Estimation of surface roughness on Ti-6Al-4V in high speed micro end milling by ANFIS model

379-389Titanium and its alloys are a few of the most suitable materials in medical applications due to their biocompatibility, anticorrosion and desirable mechanical properties compared to other materials like commercially pure Nb & Ta, Cr-Co alloys and stainless steels. High speed micro end milling is one of the favorable methods for accomplishing micro features on hard metals/alloys with better quality products delivering efficiently in shorter lead and production times. In this paper, experimental investigation of machining parameters influence on surface roughness in high speed micro end milling of Ti-6Al-4V using uncoated tungsten carbide tools under dry cutting conditions and prediction of surface roughness using adaptive neuro- fuzzy inference system (ANFIS) methodology has been presented. Using MATLAB tool box - ANFIS approach four membership functions - triangular, trapezoidal, gbell, gauss has been chosen during the training process in order to evaluate the prediction accuracy of surface roughness. The model’s predictions have been compared with experimental data for verifying the approach. From the comparison of four membership functions, the prediction accuracy of ANFIS has been reached 99.96% using general bell membership function. The most influential factor which influences the surface roughness has the feed rate followed by depth of cut

The Comparison of Cutting Tools for High Speed Machining of Ti-6Al-4V ELI Alloy (Grade 23)

Green technology is one of the major aspects in order to reduce the global pollution content from manufacturing industries. There is a need to investigate the different available tools for high-speed micromilling process of advanced alloys to achieve desired surface finish without traditional coolants. In this chapter, tool wear investigation of uncoated and PVD-coated AlTiN, TiAlN tungsten carbide end mills in high-speed micro-end milling of alpha + beta Ti-6Al-4V ELI titanium alloy (Grade 23) under dry cutting conditions was presented. A comparison for machining performance with the three tools is reported. Cutting force analysis was done under the considered machining input parameters for evaluating the tool condition. Tool wear observation was done by SEM analysis. EDX analysis was performed to know the material constituents and wear mechanisms on the cutting tool tip. It is found that diffusion, oxidation, adhesive and abrasive wear mechanisms were the major phenomena taking place on the cutting edge of micro end mills. From the comparison of cutting tools for machining Grade 23 titanium alloy, it was found that TiAlN tools performed better than AlTiN and uncoated tungsten carbide tools

Opposite effects of tissue inhibitor of metalloproteinases-1 (TIMP-1) over-expression and knockdown on colorectal liver metastases

<p>Abstract</p> <p>Background</p> <p>Tissue inhibitors of metalloproteinases (TIMPs) and the corresponding metalloproteinases are integral parts of the protease network and have been shown to be involved in cancer development and metastasis. Paradoxically, for TIMP-1, tumor promoting as well as tumor inhibitory effects have been observed.</p> <p>Methods</p> <p>To address this paradox, we utilized the BALB/c/CT26 mouse model that reliably leads to liver metastasis after splenic tumor cell injection and variegated the type of target cells for therapeutic intervention and the modalities of gene transfer. Since we have observed before that over-expression of TIMP-1 in liver host cells leads to efficient tumor growth inhibition in this model, we now examined whether targeting the tumor cells themselves will have a similar effect.</p> <p>Results</p> <p>In concordance with the earlier results, TIMP-1 over-expression in tumor cells led to a dramatic reduction of tumor growth as well. To evaluate any influence of treatment modality, we further examined whether TIMP-1 knockdown in the same animal model would have the opposite effect on tumor growth than TIMP-1 over-expression. Indeed, TIMP-1 knockdown led to a marked increase in tumor burden.</p> <p>Conclusion</p> <p>These data indicate that in the BALB/c/CT26 model, the modification of TIMP-1 has concordant effects irrespective of the type of target cell or the technique of modulation of TIMP-1 activity, and that TIMP-1 is unequivocally tumor inhibitory in this model.</p

Informing patients about their mutation tests : CDKN2A c.256G>A in melanoma as an example

Background When germline mutations are suspected as causal in cancer, patient DNA may be sequenced to detect variants in relevant genes. If a particular mutation has not been reported in reliable family studies, genetic counselors are facing a dilemma of appropriately informing patients. Many sequencing facilities provide an interpretation of the findings based on the available sequence databases or on prediction tools that are curated from bioinformatics and mechanistic datasets. The counseling dilemma is exacerbated if the pedigree data are not informative but the in silico predictions suggest pathogenicity. Methods We present here a real world example of the c.256G > ACDKN2Avariant, which was detected in one melanoma patient where two siblings were diagnosed with melanoma in situ. We investigated a detailed family history of the affected siblings in order to survey probability of the cancer risks within the context to this mutation. Results This c.256G > ACDKN2Avariant was detected in one of the brothers and in the melanoma-free mother while the other brother in the family tested negative. The variant had been previously described in one patient from a melanoma family. In the family under investigation, the mother's 16 first-and second-degree relatives had survived past the median onset age for melanoma and none presented melanoma. We tested the variant using multiple bioinformatic tools that all predicted deleteriousness of the variant. The genetic counseling report to the melanoma patient stated that theCDKN2Avariant was 'likely pathogenic' and the disease was defined as 'likely hereditary melanoma'. Conclusions The pedigree data showed at the most a low penetrance variant, which, if taken into consideration, might have altered the provided diagnosis. When dealing with 'practically' unknown variants the counselors would be advised to incorporate a detailed family history rather than basing predictions on functionality provided by sequencing facilities.Peer reviewe

