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Neoplasia (New York, N.Y.) Jul 2024Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to...
Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to the formation of benign polyps. Despite the well-established role of APC, the contribution of CUL4B to CRC initiation in the pre-tumorous stage remains poorly understood. In this investigation, we generated a murine model by crossing Apc mice with Cul4b mice to achieve specific deletion of Cul4b in the gut epithelium against an Apc background. By employing histological methods, RNA-sequencing (RNA-seq), and flow cytometry, we assessed alterations and characterized the immune microenvironment. Our results unveiled that CUL4B deficiency in gut epithelium expedited Apc adenoma formation. Notably, CUL4B in adenomas restrained the accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). In vivo inhibition of MDSCs significantly delayed the growth of CUL4B deleted Apc adenomas. Furthermore, the addition of MDSCs to in vitro cultured Apc; Cul4b adenoma organoids mitigated their alterations. Mechanistically, CUL4B directly interacted with the promoter of Csf3, the gene encoding granulocyte-colony stimulating factor (G-CSF) by coordinating with PRC2. Inhibiting CUL4B epigenetically activated the expression of G-CSF, promoting the recruitment of MDSCs. These findings offer novel insights into the tumor suppressor-like roles of CUL4B in regulating Apc adenomas, suggesting a potential therapeutic strategy for CRC initiation and progression in the context of activated Wnt signaling.
Topics: Animals; Cullin Proteins; Mice; Myeloid-Derived Suppressor Cells; Adenoma; Disease Models, Animal; Adenomatous Polyposis Coli Protein; Humans; Tumor Microenvironment; Colorectal Neoplasms; Gene Deletion; Intestinal Mucosa
PubMed: 38761506
DOI: 10.1016/j.neo.2024.101005 -
Genes, Chromosomes & Cancer May 2024Superficial fibromas are a group of mesenchymal spindle cell lesions with pathomorphological heterogeneity and diverse molecular backgrounds. In part, they may be...
Superficial fibromas are a group of mesenchymal spindle cell lesions with pathomorphological heterogeneity and diverse molecular backgrounds. In part, they may be indicators of an underlying syndrome. Among the best-known entities of superficial fibromas is Gardner fibroma, a plaque-like benign tumor, which is associated with APC germline mutations and occurs in patients with familial adenomatosis polyposis (Gardner syndrome). Affected patients also have an increased risk to develop desmoid fibromatosis (DTF), a locally aggressive neoplasm of the deep soft tissue highly prone to local recurrences. Although a minority of DTFs occur in the syndromic context and harbor APC germline mutations, most frequently their underlying molecular aberration is a sporadic mutation in Exon 3 of the CTNNB1 gene. Up to date, a non-syndromic equivalent to Gardner fibroma carrying a CTNNB1 mutation has not been defined. Here, we present two cases of (sub-)cutaneous tumors with a hypocellular and collagen-rich Gardner fibroma-like appearance and pathogenic, somatic CTNNB1 mutations. We aim to differentiate these tumors from other fibromas according to their histological appearance, immunohistochemical staining profile and underlying somatic CTNNB1 mutations. Furthermore, we distinguish them from locally aggressive desmoid fibromatosis regarding their biological behavior, prognosis and indicated therapeutic strategies. Consequently, we call them CTNNB1-mutated superficial fibromas as a sporadic counterpart lesion to syndromic Gardner fibromas.
Topics: Humans; beta Catenin; Fibroma; Male; Female; Mutation; Middle Aged; Fibromatosis, Aggressive; Adult; Gardner Syndrome; Germ-Line Mutation
PubMed: 38757718
DOI: 10.1002/gcc.23247 -
Microbial Biotechnology May 2024The distinct conjugation machineries encoded by plasmids pNP40 and pUC11B represent the most prevalent plasmid transfer systems among lactococcal strains. In the current...
The distinct conjugation machineries encoded by plasmids pNP40 and pUC11B represent the most prevalent plasmid transfer systems among lactococcal strains. In the current study, we identified genetic determinants that underpin pNP40- and pUC11B-mediated, high-frequency mobilisation of other, non-conjugative plasmids. The mobilisation frequencies of the smaller, non-conjugative plasmids and the minimal sequences required for their mobilisation were determined, owing to the determination of the oriT sequences of both pNP40 and pUC11B, which allowed the identification of similar sequences in some of the non-conjugative plasmids that were shown to promote their mobilisation. Furthermore, the auxiliary gene mobC, two distinct functional homologues of which are present in several plasmids harboured by the pNP40- and pUC11B-carrying host strains, was observed to confer a high-frequency mobilisation phenotype. These findings provide mechanistic insights into how lactococcal conjugative plasmids achieve conjugation and promote mobilisation of non-conjugative plasmids. Ultimately, these insights would be harnessed to optimise conjugation and mobilisation strategies for the rapid and predictable development of robust and technologically improved strains.
