| 1. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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| 2. |
- Zaidi, Syed H., et al.
(författare)
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Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival
- 2020
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR=0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR=1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.
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| 3. |
- Bladek, Kamila J, et al.
(författare)
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Microsphere Assemblies via Phosphonate Monoester Coordination Chemistry
- 2018
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Ingår i: Chemistry - A European Journal. - : John Wiley & Sons. - 0947-6539 .- 1521-3765. ; 24:7, s. 1533-1538
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Tidskriftsartikel (refereegranskat)abstract
- By complexing a bent phosphonate monoester ligand with cobalt(II), coupled with in situ ester hydrolysis, coordination microspheres (CALS=CALgary Sphere) are formed whereas the use of the phosphonic acid directly resulted in a sheet-like structure. Manipulation of the synthetic conditions gave spheres with different sizes, mechanical stabilities, and porosities. Time-dependent studies determined that the sphere formation likely occurred through the formation of a Co2+ and ligand chain that propagates in three dimensions through different sets of interactions. The relative rates of these assembly processes versus annealing by ester hydrolysis and metal dehydration determine the growth of the microspheres. Hardness testing by nanoindentation is carried out on the spheres and sheets. Notably, no templates or capping agents are employed, the growth of the spheres is intrinsic to the ligand geometry and the coordination chemistry of cobalt(II) and the phosphonate monoester.
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| 4. |
- Borozan, Ivan, et al.
(författare)
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Molecular and Pathology Features of Colorectal Tumors and Patient Outcomes Are Associated with Fusobacterium nucleatum and Its Subspecies animalis
- 2022
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 31:1, s. 210-220
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis.Methods: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer-specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer-specific mortality, and somatic mutations.Results: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer-specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07-3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer-specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations.Conclusions: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer-specific mortality and specific somatic mutated genes.
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| 5. |
- Hayakawa, K, et al.
(författare)
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The Osaka University Aged Twin Registry: epigenetics and identical twins discordant for aging-dependent diseases
- 2006
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Ingår i: Twin research and human genetics : the official journal of the International Society for Twin Studies. - : Cambridge University Press (CUP). - 1832-4274. ; 9:6, s. 808-810
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Tidskriftsartikel (refereegranskat)abstract
- The Osaka University Aged Twin Registry (OUATR) is the largest adult twin registry in Japan. Since its establishment in 1974, the OUATR has conducted a number of studies with particular focus on the environmental contribution to physical–cognitive–mental aging, longevity and aging-dependent diseases in later adulthood. The registry consists of 12,000 pairs of Japanese twins born between 1900 and 1935. Two hundred and fifty pairs of twins have undergone comprehensive medical examination to date. Follow-up questionnaires have been mailed out on a regular basis, for the purpose of checking current vital statuses, health conditions, and so forth. The main objective of this longitudinal twin study is to contribute to the prevention of lifestyle-related diseases and the promotion of successful aging.
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| 6. |
- Hidaka, Akihisa, et al.
(författare)
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Intake of Dietary Fruit, Vegetables, and Fiber and Risk of Colorectal Cancer According to Molecular Subtypes : A Pooled Analysis of 9 Studies
- 2020
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 80:20, s. 4578-4590
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Tidskriftsartikel (refereegranskat)abstract
- Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65–1.04)] but not BRAF-wildtype tumors [1.09 (0.97–1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case–control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (Ptrend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported.
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| 7. |
- Konishi, T, et al.
(författare)
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Electronic structure of the strongly hybridized ferromagnet CeFe2
- 2000
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Ingår i: PHYSICAL REVIEW B. - : AMERICAN PHYSICAL SOC. - 0163-1829. ; 62:21, s. 14304-14312
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Tidskriftsartikel (refereegranskat)abstract
- We report on results from high-energy spectroscopic measurements on CeFe2, a system of particular interest due to its anomalous ferromagnetism with an unusually low Curie temperature and small magnetization compared to the other rare-earth iron Laves phas
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| 8. |
- Konishi, T, et al.
(författare)
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Photoemission and inverse-photoemission study of ferromagnetic valence fluctuating system CeFe2
- 1998
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Ingår i: JOURNAL OF ELECTRON SPECTROSCOPY AND RELATED PHENOMENA. - : ELSEVIER SCIENCE BV. - 0368-2048. ; 88, s. 303-307
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Various electron-spectroscopic results including core-level X-ray photoemission, X-ray absorption, Ce 3d-4f and 4d-4f resonant photoemission, and inverse-photoemission spectroscopy on the valence fluctuating ferromagnet CeFe2 are presented and analyzed wi
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| 9. |
- Titarenko, Yu E., et al.
(författare)
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Measurement and simulation of the cross sections for nuclide production in Fe-56 and Cr-nat targets irradiated with 0.04- to 2.6-GeV protons
- 2011
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Ingår i: Physics of Atomic Nuclei. - 1063-7788 .- 1562-692X. ; 74:4, s. 523-536
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Tidskriftsartikel (refereegranskat)abstract
- The cross sections for nuclide production in thin Fe-56 and Cr-nat targets irradiated by 0.04-2.6-GeV protons are measured by direct gamma spectrometry using two gamma spectrometers with the resolutions of 1.8 and 1.7 keV for the Co-60 1332-keV gamma line. As a result, 649 yields of radioactive residual product nuclei have been obtained. The Al-27(p, x)Na-22 reaction has been used as a monitor reaction. The experimental data are compared with the MCNPX (BERTINI, ISABEL), CEM03.02, INCL4.2, INCL4.5, PHITS, and CASCADE07 calculations.
