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EBioMedicine May 2024Neurofilament light (NfL) has previously been highlighted as a potential biomarker for Huntington's Disease (HD) using cross-sectional analyses. Our study aim was to...
BACKGROUND
Neurofilament light (NfL) has previously been highlighted as a potential biomarker for Huntington's Disease (HD) using cross-sectional analyses. Our study aim was to investigate how longitudinal trajectories of plasma NfL relate to HD disease stage.
METHODS
108 participants [78 individuals with the HD mutation, and 30 healthy controls (HC)] were included in this study. Individuals with the HD mutation were categorised separately by both HD-Integrated Staging System (HD-ISS) (Study 1) and PIN score-Approximated Staging System (PASS) (Study 2) criteria. Plasma NfL trajectories were examined using Mixed Linear Modeling (MLM); associations with symptom presentation were assessed using Spearman's rho correlations.
FINDINGS
The MLM coefficients for disease stage (HD-ISS β = 32.73, p < 0.0001; PASS β = 33.00, p < 0.0001) and disease stage∗time (HD-ISS β = 7.85, p = 0.004; PASS β = 6.58, p = 0.0047) suggest these are significant contributors to plasma NfL levels. In addition, the plasma NfL rate of change varied significantly across time (HD-ISS β = 3.14, p = 0.04; PASS β = 2.94, p = 0.050). The annualised rate of change was 8.32% for HC; 10.55%, 12.75% and 15.62% for HD-ISS Stage ≤1, Stage 2, and Stage 3, respectively; and 12.13%, 10.46%, 10.33%, 17.52%, for PASS Stage 0, Stage 1, Stage 2, and Stage 3, respectively. Plasma NfL levels correlated with the Symbol Digit Modalities Test (SDMT) in HD-ISS Stage ≤1, and both SDMT and Total Motor Score in Stage 3 (ps < 0.01).
INTERPRETATION
Our findings suggest that plasma NfL levels increase linearly across earlier disease stages, correlating with the cognitive SDMT measure. Thereafter, an increase or surge in plasma NfL levels, paired with correlations with both cognitive and motor measures, suggest a late acceleration in clinical and pathological progression.
FUNDING
NIH (NS111655); the UCSD HDSA CoE; the UCSD ADRC (NIH-NIA P30 AG062429).
PubMed: 38815362
DOI: 10.1016/j.ebiom.2024.105173 -
Redox Biology May 2024Cysteine, the rate-controlling amino acid in cellular glutathione synthesis is imported as cystine, by the cystine/glutamate antiporter, xCT, and subsequently reduced to...
Cysteine, the rate-controlling amino acid in cellular glutathione synthesis is imported as cystine, by the cystine/glutamate antiporter, xCT, and subsequently reduced to cysteine. As glutathione redox is important in muscle regeneration in aging, we hypothesized that xCT exerts upstream control over skeletal muscle glutathione redox, metabolism and regeneration. Bioinformatic analyses of publicly available datasets revealed that expression levels of xCT and GSH-related genes are inversely correlated with myogenic differentiation genes. Muscle satellite cells (MuSCs) isolated from Slc7a11 mice, which harbour a mutation in the Slc7a11 gene encoding xCT, required media supplementation with 2-mercaptoethanol to support cell proliferation but not myotube differentiation, despite persistently lower GSH. Slc7a11 primary myotubes were larger compared to WT myotubes, and also exhibited higher glucose uptake and cellular oxidative capacities. Immunostaining of myogenic markers (Pax7, MyoD, and myogenin) in cardiotoxin-damaged tibialis anterior muscle fibres revealed greater MuSC activation and commitment to differentiation in Slc7a11 muscle compared to WT mice, culminating in larger myofiber cross-sectional areas at 21 days post-injury. Slc7a11 mice subjected to a 5-week exercise training protocol demonstrated enhanced insulin tolerance compared to WT mice, but blunted muscle mitochondrial biogenesis and respiration in response to exercise training. Our results demonstrate that the absence of xCT inhibits cell proliferation but promotes myotube differentiation by regulating cellular metabolism and glutathione redox. Altogether, these results support the notion that myogenesis is a redox-regulated process and may help inform novel therapeutic approaches for muscle wasting and dysfunction in aging and disease.
