GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma.

Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (OR(combined)  = 0.64, P(combined)  = 2 × 10(-21)) located 962 bp away from rs10484561 (r(2)<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:OR(adjusted)  = 0.70, P(adjusted)  =  4 × 10(-12); rs10484561:OR(adjusted)  = 1.64, P(adjusted)  = 5 × 10(-15)). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (OR(combined)  = 1.36, P(combined)  =  1.4 × 10(-7)). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.

Radiation-induced DNA double-strand breaks in cortisol exposed fibroblasts as quantified with the novel foci-integrated damage complexity score (FIDCS).

Without the protective shielding of Earth's atmosphere, astronauts face higher doses of ionizing radiation in space, causing serious health concerns. Highly charged and high energy (HZE) particles are particularly effective in causing complex and difficult-to-repair DNA double-strand breaks compared to low linear energy transfer. Additionally, chronic cortisol exposure during spaceflight raises further concerns, although its specific impact on DNA damage and repair remains unknown. This study explorers the effect of different radiation qualities (photons, protons, carbon, and iron ions) on the DNA damage and repair of cortisol-conditioned primary human dermal fibroblasts. Besides, we introduce a new measure, the Foci-Integrated Damage Complexity Score (FIDCS), to assess DNA damage complexity by analyzing focus area and fluorescent intensity. Our results show that the FIDCS captured the DNA damage induced by different radiation qualities better than counting the number of foci, as traditionally done. Besides, using this measure, we were able to identify differences in DNA damage between cortisol-exposed cells and controls. This suggests that, besides measuring the total number of foci, considering the complexity of the DNA damage by means of the FIDCS can provide additional and, in our case, improved information when comparing different radiation qualities.

Bioprinting of Cardiac Tissue in Space: Where Are We?

Bioprinting in space is the next frontier in tissue engineering. In the absence of gravity, novel opportunities arise, as well as new challenges. The cardiovascular system needs particular attention in tissue engineering, not only to develop safe countermeasures for astronauts in future deep and long-term space missions, but also to bring solutions to organ transplantation shortage. In this perspective, the challenges encountered when using bioprinting techniques in space and current gaps that need to be overcome are discussed. The recent developments that have been made in the bioprinting of heart tissues in space and an outlook on potential future bioprinting opportunities in space are described.

The Effects of Combined Exposure to Simulated Microgravity, Ionizing Radiation, and Cortisol on the In Vitro Wound Healing Process.

Human spaceflight is associated with several health-related issues as a result of long-term exposure to microgravity, ionizing radiation, and higher levels of psychological stress. Frequent reported skin problems in space include rashes, itches, and a delayed wound healing. Access to space is restricted by financial and logistical issues; as a consequence, experimental sample sizes are often small, which limits the generalization of the results. Earth-based simulation models can be used to investigate cellular responses as a result of exposure to certain spaceflight stressors. Here, we describe the development of an in vitro model of the simulated spaceflight environment, which we used to investigate the combined effect of simulated microgravity using the random positioning machine (RPM), ionizing radiation, and stress hormones on the wound-healing capacity of human dermal fibroblasts. Fibroblasts were exposed to cortisol, after which they were irradiated with different radiation qualities (including X-rays, protons, carbon ions, and iron ions) followed by exposure to simulated microgravity using a random positioning machine (RPM). Data related to the inflammatory, proliferation, and remodeling phase of wound healing has been collected. Results show that spaceflight stressors can interfere with the wound healing process at any phase. Moreover, several interactions between the different spaceflight stressors were found. This highlights the complexity that needs to be taken into account when studying the effect of spaceflight stressors on certain biological processes and for the aim of countermeasures development.

The Cardiovascular System in Space: Focus on In Vivo and In Vitro Studies.

On Earth, humans are subjected to a gravitational force that has been an important determinant in human evolution and function. During spaceflight, astronauts are subjected to several hazards including a prolonged state of microgravity that induces a myriad of physiological adaptations leading to orthostatic intolerance. This review summarises all known cardiovascular diseases related to human spaceflight and focusses on the cardiovascular changes related to human spaceflight (in vivo) as well as cellular and molecular changes (in vitro). Upon entering microgravity, cephalad fluid shift occurs and increases the stroke volume (35-46%) and cardiac output (18-41%). Despite this increase, astronauts enter a state of hypovolemia (10-15% decrease in blood volume). The absence of orthostatic pressure and a decrease in arterial pressures reduces the workload of the heart and is believed to be the underlying mechanism for the development of cardiac atrophy in space. Cellular and molecular changes include altered cell shape and endothelial dysfunction through suppressed cellular proliferation as well as increased cell apoptosis and oxidative stress. Human spaceflight is associated with several cardiovascular risk factors. Through the use of microgravity platforms, multiple physiological changes can be studied and stimulate the development of appropriate tools and countermeasures for future human spaceflight missions in low Earth orbit and beyond.

Distinct DNA methylation targets by aging and chronic inflammation: a pilot study using gastric mucosa infected with Helicobacter pylori.

BACKGROUND: Aberrant DNA methylation is induced by aging and chronic inflammation in normal tissues. The induction by inflammation is widely recognized as acceleration of age-related methylation. However, few studies addressed target genomic regions and the responsible factors in a genome-wide manner. Here, we analyzed methylation targets by aging and inflammation, taking advantage of the potent methylation induction in human gastric mucosa by Helicobacter pylori infection-triggered inflammation. RESULTS: DNA methylation microarray analysis of 482,421 CpG probes, grouped into 270,249 genomic blocks, revealed that high levels of methylation were induced in 44,461 (16.5%) genomic blocks by inflammation, even after correction of the influence of leukocyte infiltration. A total of 61.8% of the hypermethylation was acceleration of age-related methylation while 21.6% was specific to inflammation. Regions with H3K27me3 were frequently hypermethylated both by aging and inflammation. Basal methylation levels were essential for age-related hypermethylation while even regions with little basal methylation were hypermethylated by inflammation. When limited to promoter CpG islands, being a microRNA gene and high basal methylation levels strongly enhanced hypermethylation while H3K27me3 strongly enhanced inflammation-induced hypermethylation. Inflammation was capable of overriding active transcription. In young gastric mucosae, genes with high expression and frequent mutations in gastric cancers were more frequently methylated than in old ones. CONCLUSIONS: Methylation by inflammation was not simple acceleration of age-related methylation. Targets of aberrant DNA methylation were different between young and old gastric mucosae, and driver genes were preferentially methylated in young gastric mucosa.

