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American Society of Clinical Oncology... Jun 2024Germline pathogenic variants (PVs) in the and genes confer elevated risks of breast, ovarian, and other cancers. Lynch syndrome (LS) is associated with increased risks... (Review)
Review
Germline pathogenic variants (PVs) in the and genes confer elevated risks of breast, ovarian, and other cancers. Lynch syndrome (LS) is associated with increased risks of multiple cancer types including colorectal and uterine cancers. Current cancer risk mitigation strategies have focused on pharmacologic risk reduction, enhanced surveillance, and preventive surgeries. While these approaches can be effective, they stand to be improved on because of either limited efficacy or undesirable impact on quality of life. The current review summarizes ongoing investigational efforts in cancer risk prevention strategies for patients with germline PVs in , , or LS-associated genes. These efforts span radiation, surgery, and pharmacology including vaccine strategies. Understanding the molecular events involved in the premalignant to malignant transformation in high-risk individuals may ultimately contribute significantly to novel prevention strategies.
Topics: Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; BRCA1 Protein; BRCA2 Protein; Genetic Predisposition to Disease; Female; Neoplastic Syndromes, Hereditary; Germ-Line Mutation
PubMed: 38913968
DOI: 10.1200/EDBK_433576 -
PLoS Neglected Tropical Diseases Jun 2024Chagas disease predominantly affects the heart, esophagus, and colon in its chronic phase. However, the precise infection mechanisms of the causal agent Trypanosoma...
In vitro characterization of Trypanosoma cruzi infection dynamics in skeletal and cardiac myotubes models suggests a potential cell-to-cell transmission in mediating cardiac pathology.
Chagas disease predominantly affects the heart, esophagus, and colon in its chronic phase. However, the precise infection mechanisms of the causal agent Trypanosoma cruzi in these tissue types remain incompletely understood. This study investigated T. cruzi infection dynamics in skeletal (SM) and cardiac myotubes (CM) differentiated from H9c2(2-1) myoblasts (control). SM and CM were generated using 1% fetal bovine serum (FBS) without or with retinoic acid, respectively. Initial invasion efficiencies and numbers of released parasites were equivalent between undifferentiated and differentiated cells (~0.3-0.6%). Concomitantly, parasite motility patterns were similar across cell lines. However, CM demonstrated significantly higher infection kinetics over time, reaching 13.26% infected cells versus 3.12% for SM and 3.70% for myoblasts at later stages. Cellular automata modeling suggested an enhanced role for cell-to-cell transmission in driving the heightened parasitism observed in CM. The increased late-stage susceptibility of CM, potentially mediated by cell-to-cell transfer mechanisms of the parasite, aligns with reported clinical tropism patterns. The myotube infection models provide novel insights into Chagas disease pathogenesis that are not fully attainable through in vivo examination alone. Expanding knowledge in this area could aid therapeutic development for this neglected illness.
PubMed: 38913744
DOI: 10.1371/journal.pntd.0012288 -
MBio Jun 2024Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been...
Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been reported, including mutations in the () and increased copies of (). We generated a cross between a Cambodia-derived multidrug-resistant KEL1/PLA1 lineage isolate (KH004) and a drug-susceptible Malawian parasite (Mal31). Mal31 harbors a wild-type (3D7-like) allele and a single copy of , while KH004 has a chloroquine-resistant (Dd2-like) allele with an additional G367C substitution and multiple copies of . We recovered 104 unique recombinant parasites and examined a targeted set of progeny representing all possible combinations of variants at and . We performed a detailed analysis of competitive fitness and a range of PPQ susceptibility phenotypes with these progenies, including PPQ survival assay, area under the dose response curve, and a limited point IC. We find that inheritance of the KH004 allele is required for reduced PPQ sensitivity, whereas copy number variation in further decreases susceptibility but does not confer resistance in the absence of additional mutations in . A deep investigation of genotype-phenotype relationships demonstrates that progeny clones from experimental crosses can be used to understand the relative contributions , , and parasite genetic background to a range of PPQ-related traits. Additionally, we find that the resistance phenotype associated with parasites inheriting the G367C substitution in pfcrt is consistent with previously validated PPQ resistance mutations in this transporter.IMPORTANCEResistance to piperaquine, used in combination with dihydroartemisinin, has emerged in Cambodia and threatens to spread to other malaria-endemic regions. Understanding the causal mutations of drug resistance and their impact on parasite fitness is critical for surveillance and intervention and can also reveal new avenues to limiting the evolution and spread of drug resistance. An experimental genetic cross is a powerful tool for pinpointing the genetic determinants of key drug resistance and fitness phenotypes and has the distinct advantage of quantifying the effects of naturally evolved genetic variation. Our study was strengthened since the full range of copies of KH004 was inherited among the progeny clones, allowing us to directly test the role of the copy number on resistance-related phenotypes in the context of a unique allele. Our multigene model suggests an important role for both loci in the evolution of this multidrug-resistant parasite lineage.
