Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract in chronic or recurrent remission phase and is classified as Crohn's disease (CD) and ...ulcerative colitis (UC). IBD is a multifactorial disease that results from genetic and environmental factors, immunological disorders, and gut microbiota dysregulation called dysbiosis. Recently, the number of patients with IBD in Japan has been increasing. This review describes studies of T cells, such as type 1 helper T (Th1) and type 1 cytotoxic T (Tc1) cells, and cytokines, such as IL‐17 and IL‐21, as representatives of mucosal immunity in IBD. Th1 cells and Tc1 cells are involved in Peyer's patches of CD. IL‐12 significantly reduced the production of IL‐17 but significantly increased in that of IFN‐γ, and IL‐21 reduced IL‐17 production. It also describes genetic analysis studies on the cause of very early‐onset IBD (VEO‐IBD). Furthermore, 11.6% of patients with VEO‐IBD presented with monogenic IBD in Japan. Genetic analysis for patients with VEO‐IBD and suspected monogenic IBD was investigated. XIAP and heterozygous SLCO2A1 were detected owing to the result of functional confirmation, and several candidate genes were detected. Cytokine analysis and genetic analysis studies have revealed several pathophysiologies of IBD. Clinical and basic studies on mucosal immunity as well as immunological and genetic analyses are currently ongoing and are anticipated to provide an elaborate understanding of the pathophysiology of IBD.
Cancer metabolism: looking forward Martínez-Reyes, Inmaculada; Chandel, Navdeep S
Nature reviews. Cancer,
10/2021, Letnik:
21, Številka:
10
Journal Article
Recenzirano
Tumour initiation and progression requires the metabolic reprogramming of cancer cells. Cancer cells autonomously alter their flux through various metabolic pathways in order to meet the increased ...bioenergetic and biosynthetic demand as well as mitigate oxidative stress required for cancer cell proliferation and survival. Cancer driver mutations coupled with environmental nutrient availability control flux through these metabolic pathways. Metabolites, when aberrantly accumulated, can also promote tumorigenesis. The development and application of new technologies over the last few decades has not only revealed the heterogeneity and plasticity of tumours but also allowed us to uncover new metabolic pathways involved in supporting tumour growth. The tumour microenvironment (TME), which can be depleted of certain nutrients, forces cancer cells to adapt by inducing nutrient scavenging mechanisms to sustain cancer cell proliferation. There is growing appreciation that the metabolism of cell types other than cancer cells within the TME, including endothelial cells, fibroblasts and immune cells, can modulate tumour progression. Because metastases are a major cause of death of patients with cancer, efforts are underway to understand how metabolism is harnessed by metastatic cells. Additionally, there is a new interest in exploiting cancer genetic analysis for patient stratification and/or dietary interventions in combination with therapies that target metabolism. In this Perspective, we highlight these main themes that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing questions that remain unanswered.
The Prevalence of Wilson’s Disease: An Update Sandahl, Thomas Damgaard; Laursen, Tea Lund; Munk, Ditte Emilie ...
Hepatology (Baltimore, Md.),
February 2020, Letnik:
71, Številka:
2
Journal Article
Recenzirano
Background and Aims
In 1984, Scheinberg and Sternlieb estimated the prevalence of Wilson’s disease to be 1:30,000 based on the limited available data. This suggested a large number of overlooked ...cases with potentially fatal consequences. The “Scheinberg‐Sternlieb Estimate” is still widely used, although more recent clinical and genetic studies of higher quality are now available. In the present study, we included these data to update the prevalence estimate.
Approach and Results
A MEDLINE Ovid, Science Citation Index Expanded, and PubMed systematic search for all relevant studies on the prevalence of Wilson’s disease was conducted. In total, 59 studies (50 clinical and 9 population‐based genetic) were included in the final analysis. We identified 4 recent clinical studies based on nationwide databases of high quality, providing prevalence estimates from 1:29,000 to 1:40,000. Higher frequency populations do exist because of frequent first‐cousin marriages and/or a higher mutation frequency. When calculating prevalence from the incidence related to number of births, estimates were 1:40,000‐1:50,000. Clinical screening studies, including examination for Kayser‐Fleischer rings or ceruloplasmin, did not improve these estimates because of insufficient sample size or selection biases. Population‐based genetic studies in US and UK populations were not in disagreement with the clinically based estimates. At the same time, studies from France and Sardinia suggested that the genetic prevalence may be 3‐4 times higher than the clinical disease prevalence. This raises the question whether the penetrance is indeed 100% as generally assumed.
Conclusions
The original prevalence estimate from 1984 of 1:30,000‐1:50,000 still appears valid, at least for the United States, Europe, and Asia. In some population‐based studies, the genetic prevalence was 3‐4 times higher than clinically based estimates. The question of penetrance needs further evaluation.
We describe a binary expression aleatory mosaic (BEAM) system, which relies on DNA delivery by transfection or viral transduction along with nested recombinase activity to generate two genetically ...distinct, non-overlapping populations of cells for comparative analysis. Control cells labeled with red fluorescent protein (RFP) can be directly compared with experimental cells manipulated by genetic gain or loss of function and labeled with GFP. Importantly, BEAM incorporates recombinase-dependent signal amplification and delayed reporter expression to enable sharper delineation of control and experimental cells and to improve reliability relative to existing methods. We applied BEAM to a variety of known phenotypes to illustrate its advantages for identifying temporally or spatially aberrant phenotypes, for revealing changes in cell proliferation or death, and for controlling for procedural variability. In addition, we used BEAM to test the cortical protomap hypothesis at the individual radial unit level, revealing that area identity is cell autonomously specified in adjacent radial units.
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•BEAM analysis reliably, sharply, and rapidly delineates control and experimental cells•BEAM controls for cell autonomy, proliferation/survival, and procedural variability•BEAM is validated with floxed alleles, overexpression, Cas9 knockout, and Cas13 knockdown•BEAM testing of the protomap hypothesis reveals area specification in individual radial units
Greig et al. describe a dual-recombinase system for mosaic genetic analysis using DNA transfection or transduction termed BEAM. Nested recombinase activity generates two distinct populations of cells in a single experiment, labeled with either green or red fluorescent protein, enabling direct comparison of control and genetically manipulated cells.
The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma ...protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.
Pan-genomics in the human genome era Sherman, Rachel M; Salzberg, Steven L
Nature reviews. Genetics,
04/2020, Letnik:
21, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Since the early days of the genome era, the scientific community has relied on a single 'reference' genome for each species, which is used as the basis for a wide range of genetic analyses, including ...studies of variation within and across species. As sequencing costs have dropped, thousands of new genomes have been sequenced, and scientists have come to realize that a single reference genome is inadequate for many purposes. By sampling a diverse set of individuals, one can begin to assemble a pan-genome: a collection of all the DNA sequences that occur in a species. Here we review efforts to create pan-genomes for a range of species, from bacteria to humans, and we further consider the computational methods that have been proposed in order to capture, interpret and compare pan-genome data. As scientists continue to survey and catalogue the genomic variation across human populations and begin to assemble a human pan-genome, these efforts will increase our power to connect variation to human diversity, disease and beyond.
Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via ...different pathways. We studied associations between Lynch syndrome–associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients.
We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1.
Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC.
In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.
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