CDX2 expression is concordant between primary colorectal cancer lesions and corresponding liver metastases independent of chemotherapy: a single-center retrospective study in Japan.

OBJECTIVE: Loss of caudal-type homeobox transcription factor 2 (CDX2) expression in colorectal cancers (CRCs) has recently been proposed as a promising predictive biomarker for not only prognosis but also response to chemotherapy. However, the relationship between alterations in CDX2 expression during cancer progression and response to chemotherapy remains unclear. We herein aimed to determine the concordance of CDX2 expression between primary CRCs and corresponding liver metastases, in association with chemotherapy. RESULTS: Primary CRCs exhibited heterogeneous CDX2 expression. Seven of the 144 CRCs in the cohort (4.9%, 95% confidential interval, 2.0%-9.8%) were CDX2-negative. The concordance rate of the CDX2 expression status in patients who did not receive chemotherapy was 100% (P = 0.041), whereas the concordance rate among patients who received chemotherapy only after primary resection was 96.3% (P = 0.005). Moreover, the concordance rate in patients who received chemotherapy before both primary resection and liver metastasectomy was 100% (P < 0.001). CONCLUSION: CDX2 expression status was highly concordant between primary CRCs and corresponding liver metastases, independent of chemotherapy, suggesting that the CDX2 expression status in CRCs was not affected by metastasis or chemotherapy. METHODS: A total of 144 consecutive patients with CRC who were treated at a single center in Japan between 2006 and 2014 were included. Formalin-fixed paraffin-embedded whole sections of surgically resected primary CRCs and corresponding liver metastases were assessed for CDX2 expression by immunohistochemistry.

Interleukin-1ß induced by Helicobacter pylori infection enhances mouse gastric carcinogenesis.

Interleukin-1ß (Il1b) is considered to be involved in Helicobacter pylori (HP)-induced human gastric carcinogenesis, while the role of its polymorphisms in gastric cancer susceptibility remains controversial. Here, we aimed to clarify the role of HP infection-induced IL1B in gastric inflammation and carcinogenesis using Il1b(-/-) (Il1b-null) mice. In gastric mucosa of the Il1b(+/+) (WT) mice, HP infection induced Il1b expression and severe inflammation. In contrast, in Il1b-null mice, recruitment of neutrophils and macrophages by HP infection was markedly suppressed. In a carcinogenicity test, the multiplicity of gastric tumors was significantly suppressed in theIl1b-null mice (58% of WT; P<0.005). Mechanistically, HP infection induced NF-κB activation both in the inflammatory and epithelial cells in gastric mucosae, and the activation was attenuated in the Il1b-null mice. Accordingly, increased proliferation and decreased apoptosis of gastric epithelial cells induced by HP infection in the WT mice were attenuated in the Il1b-null mice. These results demonstrated that the IL1B physiologically induced by HP infection enhanced gastric carcinogenesis by affecting both inflammatory and epithelial cells.

Comprehensive DNA methylation and extensive mutation analyses reveal an association between the CpG island methylator phenotype and oncogenic mutations in gastric cancers.

Recent development of personal sequencers for extensive mutation analysis and bead array technology for comprehensive DNA methylation analysis have made it possible to obtain integrated pictures of genetic and epigenetic alterations on the same set of cancer samples. Here, we aimed to establish such pictures of gastric cancers (GCs). Comprehensive methylation analysis of 30 GCs revealed that the number of aberrantly methylated genes was highly variable among individual GCs. Extensive mutation analysis of 55 known cancer-related genes revealed that 19 of the 30 GCs had 24 somatic mutations of eight different genes (CDH1, CTNNB1, ERBB2, KRAS, MLH1, PIK3CA, SMARCB1, and TP53). Integration of information on the genetic and epigenetic alterations revealed that the GCs with the CpG island methylator phenotype (CIMP) tended to have mutations of oncogenes, CTNNB1, ERBB2, KRAS, and PIK3CA. This is one of the first studies in which both genetic and epigenetic alterations were extensively analyzed in the same set of samples. It was also demonstrated for the first time in GCs that the CIMP was associated with oncogene mutations.

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

NordicDB: a Nordic pool and portal for genome-wide control data.

A cost-efficient way to increase power in a genetic association study is to pool controls from different sources. The genotyping effort can then be directed to large case series. The Nordic Control database, NordicDB, has been set up as a unique resource in the Nordic area and the data are available for authorized users through the web portal (http://www.nordicdb.org). The current version of NordicDB pools together high-density genome-wide SNP information from ∼5000 controls originating from Finnish, Swedish and Danish studies and shows country-specific allele frequencies for SNP markers. The genetic homogeneity of the samples was investigated using multidimensional scaling (MDS) analysis and pairwise allele frequency differences between the studies. The plot of the first two MDS components showed excellent resemblance to the geographical placement of the samples, with a clear NW-SE gradient. We advise researchers to assess the impact of population structure when incorporating NordicDB controls in association studies. This harmonized Nordic database presents a unique genome-wide resource for future genetic association studies in the Nordic countries.