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Blood Advances Sep 2023A direct regulation of adaptive immunity by the coagulation protease activated protein C (aPC) has recently been established. Preincubation of T cells with aPC for 1...
A direct regulation of adaptive immunity by the coagulation protease activated protein C (aPC) has recently been established. Preincubation of T cells with aPC for 1 hour before transplantation increases FOXP3+ regulatory T cells (Tregs) and reduces acute graft-versus-host disease (aGVHD) in mice, but the underlying mechanism remains unknown. Because cellular metabolism modulates epigenetic gene regulation and plasticity in T cells, we hypothesized that aPC promotes FOXP3+ expression by altering T-cell metabolism. To this end, T-cell differentiation was assessed in vitro using mixed lymphocyte reaction or plate-bound α-CD3/CD28 stimulation, and ex vivo using T cells isolated from mice with aGVHD without and with aPC preincubation, or analyses of mice with high plasma aPC levels. In stimulated CD4+CD25- cells, aPC induces FOXP3 expression while reducing expression of T helper type 1 cell markers. Increased FOXP3 expression is associated with altered epigenetic markers (reduced 5-methylcytosine and H3K27me3) and reduced Foxp3 promoter methylation and activity. These changes are linked to metabolic quiescence, decreased glucose and glutamine uptake, decreased mitochondrial metabolism (reduced tricarboxylic acid metabolites and mitochondrial membrane potential), and decreased intracellular glutamine and α-ketoglutarate levels. In mice with high aPC plasma levels, T-cell subpopulations in the thymus are not altered, reflecting normal T-cell development, whereas FOXP3 expression in splenic T cells is reduced. Glutamine and α-ketoglutarate substitution reverse aPC-mediated FOXP3+ induction and abolish aPC-mediated suppression of allogeneic T-cell stimulation. These findings show that aPC modulates cellular metabolism in T cells, reducing glutamine and α-ketoglutarate levels, which results in altered epigenetic markers, Foxp3 promoter demethylation and induction of FOXP3 expression, thus favoring a Treg-like phenotype.
Topics: Mice; Animals; Ketoglutaric Acids; Protein C; Glutamine; T-Lymphocytes, Regulatory; Epigenesis, Genetic; Forkhead Transcription Factors
PubMed: 37315174
DOI: 10.1182/bloodadvances.2023010083 -
Familial Cancer May 2024As in Western countries, familial pancreatic cancer accounts for 5-7% of pancreatic cancer (PC) in Japan. Opportunities for diagnosing hereditary pancreatic cancer (HPC)... (Review)
Review
As in Western countries, familial pancreatic cancer accounts for 5-7% of pancreatic cancer (PC) in Japan. Opportunities for diagnosing hereditary pancreatic cancer (HPC) are increasing owing to the coverage of companion diagnostics and cancer genomic profiling by national health insurance in patients with unresectable or recurrent PC refractory to standard chemotherapies. HPC is recognized in 7% of PCs and 15% of familial pancreatic cancer, including germline variants of BRCA1/2, ATM, PALB2, APC, and mismatch repair genes. Individuals with 5-fold or greater inherited risks of PC are recommended to undergo pancreatic surveillance according to Japanese guidelines. The imaging modalities for this surveillance include endoscopic ultrasound, magnetic resonance cholangiopancreatography, abdominal ultrasound, and enhanced computed tomography. Currently, a nationwide prospective surveillance study is ongoing in Japan. Platinum-based chemotherapy is an effective pancreatic cancer treatment in patients with variants of homologous recombination repair genes (BRCA1/2 and PALB2); however, the use of platinum regimens solely based on familial/personal cancer history remains controversial. The efficacy of olaparib maintenance therapy, as confirmed by the POLO study, has significantly impacted the clinical treatment of advanced PC patients in Japan. Since the initiation of precision cancer medicine in 2019, genetic medicine for PC patients has expanded in Japan.
PubMed: 38733422
DOI: 10.1007/s10689-024-00395-y -
Internal Medicine (Tokyo, Japan) Sep 2023A 36-year-old man was diagnosed with multiple gastric polyps by esophagogastroduodenoscopy. Subsequent colonoscopy identified two tubular adenomas, and computed...