Topics: Plasmids; Conjugation, Genetic; Gene Transfer, Horizontal; Bacterial Proteins; Lactococcus lactis
PubMed: 38752994
DOI: 10.1111/1751-7915.14421 -
Gut Microbes 2024Members of the genus are commonly found in the human gut and are known to utilize complex carbohydrates that are indigestible by the human host. Members of the subsp....
Members of the genus are commonly found in the human gut and are known to utilize complex carbohydrates that are indigestible by the human host. Members of the subsp. taxon can metabolize various plant-derived carbohydrates common to the human diet. To metabolize such polysaccharides, which include arabinoxylan, bifidobacteria need to encode appropriate carbohydrate-active enzymes in their genome. In the current study, we describe two GH43 family enzymes, denoted here as AxuA and AxuB, which are encoded by subsp. NCIMB 8809 and are shown to be required for cereal-derived arabinoxylan metabolism by this strain. Based on the observed hydrolytic activity of AxuA and AxuB, assessed by employing various synthetic and natural substrates, and based on analyses, it is proposed that both AxuA and AxuB represent extracellular α-L-arabinofuranosidases with distinct substrate preferences. The variable presence of the and genes and other genes previously described to be involved in the metabolism of arabinose-containing glycans can in the majority cases explain the (in)ability of individual subsp. strains to grow on cereal-derived arabinoxylans and arabinan.
Topics: Xylans; Glycoside Hydrolases; Edible Grain; Bifidobacterium longum; Substrate Specificity; Bacterial Proteins; Humans
PubMed: 38752423
DOI: 10.1080/19490976.2024.2353229 -
Oncology Letters Jul 2024There is a correlation between tumors and immunity with the degree of immune cell infiltration in tumors being closely related to tumor growth and progression....
There is a correlation between tumors and immunity with the degree of immune cell infiltration in tumors being closely related to tumor growth and progression. Therefore, the present study identified immune-related prognostic genes and evaluated the immune infiltration level in lung adenocarcinoma (LUAD). This study performed Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and Gene Set Enrichment Analysis (GSEA) enrichment analyses on differential immune-associated genes. A risk model was created and validated using six immune-related prognostic genes. Reverse transcription-quantitative PCR was used to assess the prognostic gene expression in non-small cell lung cancer cells. Immune cell infiltration in LUAD was analyzed using the CIBERSORT method. Single sample GSEA was used to compare Tumor Immune Dysfunction and Exclusion (TIDE) scores between high and low-risk groups and to assess the activation of thirteen immune-related pathways. Multifactor Cox proportional hazards model analysis identified six prognostic risk genes ( and ) to construct a risk model. The survival and receiver operating characteristic curves indicated that patients with higher risk scores had lower overall survival rates. The expression levels of prognostic genes and were significantly increased in LUAD. B cells naive, plasma cells, T cells CD4 memory activated, T cells follicular helper, T cells regulatory, NK cells activated, macrophages M1, macrophages M2, and Dendritic cells resting cells showed elevated expression in LUAD. The prognostic genes were differentially associated with individual immune cells. Immune-related function scores, such as those for antigen presenting cell (APC) co-stimulation, APC co-inhibition, check-point, Cytolytic-activity, chemokine receptor, parainflammation, major histocompatibility complex-class-I, type-I-IFN-reponse and T-cell-co-inhibition, were higher in the high-risk group compared with the low-risk group. Furthermore, the TIDE score of the high-risk group was significantly lower than the low-risk group. This immune-related gene prognostic model has the potential to predict the prognosis of LUAD patients, supporting the development of a personalized clinical diagnosis and treatment plan.
PubMed: 38751753
DOI: 10.3892/ol.2024.14430 -
Cancer Medicine May 2024Microsatellite instability-high (MSI-H) colorectal cancer (CRC) is known for its heightened responsiveness to immunotherapy. However, establishing robust predictive...
BACKGROUND
Microsatellite instability-high (MSI-H) colorectal cancer (CRC) is known for its heightened responsiveness to immunotherapy. However, establishing robust predictive markers for immunotherapy efficacy remains imperative. This retrospective study aimed to elucidate the genetic landscape of MSI-H CRC and correlate these genetic alterations with immunotherapy outcomes in a cohort of 121 patients.
