Rare cancers comprise almost a quarter of all cancers in Europe, and patients generally have poorer outcomes than those suffering from more common cancers. This is attributed in part to a general ...lack of knowledge and awareness of rare cancers. This review aims to examine the communication strategies being used throughout the world to inform on rare cancers and to highlight any opportunities for improvement.
A systematic review of literature published in English prior to November 2018 will be conducted, screening articles from the electronic databases MEDLINE, PubMed, EMBASE, Web of Science, PsycINFO, CINAHL Plus and the Cochrane Database of Systematic Reviews. Grey literature databases (GreyLit, OpenGrey) will also be searched in order to screen for any unpublished works. As well as primary literature, reference lists will be examined via forward and reverse citation screening. The review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Titles and abstracts will first be examined for eligibility, with remaining studies undergoing a full-text screening before being included in the final review. Individual studies will be screened for bias, and a meta-analysis performed provided there is enough data. If insufficient homogenous literature exists, a narrative summary of the literature will be produced.
Despite the broad topic and width of study type that will be considered, this review hopes to provide a reflective summary of the communication strategies available for people living with and working with rare cancer. It aims to reveal any gaps in the resources available, to contribute to the long-term improvement of diagnosis and management of rare cancers.
PROSPERO CRD42018099784.
Many people living with a rare disease (RD) are cared for by a family member. Due to a frequent lack of individual RD knowledge from healthcare professionals, the patient and their informal caregiver ...are frequently obliged to become 'experts' in their specific condition. This puts a huge strain on family life and results in caregivers juggling multiple roles in addition to unique caring roles including as advocate, case manager and medical navigator. We conducted a rapid review of literature reporting on the unmet needs of informal caregivers for people living with an RD. All searches were conducted on 14 September 2021, followed by a manual searches of reference lists on 21 September 2021.
Searches were conducted in Medline, Embase, Web of Science, GreyLit and OpenGrey.
Thirty-five papers were included in the final review and data extracted. This rapid review presents several unmet needs identified by informal caregivers of persons with an RD. The related literature was organised thematically: caregiver burden, support through the diagnosis process, social needs, financial needs, psychological needs, information and communication needs and acknowledgement from healthcare professionals.
This review provides evidence that increased meaningful support is required for caregivers. Active engagement should be encouraged from this cohort in future research and awareness raised of the support available to improve the quality of life for families living with an RD. The unmet needs identified through this review will benefit people living with an RD, caregivers, healthcare professionals and policy makers.
Altered DNA methylation and microRNA profiles are associated with diabetic kidney disease. This study compared different sequencing approaches to define the genetic and epigenetic architecture of ...sequences surrounding microRNAs associated with diabetic kidney disease.
We compared Sanger and next generation sequencing to validate microRNAs associated with diabetic kidney disease identified from an epigenome-wide association study (EWAS). These microRNAs demonstrated differential methylation levels in cases with diabetic kidney disease compared to controls with long duration of type 1 diabetes and no evidence of kidney disease (P
< 10
). Targeted next generation sequencing analysis of genomic DNA and matched cell-line transformed DNA samples identified four genomic variants within the microRNAs, two within miR-329-2 and two within miR-429. Sanger sequencing of genomic DNA replicated these findings and confirmed the altered methylation status of the CpG sites identified by the EWAS in bisulphite-treated DNA. This investigation successfully fine-mapped the genetic sequence around key microRNAs. Variants have been detected which may affect their methylation status and methylated CpG sites have been confirmed. Additionally, we explored both the fidelity of next generation sequencing analysis and the potential efficacy of cell-line transformed DNA samples in place of finite patient samples in discovery genetic and epigenetic research.
