Chemopreventive effects of n-3 polyunsaturated fatty acids and fish in human colon cells

The molecular mechanisms of how n-3 PUFA excert anticancer properties are not well understood. Thus, the cancer chemopreventive properties of EPA and DHA were the core subject of in vitro studies. Furthermore, samples (n=89) of the first randomised controlled human trial intervening with lean and oil-rich fish, the FISHGASTRO trial, were screened ex vivo for markers of chemoprevention. It was shown that EPA and DHA impair cell growth and induce apoptosis. Gene expression was affected in a time- and substance-specific manner. Overall, genes connected with biotransformation, cell cycle control, signalling pathways, apoptosis, and inflammation were altered. More specifically, SOD2 induction and probably an enhanced peroxidase activity due to GSTT2 induction indicate reduction of oxidative stress. Whereas GSTT2 was induced by EPA it was reduced by DHA in HT29 cells. Anti-inflammatory activity can be attributed to COX-2 decrease by DHA in both cell types. In contrast, EPA induced COX-2 in LT97 cells. It was not possible to prove that faecal water (FW)-incubated LT97 cells were an appropriate source for biomarker identification to test the hypothesis that additional consumption of fish is beneficial for gut health. There was no marked alteration of genotoxicity or apoptosis by fish-intervention. The evidence of the comparably small impact of FW on the modulation of global gene expression in LT97 cells and the influence of an additional consumption of fish still require final assessment. The extent to which these findings may be related to a lack of impact of oil-rich fish needs further clarification. In conclusion it was shown, that EPA and DHA exert chemopreventive properties in vitro. As the results from the human intervention study were not appropriate to judge the in vivo situation, there is still a need to prove the hypothesis that oil-rich fish acts in a colon cancer chemopreventive manner

A longitudinal study of kinematic stride characteristics in maximal sprint running

Purpose of the present study was to measure the kinematic stride characteristics of track-and-field-sprinters and jumpers in maximal sprint-running during different training periods (TP) of a double-periodisation (DP). 26 participants (7 females, age: 22.7 ± 5.7yrs, body mass: 60.1 ± 6.7kg, body height: 172.1 ± 4.4cm; 19 males, age: 20.9 ± 3.3yrs, body mass: 73.7 ± 6.5kg, body height: 182.3 ± 7.5cm) participated in flying 30-meter-sprints. Kinematic stride parameters (stride-velocity, stride-length, stride-frequency, contact-time, flight-time and stride-rhythm) were measured for every single stride with Optojump (Microgate S.r.L., Italy). The training data were collected via protocol. A variance analysis with repeated measures was calculated for 3 respectively 6 TPs as well as multiple regression functions for the stride-velocity. The longitudinal results showed significant values for the 6 TPs, however cyclic increase of maximal sprint-velocity (on average 0.42 ± 0.08m/s) with a DP that corresponded with the recorded training data. 3 TPs differed significantly in average stride-velocity, stride-length, stride-frequency and contact-time of the maximal sprint, but not in flight-time and stride-rhythm. Our findings suggest that kinematic stride characteristics depend on TP. A systematic training control to increase the sprint-speed must take into account these changes of the kinematic parameter during the training year

One-carbon metabolites, B vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients:results from the ColoCare Study

B-vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- A nd angiogenesis-related chronic diseases, such as colorectal cancer. Yet, the role of one-carbon metabolism in inflammation and angiogenesis among colorectal cancer patients remains unclear.The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed colorectal cancer patients (n=238) in the prospective ColoCare Study, Heidelberg.We cross-sectionally analyzed associations between 12 B-vitamins and one-carbon metabolites and 10 inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesized that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers.We observed that PLP was inversely associated with CRP (r=-0.33, plinearlinear=0.003), IL-6 (r=-0.39, plinear linear=0.02) and TNFα (r=-0.12, plinear=0.045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r=-0.14), SAA (r=-0.14) and TNFα (r=-0.15) among colorectal cancer patients. Folate catabolite apABG was positively correlated with IL-6 (r= 0.27, plinearlinear<0.0001), indicating higher folate utilization during inflammation.Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among colorectal cancer patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for colorectal cancer patients.</p