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| 10. |
- Titarenko, Yu E., et al.
(författare)
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Measurement and simulation of the cross sections for nuclide production in Nb-93 and Ni-nat targets irradiated with 0.04- to 2.6-GeV protons
- 2011
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Ingår i: Physics of Atomic Nuclei. - 1063-7788 .- 1562-692X. ; 74:4, s. 537-550
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Tidskriftsartikel (refereegranskat)abstract
- The cross sections for nuclide production in thin Nb-93 and Ni-nat targets irradiated by 0.04- to 2.6-GeV protons have been measured by direct gamma spectrometry using two gamma spectrometers with the resolutions of 1.8 and 1.7 keV in the Co-60 1332-keV gamma line. As a result, 1112 yields of radioactive residual nuclei have been obtained. The Al-27(p, x)Na-22 reaction has been used as a monitor reaction. The experimental data have been compared with the MCNPX (BERTINI, ISABEL), CEM03.02, INCL4.2, INCL4.5, PHITS, and CASCADE07 calculations.
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| 11. |
- Titarenko, Yu E., et al.
(författare)
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Measurement and simulation of the cross sections for nuclide production in W-nat and Ta-181 targets irradiated with 0.04- to 2.6-GeV protons
- 2011
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Ingår i: Physics of Atomic Nuclei. - 1063-7788 .- 1562-692X. ; 74:4, s. 551-572
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Tidskriftsartikel (refereegranskat)abstract
- The cross sections for nuclide production in thin (nat)Wand Ta-181 targets irradiated by 0.04-2.6-GeV protons have been measured by direct gamma spectrometry using two gamma spectrometers with the resolutions of 1.8 and 1.7 keV in the Co-60 1332-keV gamma line. As a result, 1895 yields of radioactive residual product nuclei have been obtained. The Al-27(p, x)Na-22 reaction has been used as a monitor reaction. The experimental data have been compared with the MCNPX (BERTINI, ISABEL), CEM03.02, INCL4.2, INCL4.5, PHITS, and CASCADE07 calculations.
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| 12. |
- Titarenko, Yu E., et al.
(författare)
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Measurement and simulation of the cross sections for the production of Gd-148 in thin W-nat and Ta-181 targets irradiated with 0.4- to 2.6-GeV protons
- 2011
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Ingår i: Physics of Atomic Nuclei. - 1063-7788 .- 1562-692X. ; 74:4, s. 573-579
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Tidskriftsartikel (refereegranskat)abstract
- The cross sections for the production of Gd-148 in W-nat and Ta-181 targets irradiated by 0.4-, 0.6-, 0.8-, 1.2-, 1.6-, and 2.6-GeV protons at the ITEP accelerator complex have been measured by direct alpha spectrometry without chemical separation. The experimental data have been compared with the data obtained at other laboratories and with the theoretical simulations of the yields on the basis of the BERTINI, ISABEL, CEM03.02, INCL4.2, INCL4.5, CASCADE07, and PHITS codes.
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| 13. |
- Titarenko, Yu. E., et al.
(författare)
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Verification of high-energy transport codes on the basis of activation data
- 2011
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 84:6, s. 064612-
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Tidskriftsartikel (refereegranskat)abstract
- Nuclide production cross sections measured at the Institute for Theoretical and Experimental Physics (ITEP) for the targets of (nat)Cr, (56)Fe, (nat)Ni, (93)Nb, (181)Ta, (nat)W, (nat)Pb, and (209)Bi irradiated by protons with energies from 40 to 2600 MeV were used to estimate the predictive accuracy of several popular high-energy transport codes. A general agreement of the ITEP data with the data obtained by other groups, including the numerous GSI data measured by the inverse kinematics method was found. Simulations of the measured data were performed with the MCNPX (BERTINI and ISABEL options), CEM03.02, INCL4.2 + ABLA, INCL4.5 + ABLA07, PHITS, and CASCADE.07 codes. Deviation factors between the calculated and experimental cross sections have been estimated for each target and for the whole energy range covered by our measurements. Two-dimensional diagrams of deviation factor values were produced for estimating the predictive power of every code for intermediate, not measured masses of nuclei targets and bombarding energies of protons. Further improvements of all tested here codes are recommended. In addition, new measurements at ITEP of nuclide yields from the (208)Pb target irradiated by 500-MeV protons are presented. A good agreement between these new data and the GSI measurements obtained by the inverse kinematics method was found.
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| 14. |
- Ugai, Tomotaka, et al.
(författare)
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Molecular characteristics of early-onset colorectal cancer according to detailed anatomical locations : comparison with later-onset cases
- 2023
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Ingår i: American Journal of Gastroenterology. - : Wolters Kluwer. - 0002-9270 .- 1572-0241. ; 118:4, s. 712-726
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION:Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management.METHODS:Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases.RESULTS:The proportions of MSI-high, CIMP-high, and BRAF-mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF-mutated) (all Ptrend<0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors (P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend<0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend.DISCUSSION:Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.
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| 15. |
- Ugai, Tomotaka, et al.
(författare)
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Prognostic role of detailed colorectal location and tumor molecular features : analyses of 13,101 colorectal cancer patients including 2994 early-onset cases
- 2023
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Ingår i: Journal of gastroenterology. - : Springer. - 0944-1174 .- 1435-5922. ; 58, s. 229-245
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Tidskriftsartikel (refereegranskat)abstract
- Background: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics.Methods: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation.Results: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (Ptrend = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (Pinteraction = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [Ptrend < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70–0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI 1.15–3.92). The prognostic association of colon tumor location also differed by CIMP status (Pinteraction = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages.Conclusions: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research.
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