Abstract Background Kidney transplantation is a procedure that transforms recipients' lives, and 1-year transplant and patient survival are now excellent. However, improvements in long-term outcomes ...after kidney transplantation have been disappointing. New onset diabetes after transplantation (NODAT) is a common complication that reduces recipient survival. The aim of this study was to investigate clinical, genetic, and epigenetic risk factors for NODAT. Methods We included all adult recipients of first, deceased-donor kidney transplants in Northern Ireland between 1986 and 2005 who had a functioning transplant at 12 months. NODAT was defined as diabetes developing after transplantation that required pharmacotherapy. Clinical data were recorded prospectively and variables associated with NODAT were identified in multivariate analysis. A genome-wide association study (GWAS) was done in a subset of NODAT cases and controls (Illumina 660K array). Single nucleotide polymorphisms (SNPs) associated with NODAT and SNPs previously reported to be associated with NODAT in a white population were subsequently genotyped in all NODAT cases and controls. Epigenome wide DNA methylation analysis was performed (Infinium Methylation 450K array) on blood-derived DNA acquired immediately before transplantation. Findings Of 529 patients receiving kidney transplants, 57 developed NODAT. In multivariate analysis, recipient age (odds ratio OR 1·4 per decade, 95% CI 1·1–1·8), female gender (2·2, 1·2–4·3), weight at transplantation (1·03 per kg, 1·01–1·05), and percentage weight gain in the first year (2·0, 1·3–3·1) were associated with NODAT. There were 561 233 SNPs genotyped in the subset of 26 NODAT cases and 230 controls; 26 SNPs were associated with NODAT (p<10−5 ). De-novo genotyping was undertaken in 57 NODAT cases and 383 controls. In multivariate analysis, eight novel SNPs remained associated with NODAT (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, rs4394754). In gene enrichment analysis, the response to stimulus gene set had the highest enrichment score (p=0·006). DNA methylation was analysed at 485 577 CpG sites. After quality control, differential methylation at 14 CpG sites remained associated with NODAT (ANOVA p<10−5 ). These associations did not persist after adjustment for multiple testing. Interpretation This is the first genome and epigenome wide association study, to our knowledge, to investigate variants for association with NODAT. Eight novel SNPs remained associated with NODAT after adjustment for potentially confounding clinical variables. Seven of these SNPs are implicated in β-cell apoptosis. Our results corroborate recent reports suggesting that β-cell stress due to post-transplant hyperglycaemia could be crucial in the pathogenesis of NODAT. There was no association between DNA methylation before transplantation and NODAT. However, it is plausible that hyperglycemia post-transplantation alters DNA methylation in key genes and might contribute to NODAT pathogenesis in this manner. This hypothesis requires further investigation. Funding Funding Kidney Research UK, Northern Ireland Kidney Research Fund.
Biologically active vitamin D has an important regulatory role within the genome. It binds the vitamin D receptor (VDR) in order to control the expression of a wide range of genes as well as ...interacting with the epigenome to modify chromatin and methylation status. Vitamin D deficiency is associated with several human diseases including end-stage renal disease.
This article describes the design and testing of a custom, targeted next generation sequencing (NGS) panel for selected vitamin D associated genes. Sequencing runs were used to determine the effectiveness of the panel for variant calling, to compare efficiency and data across different sequencers, and to perform representative, proof of principle association analyses. These analyses were underpowered for significance testing. Amplicons were designed in two pools (163 and 166 fragments respectively) and used to sequence two cohorts of renal transplant recipients on the Ion Personal Genome Machine (PGM)™ and Ion S5™ XL desktop sequencers.
Coverage was provided for 43.8 kilobases across seven vitamin D associated genes (CYP24A1, CUBN, VDR, GC, NADSYN1, CYP27B1, CYP2R1) as well as 38 prioritised SNPs. Sequencing runs provided sufficient sequencing quality, data output and validated the effective library preparation and panel design.
This novel, custom-designed, validated panel provides a fast, cost effective, and specific approach for the analysis of vitamin D associated genes in a wide range of patient cohorts. This article does not report results from a controlled health-care intervention.
Immunosuppression is cornerstone treatment of antineutrophil cytoplasmic antibody associated vasculitis (AAV) but is later complicated by infection, cancer, cardiovascular and chronic kidney disease. ...Caveolin-1 is an essential structural protein for small cell membrane invaginations known as caveolae. Its functional role has been associated with these complications. For the first time, caveolin-1 (CAV1) gene variation is studied in AAV.