A 36-year-old man was diagnosed with multiple gastric polyps by esophagogastroduodenoscopy. Subsequent colonoscopy identified two tubular adenomas, and computed tomography revealed subcutaneous tumors. Based on these findings, we suspected that gastric polyposis was associated with the APC gene, either attenuated familial adenomatous polyposis (AFAP) or gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). A genetic analysis demonstrated that he had a frameshift variant at codon 1928 of APC, suggesting AFAP. In this era of less Helicobacter pylori infection and frequent use of proton pump inhibitors, diagnoses of AFAP and GAPPS should be considered in patients with prominent gastric fundic gland polyposis.
Topics: Male; Humans; Adult; Helicobacter Infections; Helicobacter pylori; Adenomatous Polyposis Coli; Stomach Neoplasms
PubMed: 36725040
DOI: 10.2169/internalmedicine.1101-22 -
FEMS Microbiology Reviews Nov 2023A number of bacterial species are found in high abundance in the faeces of healthy breast-fed infants, an occurrence that is understood to be, at least in part, due to... (Review)
Review
A number of bacterial species are found in high abundance in the faeces of healthy breast-fed infants, an occurrence that is understood to be, at least in part, due to the ability of these bacteria to metabolize human milk oligosaccharides (HMOs). HMOs are the third most abundant component of human milk after lactose and lipids, and represent complex sugars which possess unique structural diversity and are resistant to infant gastrointestinal digestion. Thus, these sugars reach the infant distal intestine intact, thereby serving as a fermentable substrate for specific intestinal microbes, including Firmicutes, Proteobacteria, and especially infant-associated Bifidobacterium spp. which help to shape the infant gut microbiome. Bacteria utilising HMOs are equipped with genes associated with their degradation and a number of carbohydrate-active enzymes known as glycoside hydrolase enzymes have been identified in the infant gut, which supports this hypothesis. The resulting degraded HMOs can also be used as growth substrates for other infant gut bacteria present in a microbe-microbe interaction known as 'cross-feeding'. This review describes the current knowledge on HMO metabolism by particular infant gut-associated bacteria, many of which are currently used as commercial probiotics, including the distinct strategies employed by individual species for HMO utilisation.
Topics: Infant; Humans; Milk, Human; Oligosaccharides; Bacteria; Gastrointestinal Microbiome; Sugars
PubMed: 37793834
DOI: 10.1093/femsre/fuad056 -
Journal of Clinical Oncology : Official... Sep 2023The early-onset colorectal cancer (EOCRC) burden differs across racial/ethnic groups, yet the role of germline genetic predisposition in EOCRC disparities remains...
PURPOSE
The early-onset colorectal cancer (EOCRC) burden differs across racial/ethnic groups, yet the role of germline genetic predisposition in EOCRC disparities remains uncharacterized. We defined the prevalence and spectrum of inherited colorectal cancer (CRC) susceptibility gene variations among patients with EOCRC by race and ethnicity.
PATIENTS AND METHODS
We included individuals diagnosed with a first primary CRC between age 15 and 49 years who identified as Ashkenazi Jewish, Asian, Black, Hispanic, or White and underwent germline genetic testing of 14 CRC susceptibility genes performed by a clinical testing laboratory. Variant comparisons by racial and ethnic groups were evaluated using chi-square tests and multivariable logistic regression adjusted for sex, age, CRC site, and number of primary colorectal tumors.
RESULTS
Among 3,980 patients with EOCRC, a total of 530 germline pathogenic or likely pathogenic variants were identified in 485 individuals (12.2%). By race/ethnicity, 12.7% of Ashkenazim patients, 9.5% of Asian patients, 10.3% of Black patients, 14.0% of Hispanic patients, and 12.4% of White patients carried a germline variant. The prevalence of Lynch syndrome ( = .037), as well as , , , monoallelic , and variants, varied by race/ethnicity among patients with EOCRC (all < .026). Ashkenazim and Hispanic patients had significantly higher odds of presenting with a pathogenic variant, which included p.I1307K (odds ratio [OR], 2.67; 95% CI, 1.30 to 5.49; = .007) and variant (OR, 8.69; 95% CI, 2.68 to 28.20; = .0003), respectively, versus White patients in adjusted models.