PubMed: 38912775
DOI: 10.1128/mbio.00805-24 -
Frontiers in Immunology 2024Advanced age is associated with an increased susceptibility to Coronavirus Disease (COVID)-19 and more severe outcomes, although the underlying mechanisms are...
Advanced age is associated with an increased susceptibility to Coronavirus Disease (COVID)-19 and more severe outcomes, although the underlying mechanisms are understudied. The lung endothelium is located next to infected epithelial cells and bystander inflammation may contribute to thromboinflammation and COVID-19-associated coagulopathy. Here, we investigated age-associated SARS-CoV-2 pathogenesis and endothelial inflammatory responses using humanized K18-hACE2 mice. Survival was reduced to 20% in aged mice (85-112 weeks) versus 50% in young mice (12-15 weeks) at 10 days post infection (dpi). Bulk RNA-sequencing of endothelial cells from mock and infected mice at 2dpi of both age groups (aged: 72-85 weeks; young: 15 weeks) showed substantially lower significant differentially regulated genes in infected aged mice than in young mice (712 versus 2294 genes). Viral recognition and anti-viral pathways such as RIG-I-like receptor signaling, NOD-like receptor signaling and interferon signaling were regulated in response to SARS-CoV-2. Young mice showed several fold higher interferon responses (, , ) and interferon-induced chemokines ( and ) than aged mice. Endothelial cells from infected young mice displayed elevated expression of chemokines (, ) and leukocyte adhesion markers () underscoring that inflammation of lung endothelium during infection could facilitate leukocyte adhesion and thromboinflammation. TREM1 and acute phase response signaling were particularly prominent in endothelial cells from infected young mice. Immunohistochemistry was unable to detect viral protein in pulmonary endothelium. In conclusion, our data demonstrate that the early host response of the endothelium to SARS-CoV-2 infection declines with aging, which could be a potential contributor to disease severity.
Topics: Animals; COVID-19; SARS-CoV-2; Endothelial Cells; Mice; Lung; Humans; Aging; Disease Models, Animal; Inflammation; Angiotensin-Converting Enzyme 2; Mice, Transgenic
PubMed: 38911865
DOI: 10.3389/fimmu.2024.1397990 -
Frontiers in Genetics 2024Visna/Maedi virus (VMV) is lentiviral disease of sheep responsible for severe production losses. Multiple genomic regions associated with infection were reported...
Visna/Maedi virus (VMV) is lentiviral disease of sheep responsible for severe production losses. Multiple genomic regions associated with infection were reported indicating genetic complexity. In this study, a combined genome-wide approach using a high-density SNP array has been performed, comparing VMV-infected ( = 78) and non-infected ( = 66) individuals of the Valle del Belice breed. The serological tests showed a seroprevalence of 26%. The comparison among results from different approaches (GWAS, Fisher's exact test and the F analysis) revealed two association signals: on OAR03 close to the gene and on OAR05 close to the gene. To the best of our knowledge, there has been no previous association between these genes and lentiviral infection in any species. The gene plays a role in pain response, synaptic transmission, and receptor clustering, while is involved in the development of immune-related disorders. The results highlighted new aspects of the genetic complexity related to the resistance/susceptibility to VMV in sheep, confirming that studies on different breeds can lead to different results. The ideal approach for validation of the markers identified in our study is to use samples from a population independent from the discovery population with the same phenotype used in the discovery stage.
PubMed: 38911298
DOI: 10.3389/fgene.2024.1376883 -
BMC Infectious Diseases Jun 2024Respiratory infections have long been recognized as a primary cause of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). Additionally, the emergence...
BACKGROUND
Respiratory infections have long been recognized as a primary cause of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). Additionally, the emergence of antimicrobial resistance has led to an urgent and critical situation in developing countries, including Vietnam. This study aimed to investigate the distribution and antimicrobial resistance of bacteria in patients with AE-COPD using both conventional culture and multiplex real-time PCR. Additionally, associations between clinical characteristics and indicators of pneumonia in these patients were examined.
METHODS
This cross-sectional prospective study included 92 AE-COPD patients with pneumonia and 46 without pneumonia. Sputum specimens were cultured and examined for bacterial identification, and antimicrobial susceptibility was determined for each isolate. Multiplex real-time PCR was also performed to detect ten bacteria and seven viruses.