PubMed: 38815331
DOI: 10.1016/j.redox.2024.103213 -
Frontiers in Endocrinology 2024Radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC) has received increasing attention due to its poor prognosis. However, outcomes may vary among...
BACKGROUND
Radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC) has received increasing attention due to its poor prognosis. However, outcomes may vary among patients with RAIR-DTC. The role of clinico-pathological and molecular prognostic factors in survival remains controversial, resulting in difficulty in selecting patients for new targeted therapies. We assessed mortality rate and DTC-specific survival in Middle Eastern RAIR-DTC to identify prognostic factors associated with survival.
METHODS
This single center, retrospective study enrolled 268 patients with RAIR-DTC. Mortality rate and DTC-specific survival were analyzed to identify prognostic factors related to survival. Univariate and multivariate analysis were performed using Cox proportional hazards model.
RESULTS
Of the 268 cases of RAIR-DTC, 40.3% (108/268) had absent 131I uptake (either on diagnostic or post-therapy whole body scan), 15.3% (41/268) had progressive disease (PD) despite I, 7.5% (20/268) had persistent disease despite cumulative activity of I of >600 mCi and 36.9% (n=99/268) developed distant metastasis. On multivariate analysis, age (more than 45 years), presence of metastatic disease and tumors harboring () promoter mutations were independent prognostic factors for poor DTC-specific survival. Subjects were divided into 3 groups according to the number of risk factors; low risk (no risk factors); intermediate (≤ 2 risk factors); and high risk (all the 3 risk factors). Ten-year DTC-specific survival rates in low, intermediate and high-risk groups were 100.0%, 92.9% and 53.6%, respectively.
CONCLUSIONS
The contribution of age greater than 45 years to RAIR-DTC mortality is impactful. Older age, presence of distant metastasis and mutations could be used as early predictors of RAIR-DTC cases. The identification of prognostic factors for poor survival in RAIR-DTC may improve the selection of patients for more personalized surveillance and therapeutic modalities.
Topics: Humans; Iodine Radioisotopes; Thyroid Neoplasms; Female; Male; Middle Aged; Retrospective Studies; Adult; Risk Factors; Prognosis; Telomerase; Aged; Survival Rate; Treatment Outcome; Young Adult; Middle East
PubMed: 38812819
DOI: 10.3389/fendo.2024.1326976 -
PloS One 2024Recently, a low-level somatic mutation in the NRAS gene (c.182 A > G, Q61R) was identified in various specimens from patients with kaposiform lymphangiomatosis. However,...
Recently, a low-level somatic mutation in the NRAS gene (c.182 A > G, Q61R) was identified in various specimens from patients with kaposiform lymphangiomatosis. However, it is unknown how these low-frequency mutated cells can affect the characterization and surrounding environment of their lesions. To understand the pathogenesis and association of these gene abnormalities, we established NRASQ61R mutated lymphatic endothelial cells transfected with lentivirus vector and undertook morphological and functional characterization, protein expression profiling, and metabolome analysis. NRASQ61R human dermal lymphatic endothelial cells showed poor tube formation, a low proliferation rate, and high migration ability, with an increase in the ratio of mutated cells. An analysis of signaling pathways showed inactivation of the PIK3/AKT/mTOR pathway and hyperactivation of the RAS/MAPK/ERK pathway, which was improved by MAPK kinase (MEK) inhibitor treatment. This study shows the theoretical circumstances induced in vitro by NRASQ61R-mutated cells in the affected lesions of kaposiform lymphangiomatosis patients.
