-
Hepatology (Baltimore, Md.) Apr 2024Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly... (Review)
Review
Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly classified according to their anatomical location and include diverse molecular subclasses harboring inter-tumoral and intratumoral heterogeneity. Besides the tumor cell component, CCA is also characterized by a complex and dynamic tumor microenvironment where tumor cells and stromal cells crosstalk in an intricate network of interactions. Cancer-associated fibroblasts, one of the most abundant cell types in the tumor stroma of CCA, are actively involved in cholangiocarcinogenesis by participating in multiple aspects of the disease including extracellular matrix remodeling, immunomodulation, neo-angiogenesis, and metastasis. Despite their overall tumor-promoting role, recent evidence indicates the presence of transcriptional and functional heterogeneous CAF subtypes with tumor-promoting and tumor-restricting properties. To elucidate the complexity and potentials of cancer-associated fibroblasts as therapeutic targets in CCA, this review will discuss the origin of cancer-associated fibroblasts, their heterogeneity, crosstalk, and role during tumorigenesis, providing an overall picture of the present and future perspectives toward cancer-associated fibroblasts targeting CCA.
Topics: Humans; Cancer-Associated Fibroblasts; Cholangiocarcinoma; Biliary Tract; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Tumor Microenvironment; Contracture; Arachnodactyly
PubMed: 37018128
DOI: 10.1097/HEP.0000000000000206 -
Genetics Jan 2024The fibrillinopathies represent a group of diseases in which the 10-12 nm extracellular microfibrils are disrupted by genetic variants in one of the genes encoding... (Review)
Review
The fibrillinopathies represent a group of diseases in which the 10-12 nm extracellular microfibrils are disrupted by genetic variants in one of the genes encoding fibrillin molecules, large glycoproteins of the extracellular matrix. The best-known fibrillinopathy is Marfan syndrome, an autosomal dominant condition affecting the cardiovascular, ocular, skeletal, and other systems, with a prevalence of around 1 in 3,000 across all ethnic groups. It is caused by variants of the FBN1 gene, encoding fibrillin-1, which interacts with elastin to provide strength and elasticity to connective tissues. A number of mouse models have been created in an attempt to replicate the human phenotype, although all have limitations. There are also natural bovine models and engineered models in pig and rabbit. Variants in FBN2 encoding fibrillin-2 cause congenital contractural arachnodactyly and mouse models for this condition have also been produced. In most animals, including birds, reptiles, and amphibians, there is a third fibrillin, fibrillin-3 (FBN3 gene) for which the creation of models has been difficult as the gene is degenerate and nonfunctional in mice and rats. Other eukaryotes such as the nematode C. elegans and zebrafish D. rerio have a gene with some homology to fibrillins and models have been used to discover more about the function of this family of proteins. This review looks at the phenotype, inheritance, and relevance of the various animal models for the different fibrillinopathies.
Topics: Animals; Cattle; Humans; Mice; Rats; Rabbits; Swine; Mutation; Caenorhabditis elegans; Models, Genetic; Zebrafish; Fibrillins
PubMed: 37972149
DOI: 10.1093/genetics/iyad189 -
BMC Pediatrics Oct 2023Marfan syndrome is a genetic connective tissue disorder affecting skeletal, ocular, and cardiovascular organ systems. Previous research found that pathogenic variants...
BACKGROUND
Marfan syndrome is a genetic connective tissue disorder affecting skeletal, ocular, and cardiovascular organ systems. Previous research found that pathogenic variants clustered in exons 24-32 of fibrillin-1 (FBN1) gene result in more severe clinical phenotypes. Furthermore, genotype-phenotype correlation studies suggested that more severe cardiovascular phenotypes were related to variants held responsible for haploinsufficiency. Our objective was to analyze the differences in clinical manifestations and genotypes of individuals with early-onset Marfan syndrome and to assess their impact on management strategies.
METHODS
We analyzed clinical and genetic data of a new patient with early-onset Marfan syndrome together with 51 previously reported ones in the PubMed database between 1991 and 2022.
RESULTS
Analysis showed 94% (49/52) of pathogenic variants clustered in exons 24-32 of the FBN1. The most common skeletal features were arachnodactyly (98%), reduced elbow extension (48%), pectus deformity (40%), and scoliosis (39%). Haploinsufficiency variants were reported as having poor outcome in 87.5% of the cases. Among patients carrying variants that substitute a cysteine for another amino acid and those that do not change cysteine content, cardiac intervention was found to be associated with a better outcome (p = 0.035 vs. p = 0.002). Variants that create an extra cysteine residue were found to be associated with a higher risk of ectopia lentis. Additionally, children up to 36-months-old were more often reported as still alive at the time of publication compared to newborns (p < 0.01).
CONCLUSIONS
Our findings have implications for prognosis, because different genotype groups and their resulting phenotype may require personalized care and management.
