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Food and Chemical Toxicology : An... Jun 2024High levels of reactive oxygen species (ROS) have been associated with the progression of neurodegenerative diseases such as Alzheimer's disease. The activation of the...
High levels of reactive oxygen species (ROS) have been associated with the progression of neurodegenerative diseases such as Alzheimer's disease. The activation of the NFE2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway may restore the neuron's redox balance and provide a therapeutic impact. Hydroxygenkwanin (HGK), a dominant flavone from Genkwa Flos, has received expanding attention due to its medicinal activities. Our investigation results demonstrated the ability of HGK to protect the PC12 cells from oxidative damage caused by an excessive hydrogen peroxide load. HGK also showed the ability to upregulate a panel of endogenous antioxidant proteins. Further investigations have demonstrated that the neuroprotection mechanism of HGK is dependent on the activation of the Nrf2/ARE signaling pathway. Activating the Nrf2/ARE pathway by HGK reveals a novel mechanism for understanding the pharmacological functions of HGK. These findings suggest that HGK could be considered for further development as an oxidative stress-related neurological pathologies potential therapeutic drug.
PubMed: 38942164
DOI: 10.1016/j.fct.2024.114842 -
Journal of Lipid Research Jun 2024The roles of lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPL) in the development and progression of coronary disease is known, but their influence on...
The roles of lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPL) in the development and progression of coronary disease is known, but their influence on extra-coronary vascular disease is not well-established. We sought to evaluate associations between Lp(a), OxPL apolipoprotein B (OxPL-apoB), and apolipoprotein(a) (OxPL-apo(a)) with angiographic extra-coronary vascular disease and incident major adverse limb events (MALE). 446 participants who underwent coronary and/or peripheral angiography were followed up for a median of 3.7 years. Lp(a) and OxPLs were measured before angiography. Elevated Lp(a) was defined as ≥150 nmol/L. Elevated OxPL-apoB and OxPL-apo(a) were defined as greater than or equal to the 75th percentile (OxPL-apoB ≥8.2 nmol/L and OxPL-apo(a) ≥35.8 nmol/L, respectively). Elevated Lp(a) had a stronger association with the presence of extra-coronary vascular disease compared to OxPLs and was minimally improved with the addition of OxPLs in multivariable models. Compared to participants with normal Lp(a) and OxPL concentrations, participants with elevated Lp(a) levels were twice as likely to experience a MALE (OR 2.14 95% CI: 1.03, 4.44) and the strength of the association as well as the C statistic of 0.82 was largely unchanged with the addition of OxPL-apoB and OxPL-apo(a). Elevated Lp(a) and OxPLs are risk factors for progression and complications of extra-coronary vascular disease. However, the addition of OxPLs to Lp(a) does not provide additional information about risk of extra-coronary vascular disease. Therefore, Lp(a) alone captures the risk profile of Lp(a), OxPL-apoB, and OxPL-apo(a) in the development and progression of atherosclerotic plaque in peripheral arteries. These results lay a foundation in support of studying Lp(a) lowering medications and their effect on limb-related complications.
PubMed: 38942114
DOI: 10.1016/j.jlr.2024.100585 -
NeuroImage Jun 2024The prediction of Alzheimer's disease (AD) progression from its early stages is a research priority. In this context, the use of Artificial Intelligence (AI) in AD has...
BACKGROUND
The prediction of Alzheimer's disease (AD) progression from its early stages is a research priority. In this context, the use of Artificial Intelligence (AI) in AD has experienced a notable surge in recent years. However, existing investigations predominantly concentrate on distinguishing clinical phenotypes through cross-sectional approaches. This study aims to investigate the potential of modeling additional dimensions of the disease, such as variations in brain metabolism assessed via [F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and utilize this information to identify patients with mild cognitive impairment (MCI) who will progress to dementia (pMCI).
METHODS
We analyzed data from 1,617 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had undergone at least one FDG-PET scan. We identified the brain regions with the most significant hypometabolism in AD and used Deep Learning (DL) models to predict future changes in brain metabolism. The best-performing model was then adapted under a multi-task learning framework to identify pMCI individuals. Finally, this model underwent further analysis using eXplainable AI (XAI) techniques.
RESULTS
Our results confirm a strong association between hypometabolism, disease progression, and cognitive decline. Furthermore, we demonstrated that integrating data on changes in brain metabolism during training enhanced the models' ability to detect pMCI individuals (sensitivity=88.4%, specificity=86.9%). Lastly, the application of XAI techniques enabled us to delve into the brain regions with the most significant impact on model predictions, highlighting the importance of the hippocampus, cingulate cortex, and some subcortical structures.
CONCLUSION
This study introduces a novel dimension to predictive modeling in AD, emphasizing the importance of projecting variations in brain metabolism under a multi-task learning paradigm.
