Gordonholland9630

Previous research has identified differences in mutation frequency in genes implicated in chemotherapy resistance between mucinous and non-mucinous colorectal cancers (CRC). We hypothesized that outcomes in mucinous and non-mucinous CRC may be influenced by expression of genes responsible for chemotherapy resistance. Gene expression data from primary tumor samples were extracted from The Cancer Genome Atlas PanCancer Atlas. The distribution of clinical, pathological, and gene expression variables was compared between 74 mucinous and 521 non-mucinous CRCs. Predictors of overall survival (OS) were assessed in a multivariate analysis. Kaplan-Meier curves were constructed to compare survival according to gene expression using the log rank test. The median expression of 5-FU-related genes TYMS, TYMP, and DYPD was significantly higher in mucinous CRC compared to non-mucinous CRC (p  less then  0.001, p = 0.003, p  less then  0.001, respectively). The median expression of oxaliplatin-related genes ATP7B and SRPK1 was significantly reduced in mucinous versus non-mucinous CRC (p = 0.004, p = 0.007, respectively). At multivariate analysis, age (odds ratio (OR) = 0.96, p  less then  0.001), node positive disease (OR = 0.49, p = 0.005), and metastatic disease (OR = 0.32, p  less then  0.001) remained significant negative predictors of OS, while high SRPK1 remained a significant positive predictor of OS (OR = 1.59, p = 0.037). Subgroup analysis of rectal cancers demonstrated high SRPK1 expression was associated with significantly longer OS compared to low SRPK1 expression (p = 0.011). This study highlights that the molecular differences in mucinous CRC and non-mucinous CRC extend to chemotherapy resistance gene expression. SRPK1 gene expression was associated with OS, with a prognostic role identified in rectal cancers.

Pregnant women have unprecedented choices for prenatal screening and testing. Cell-free DNA (cfDNA) offers the option to screen for aneuploidy of all chromosomes and genome-wide copy-number variants (CNVs), expanding screening beyond the common trisomies ("traditional" cfDNA). We sought to review the utilization trends and clinical performance characteristics of a commercially available genome-wide cfDNA test, with a subset having available diagnostic testing outcomes.

Retrospective analysis of 55,517 samples submitted for genome-wide cfDNA screening at a commercial laboratory, assessing indications, demographics, results, and performance. The cohort was broken into three "testing years"' to compare trends.

Indications shifted over time, with a decrease in referrals for ultrasound findings (22.0% to 12.0%) and an increase in no known high-risk indication (3.0% to 16.6%). Of the positive results, 25% would be missed with traditional cfDNA screening. High sensitivity and specificity were observed with a positive predictive value (PPV) of 72.6% for genome-wide CNVs and 22.4% for rare autosomal trisomies (RATs).

A broader patient population is utilizing genome-wide cfDNA, yet positivity rates and the contribution of genome-wide events have remained stable at approximately 5% and 25%, respectively. Test performance in a real-world clinical population shows high PPVs in those CNVs tested, with diagnostic outcomes in over 40% of positive cases.

A broader patient population is utilizing genome-wide cfDNA, yet positivity rates and the contribution of genome-wide events have remained stable at approximately 5% and 25%, respectively. Test performance in a real-world clinical population shows high PPVs in those CNVs tested, with diagnostic outcomes in over 40% of positive cases.

Variants in NUS1 are associated with a congenital disorder of glycosylation, developmental and epileptic encephalopathies, and are possible contributors to Parkinson disease pathogenesis. How the diverse functions of the NUS1-encoded Nogo B receptor (NgBR) relate to these different phenotypes is largely unknown. Peptide 17 molecular weight We present three patients with de novo heterozygous variants in NUS1 that cause a complex movement disorder, define pathogenic mechanisms in cells and zebrafish, and identify possible therapy.

Comprehensive functional studies were performed using patient fibroblasts, and a zebrafish model mimicking NUS1 haploinsufficiency.

We show that de novo NUS1 variants reduce NgBR and Niemann-Pick type C2 (NPC2) protein amount, impair dolichol biosynthesis, and cause lysosomal cholesterol accumulation. Reducing nus1 expression 50% in zebrafish embryos causes abnormal swim behaviors, cholesterol accumulation in the nervous system, and impaired turnover of lysosomal membrane proteins. Reduction of cholesterol buildup with 2-hydroxypropyl-ß-cyclodextrin significantly alleviates lysosomal proteolysis and motility defects.

Our results demonstrate that these NUS1 variants cause multiple lysosomal phenotypes in cells. We show that the movement deficits associated with nus1 reduction in zebrafish arise in part from defective efflux of cholesterol from lysosomes, suggesting that treatments targeting cholesterol accumulation could be therapeutic.

Our results demonstrate that these NUS1 variants cause multiple lysosomal phenotypes in cells. We show that the movement deficits associated with nus1 reduction in zebrafish arise in part from defective efflux of cholesterol from lysosomes, suggesting that treatments targeting cholesterol accumulation could be therapeutic.

Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype-phenotype correlations have been found in proband studies only.

In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype-phenotype correlations.

A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants.

This study shows that FBN1 genotype-phenotype correlations exist for both aortic and extra-aortic features.