Topics: Child; Humans; Infant, Newborn; Child, Preschool; Marfan Syndrome; Fibrillins; Cysteine; Mutation; Genotype; Phenotype; Prognosis
PubMed: 37891508
DOI: 10.1186/s12887-023-04357-8 -
Human Genetics Nov 2023CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been...
CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been documented with a varied phenotypic spectrum, spanning from a severe manifestation involving skull anomalies, craniosynostosis, encephalocele, radio-humeral fusion, oligodactyly, and a narrow thorax, to a milder presentation characterized by craniosynostosis, restricted radio-humeral joint mobility, hearing loss, and intellectual disability. Here, we report two families with CYP26B1-related phenotypes and describe the data obtained from functional studies of the variants. Exome and Sanger sequencing were used for variant identification in family 1 and family 2, respectively. Family 1 reflects a mild phenotype, which includes craniofacial dysmorphism with brachycephaly (without craniosynostosis), arachnodactyly, reduced radioulnar joint movement, conductive hearing loss, learning disability-and compound heterozygous CYP26B1 variants: (p.[(Pro118Leu)];[(Arg234Gln)]) were found. In family 2, a stillborn fetus presented a lethal phenotype with spina bifida occulta, hydrocephalus, poor skeletal mineralization, synostosis, limb defects, and a synonymous homozygous variant in CYP26B1: c.1083C > A. A minigene assay revealed that the synonymous variant created a new splice site, removing part of exon 5 (p.Val361_Asp382del). Enzymatic activity was assessed using a luciferase assay, demonstrating a notable reduction in exogenous retinoic acid metabolism for the variant p.Val361_Asp382del. (~ 3.5 × decrease compared to wild-type); comparatively, the variants p.(Pro118Leu) and p.(Arg234Gln) demonstrated a partial loss of metabolism (1.7× and 2.3× reduction, respectively). A proximity-dependent biotin identification assay reaffirmed previously reported ER-resident protein interactions. Additional work into these interactions is critical to determine if CYP26B1 is involved with other biological events on the ER. Immunofluorescence assay suggests that mutant CYP26B1 is still localized in the endoplasmic reticulum. These results indicate that novel pathogenic variants in CYP26B1 result in varying levels of enzymatic activity that impact retinoic acid metabolism and relate to the distinct phenotypes observed.
Topics: Humans; Retinoic Acid 4-Hydroxylase; Tretinoin; Homozygote; Exons; Craniosynostoses
PubMed: 37755482
DOI: 10.1007/s00439-023-02598-2 -
American Journal of Medical Genetics.... Jun 2024Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis,...
Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense-medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1-associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.
Topics: Humans; Haploinsufficiency; Female; Marfan Syndrome; Extracellular Matrix Proteins; Phenotype; Connective Tissue Diseases; Pedigree; Mutation; Nonsense Mediated mRNA Decay; Male; Adult; Alleles; Genetic Predisposition to Disease; Child
PubMed: 38348595
DOI: 10.1002/ajmg.a.63556 -
Journal of Vascular Surgery Dec 2023Transcarotid artery revascularization (TCAR) has emerged as an effective method for carotid artery stenting. However, anatomic eligibility for TCAR is most often limited...
OBJECTIVE
Transcarotid artery revascularization (TCAR) has emerged as an effective method for carotid artery stenting. However, anatomic eligibility for TCAR is most often limited by an inadequate clavicle-to-carotid bifurcation length of <5 cm. Preoperative clavicle-to-carotid bifurcation distances may be underestimated when using conventional straight-line measurements on computed tomographic angiography (CTA) imaging. We therefore compared clavicle-to-carotid bifurcation lengths as measured by straight-line CTA, center-line CTA, and intraoperative duplex ultrasound (US), to assess potential differences.
METHODS
We conducted a single-center, retrospective review of consecutive TCAR procedures performed between 2016 and 2019 for atherosclerotic carotid disease. For each patient, we compared clavicle-to-carotid bifurcation lengths measured by straight-line CTA, center-line CTA using TeraRecon image reconstruction, and intraoperative duplex US with neck extension and rotation. We further assessed patient and imaging characteristics in individuals with a ≥0.5 cm difference among the measurement methods. In particular, common carotid artery (CCA) tortuosity, defined as the inability to visualize the entire CCA from clavicle to carotid bifurcation on both a single coronal and sagittal imaging cut, was examined as a contributing factor for these discrepancies.