CAV1 single nucleotide polymorphism rs4730751 was analysed in genomic DNA from 187 white patients with AAV from Birmingham, United Kingdom. The primary outcome measure was the composite endpoint of time to all-cause mortality or renal replacement therapy. Secondary endpoints included time to all-cause mortality, death from sepsis or vascular disease, cancer and renal replacement therapy. Validation of results was sought from 589 white AAV patients, from two European cohorts.
The primary outcome occurred in 41.7% of Birmingham patients. In a multivariate model, non-CC genotype variation at the studied single nucleotide polymorphism was associated with increased risk from: the primary outcome measure HR 1.86; 95% CI: 1.14-3.04; p=0.013, all-cause mortality HR:1.83; 95% CI: 1.02-3.27; p=0.042, death from infection HR:3.71; 95% CI: 1.28-10.77; p=0.016, death from vascular disease HR:3.13; 95% CI: 1.07-9.10; p=0.037, and cancer HR:5.55; 95% CI: 1.59-19.31; p=0.007. In the validation cohort, the primary outcome rate was far lower (10.4%); no association between genotype and the studied endpoints was evident.
The presence of a CC genotype in Birmingham is associated with protection from adverse outcomes of immunosuppression treated AAV. Lack of replication in the European cohort may have resulted from low clinical event rates. These findings are worthy of further study in larger cohorts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Caveolae are plasma membrane structures formed from a complex of the proteins caveolin-1 and caveolin-2. Caveolae interact with pro-inflammatory cytokines and are dysregulated in fibrotic disease. ...Although caveolae are present infrequently in healthy kidneys, they are abundant during kidney injury. An association has been identified between a CAV1 gene variant and long term kidney transplant survival. Chronic, gradual decline in transplant function is a persistent problem in kidney transplantation. The aetiology of this is diverse but fibrosis within the transplanted organ is the common end point. This study is the first to investigate the association of CAV2 gene variants with kidney transplant outcomes. Genomic DNA from donors and recipients of 575 kidney transplants performed in Belfast was investigated for common variation in CAV2 using a tag SNP approach. The CAV2 SNP rs13221869 was nominally significant for kidney transplant failure. Validation was sought in an independent group of kidney transplant donors and recipients from Dublin, Ireland using a second genotyping technology. Due to the unexpected absence of rs13221869 from this cohort, the CAV2 gene was resequenced. One novel SNP and a novel insertion/deletion in CAV2 were identified; rs13221869 is located in a repetitive region and was not a true variant in resequenced populations. CAV2 is a plausible candidate gene for association with kidney transplant outcomes given its proximity to CAV1 and its role in attenuating fibrosis. This study does not support an association between CAV2 variation and kidney transplant survival. Further analysis of CAV2 should be undertaken with an awareness of the sequence complexities and genetic variants highlighted by this study.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multiple Superoxide Dismutase 1/Splicing Factor Serine Alanine 15 Variants Are Associated With the Development and Progression
of Diabetic Nephropathy
The Diabetes Control and Complications ...Trial/Epidemiology of Diabetes Interventions and Complications Genetics Study
Hussam Al-Kateb 1 ,
Andrew P. Boright 2 ,
Lucia Mirea 3 4 ,
Xinlei Xie 3 ,
Rinku Sutradhar 3 5 ,
Alireza Mowjoodi 1 ,
Bhupinder Bharaj 1 ,
Michelle Liu 1 ,
Jean M. Bucksa 6 ,
Valerie L. Arends 6 ,
Michael W. Steffes 6 ,
Patricia A. Cleary 7 ,
Wanjie Sun 7 ,
John M. Lachin 7 ,
Paul S. Thorner 8 9 ,
Michael Ho 8 ,
Amy Jayne McKnight 10 ,
A. Peter Maxwell 10 ,
David A. Savage 10 ,
Kenneth K. Kidd 11 ,
Judith R. Kidd 11 ,
William C. Speed 11 ,
Trevor J. Orchard 12 ,
Rachel G. Miller 12 ,
Lei Sun 1 4 ,
Shelley B. Bull 3 4 ,
Andrew D. Paterson 1 4 and
the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group *
1 Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
2 Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
3 Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Ontario, Canada
4 Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada
5 Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
6 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
7 The Biostatistics Center, The George Washington University, Rockville, Maryland
8 Division of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada
9 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
10 Nephrology Research Group, Queen's University of Belfast, Belfast, Northern Ireland, U.K
11 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
12 University of Pittsburgh, Pittsburgh, Pennsylvania
Address correspondence and reprint requests to Dr. Andrew Paterson, Program in Genetics and Genome Biology, The Hospital for
Sick Children, TMDT Building East Tower, Rm. 15-707, 101 College St., Toronto, Ontario, Canada M5G 1L7. E-mail: andrew.paterson{at}utoronto.ca
Abstract
BACKGROUND— Despite familial clustering of nephropathy and retinopathy severity in type 1 diabetes, few gene variants have been consistently
associated with these outcomes.