Topics: Humans; Endothelial Cells; GTP Phosphohydrolases; Membrane Proteins; Mutation; Cell Proliferation; Signal Transduction; Cell Movement; TOR Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt
PubMed: 38809881
DOI: 10.1371/journal.pone.0289187 -
PloS One 2024Epidemic or pathogen emergence is the phenomenon by which a poorly transmissible pathogen finds its evolutionary pathway to become a mutant that can cause an epidemic....
Epidemic or pathogen emergence is the phenomenon by which a poorly transmissible pathogen finds its evolutionary pathway to become a mutant that can cause an epidemic. Many mathematical models of pathogen emergence rely on branching processes. Here, we discuss pathogen emergence using Markov chains, for a more tractable analysis, generalizing previous work by Kendall and Bartlett about disease invasion. We discuss the probability of emergence failure for early epidemics, when the number of infected individuals is small and the number of the susceptible individuals is virtually unlimited. Our formalism addresses both directly transmitted and vector-borne diseases, in the cases where the original pathogen is 1) one step-mutation away from the epidemic strain, and 2) undergoing a long chain of neutral mutations that do not change the epidemiology. We obtain analytic results for the probabilities of emergence failure and two features transcending the transmission mechanism. First, the reproduction number of the original pathogen is determinant for the probability of pathogen emergence, more important than the mutation rate or the transmissibility of the emerged pathogen. Second, the probability of mutation within infected individuals must be sufficiently high for the pathogen undergoing neutral mutations to start an epidemic, the mutation threshold depending again on the basic reproduction number of the original pathogen. Finally, we discuss the parameterization of models of pathogen emergence, using SARS-CoV1 as an example of zoonotic emergence and HIV as an example for the emergence of drug resistance. We also discuss assumptions of our models and implications for epidemiology.
Topics: Humans; Epidemics; Mutation; Markov Chains; Models, Theoretical; COVID-19; Basic Reproduction Number; Probability; Animals
PubMed: 38809831
DOI: 10.1371/journal.pone.0301415 -
Frontiers in Pediatrics 2024Cryopyrin-associated periodic syndrome (CAPS) is a genetic disorder and autoinflammatory disease characterized by chronic inflammation throughout the body. The most...
Cryopyrin-associated periodic syndrome (CAPS) is a genetic disorder and autoinflammatory disease characterized by chronic inflammation throughout the body. The most severe form of CAPS, Chronic Infantile Neurologic Cutaneous, and Articular (CINCA) syndrome, also known as Neonatal Onset Multisystem Inflammatory Disease (NOMID), has three main features: skin rash, CNS involvement, and joint symptoms. Although these symptoms are typically reported shortly after birth, there have been a few reports of prenatal inflammation. Here, we report our experience managing a case of a CAPS infant born in severe neonatal asphyxia due to a ruptured cord associated with severe funisitis. The baby was born at 38 weeks and 6 days of gestation, weighing 2,898 g, through an ultra-emergency Caesarian section prompted by variable deceleration. The Apgar score was 1 point at 1 min and 4 points at 5 min, necessitating intensive care due to hypoxic-ischemic encephalopathy. Upon delivery, it was observed that the umbilical cord had partially ruptured at the site of attachment to the baby, accompanied by arterial hemorrhage. Umbilical cord rupture was considered to be the cause of the sudden decrease in fetal heart rate. Pathological examination also showed that the inflammation of the cord was more severe on the side attached to the fetus and on the arterial side, suggesting that the inflammation had extended from the fetus. The father carried a genetic mutation associated with CINCA syndrome/NOMID ( c.2068G>A p.Glu690Lys Hetero), which was also found in the child. Histopathologic examination of the placenta and umbilical cord can provide crucial insights into the intrauterine onset of inflammation, which is the first manifestation of CINCA syndrome/NOMID in newborns. It should be noted that births with a genetic predisposition to CAPS may have complications related to the placenta and umbilical cord.