RESULTS
The detection rates of pathogens in AE-COPD patients with pneumonia were 92.39%, compared to 86.96% in those without pneumonia. A total of 26 pathogenic species were identified, showing no significant difference in distribution between the two groups. The predominant bacteria included Klebsiella pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae, followed by Acinetobacter baumannii and Streptococcus mitis. There was a slight difference in antibiotic resistance between bacteria isolated from two groups. The frequency of H. influenzae was notably greater in AE-COPD patients who experienced respiratory failure (21.92%) than in those who did not (9.23%). S. pneumoniae was more common in patients with stage I (44.44%) or IV (36.36%) COPD than in patients with stage II (17.39%) or III (9.72%) disease. ROC curve analysis revealed that C-reactive protein (CRP) levels could distinguish patients with AE-COPD with and without pneumonia (AUC = 0.78).
CONCLUSION
Gram-negative bacteria still play a key role in the etiology of AE-COPD patients, regardless of the presence of pneumonia. This study provides updated evidence for the epidemiology of AE-COPD pathogens and the appropriate selection of antimicrobial agents in Vietnam.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Cross-Sectional Studies; Vietnam; Prospective Studies; Male; Female; Aged; Middle Aged; Anti-Bacterial Agents; Drug Resistance, Bacterial; Bacteria; Pneumonia, Bacterial; Microbial Sensitivity Tests; Sputum; Aged, 80 and over; Pneumonia
PubMed: 38910264
DOI: 10.1186/s12879-024-09515-6 -
BMC Genomics Jun 2024Modern broiler breeds allow for high feed efficiency and rapid growth, which come at a cost of increased susceptibility to pathogens and disease. Broiler growth rate,...
Modern broiler breeds allow for high feed efficiency and rapid growth, which come at a cost of increased susceptibility to pathogens and disease. Broiler growth rate, feed efficiency, and health are affected by the composition of the gut microbiota, which in turn is influenced by diet. In this study, we therefore assessed how diet composition can affect the broiler jejunal gut microbiota. A total of 96 broiler chickens were divided into four diet groups: control, coated butyrate supplementation, medium-chain fatty acid supplementation, or a high-fibre low-protein content. Diet groups were sub-divided into age groups (4, 12 and 33 days of age) resulting in groups of 8 broilers per diet per age. The jejunum content was used for metagenomic shotgun sequencing to determine the microbiota taxonomic composition at species level. The composed diets resulted in a total of 104 differentially abundant bacterial species. Most notably were the butyrate-induced changes in the jejunal microbiota of broilers 4 days post-hatch, resulting in the reduced relative abundance of mainly Enterococcus faecium (-1.8 l2fc, P = 9.9E-05) and the opportunistic pathogen Enterococcus hirae (-2.9 l2fc, P = 2.7E-08), when compared to the control diet. This effect takes place during early broiler development, which is critical for broiler health, thus exemplifying the importance of how diet can influence the microbiota composition in relation to broiler health. Future studies should therefore elucidate how diet can be used to promote a beneficial microbiota in the early stages of broiler development.
Topics: Animals; Chickens; Enterococcus faecium; Gastrointestinal Microbiome; Jejunum; Enterococcus hirae; Animal Feed; Diet; Metagenomics; Dietary Supplements
PubMed: 38910254
DOI: 10.1186/s12864-024-10496-8 -
The Lancet. Microbe Jun 2024Microbiota alterations are common in patients hospitalised for severe infections, and preclinical models have shown that anaerobic butyrate-producing gut bacteria...
Association between butyrate-producing gut bacteria and the risk of infectious disease hospitalisation: results from two observational, population-based microbiome studies.
BACKGROUND
Microbiota alterations are common in patients hospitalised for severe infections, and preclinical models have shown that anaerobic butyrate-producing gut bacteria protect against systemic infections. However, the relationship between microbiota disruptions and increased susceptibility to severe infections in humans remains unclear. We investigated the relationship between gut microbiota and the risk of future infection-related hospitalisation in two large population-based cohorts.
METHODS
In this observational microbiome study, gut microbiota were characterised using 16S rRNA gene sequencing in independent population-based cohorts from the Netherlands (HELIUS study; derivation cohort) and Finland (FINRISK 2002 study; validation cohort). HELIUS was conducted in Amsterdam, Netherlands, and included adults (aged 18-70 years at inclusion) who were randomly sampled from the municipality register of Amsterdam. FINRISK 2002 was conducted in six regions in Finland and is a population survey that included a random sample of adults (aged 25-74 years). In both cohorts, participants completed questionnaires, underwent a physical examination, and provided a faecal sample at inclusion (Jan 3, 2013, to Nov 27, 2015, for HELIUS participants and Jan 21 to April 19, 2002, for FINRISK participants. For inclusion in our study, a faecal sample needed to be provided and successfully sequenced, and national registry data needed to be available. Primary predictor variables were microbiota composition, diversity, and relative abundance of butyrate-producing bacteria. Our primary outcome was hospitalisation or mortality due to any infectious disease during 5-7-year follow-up after faecal sample collection, based on national registry data. We examined associations between microbiota and infection risk using microbial ecology and Cox proportional hazards.