RESEARCH DESIGN AND METHODS— We performed an individual-based genetic association study with time to renal and retinal outcomes in 1,362 white probands
with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications
(DCCT/EDIC) study. Specifically, we genotyped 1,411 SNPs that capture common variations in 212 candidate genes for long-term
complications and analyzed them for association with the time from DCCT baseline to event for renal and retinal outcomes using
multivariate Cox proportion hazards models. To address multiple testing and assist interpretation of the results, false discovery
rate q values were calculated separately for each outcome.
RESULTS— We observed association between rs17880135 in the 3′ region of superoxide dismutase 1 (SOD1) and the incidence of both severe
nephropathy (hazard ratio HR 2.62 95% CI 1.64–4.18, P = 5.6 × 10 −5 , q = 0.06) and persistent microalbuminuria (1.82 1.29–2.57, P = 6.4 × 10 −4 , q = 0.46). Sequencing and fine-mapping identified additional SOD1 variants, including rs202446, rs9974610, and rs204732, which
were also associated ( P < 10 −3 ) with persistent microalbuminuria, whereas rs17880135 and rs17881180 were similarly associated with the development of severe
nephropathy. Attempts to replicate the findings in three cross-sectional case-control studies produced equivocal results.
We observed no striking differences between risk genotypes in serum SOD activity, serum SOD1 mass, or SOD1 mRNA expression
in lymphoblastoid cell lines.
CONCLUSIONS— Multiple variations in SOD1 are significantly associated with persistent microalbuminuria and severe nephropathy in the DCCT/EDIC
study.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on October 2007. DOI: 10.2337/db07-1059. DCCT clinical trial reg. no. NCT00360815, EDIC clinical trial reg. no. NCT00360893,
clinicaltrials.gov.
H.A.-K. and A.P.B. contributed equally to this work, and L.M. and X.X. contributed equally to this work.
*
* A complete list of investigators and members of the research group appears in N Engl J Med 353:2643–2653, 2005.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted September 30, 2007.
Received July 31, 2007.
DIABETES
Gremlin, a cell growth and differentiation factor, promotes the development of diabetic nephropathy in animal models, but whether GREM1 gene variants associate with diabetic nephropathy is unknown. ...We comprehensively screened the 5' upstream region (including the predicted promoter), all exons, intron-exon boundaries, complete untranslated regions, and the 3' region downstream of the GREM1 gene. We identified 31 unique variants, including 24 with a minor allele frequency exceeding 5%, and 9 haplotype-tagging single nucleotide polymorphisms (htSNPs). We selected one additional variant that we predicted to alter transcription factor binding. We genotyped 709 individuals with type 1 diabetes of whom 267 had nephropathy (cases) and 442 had no evidence of kidney disease (controls). Three individual SNPs significantly associated with nephropathy at the 5% level, and two remained significant after adjustment for multiple testing. Subsequently, we genotyped a replicate population comprising 597 cases and 502 controls: this population supported an association with one of the SNPs (rs1129456; P = 0.0003). Combined analysis, adjusted for recruitment center (n = 8), suggested that the T allele conferred greater odds of nephropathy (OR 1.69; 95% CI 1.36 to 2.11). In summary, the GREM1 variant rs1129456 associates with diabetic nephropathy, perhaps explaining some of the genetic susceptibility to this condition.
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