RESULTS
Of the 70 TCAR procedures identified, 46 had all three imaging modalities available for review. The median clavicle-to-carotid bifurcation length was found to be 6.4 cm (interquartile range [IQR], 5.4-6.7 cm) on straight-line CTA, 7.0 cm (IQR, 6.0-7.5 cm) on intraoperative duplex US, and 7.2 cm (IQR, 6.5-7.5 cm) on center-line CTA (P < .001). Patients with a ≥0.5 cm difference between their straight-line CTA and either their intraoperative duplex US or center-line CTA measurements were more likely to have tortuous CCAs (60.0% vs 19.1%; P = .01; 51.4% vs 0.0%; P = .01). There were no notable differences in age, gender, prior neck/cervical spine surgery, or neck immobility among these individuals. In patients with tortuous CCAs, duplex US and center-line CTA measurements added 1.0 cm (IQR, 0.6-1.5 cm) and 1.1 cm (IQR, 0.9-1.6 cm) more in length than straight-line CTA measurements, respectively. There was a strong linear correlation between the additional lengths provided by duplex US measurements and those provided by center-line CTA measurements for each individual within the tortuous CCA group (r = 0.83).
CONCLUSIONS
The use of straight-line CTA during preoperative planning can underestimate the clavicle-to-carotid bifurcation lengths in patients undergoing carotid revascularization, particularly in those with tortuous CCAs. Both duplex US performed with extended-neck surgical positioning and center-line CTA provide similar and longer carotid length measurements, and should be utilized in patients with tortuous carotid vessels to better determine TCAR anatomic eligibility.
Topics: Humans; Carotid Stenosis; Clavicle; Stents; Vascular Surgical Procedures; Carotid Artery, Common
PubMed: 37657687
DOI: 10.1016/j.jvs.2023.08.124 -
International Journal of Molecular... May 2024Fibrillin-1 and fibrillin-2, encoded by and , respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of...
Fibrillin-1 and fibrillin-2, encoded by and , respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.
Topics: Humans; Fibrillin-1; Marfan Syndrome; Fibrillin-2; Male; Infant, Newborn; Heart Defects, Congenital; High-Throughput Nucleotide Sequencing; Female; Polymorphism, Single Nucleotide; Mutation; Genomics; Phenotype; Exome Sequencing; Adipokines
PubMed: 38791509
DOI: 10.3390/ijms25105469 -
Philosophical Transactions of the Royal... Oct 2023Over 240 million people are infected with schistosomiasis. Detecting eggs in stool using Kato-Katz thick smears (Kato-Katzs) is highly specific but lacks sensitivity....
Over 240 million people are infected with schistosomiasis. Detecting eggs in stool using Kato-Katz thick smears (Kato-Katzs) is highly specific but lacks sensitivity. The urine-based point-of-care circulating cathodic antigen test (POC-CCA) has higher sensitivity, but issues include specificity, discrepancy between batches and interpretation of trace results. A semi-quantitative G-score and latent class analyses making no assumptions about trace readings have helped address some of these issues. However, intra-sample and inter-sample variation remains unknown for POC-CCAs. We collected 3 days of stool and urine from 349 and 621 participants, from high- and moderate-endemicity areas, respectively. We performed duplicate Kato-Katzs and one POC-CCA per sample. In the high-endemicity community, we also performed three POC-CCA technical replicates on one urine sample per participant. Latent class analysis was performed to estimate the relative contribution of intra- (test technical reproducibility) and inter-sample (day-to-day) variation on sensitivity and specificity. Within-sample variation for Kato-Katzs was higher than between-sample, with the opposite true for POC-CCAs. A POC-CCA G3 threshold most accurately assesses individual infections. However, to reach the WHO target product profile of the required 95% specificity for prevalence and monitoring and evaluation, a threshold of G4 is needed, but at the cost of reducing sensitivity. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.
Topics: Humans; Animals; Uganda; Point-of-Care Systems; Reproducibility of Results; Schistosoma mansoni; Neglected Diseases
PubMed: 37598698
DOI: 10.1098/rstb.2022.0275 -
Biochemical Genetics Nov 2023Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder characterized by arachnodactyly, multiple joint contractures, progressive...
Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder characterized by arachnodactyly, multiple joint contractures, progressive kyphoscoliosis, pectus deformity and abnormal crumpled ears. FBN2 is the only gene currently known to be associated with CCA. In this study, we report on a prenatal case presented with skeletal, cardiac and spinal malformations. And his father had elongated limbs, contractures of the proximal interphalangeal joints, high myopia and scoliosis. We conducted whole exome sequencing (WES) on the fetus-parental trio and a heterozygous variant (hg19 chr5:127,673,685, c.3598 + 4A > G, NM_001999.4) in intron 27 of the FBN2 gene was successfully identified, inherited from the father. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to evaluate the potential splicing effect of this variant, which confirmed that the variant caused a deletion of exon 27 (126 bp) by disrupting the splice-donor site and destroyed the 17th calcium-binding epidermal growth factor-like (cbEGF) domain. Our research not only finds the etiology of the disease in affected individuals and expands the mutation spectrum of FBN2 gene, but also provides genetic counseling and fertility guidance for this family.
PubMed: 37962692
DOI: 10.1007/s10528-023-10550-2