Cross-species comparison of biological themes and underlying genes on a global gene expression scale in a mouse model of colorectal liver metastasis and in clinical specimens

<p>Abstract</p> <p>Background</p> <p>Invasion-related genes over-expressed by tumor cells as well as by reacting host cells represent promising drug targets for anti-cancer therapy. Such candidate genes need to be validated in appropriate animal models.</p> <p>Results</p> <p>This study examined the suitability of a murine model (CT26/Balb/C) of colorectal liver metastasis to represent clinical liver metastasis specimens using a global gene expression approach. Cross-species similarity was examined between pure liver, liver invasion, tumor invasion and pure tumor compartments through overlap of up-regulated genes and gene ontology (GO)-based biological themes on the level of single GO-terms and of condensed GO-term families. Three out of four GO-term families were conserved in a compartment-specific way between the species: secondary metabolism (liver), invasion (invasion front), and immune response (invasion front and liver). Among the individual GO-terms over-represented in the invasion compartments in both species were "extracellular matrix", "cell motility", "cell adhesion" and "antigen presentation" indicating that typical invasion related processes are operating in both species. This was reflected on the single gene level as well, as cross-species overlap of potential target genes over-expressed in the combined invasion front compartments reached up to 36.5%.</p> <p>Generally, histopathology and gene expression correlated well as the highest single gene overlap was found to be 44% in syn-compartmental comparisons (liver versus liver) whereas cross-compartmental overlaps were much lower (e.g. liver versus tumor: 9.7%). However, single gene overlap was surprisingly high in some cross-compartmental comparisons (e.g. human liver invasion compartment and murine tumor invasion compartment: 9.0%) despite little histolopathologic similarity indicating that invasion relevant genes are not necessarily confined to histologically defined compartments.</p> <p>Conclusion</p> <p>In summary, cross-species comparison on a global gene expression scale suggests the validity of an animal model representing the human situation. The actual yield of potential target genes depends on several variables including the animal model, choice of inclusion criteria, inherent species differences and histologic assessment.</p

Whole exome sequencing identifies APCDD1 and HDAC5 genes as potentially cancer predisposing in familial colorectal cancer

Germline mutations in predisposition genes account for only 20% of all familial colorectal cancers (CRC) and the remaining genetic burden may be due to rare high- to moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer-predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants: a coding variant in APC downregulated 1 gene (APCDD1, p.R299H) and a non-coding variant in the 5' untranslated region (UTR) of histone deacetylase 5 gene (HDAC5). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additional APCDD1 variants in a cohort of 1705 familial CRC patients and no further HDAC5 variants. Proliferation assays indicated an insignificant proliferative impact for the APCDD1 variant. Luciferase reporter assays using the HDAC5 variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by the HDAC5 variant showed a significant impact of TCF4 on promoter activity of mutated HDAC5. Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5'UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders.This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology) and Transcan ERA-NET funding from the German Federal Ministry of Education and Research (BMBF). K.H. was supported from the EU Horizon 2020 program, grant No. 856620

Search for markers of invasive growth in breast cancer: association with disease prognosis

In the present study, we analyzed the gene expression profiles of various morphological structures of breast cancer (GEO, GSE80754) to identify new markers of invasion and to assess their association with disease prognosis. Nine proteins (KIF14, DSC3, WAVE, etc.) was selected based on the literature analysis of the involvement of genes up- and down-regulated in solid and trabecular structures in cancer invasion and a heterogeneity in expression of their proteins in breast tumors. The association of these proteins with patients' survival was assessed

Cancer Predisposition Genes in Cancer-Free Families

Familial clustering, twin concordance, and identification of high- and low-penetrance cancer predisposition variants support the idea that there are families that are at a high to moderate excess risk of cancer. To what extent there may be families that are protected from cancer is unknown. We wanted to test genetically whether cancer-free families share fewer breast, colorectal, and prostate cancer risk alleles than the population at large. We addressed this question by whole-genome sequencing (WGS) of 51 elderly cancer-free individuals whose numerous (ca. 1000) family members were found to be cancer-free ('cancer-free families', CFFs) based on face-to-face interviews. The average coverage of the 51 samples in the WGS was 42x. We compared cancer risk allele frequencies in cancer-free individuals with those in the general population available in public databases. The CFF members had fewer loss-of-function variants in suggested cancer predisposition genes compared to the ExAC data, and for high-risk cancer predisposition genes, no pathogenic variants were found in CFFs. For common low-penetrance breast, colorectal, and prostate cancer risk alleles, the results were not conclusive. The results suggest that, in line with twin and family studies, random environmental causes are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible.</p