FINDINGS
We profiled gut microbiota from 10 699 participants (4248 [39·7%] from the derivation cohort and 6451 [60·3%] from the validation cohort). 602 (5·6%) participants (152 [3·6%] from the derivation cohort; 450 [7·0%] from the validation cohort) were hospitalised or died due to infections during follow-up. Gut microbiota composition of these participants differed from those without hospitalisation for infections (derivation p=0·041; validation p=0·0002). Specifically, higher relative abundance of butyrate-producing bacteria was associated with a reduced risk of hospitalisation for infections (derivation cohort cause-specific hazard ratio 0·75 [95% CI 0·60-0·94] per 10% increase in butyrate producers, p=0·013; validation cohort 0·86 [0·77-0·96] per 10% increase, p=0·0077). These associations remained unchanged following adjustment for demographics, lifestyle, antibiotic exposure, and comorbidities.
INTERPRETATION
Gut microbiota composition, specifically colonisation with butyrate-producing bacteria, was associated with protection against hospitalisation for infectious diseases in the general population across two independent European cohorts. Further studies should investigate whether modulation of the microbiome can reduce the risk of severe infections.
FUNDING
Amsterdam UMC, Porticus, National Institutes of Health, Netherlands Organisation for Health Research and Development (ZonMw), and Leducq Foundation.
PubMed: 38909617
DOI: 10.1016/S2666-5247(24)00079-X -
Human Genomics Jun 2024We previously identified a genetic subtype (C4) of type 2 diabetes (T2D), benefitting from intensive glycemia treatment in the Action to Control Cardiovascular Risk in...
INTRODUCTION
We previously identified a genetic subtype (C4) of type 2 diabetes (T2D), benefitting from intensive glycemia treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Here, we characterized the population of patients that met the C4 criteria in the UKBiobank cohort.
RESEARCH DESIGN AND METHODS
Using our polygenic score (PS), we identified C4 individuals in the UKBiobank and tested C4 status with risk of developing T2D, cardiovascular disease (CVD) outcomes, and differences in T2D medications.
RESULTS
C4 individuals were less likely to develop T2D, were slightly older at T2D diagnosis, had lower HbA1c values, and were less likely to be prescribed T2D medications (P < .05). Genetic variants in MAS1 and IGF2R, major components of the C4 PS, were associated with fewer overall T2D prescriptions.
CONCLUSION
We have confirmed C4 individuals are a lower risk subpopulation of patients with T2D.
Topics: Humans; Diabetes Mellitus, Type 2; Male; Female; Middle Aged; United Kingdom; Multifactorial Inheritance; Aged; Phenotype; Cardiovascular Diseases; Genetic Predisposition to Disease; Glycated Hemoglobin; Biological Specimen Banks; Polymorphism, Single Nucleotide
PubMed: 38909264
DOI: 10.1186/s40246-024-00639-z -
Scientific Reports Jun 2024Inherited and developmental eye diseases are quite diverse and numerous, and determining their genetic cause is challenging due to their high allelic and locus...
Inherited and developmental eye diseases are quite diverse and numerous, and determining their genetic cause is challenging due to their high allelic and locus heterogeneity. New molecular approaches, such as whole exome sequencing (WES), have proven to be powerful molecular tools for addressing these cases. The present study used WES to identify the genetic etiology in ten unrelated Mexican pediatric patients with complex ocular anomalies and other systemic alterations of unknown etiology. The WES approach allowed us to identify five clinically relevant variants in the GZF1, NFIX, TRRAP, FGFR2 and PAX2 genes associated with Larsen, Malan, developmental delay with or without dysmorphic facies and autism, LADD1 and papillorenal syndromes. Mutations located in GZF1 and NFIX were classified as pathogenic, those in TRRAP and FGFR2 were classified as likely pathogenic variants, and those in PAX2 were classified as variants of unknown significance. Protein modeling of the two missense FGFR2 p.(Arg210Gln) and PAX2 p.(Met3Thr) variants showed that these changes could induce potential structural alterations in important functional regions of the proteins. Notably, four out of the five variants were not previously reported, except for the TRRAP gene. Consequently, WES enabled the identification of the genetic cause in 40% of the cases reported. All the syndromes reported herein are very rare, with phenotypes that may overlap with other genetic entities.
Topics: Humans; Exome Sequencing; Male; Female; Child; Receptor, Fibroblast Growth Factor, Type 2; PAX2 Transcription Factor; Child, Preschool; Eye Abnormalities; Infant; Mutation; Adolescent; Genetic Predisposition to Disease
PubMed: 38909058
DOI: 10.1038/s41598-024-65227-6