, value was to iwestigste the impact of the utility of iron Jillings waste as a subtitute matqlal for the mtmber of suprisingly small sggregates in the mixture of asphalt. In lhis research, the portion of irontilings waste which given were 5 %o, I0 % and I 5 % of the heauy mixture smooth aggregotes. The stobility quantitative value was 2093 kg in 15 % iron Jilings contents. The higatflow quaftitative value was 3,5 mm in 5 % iron tilings contents. The result of characteristic validdion Mmshall on the number of sabtituted smooth aggregates which used iron/ilings gave o standard coflictent specfrcation 8M.2005. So based on thal, the iron/illings waste technically could be received as a subtitute material for the mixture of suprisingly small aggregates

Spatial Immunology in Liver Metastases from Colorectal Carcinoma according to the Histologic Growth Pattern

In the era of immunotherapy, the tumor microenvironment (TME) has attracted special interest. However, colorectal liver metastases (CRC-LM) present histological peculiarities that could affect the interaction of immune and tumor cells such as fibrotic encapsulation and dense intratumoral stroma. We explored the spatial distribution of lymphocytic infiltrates in CRC-LM in the context of the histologic growth patterns using multispectral digital pathology providing data on three different scenarios, tumor periphery, invasive margin, and central tumoral areas. Our results illustrate a similar poor cell density of CD8(+) cells between different metastases subtypes in intratumoral regions. However, in encapsulated metastases, cytotoxic cells reach the tumor cells while remaining retained in stromal areas in non-encapsulating metastases. Some aspects are still unresolved, such as understanding the reason why most lymphocytes are largely retained in the capsule. Colorectal cancer liver metastases (CRC-LM) present differential histologic growth patterns (HGP) that determine the interaction between immune and tumor cells. We explored the spatial distribution of lymphocytic infiltrates in CRC-LM in the context of the HGP using multispectral digital pathology. We did not find statistically significant differences of immune cell densities in the central regions of desmoplastic ((d)HGP) and non-desmoplastic ((nd)HGP) metastases. The spatial evaluation reported that (d)HGP-metastases displayed higher infiltration by CD8(+) and CD20(+) cells in peripheral regions as well as CD4(+) and CD45RO(+) cells in (nd)HGP-metastases. However, the reactive stroma regions at the invasive margin (IM) of (nd)HGP-metastases displayed higher density of CD4(+), CD20(+), and CD45RO(+) cells. The antitumor status of the TIL infiltrates measured as CD8/CD4 reported higher values in the IM of encapsulated metastases up to 400 mu m towards the tumor center (p < 0.05). Remarkably, the IM of (d)HGP-metastases was characterized by higher infiltration of CD8(+) cells in the epithelial compartment parameter assessed with the ratio CD8(epithelial)/CD8(stromal), suggesting anti-tumoral activity in the encapsulating lesions. Taking together, the amount of CD8(+) cells is comparable in the IM of both HGP metastases types. However, in (d)HGP-metastases some cytotoxic cells reach the tumor nests while remaining retained in the stromal areas in (nd)HGP-metastases

Изучение байесовского подхода к анализу медико-биологических данных в курсе медицинской и биологической физики

Background: The clinical behaviour of colon cancer is heterogeneous. Five-year overall survival is 50-65% with all stages included. Recurring somatic chromosomal alterations have been identified and some have shown potential as markers for dissemination of the tumour, which is responsible for most colon cancer deaths. We investigated 115 selected stage II-IV primary colon cancers for associations between chromosomal alterations and tumour dissemination. Methods: Follow-up was at least 5 years for stage II-III patients without distant recurrence. Affymetrix SNP 6.0 microarrays and allele-specific copy number analysis were used to identify chromosomal alterations. Fisher's exact test was used to associate alterations with tumour dissemination, detected at diagnosis (stage IV) or later as recurrent disease (stage II-III). Results: Loss of 1p36.11-21 was associated with tumour dissemination in microsatellite stable tumours of stage II-IV (odds ratio = 5.5). It was enriched to a similar extent in tumours with distant recurrence within stage II and stage III subgroups, and may therefore be used as a prognostic marker at diagnosis. Loss of 1p36.11-21 relative to average copy number of the genome showed similar prognostic value compared to absolute loss of copies. Therefore, the use of relative loss as a prognostic marker would benefit more patients by applying also to hyperploid cancer genomes. The association with tumour dissemination was supported by independent data from the The Cancer Genome Atlas. Conclusion: Deletions on 1p36 may be used to guide adjuvant treatment decisions in microsatellite stable colon cancer of stages II and III

Quantification of Normal Cell Fraction and Copy Number Neutral LOH in Clinical Lung Cancer Samples Using SNP Array Data

Technologies based on DNA microarrays have the potential to provide detailed information on genomic aberrations in tumor cells. In practice a major obstacle for quantitative detection of aberrations is the heterogeneity of clinical tumor tissue. Since tumor tissue invariably contains genetically normal stromal cells, this may lead to a failure to detect aberrations in the tumor cells.Using SNP array data from 44 non-small cell lung cancer samples we have developed a bioinformatic algorithm that accurately models the fractions of normal and tumor cells in clinical tumor samples. The proportion of normal cells in combination with SNP array data can be used to detect and quantify copy number neutral loss-of-heterozygosity (CNNLOH) in the tumor cells both in crude tumor tissue and in samples enriched for tumor cells by laser capture microdissection.Genome-wide quantitative analysis of CNNLOH using the CNNLOH Quantifier method can help to identify recurrent aberrations contributing to tumor development in clinical tumor samples. In addition, SNP-array based analysis of CNNLOH may become important for detection of aberrations that can be used for diagnostic and prognostic purposes