CONCLUSION
Germline genetic features differed by race/ethnicity in young patients with CRC, suggesting that current multigene panel tests may not be representative of EOCRC risk in diverse populations. Further study is needed to optimize genes selected for genetic testing in EOCRC via ancestry-specific gene and variant discovery to yield equitable clinical benefits for all patients and to mitigate inequities in disease burden.
Topics: Humans; Adolescent; Young Adult; Adult; Middle Aged; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Germ-Line Mutation; Genetic Testing; Genetic Predisposition to Disease
PubMed: 37319387
DOI: 10.1200/JCO.22.02378 -
Cancers Sep 2023Colorectal cancer (CRC) is one of the most common and severe malignancies worldwide. Recent advances in diagnostic methods allow for more accurate identification and... (Review)
Review
Colorectal cancer (CRC) is one of the most common and severe malignancies worldwide. Recent advances in diagnostic methods allow for more accurate identification and detection of several molecular biomarkers associated with this cancer. Nonetheless, non-invasive and effective prognostic and predictive testing in CRC patients remains challenging. Classical prognostic genetic markers comprise mutations in several genes (e.g., , , and ). Furthermore, CIN and MSI serve as chromosomal markers, while epigenetic markers include CIMP and many other candidates such as , , , , and . The number of proliferation-related long non-coding RNAs (e.g., SNHG1, SNHG6, MALAT-1, CRNDE) and microRNAs (e.g., miR-20a, miR-21, miR-143, miR-145, miR-181a/b) that could serve as potential CRC markers has also steadily increased in recent years. Among the immunohistochemical (IHC) proliferative markers, the prognostic value regarding the patients' overall survival (OS) or disease-free survival (DFS) has been confirmed for thymidylate synthase (TS), cyclin B1, cyclin D1, proliferating cell nuclear antigen (PCNA), and Ki-67. In most cases, the overexpression of these markers in tissues was related to worse OS and DFS. However, slowly proliferating cells should also be considered in CRC therapy (especially radiotherapy) as they could represent a reservoir from which cells are recruited to replenish the rapidly proliferating population in response to cell-damaging factors. Considering the above, the aim of this article is to review the most common proliferative markers assessed using various methods including IHC and selected molecular biology techniques (e.g., qRT-PCR, in situ hybridization, RNA/DNA sequencing, next-generation sequencing) as prognostic and predictive markers in CRC.
PubMed: 37760539
DOI: 10.3390/cancers15184570 -
International Journal of Surgical... May 2024Current treatments for gastric cancer (GC) are suboptimal. Potential therapeutic targets for GC were screened using next-generation sequencing. We examined many mutation...
Current treatments for gastric cancer (GC) are suboptimal. Potential therapeutic targets for GC were screened using next-generation sequencing. We examined many mutation genes linked to GC, including (60%), (19%), (13%), and (12%), (9%), (9%), and (7%). The , , and wild-type genes were dominant in diffuse-type GC ( < .05), but mutations did not influence prognosis. Patients with (6%) and (8%) wild-type GC presented with vascular invasion ( < .05). Patients with (2%) wild-type GC were prone to lymph node metastasis ( < .05). Patients with (9%) wild-type GC had reduced programmed death ligand 1 expression (<1, < .05). We found that patients who received chemotherapy had a better prognosis than those who did not (although there was no statistical difference), with platinum-based group having better prognosis and uracil combined with paclitaxel group having worse prognosis.