The ELIXIR Human Copy Number Variations Community:building bioinformatics infrastructure for research

Copy number variations (CNVs) are major causative contributors both in the genesis of genetic diseases and human neoplasias. While 'High-Throughput' sequencing technologies are increasingly becoming the primary choice for genomic screening analysis, their ability to efficiently detect CNVs is still heterogeneous and remains to be developed. The aim of this white paper is to provide a guiding framework for the future contributions of ELIXIR's recently established h uman CNV Community, with implications beyond human disease diagnostics and population genomics. This white paper is the direct result of a strategy meeting that took place in September 2018 in Hinxton (UK) and involved representatives of 11 ELIXIR Nodes. The meeting led to the definition of priority objectives and tasks, to address a wide range of CNV-related challenges ranging from detection and interpretation to sharing and training. Here, we provide suggestions on how to align these tasks within the ELIXIR Platforms strategy, and on how to frame the activities of this new ELIXIR Community in the international context

Genetic variation in prostaglandin synthesis and related pathways, NSAID use and colorectal cancer risk in the Colon Cancer Family Registry

Although use of non-steroidal anti-inflammatory drugs (NSAIDs) generally decreases colorectal cancer (CRC) risk, inherited genetic variation in inflammatory pathways may alter their potential as preventive agents. We investigated whether variation in prostaglandin synthesis and related pathways influences CRC risk in the Colon Cancer Family Registry by examining associations between 192 single nucleotide polymorphisms (SNPs) and two variable nucleotide tandem repeats (VNTRs) within 17 candidate genes and CRC risk. We further assessed interactions between these polymorphisms and NSAID use on CRC risk. Using a case-unaffected-sibling-control design, this study included 1621 primary invasive CRC cases and 2592 sibling controls among Caucasian men and women aged 18–90. After adjustment for multiple comparisons, two intronic SNPs were associated with rectal cancer risk: rs11571364 in ALOX12 [ORhet/hzv = 1.87, 95% confidence interval (CI) = 1.19–2.95, P = 0.03] and rs45525634 in PTGER2 (ORhet/hzv = 0.49, 95% CI = 0.29–0.82, P = 0.03). Additionally, there was an interaction between NSAID use and the intronic SNP rs2920421 in ALOX12 on risk of CRC (P = 0.03); among those with heterozygous genotypes, risk was reduced for current NSAID users compared with never or former users (ORhet = 0.60, 95% CI = 0.45–0.80), though not among those with homozygous wild-type or variant genotypes. The results of this study suggest that genetic variation in ALOX12 and PTGER2 may affect the risk of rectal cancer. In addition, this study suggests plausible interactions between NSAID use and variants in ALOX12 on CRC risk. These results may aid in the development of genetically targeted cancer prevention strategies with NSAIDs

Downregulation of TFPI in breast cancer cells induces tyrosine phosphorylation signaling and increases metastatic growth by stimulating cell motility

<p>Abstract</p> <p>Background</p> <p>Increased hemostatic activity is common in many cancer types and often causes additional complications and even death. Circumstantial evidence suggests that tissue factor pathway inhibitor-1 (TFPI) plays a role in cancer development. We recently reported that downregulation of TFPI inhibited apoptosis in a breast cancer cell line. In this study, we investigated the effects of TFPI on self-sustained growth and motility of these cells, and of another invasive breast cancer cell type (MDA-MB-231).</p> <p>Methods</p> <p>Stable cell lines with TFPI (both α and β) and only TFPIβ downregulated were created using RNA interference technology. We investigated the ability of the transduced cells to grow, when seeded at low densities, and to form colonies, along with metastatic characteristics such as adhesion, migration and invasion.</p> <p>Results</p> <p>Downregulation of TFPI was associated with increased self-sustained cell growth. An increase in cell attachment and spreading was observed to collagen type I, together with elevated levels of integrin α2. Downregulation of TFPI also stimulated migration and invasion of cells, and elevated MMP activity was involved in the increased invasion observed. Surprisingly, equivalent results were observed when TFPIβ was downregulated, revealing a novel function of this isoform in cancer metastasis.</p> <p>Conclusions</p> <p>Our results suggest an anti-metastatic effect of TFPI and may provide a novel therapeutic approach in cancer.</p