PubMed: 38808101
DOI: 10.3389/fped.2024.1397412 -
NPJ Precision Oncology May 2024Interval breast cancers (IBCs) are cancers diagnosed between screening episodes. Understanding the biological differences between IBCs and screen-detected breast-cancers...
Interval breast cancers (IBCs) are cancers diagnosed between screening episodes. Understanding the biological differences between IBCs and screen-detected breast-cancers (SDBCs) has the potential to improve mammographic screening and patient management. We analysed and compared the genomic landscape of 288 IBCs and 473 SDBCs by whole genome sequencing of paired tumour-normal patient samples collected as part of the UK 100,000 Genomes Project. Compared to SDBCs, IBCs were more likely to be lobular, higher grade, and triple negative. A more aggressive clinical phenotype was reflected in IBCs displaying features of genomic instability including a higher mutation rate and number of chromosomal structural abnormalities, defective homologous recombination and TP53 mutations. We did not however, find evidence to indicate that IBCs are associated with a significantly different immune response. While IBCs do not represent a unique molecular class of invasive breast cancer they exhibit a more aggressive phenotype, which is likely to be a consequence of the timing of tumour initiation. This information is relevant both with respect to treatment as well as informing the screening interval for mammography.
PubMed: 38806682
DOI: 10.1038/s41698-024-00618-6 -
PLoS Computational Biology May 2024Exposure to environmental stressors, including certain antibiotics, induces stress responses in bacteria. Some of these responses increase mutagenesis and thus...
Exposure to environmental stressors, including certain antibiotics, induces stress responses in bacteria. Some of these responses increase mutagenesis and thus potentially accelerate resistance evolution. Many studies report increased mutation rates under stress, often using the standard experimental approach of fluctuation assays. However, single-cell studies have revealed that many stress responses are heterogeneously expressed in bacterial populations, which existing estimation methods have not yet addressed. We develop a population dynamic model that considers heterogeneous stress responses (subpopulations of cells with the response off or on) that impact both mutation rate and cell division rate, inspired by the DNA-damage response in Escherichia coli (SOS response). We derive the mutant count distribution arising in fluctuation assays under this model and then implement maximum likelihood estimation of the mutation-rate increase specifically associated with the expression of the stress response. Using simulated mutant count data, we show that our inference method allows for accurate and precise estimation of the mutation-rate increase, provided that this increase is sufficiently large and the induction of the response also reduces the division rate. Moreover, we find that in many cases, either heterogeneity in stress responses or mutant fitness costs could explain similar patterns in fluctuation assay data, suggesting that separate experiments would be required to identify the true underlying process. In cases where stress responses and mutation rates are heterogeneous, current methods still correctly infer the effective increase in population mean mutation rate, but we provide a novel method to infer distinct stress-induced mutation rates, which could be important for parameterising evolutionary models.
PubMed: 38805543
DOI: 10.1371/journal.pcbi.1012146 -
Journal of Cancer Research and Clinical... May 2024In metastatic colorectal cancer (mCRC), RAS mutation loss may occur during the standard-of-care regimen. In this study, we aimed to investigate the temporal dynamics of...
PURPOSE
In metastatic colorectal cancer (mCRC), RAS mutation loss may occur during the standard-of-care regimen. In this study, we aimed to investigate the temporal dynamics of the RAS gene and its clinical significance.
METHODS
This was a retrospective, single-center study that included 82 patients with tissue RAS-mutant (RAS-MT) mCRC who underwent circulating tumor DNA (ctDNA) RAS monitoring between January, 2013-April, 2023. Patients were analyzed for the rate of change over time to acquired RAS mutation loss (aRAS-ML) and clinicopathological factors. The prognostic relevance of mutation loss was assessed.