Повышение доходности лесоохотничьих хозяйств на основе развития новых туристических услуг

The comprehensive transcriptomic analysis of clinically annotated human tissue has found widespread use in oncology, cell biology, immunology, and toxicology. In cancer research, microarray-based gene expression profiling has successfully been applied to subclassify disease entities, predict therapy response, and identify cellular mechanisms. Public accessibility of raw data, together with corresponding information on clinicopathological parameters, offers the opportunity to reuse previously analyzed data and to gain statistical power by combining multiple datasets. However, results and conclusions obviously depend on the reliability of the available information. Here, we propose gene expression-based methods for identifying sample misannotations in public transcriptomic datasets. Sample mix-up can be detected by a classifier that differentiates between samples from male and female patients. Correlation analysis identifies multiple measurements of material from the same sample. The analysis of 45 datasets (including 4913 patients) revealed that erroneous sample annotation, affecting 40 % of the analyzed datasets, may be a more widespread phenomenon than previously thought. Removal of erroneously labelled samples may influence the results of the statistical evaluation in some datasets. Our methods may help to identify individual datasets that contain numerous discrepancies and could be routinely included into the statistical analysis of clinical gene expression data

Fibroblast subsets in non-small cell lung cancer : Associations with survival, mutations, and immune features

Background Cancer-associated fibroblasts (CAFs) are molecularly heterogeneous mesenchymal cells that interact with malignant cells and immune cells and confer anti- and protumorigenic functions. Prior in situ profiling studies of human CAFs have largely relied on scoring single markers, thus presenting a limited view of their molecular complexity. Our objective was to study the complex spatial tumor microenvironment of non-small cell lung cancer (NSCLC) with multiple CAF biomarkers, identify novel CAF subsets, and explore their associations with patient outcome. Methods Multiplex fluorescence immunohistochemistry was employed to spatially profile the CAF landscape in 2 population-based NSCLC cohorts (n = 636) using antibodies against 4 fibroblast markers: platelet-derived growth factor receptor-alpha (PDGFRA) and -beta (PDGFRB), fibroblast activation protein (FAP), and alpha-smooth muscle actin (alpha SMA). The CAF subsets were analyzed for their correlations with mutations, immune characteristics, and clinical variables as well as overall survival. Results Two CAF subsets, CAF7 (PDGFRA-/PDGFRB+/FAP+/alpha SMA+) and CAF13 (PDGFRA+/PDGFRB+/FAP-/alpha SMA+), showed statistically significant but opposite associations with tumor histology, driver mutations (tumor protein p53 [TP53] and epidermal growth factor receptor [EGFR]), immune features (programmed death-ligand 1 and CD163), and prognosis. In patients with early stage tumors (pathological tumor-node-metastasis IA-IB), CAF7 and CAF13 acted as independent prognostic factors. Conclusions Multimarker-defined CAF subsets were identified through high-content spatial profiling. The robust associations of CAFs with driver mutations, immune features, and outcome suggest CAFs as essential factors in NSCLC progression and warrant further studies to explore their potential as biomarkers or therapeutic targets. This study also highlights multiplex fluorescence immunohistochemistry-based CAF profiling as a powerful tool for the discovery of clinically relevant CAF subsets.Peer reviewe

Diagnostic gastrointestinal markers in primary lung cancer and pulmonary metastases

Funding Information: Open access funding provided by Lund University. The study was supported by Swedish governmental funding of clinical research (ALF), the Franke and Margareta Bergqvist Foundation, and the Swedish Cancer Society. The funding sources had no role in the design or conduct of the study. Publisher Copyright: © 2023, The Author(s).Histopathological diagnosis of pulmonary tumors is essential for treatment decisions. The distinction between primary lung adenocarcinoma and pulmonary metastasis from the gastrointestinal (GI) tract may be difficult. Therefore, we compared the diagnostic value of several immunohistochemical markers in pulmonary tumors. Tissue microarrays from 629 resected primary lung cancers and 422 resected pulmonary epithelial metastases from various sites (whereof 275 colorectal cancer) were investigated for the immunohistochemical expression of CDH17, GPA33, MUC2, MUC6, SATB2, and SMAD4, for comparison with CDX2, CK20, CK7, and TTF-1. The most sensitive markers for GI origin were GPA33 (positive in 98%, 60%, and 100% of pulmonary metastases from colorectal cancer, pancreatic cancer, and other GI adenocarcinomas, respectively), CDX2 (99/40/100%), and CDH17 (99/0/100%). In comparison, SATB2 and CK20 showed higher specificity, with expression in 5% and 10% of mucinous primary lung adenocarcinomas and both in 0% of TTF-1-negative non-mucinous primary lung adenocarcinomas (25-50% and 5-16%, respectively, for GPA33/CDX2/CDH17). MUC2 was negative in all primary lung cancers, but positive only in less than half of pulmonary metastases from mucinous adenocarcinomas from other organs. Combining six GI markers did not perfectly separate primary lung cancers from pulmonary metastases including subgroups such as mucinous adenocarcinomas or CK7-positive GI tract metastases. This comprehensive comparison suggests that CDH17, GPA33, and SATB2 may be used as equivalent alternatives to CDX2 and CK20. However, no single or combination of markers can categorically distinguish primary lung cancers from metastatic GI tract cancer.Peer reviewe