METHODS
We analyzed clinical and molecular data from 121 patients with MSI-H CRC. We conducted a thorough genetic analysis of MSI-H CRC patients, with a specific emphasis on the APC, TP53, RAS, and MMR genes. We further analyzed the relationship between gene mutations and immunotherapy efficacy. The primary endpoints analyzed were objective response rate (ORR) and progression-free survival (PFS). All statistical analysis was conducted using SPSS26.0 and R 4.2.0 software.
RESULTS
Our findings underscored the complexity of the genetic landscape in MSI-H CRC, shedding light on the intricate interplay of these genes in CRC development. Notably, mutations in MMR genes exhibited a distinctive pattern, providing insights into the underlying mechanisms of MSI-H. Furthermore, our results revealed correlations between specific genetic alterations and immunotherapy outcomes, with a particular focus on treatment response rates and progression-free survival.
CONCLUSION
This study represents a significant step toward unraveling the genetic nuances of MSI-H CRC. The distinctive pattern of MMR gene mutations not only adds depth to our understanding of MSI-H CRC but also hints at potential avenues for targeted therapies. This research sets the stage for future investigations aimed at refining therapeutic strategies and improving outcomes for patients with MSI-H CRC.
Topics: Humans; Microsatellite Instability; Colorectal Neoplasms; Retrospective Studies; Male; Female; Middle Aged; Mutation; Aged; Adult; Immunotherapy; Aged, 80 and over; Progression-Free Survival; Biomarkers, Tumor; DNA Mismatch Repair; Treatment Outcome
PubMed: 38746969
DOI: 10.1002/cam4.6910 -
MedRxiv : the Preprint Server For... May 2024Pathogenic constitutional variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant...
Systematic large-scale application of ClinGen InSiGHT -specific ACMG/AMP variant classification criteria substantially alleviates the burden of variants of uncertain significance in ClinVar and LOVD databases.
BACKGROUND
Pathogenic constitutional variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUS), APC-specific ACMG/AMP variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP).
METHODS
A streamlined algorithm using the -specific criteria was developed and applied to assess all variants in ClinVar and the InSiGHT international reference LOVD variant database.
RESULTS
A total of 10,228 unique variants were analysed. Among the ClinVar and LOVD variants with an initial classification of (Likely) Benign or (Likely) Pathogenic, 94% and 96% remained in their original categories, respectively. In contrast, 41% ClinVar and 61% LOVD VUS were reclassified into clinically actionable classes, the vast majority as (Likely) Benign. The total number of VUS was reduced by 37%. In 21 out of 36 (58%) promising variants that remained VUS despite evidence for pathogenicity, a data mining-driven work-up allowed their reclassification as (Likely) Pathogenic.
CONCLUSIONS
The application of -specific criteria substantially reduced the number of VUS in ClinVar and LOVD. The study also demonstrated the feasibility of a systematic approach to variant classification in large datasets, which might serve as a generalisable model for other gene-/disease-specific variant interpretation initiatives. It also allowed for the prioritization of VUS that will benefit from in-depth evidence collection. This subset of variants was approved by the VCEP and made publicly available through ClinVar and LOVD for widespread clinical use.
PubMed: 38746299
DOI: 10.1101/2024.05.03.24306761 -
EClinicalMedicine Jun 2024Anemia is a significant contributor to the global disease burden, of which thalassemia is the most common hereditary anaemic disease. Previous estimates were based on...
BACKGROUND
Anemia is a significant contributor to the global disease burden, of which thalassemia is the most common hereditary anaemic disease. Previous estimates were based on data that were geographically limited and lacked comprehensive global analysis. This study provides the prevalence, incidence, mortality and disability-adjusted life years (DALYs) of thalassemia in 204 countries and regions of thalassemia between 1990 and 2021, focusing on the age structure and time trends of the disease burden. To provide effective information for health policy, allocation of medical resources and optimization of patient management programs.
METHODS
Using the standardised Global Burden of Disease (GBD) methodologies, we aimed to derive a more precise representation of the health burden posed by thalassemia by considering four distinct types of epidemiological data, namely the incidence at birth, prevalence, mortality and DALYs. The presented data were meticulously estimated and displayed both as numerical counts and as age-standardised rates per 100,000 persons of the population, accompanied by uncertainty interval (UI) to highlight potential statistical variability. The temporal trends spanning the years 1990-2021 were subjected to a rigorous examination utilizing Joinpoint regression analysis. This methodological approach facilitated the computation of the annual percentage change (APC) and the average annual percentage change (AAPC), along with their corresponding 95% confidence intervals (CIs).
