| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Smith, RM, et al.
(författare)
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Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis
- 2020
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 79:9, s. 1243-1249
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Tidskriftsartikel (refereegranskat)abstract
- Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.MethodsPatients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.Results188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections.ConclusionsThis large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.
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| 4. |
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| 5. |
- Smith, RM, et al.
(författare)
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Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial
- 2023
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 82:7, s. 937-944
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Tidskriftsartikel (refereegranskat)abstract
- Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab.MethodsRITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse).ResultsRituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups.ConclusionsFollowing induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse.Trial registration numberNCT01697267; ClinicalTrials.gov identifier
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| 6. |
- Mendoza, P., et al.
(författare)
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Starch and fiber intake effects on energy metabolism, growth, and carapacial scute pyramiding of red-footed tortoise hatchlings (Chelonoidis carbonaria)
- 2022
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Ingår i: Comparative Biochemistry and Physiology a-Molecular & Integrative Physiology. - : Elsevier BV. - 1095-6433. ; 265
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Tidskriftsartikel (refereegranskat)abstract
- Tortoise husbandry includes reports of excessive growth and carapace pyramiding, although triggers still remain to be fully elucidated. Juvenile red-footed tortoises (Chelonoidis carbonaria) were fed with two different diets, one high in fiber (HF; 14.2% crude fiber; 39.2% neutral detergent fiber, NDF; dry matter basis, DMB) and one high in starch (HS; 27.7% DMB), to assess effects on energy metabolism, nutrient digestibility, and growth. A total of 20 hatchlings (10 per diet) were used to evaluate: apparent digestibility coefficients (Da) of nutrients and gross energy (GE), passage times at 5 and 11 months of age; resting and post-prandial metabolic rates at 6 and 12 months of age; growth rates; pyramiding; and estimated body composition. Animals fed HS showed higher mass-specific intake of digestible energy (113.9 +/- 32.1 kJ kg(-1) day(-1) vs. 99.6 +/- 35.3 kJ kg(-1) day(-1); P < 0.05), digestible DM (6.1 +/- 1.8 g kg(-1) day(-1) vs. 5.0 +/- 1.8 g kg(-1) day(-1); P < 0.01), shorter transit (3 +/- 1 days vs. 4 +/- 1 days; P < 0.01) and retention times (8 +/- 2 days vs. 10 +/- 2 days; P < 0.01), and higher Da of DM, starch, NDF, and GE. Crude protein Da was higher for HF. Rest and post-prandial metabolic rates, and pyramiding degree were not affected by diets. At 13 months, the animals from HS presented wider plastrons and carapaces, and higher carapace width growth rates. In addition, these animals had lower body mineral content (1.88 +/- 0.15% vs. 2.15 +/- 0.19%; P < 0.01) and bone density (0.13 +/- 0.01 g mm(-2) vs. 0.15 +/- 0.02 g mm(-2); P < 0.02). Results provide evidence that highly digestible foods can accelerate shell growth and lower mineralization in this species.
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| 7. |
- Mendoza, P., et al.
(författare)
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Temperature effects on metabolism and energy requirement during the fast growth phase in the red-footed tortoise, Chelonoidis carbonaria
- 2023
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Ingår i: Journal of Comparative Physiology B-Biochemical Systems and Environmental Physiology. - 0174-1578. ; 193:6, s. 661-676
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Tidskriftsartikel (refereegranskat)abstract
- Early life is a challenging phase because of the high rates of morphophysiological development and growth. Changes in ambient temperature, which directly affect energy metabolism and digestive functions in ectotherms, may be of great impact during this phase. We addressed this issue in red-footed tortoise (Chelonoidis carbonaria) hatchlings kept in captivity. To this end, we investigated the effect of temperature (28 degrees C and 18 degrees C) on mass-specific gross energy intake ( GEI(m)), daily body mass gain (MG), daily intake of gross energy (GEI), digestible energy (DEI), resting metabolic rate (RMR), and specific dynamic action (SDA) components during different seasons in the first 13 months after hatching. Greater GEI(m) and MG were observed in spring (381.7 +/- 84.9 J.g(-0.86).day(-1) and 0.9 +/- 0.4 g.day(-1)) and summer (356.9 +/- 58.9 J.g(-0.86).day(-1) and 1.0 +/- 0.4 g.day(-1)). The highest and lowest RMRs at 28 degrees C were observed in spring (36.4 +/- 5.1 kJ.kg(-1).day(-1)) and winter (22.4 +/- 6.2 kJ.kg(-1). day(-1)), respectively. Regardless season, hatchlings showed greater GEI and DEI, O-2 consumption, CO2 production, RMR, maximum metabolic rate after feeding (FMRMAX), and heat increment ( FMRMAX- RMR) at 28 degrees C compared to 18 degrees C. In addition, the significant body mass influence showed allometric exponents of 0.62 at 28 degrees C and 0.92 at 18 degrees C for RMR. Our results indicate an important effect of environmental temperature on energy requirements and utilization in C. carbonaria hatchlings, which is seasonally influenced even in this early phase of life.
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| 8. |
- Yasuda, Kazuki, et al.
(författare)
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Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:9, s. 1092-1097
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Tidskriftsartikel (refereegranskat)abstract
- We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest P value (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.
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| 9. |
- Danno, A., et al.
(författare)
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Effect of cold severe deformation by multi directional forging on elastic modulus of multi functional Ti+25mol% (Ta,Nb,V)+(Zr,Hr,O) alloy
- 2010
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Ingår i: Materials & Design. - : Elsevier BV. - 0261-3069. ; 31:SUPPL. 1, s. S61-S65
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Tidskriftsartikel (refereegranskat)abstract
- A new and unique beta-titanium alloy (Ti. +. 25. mol% (Ta,Nb,V). +. (Zr,Hr,O) has interesting properties such as low elastic modulus, high strength and high elastic deformability as well as Invar and Elinvar properties. These properties have been successfully realized for the round wire or rods by cold working process but not enough for the sheet made by the cold rolling.To improve the mechanical properties of the alloy sheet, the effect of cold severe deformation on the elastic modulus and microstructure of the alloy sheet was experimentally investigated. The samples were processed using the multi directional forging (MDF) and cold plain rolling.The elastic modulus of the alloy sheet which was cold rolled after MDF was lower than that of cold rolled sheet without MDF. The severe cold plastic deformation by MDF was also effective for obtaining isotropic elastic modulus and very fine grain size (∌1ÎŒm) of sheet after plain rolling. The prototype sheet with low elastic modulus (60-65. GPa), high strength (1100. MPa) and high ductility (total elongation more than 10%) was successfully made in the laboratory test by combining MDF and plain rolling at room temperature. © 2009 Elsevier Ltd.
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| 10. |
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