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Beyond 1 Million Genomes (B1MG) D1.4 Report of Stakeholders Forum 2022 including recommendations to the 1+MG Working Groups

&lt;p&gt;The Beyond 1 Million Genomes (B1MG) project aims to facilitate the 1+MG initiative to provide access to genomics data and associated health data across borders and drive the development of personalised health strategies within Europe. The 1+MG/B1MG Stakeholder Forum 2022 held in October 2022, assembled for the third time a broad range of stakeholder experts, active in scientific and technical communities, international initiatives, projects, national healthcare systems, as well as industry to capture their input in the design of the infrastructure, the legal guidance and the best practices to realise the 1+MG infrastructure.&nbsp;&lt;/p&gt;&lt;p&gt;Being the last Stakeholder Forum (SF) organised by the B1MG project, this meeting centred on identifying how &lt;strong&gt;stakeholders&lt;/strong&gt; could &lt;strong&gt;contribute to the scale up and sustainability of the 1+MG/B1MG efforts&lt;/strong&gt;. The day included key updates on the progress of 1+MG/B1MG, specifically on the 1+MG Trust Framework (focussed on the ELSI and technical recommendations and guidelines for privacy-preserving access to genomics data), and including the B1MG Maturity Level Model as a tool for countries to assess progress towards implementation of genomics-based personalised health strategies into healthcare. This was then followed by a session on the next steps towards scale-up and implementation of the genomics data-sharing landscape by speakers from the recently established (1+MG-associated and EC-funded) Genomic Data Infrastructure (GDI) project, TEHDAS/EHDS and GAIA-X.&nbsp;&lt;/p&gt;&lt;p&gt;Acknowledging the role of industries in the scale-up and sustainability of these efforts, the day specifically included several ways to explore the role of companies as key stakeholders in realising cross-border genomic data sharing efforts and in developing a practice of genomics-based personalised health in 1+MG associated countries. A dedicated panel discussion included representatives from 1+MG WG7 (industry engagement), an umbrella industry organisation (EFPIA), an SME (Hyve - EHDEN project), as well as Australian Genomics, an initiative outside of Europe that has considered industry as part of their genomics activities. Clear recommendations were made to build a continuous exchange with industry to build mutual trust between public and private stakeholders. Further to this there was a proposal to explore the opportunity to establish a set of projects, such as under the framework of IHI. This clear output from the SF meeting should be explored further by the 1+MG initiative.&lt;/p&gt;&lt;p&gt;The second half of the day led into parallel workshops to consider scale up and sustainability in the context of rare diseases, cancer, common complex disease and infectious disease. The Trust Framework was regarded and the user communities addressed the question how stakeholders, including industry, could help realise these key components of the 1+MG infrastructure. It is clear that there are requirements specific to each disease community that are important to continuously review, discuss and understand in order to develop and sustain the 1+MG Trust Framework. The balance between how much research and care are entangled differs across use cases (rare diseases and cancer breakouts are already intertwined) and discussions stressed how the 1+MG infrastructure must be able to support primary and secondary use equally well.&nbsp;&nbsp;&lt;/p&gt;&lt;p&gt;The annual Stakeholder Forum meetings run by the B1MG project have all been very successful. They have strengthened the alignment of the stakeholders with the 1+MG initiative, enabling the leads of various activities to take on board suggestions and ensuring the outcomes of the project fit with stakeholder needs, encouraging innovation and alignment across a broader landscape. To continue stakeholder engagement and ensure further impact, these events will be continued as part of the GDI project.&lt;/p&gt