Topics: Humans; Stomach Neoplasms; Proto-Oncogene Proteins p21(ras); Prognosis; Mutation
PubMed: 37545327
DOI: 10.1177/10668969231188421 -
International Journal of Cell Biology 2023Defective Wnt signaling is found to be associated with various neurodegenerative diseases. In the canonical pathway, the Frizzled receptor (Fzd) and the lipoprotein... (Review)
Review
Defective Wnt signaling is found to be associated with various neurodegenerative diseases. In the canonical pathway, the Frizzled receptor (Fzd) and the lipoprotein receptor-related proteins 5/6 (LRP5/LRP6) create a seven-pass transmembrane receptor complex to which the Wnt ligands bind. This interaction causes the tumor suppressor adenomatous polyposis coli gene product (APC), casein kinase 1 (CK1), and GSK-3 (glycogen synthase kinase-3 beta) to be recruited by the scaffold protein Dishevelled (Dvl), which in turn deactivates the -catenin destruction complex. This inactivation stops the destruction complex from phosphorylating -catenin. As a result, -catenin first builds up in the cytoplasm and then migrates into the nucleus, where it binds to the Lef/Tcf transcription factor to activate the transcription of more than 50 Wnt target genes, including those involved in cell growth, survival, differentiation, neurogenesis, and inflammation. The treatments that are currently available for neurodegenerative illnesses are most commonly not curative in nature but are only symptomatic. According to all available research, restoring Wnt/-catenin signaling in the brains of patients with neurodegenerative disorders, particularly Alzheimer's and Parkinson's disease, would improve the condition of several patients with neurological disorders. The importance of Wnt activators and modulators in patients with such illnesses is to mainly restore rather than overstimulate the Wnt/-catenin signaling, thereby reestablishing the equilibrium between Wnt-OFF and Wnt-ON states. In this review, we have tried to summarize the significance of the Wnt canonical pathway in the pathophysiology of certain neurodegenerative diseases, such as Alzheimer's disease, cerebral ischemia, Parkinson's disease, Huntington's disease, multiple sclerosis, and other similar diseases, and as to how can it be restored in these patients.
PubMed: 37780577
DOI: 10.1155/2023/9296092 -
Critical Reviews in Microbiology Nov 2023High-throughput DNA sequencing-based approaches continue to revolutionise our understanding of microbial ecosystems, including those associated with fermented foods.... (Review)
Review
High-throughput DNA sequencing-based approaches continue to revolutionise our understanding of microbial ecosystems, including those associated with fermented foods. Metagenomic and metatranscriptomic approaches are state-of-the-art biological profiling methods and are employed to investigate a wide variety of characteristics of microbial communities, such as taxonomic membership, gene content and the range and level at which these genes are expressed. Individual groups and consortia of researchers are utilising these approaches to produce increasingly large and complex datasets, representing vast populations of microorganisms. There is a corresponding requirement for the development and application of appropriate bioinformatic tools and pipelines to interpret this data. This review critically analyses the tools and pipelines that have been used or that could be applied to the analysis of metagenomic and metatranscriptomic data from fermented foods. In addition, we critically analyse a number of studies of fermented foods in which these tools have previously been applied, to highlight the insights that these approaches can provide.
Topics: Microbiota; Metagenome; Computational Biology; Fermented Foods; High-Throughput Nucleotide Sequencing
PubMed: 36287644
DOI: 10.1080/1040841X.2022.2132850 -
Genetics in Medicine : Official Journal... Feb 2024The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and...
Gene-specific ACMG/AMP classification criteria for germline APC variants: Recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel.
PURPOSE
The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and the Clinical Genome Resource, who set out to develop recommendations for the interpretation of germline APC variants underlying Familial Adenomatous Polyposis, the most frequent hereditary polyposis syndrome.
METHODS
Through a rigorous process of database analysis, literature review, and expert elicitation, the APC VCEP derived gene-specific modifications to the ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) variant classification guidelines and validated such criteria through the pilot classification of 58 variants.
RESULTS
The APC-specific criteria represented gene- and disease-informed specifications, including a quantitative approach to allele frequency thresholds, a stepwise decision tool for truncating variants, and semiquantitative evaluations of experimental and clinical data. Using the APC-specific criteria, 47% (27/58) of pilot variants were reclassified including 14 previous variants of uncertain significance (VUS).
CONCLUSION
The APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25). Moving forward, the APC VCEP will continue to interpret prioritized lists of VUS, the results of which will represent the most authoritative variant classification for widespread clinical use.
Topics: Humans; Genetic Testing; Genetic Variation; Adenomatous Polyposis Coli; Germ-Line Mutation; Germ Cells
PubMed: 37800450
DOI: 10.1016/j.gim.2023.100992