To identify predictors of carotid artery stenosis (CAS) progression in head and neck cancer (HNC) patients after radiation therapy (RT).
We included 217 stroke-naïve HNC patients with mild carotid ...artery stenosis after RT in our hospital. These patients underwent annual carotid duplex ultrasound (CDU) studies to monitor CAS progression. CAS progression was defined as the presence of ≥50% stenosis of the internal/common carotid artery on follow-up CDU. We recorded total plaque score (TPS) and determined the cut-off TPS to predict CAS progression. We categorized patients into high (HP) and low plaque (LP) score groups based on their TPS at enrolment. We analyzed the cumulative events of CAS progression in the two groups.
The TPS of the CDU study at enrolment was a significant predictor for CAS progression (adjusted odds ratio aOR = 1.69, p = 0.002). The cut-off TPS was 7 (area under the curve: 0.800), and a TPS ≥ 7 strongly predicted upcoming CAS progression (aOR = 41.106, p = 0.002). The HP group had a higher risk of CAS progression during follow-up (adjusted hazard ratio = 6.15; 95% confident interval: 2.29-16.53) in multivariable Cox analysis, and also a higher trend of upcoming ischemic stroke (HP vs. LP: 8.3% vs. 2.2%, p = 0.09).
HNC patients with a TPS ≥ 7 in any CDU study after RT are susceptible to CAS progression and should receive close monitoring within the following 2 years.
Brain-derived neurotrophic factor (BDNF) has a unique role in the neuronal development, differentiation, and survival in the developing and adult nervous system. A common single-nucleotide ...polymorphism in the pro-region of the human BDNF gene, resulting in a valine to methionine substitution (Val66Met), has been associated with the susceptibility, incidence, and clinical features of several neurodegenerative disorders. Much research has been dedicated to evaluating the effects of polymorphism in the past decade, and functional effects of this genetic variation. A better understanding of how this naturally occurring polymorphism associates with or influences physiology, anatomy, and cognition in both healthy and diseased adults in neurodegenerative conditions will help understand neurochemical mechanisms and definable clinical outcomes in humans. Here we review the role and relevance of the BDNF Val66Met polymorphism in neurodegenerative diseases, with particular emphasis on glaucoma, multiple sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). Several controversies and unresolved issues, including small effect sizes, possible ethnicity, gender, and age effects of the BDNF Val66Met are also discussed with respect to future research.
Background The role of microRNAs (miRNAs), a key class of regulators of mRNA expression and translation, in patients with eosinophilic esophagitis (EoE) has not been explored. Objective We aimed to ...identify miRNAs dysregulated in patients with EoE and assess the potential of these miRNAs as disease biomarkers. Methods Esophageal miRNA expression was profiled in patients with active EoE and those with glucocorticoid-induced disease remission. Expression profiles were compared with those of healthy control subjects and patients with chronic (noneosinophilic) esophagitis. Expression levels of the top differentially expressed miRNAs from the plasma of patients with active EoE and patients with EoE remission were compared with those of healthy control subjects. Results EoE was associated with 32 differentially regulated miRNAs and was distinguished from noneosinophilic forms of esophagitis. The expression levels of the most upregulated miRNAs (miR-21 and miR-223) and the most downregulated miRNA (miR-375) strongly correlated with esophageal eosinophil levels. Bioinformatic analysis predicted interplay of miR-21 and miR-223 with key roles in the polarization of adaptive immunity and regulation of eosinophilia, and indeed, these miRNAs correlated with key elements of the EoE transcriptome. The differentially expressed miRNAs were largely reversible in patients who responded to glucocorticoid treatment. EoE remission induced a single miRNA (miR-675) likely to be involved in DNA methylation. Plasma analysis of the most upregulated esophageal miRNAs identified miR-146a, miR-146b, and miR-223 as the most differentially expressed miRNAs in the plasma. Conclusions We have identified a marked dysregulated expression of a select group of miRNAs in patients with EoE and defined their reversibility with glucocorticoid treatment and their potential value as invasive and noninvasive biomarkers.
Abstract Motivation With single-cell DNA methylation studies yielding vast datasets, existing data formats struggle with the unique challenges of storage and efficient operations, highlighting a need ...for improved solutions. Results BAllC (Binary All Cytosines) emerges as a tailored format for methylation data, addressing these challenges. BAllCools, its complementary software toolkit, enhances parsing, indexing, and querying capabilities, promising superior operational speeds and reduced storage needs. Availability and implementation https://github.com/jksr/ballcools
Herbicides in the widely used chloroacetanilide class harbor a potent electrophilic moiety, which can damage proteins through nucleophilic substitution. In general, damaged proteins are subject to ...misfolding. Accumulation of misfolded proteins compromises cellular integrity by disrupting cellular proteostasis networks, which can further destabilize the cellular proteome. While direct conjugation targets can be discovered through affinity-based protein profiling, there are few approaches to probe how cellular exposure to toxicants impacts the stability of the proteome. We apply a quantitative proteomics methodology to identify chloroacetanilide-destabilized proteins in HEK293T cells based on their binding to the H31Q mutant of the human Hsp40 chaperone DNAJB8. We find that a brief cellular exposure to the chloroacetanilides acetochlor, alachlor, and propachlor induces misfolding of dozens of cellular proteins. These herbicides feature distinct but overlapping profiles of protein destabilization, highly concentrated in proteins with reactive cysteine residues. Consistent with the recent literature from the pharmacology field, reactivity is driven by neither inherent nucleophilic nor electrophilic reactivity but is idiosyncratic. We discover that propachlor induces a general increase in protein aggregation and selectively targets GAPDH and PARK7, leading to a decrease in their cellular activities. Hsp40 affinity profiling identifies a majority of propachlor targets identified by competitive activity-based protein profiling (ABPP), but ABPP can only identify about 10% of protein targets identified by Hsp40 affinity profiling. GAPDH is primarily modified by the direct conjugation of propachlor at a catalytic cysteine residue, leading to global destabilization of the protein. The Hsp40 affinity strategy is an effective technique to profile cellular proteins that are destabilized by cellular toxin exposure. Raw proteomics data is available through the PRIDE Archive at PXD030635.