RESULTS
aRAS-ML was detected in 33 (40.2%) patients, 32 of whom had a mutation loss in the first ctDNA RAS assay. Patients with a RAS mutation detected in the first assay had a median time of 8 months until the second ctDNA RAS assay, with 4.5% cases newly converted to aRAS-ML; no new conversions were detected at the third assay. The aRAS-ML group exhibited more single-organ metastases in the target organ during ctDNA measurement (aRAS-ML: 84.8% vs. RAS-MT: 59.2%, p = 0.02). Of the 33 patients with aRAS-ML, seven (21.2%) received anti-epidermal growth factor receptor (EGFR) therapy, with a median progression-free survival of 8 months. Multivariate analysis revealed that persistent ctDNA RAS mutation was an independent prognostic factor for overall survival (hazard ratio: 2.7, 95% confidence interval: 1.1-6.3, p = 0.02).
CONCLUSION
The rate of ctDNA mutation loss in patients with RAS-MT mCRC decreases over time. Therefore, using a ctDNA RAS assay early in treatment will assist in challenging the use of EGFR regimens.
Topics: Humans; Colorectal Neoplasms; Circulating Tumor DNA; Male; Female; Mutation; Retrospective Studies; Middle Aged; Aged; Prognosis; Adult; Aged, 80 and over; Neoplasm Metastasis; Biomarkers, Tumor; Genes, ras; Clinical Relevance
PubMed: 38805050
DOI: 10.1007/s00432-024-05805-3 -
Frontiers in Oncology 2024The safety and feasibility of repeat biopsy after systemic treatment for non-small cell lung cancer have received extensive attention in recent years. The purpose of...
Repeat biopsy versus initial biopsy in terms of complication risk factors and clinical outcomes for patients with non-small cell lung cancer: a comparative study of 113 CT-guided needle biopsy of lung lesions.
OBJECTIVES
The safety and feasibility of repeat biopsy after systemic treatment for non-small cell lung cancer have received extensive attention in recent years. The purpose of this research was to compare complication rates between initial biopsy and rebiopsy in non-small cell lung cancer patients with progressive disease and to assess complication risk factors and clinical results after rebiopsy.
METHODS
The study included 113 patients initially diagnosed with non-small cell lung cancer who underwent lung biopsy at initial biopsy and rebiopsy after progression while on epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and/or chemotherapy from January 2018 to December 2021. We compared the incidence of complications between the initial biopsy and rebiopsy and analyzed the predictors factors that influenced complications in patients who underwent rebiopsy.
RESULTS
The successful rate of rebiopsy was 88.5% (100/113). With the exception of two cases where lung adenocarcinoma changed into small cell lung cancer with gefitinib treatment, 98 individuals retained their initial pathological type. The secondary EGFR T790M mutation accounts for 55.6% of acquired resistance. The total number of patients with complications in initial biopsy was 25 (22.1%) and 37 (32.7%) in the rebiopsy. The incidence of pulmonary hemorrhage increased from 7.1% at the initial biopsy to 10.6% at rebiopsy, while the incidence of pneumothorax increased from 14.2% to 20.4%. Compared with the initial biopsy, the incidence of overall complications, parenchymal hemorrhage, and pneumothorax increased by 10.6%, 3.5%, and 6.2%, respectively. In all four evaluations (pneumorrhagia, pneumothorax, pleural reaction, and overall complication), there were no significant differences between the rebiopsy and initial biopsy (all > 0.05). The multivariate logistic regression analysis suggested that male sex (odds ratio [OR] = 5.064, = 0.001), tumor size ≤ 2 cm (OR = 3.367, = 0.013), EGFR-TKIs with chemotherapy (OR = 3.633, =0.023), and transfissural approach (OR = 7.583, = 0.026) were independent risk factors for overall complication after rebiopsy.
CONCLUSION
Compared with the initial biopsy, the complication rates displayed a slight, but not significant, elevation in rebiopsy. Male sex, tumor size ≤ 2 cm, transfissural approach, and EGFR-TKIs combined with chemotherapy were independent risk factors for rebiopsy complications.
PubMed: 38803532
DOI: 10.3389/fonc.2024.1367603