FINDINGS
Globally, the age-standardized prevalence rates (ASPR), age-standardized incidence rates (ASIR), age-standardized mortality rates (ASMR), and age-standardized DALYs rates for thalassemia in 2021 were 18.28 per 100,000 persons (95% UI 15.29-22.02), 1.93 per 100,000 persons (95% UI 1.51-2.49), 0.15 per 100,000 persons(95% UI 0.11-0.20), and 11.65 per 100,000 persons (95% UI 8.24-14.94), respectively. Compared to 1990, these rates have decreased by 0.18 (95% UI -0.22 to -0.14), 0.25 (95% UI -0.30 to -0.19), 0.48 (95% UI -0.60 to -0.28), and 0.49 (95% UI -0.62 to -0.29) respectively. In 2021, the ASIR of thalassemia was highest in East Asia at 7.35 per 100,000 persons (95% UI 5.37-10.04), and ASMR was highest in Southeast Asia at 0.37 per 100,000 persons (95% UI 0.29-0.45).Gender comparisons showed negligible differences in disease burden, with the highest prevalence noted in children under five, decreasing with age. The global ASPR and ASMR declined from 1990 to 2021 overall, though an increasing trend in prevalence was found among the elderly. Joinpoint analysis revealed that the global ASPR increased between 2018 and 2021 (APC = 9.2%, 95% CI: 4.8%-13.8%, P < 0.001), ASIR decreased (APC = -7.68%, 95% CI: -10.88% to -4.36%, P < 0.001), and there was a significant rise in ASMR from 2019 to 2021 (APC = 4.8%, 95% CI: 0.1%-9.6%, P < 0.05). Trends in ASPR and ASMR varied across regions, with notable changes in South Asia.
INTERPRETATION
The global burden of thalassemia, reflected in its prevalence, incidence, mortality, and DALYs, exhibits significant disparities. Geographic and demographic shifts in disease distribution have been observed from 1990 to 2021, with an overall decrease in burden, yet an increase in cases among the elderly population. Analysis of epidemiological trends over time highlights the influence of health policies and significant public health interventions on thalassemia outcomes. There data are crucial for healthcare professionals, policymakers, and researchers to refine and enhance management strategies, aiming to further mitigate thalassemia's global impact.
FUNDING
National Natural Science Foundation of China; Guizhou Province Science and Technology Project; Guizhou Province Science and Technology Foundation of Health Commission.
PubMed: 38745964
DOI: 10.1016/j.eclinm.2024.102619 -
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 -
Nutrients Apr 2024Iron supplements are widely consumed. However, excess iron may accelerate intestinal tumorigenesis. To determine the effect of excess iron on intestinal tumor burden and...
Iron supplements are widely consumed. However, excess iron may accelerate intestinal tumorigenesis. To determine the effect of excess iron on intestinal tumor burden and protein expression changes between tumor and normal tissues, mice were fed control (adequate) and excess iron (45 and 450 mg iron/kg diet, respectively; 9/group) for 10 wk. Tumor burden was measured, and two-dimensional fluorescence difference gel electrophoresis was used to identify differentially expressed proteins in tumor and normal intestinal tissues. There was a significant increase (78.3%; ≤ 0.05) in intestinal tumor burden (mm/cm) with excess iron at wk 10. Of 980 analyzed protein spots, 69 differentially expressed ( ≤ 0.05) protein isoforms were identified, representing 55 genes. Of the isoforms, 56 differed ( ≤ 0.05) between tumor vs. normal tissues from the adequate iron group and 23 differed ( ≤ 0.05) between tumors from the adequate vs. excess iron. Differentially expressed proteins include those involved in cell integrity and adaptive response to reactive oxygen species (including, by gene ID: ANPEP, DPP7, ITGB1, PSMA1 HSPA5). Biochemical pathway analysis found that iron supplementation modulated four highly significant ( ≤ 0.05) functional networks. These findings enhance our understanding of interplay between dietary iron and intestinal tumorigenesis and may help develop more specific dietary guidelines regarding trace element intake.
Topics: Animals; Dietary Supplements; Mice; Disease Models, Animal; Tumor Burden; Humans; Intestinal Neoplasms; Iron; Iron, Dietary; Mice, Inbred C57BL; Male; Gene Expression Regulation, Neoplastic; Proteomics
PubMed: 38732562
DOI: 10.3390/nu16091316