Abstract
We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple ...variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.
BACKGROUND:Metastatic carcinoma of a renal allograft is a rare but life threatening event with a difficult clinical management. Recent reports suggested a potential role of BK polyomavirus (BKPyV) in ...the development of urologic tract malignancies in kidney transplant recipients.
CASE STUDY:We investigated a kidney-pancreas female recipient with an history of BKPyV nephritis who developed a rapidly progressive and widely metastatic donor-derived renal carcinoma 9 years after transplantation. Histology and FISH analysis revealed a donor-derived (XY tumor cells) collecting (Bellini) duct carcinoma. The presence of BKPyV oncogenic large tumor antigen (LTag) was identified in large amount within the kidney tumor and the bowel metastases. Whole genome sequencing of the tumor confirmed multiple genome BKPyV integrations. The transplanted kidney was removed, immunosuppression was withdrawn, and recombinant interleukin-2 (IL-2) was administered for 3 months, inducing a complete tumor clearance, with no evidence of disease at 6-year follow-up. The immunological profiling during IL-2 therapy revealed the presence of donor-specific T cells and expanded cytokine-producing bright NK cells but no donor-specific antibodies. Finally, we found persistently elevated anti-BK virus IgG titers and a specific anti-BKPyV T cell response.
CONCLUSION:This investigation showed evidence for the potential oncogenic role of BKPyV in collecting duct carcinoma in renal allografts and demonstrated that immunosuppression withdrawal and IL-2 therapy can lead to an efficient antitumor cellular mediated rejection possibly via 3 distinct mechanisms including (1) host-versus-graft, (2) host-versus-tumor and (3) anti-BKPyV responses.
Abstract
Summary
Admixed populations, with their unique and diverse genetic backgrounds, are often underrepresented in genetic studies. This oversight not only limits our understanding but also ...exacerbates existing health disparities. One major barrier has been the lack of efficient tools tailored for the special challenges of genetic studies of admixed populations. Here, we present admix-kit, an integrated toolkit and pipeline for genetic analyses of admixed populations. Admix-kit implements a suite of methods to facilitate genotype and phenotype simulation, association testing, genetic architecture inference, and polygenic scoring in admixed populations.
Availability and implementation
Admix-kit package is open-source and available at https://github.com/KangchengHou/admix-kit. Additionally, users can use the pipeline designed for admixed genotype simulation available at https://github.com/UW-GAC/admix-kit_workflow.
Abstract Background Acute disseminated encephalomyelitis is an inflammatory-demyelinating disorder of the central nervous system usually with a monophasic course and a favorable neurological outcome. ...Long-term neurocognitive sequelae and quality of life have not yet been fully investigated. Aim To examine neurocognitive outcome and quality of life in pediatric monophasic acute disseminated encephalomyelitis. Methods Of the 36 patients diagnosed with acute disseminated encephalomyelitis at our institution, six were lost to follow-up and eight relapsed (two with multiphasic forms and six with multiple sclerosis). The outcome of the 22 remaining patients was evaluated using four subscales of the Wechsler Intelligence Scales for estimation of IQ, a battery of neuropsychological tests, and semistructured and PedsQL questionnaires for quality of life. The effect of age at onset, neuroradiological recovery, and time elapsed from the acute event on outcome was also investigated. Results Estimated IQ, neuropsychological mean group scores, and quality of life at follow-up were within the normal range, but 23% of the patients had pathological scores in various neuropsychological functions, among which attention was the most clearly affected. The neuroradiological recovery was not correlated with the result of the neuropsychological tests. Age at onset correlated with linguistic skills, whereas the time elapsed from the acute event had a significant effect on attention tasks: scores were worse in the group of patients with a follow-up shorter than 7 years. Conclusion Our results suggest that pediatric monophasic acute disseminated encephalomyelitis has a favorable neurocognitive outcome. Patients with longer follow-up had a better outcome, suggesting a neurocognitive course that is different from that of multiple sclerosis and a potential for long-term recovery of affected functions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Recent data suggest a potential activity and a good tolerability of capecitabine in advanced hepatocellular carcinoma (HCC).
To evaluate capecitabine activity and safety in a wide cohort of advanced ...HCC patients.
Retrospective analysis of 143 capecitabine-treated patients (January 2010 to December 2017) in three centers of the Veneto Oncology Network.
Capecitabine was administered in second and third line, but also in first line instead of sorafenib in Child-Pugh B patients (70%), compromised clinical conditions (14%) or contraindications to antiangiogenetics (16%). Median overall survival (OS) and time to progression (TTP) were 6.9 and 2.8 months, respectively. There were no differences in OS and TTP between the 32 patients treated with non-metronomic scheme (2000 mg/day for 14 days) and the 111 patients treated with metronomic scheme (1000 mg/day) after correction for prognostic factors at baseline with a propensity score analysis. Capecitabine was more active in patients intolerant to sorafenib than in those progressing during treatment (p = 0.024). At least one adverse event (mainly hematological) was experienced by 73% of patients but discontinuation was necessary only in 11 (8%).
Capecitabine can be considered an active and safe option in advanced HCC, especially for patients unfit for other treatments.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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