Bending-active kirigami Lee, Ting-Uei; Gattas, Joseph M.; Xie, Yi Min
International journal of solids and structures,
11/2022, Letnik:
254-255
Journal Article
The Skeletal Oncology Research Group machine-learning algorithms (SORG-MLAs) estimate 90-day and 1-year survival in patients with long-bone metastases undergoing surgical treatment and have ...demonstrated good discriminatory ability on internal validation. However, the performance of a prediction model could potentially vary by race or region, and the SORG-MLA must be externally validated in an Asian cohort. Furthermore, the authors of the original developmental study did not consider the Eastern Cooperative Oncology Group (ECOG) performance status, a survival prognosticator repeatedly validated in other studies, in their algorithms because of missing data.
(1) Is the SORG-MLA generalizable to Taiwanese patients for predicting 90-day and 1-year mortality? (2) Is the ECOG score an independent factor associated with 90-day and 1-year mortality while controlling for SORG-MLA predictions?
All 356 patients who underwent surgery for long-bone metastases between 2014 and 2019 at one tertiary care center in Taiwan were included. Ninety-eight percent (349 of 356) of patients were of Han Chinese descent. The median (range) patient age was 61 years (25 to 95), 52% (184 of 356) were women, and the median BMI was 23 kg/m2 (13 to 39 kg/m2). The most common primary tumors were lung cancer (33% 116 of 356) and breast cancer (16% 58 of 356). Fifty-five percent (195 of 356) of patients presented with a complete pathologic fracture. Intramedullary nailing was the most commonly performed type of surgery (59% 210 of 356), followed by plate screw fixation (23% 81 of 356) and endoprosthetic reconstruction (18% 65 of 356). Six patients were lost to follow-up within 90 days; 30 were lost to follow-up within 1 year. Eighty-five percent (301 of 356) of patients were followed until death or for at least 2 years. Survival was 82% (287 of 350) at 90 days and 49% (159 of 326) at 1 year. The model's performance metrics included discrimination (concordance index c-index), calibration (intercept and slope), and Brier score. In general, a c-index of 0.5 indicates random guess and a c-index of 0.8 denotes excellent discrimination. Calibration refers to the agreement between the predicted outcomes and the actual outcomes, with a perfect calibration having an intercept of 0 and a slope of 1. The Brier score of a prediction model must be compared with and ideally should be smaller than the score of the null model. A decision curve analysis was then performed for the 90-day and 1-year prediction models to evaluate their net benefit across a range of different threshold probabilities. A multivariate logistic regression analysis was used to evaluate whether the ECOG score was an independent prognosticator while controlling for the SORG-MLA's predictions. We did not perform retraining/recalibration because we were not trying to update the SORG-MLA algorithm in this study.
The SORG-MLA had good discriminatory ability at both timepoints, with a c-index of 0.80 (95% confidence interval 0.74 to 0.86) for 90-day survival prediction and a c-index of 0.84 (95% CI 0.80 to 0.89) for 1-year survival prediction. However, the calibration analysis showed that the SORG-MLAs tended to underestimate Taiwanese patients' survival (90-day survival prediction: calibration intercept 0.78 95% CI 0.46 to 1.10, calibration slope 0.74 95% CI 0.53 to 0.96; 1-year survival prediction: calibration intercept 0.75 95% CI 0.49 to 1.00, calibration slope 1.22 95% CI 0.95 to 1.49). The Brier score of the 90-day and 1-year SORG-MLA prediction models was lower than their respective null model (0.12 versus 0.16 for 90-day prediction; 0.16 versus 0.25 for 1-year prediction), indicating good overall performance of SORG-MLAs at these two timepoints. Decision curve analysis showed SORG-MLAs provided net benefits when threshold probabilities ranged from 0.40 to 0.95 for 90-day survival prediction and from 0.15 to 1.0 for 1-year prediction. The ECOG score was an independent factor associated with 90-day mortality (odds ratio 1.94 95% CI 1.01 to 3.73) but not 1-year mortality (OR 1.07 95% CI 0.53 to 2.17) after controlling for SORG-MLA predictions for 90-day and 1-year survival, respectively.
SORG-MLAs retained good discriminatory ability in Taiwanese patients with long-bone metastases, although their actual survival time was slightly underestimated. More international validation and incremental value studies that address factors such as the ECOG score are warranted to refine the algorithms, which can be freely accessed online at https://sorg-apps.shinyapps.io/extremitymetssurvival/.
Level III, therapeutic study.
Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We ...established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTC
score identifies a high-risk population with poor overall survival (HR = 6.0;
= 0.01) and short radiographic progression-free survival (HR = 3.2;
= 0.046). Expression of
in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the
splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTC
score predicts microscopic dissemination to seminal vesicles and/or lymph nodes (
< 0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer.
There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer.
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