PubMed: 38942101
DOI: 10.1016/j.neuroimage.2024.120695 -
Behavioural Brain Research Jun 2024Alzheimer's disease (AD), the most frequent neurodegenerative disease within dementias, affects the CNS, leading to gradual memory issues and cognitive dysfunction....
Alzheimer's disease (AD), the most frequent neurodegenerative disease within dementias, affects the CNS, leading to gradual memory issues and cognitive dysfunction. Oxidative stress in AD contributes to ongoing neuronal loss and hastens disease progression. Notably, the potent antioxidant compounds morin and hesperidin have demonstrated significant effectiveness in addressing oxidative stress. This study explores the impact of morin and hesperidin on behavior and oxidative stress in the streptozotocin (STZ)-induced AD rat model. The experiment involved five groups: control, STZ, STZ+morin, STZ+hesperidin, and STZ+morin+hesperidin. The rat model of AD was created by injecting STZ with the stereotaxic surgery. Morin and hesperidin were applied to the groups for 7-days. After the applications, the Morris water maze (MWM) and novel object recognition (NOR) tests were used and the rats were sacrificed. Malondialdehyde (MDA), glutathione (GSH), nitric oxide (NOx), and protein carbonyl (PC) levels were measured. In the STZ group, the levels of NOx and PC exhibited a noteworthy increase compared to the control. Conversely, the application of morin and/or hesperidin treatments reduced NOx and PC levels compared to the STZ group. The co-administration of morin and hesperidin improved the antioxidant status and decreased lipid peroxidation in STZ-induced rats. In the STZ group, serum advanced oxidation protein products (AOPP) levels were statistically elevated compared to the control. However, in the treatment groups, morin and/or hesperidin successfully decreased AOPP levels to those observed in the control. The combined use of these flavonoids may have a neuroprotective effect regarding memory problems and decreasing oxidative/nitrosative stress.
PubMed: 38942085
DOI: 10.1016/j.bbr.2024.115131 -
Annals of Oncology : Official Journal... Jun 2024Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant...
Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.
BACKGROUND
Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups.
PATIENTS AND METHODS
This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR).
RESULTS
Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004].
CONCLUSIONS
Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.
PubMed: 38942080
DOI: 10.1016/j.annonc.2024.05.541 -
Cell Reports. Medicine Jun 2024Resistance to targeted therapy remains a major clinical challenge in melanoma. To uncover resistance mechanisms, we perform single-cell RNA sequencing on fine-needle...
Resistance to targeted therapy remains a major clinical challenge in melanoma. To uncover resistance mechanisms, we perform single-cell RNA sequencing on fine-needle aspirates from resistant and responding tumors of patients undergoing BRAFi/MEKi treatment. Among the genes most prominently expressed in resistant tumors is POSTN, predicted to signal to a macrophage population associated with targeted therapy resistance (TTR). Accordingly, tumors from patients with fast disease progression after therapy exhibit high POSTN expression levels and high numbers of TTR macrophages. POSTN polarizes human macrophages toward a TTR phenotype and promotes resistance to targeted therapy in a melanoma mouse model, which is associated with a phenotype change in intratumoral macrophages. Finally, polarized TTR macrophages directly protect human melanoma cells from MEKi-induced killing via CD44 receptor expression on melanoma cells. Thus, interfering with the protective activity of TTR macrophages may offer a strategy to overcome resistance to targeted therapy in melanoma.
PubMed: 38942020
DOI: 10.1016/j.xcrm.2024.101611 -
Medical Image Analysis Jun 2024The conventional pretraining-and-finetuning paradigm, while effective for common diseases with ample data, faces challenges in diagnosing data-scarce occupational...
The conventional pretraining-and-finetuning paradigm, while effective for common diseases with ample data, faces challenges in diagnosing data-scarce occupational diseases like pneumoconiosis. Recently, large language models (LLMs) have exhibits unprecedented ability when conducting multiple tasks in dialogue, bringing opportunities to diagnosis. A common strategy might involve using adapter layers for vision-language alignment and diagnosis in a dialogic manner. Yet, this approach often requires optimization of extensive learnable parameters in the text branch and the dialogue head, potentially diminishing the LLMs' efficacy, especially with limited training data. In our work, we innovate by eliminating the text branch and substituting the dialogue head with a classification head. This approach presents a more effective method for harnessing LLMs in diagnosis with fewer learnable parameters. Furthermore, to balance the retention of detailed image information with progression towards accurate diagnosis, we introduce the contextual multi-token engine. This engine is specialized in adaptively generating diagnostic tokens. Additionally, we propose the information emitter module, which unidirectionally emits information from image tokens to diagnosis tokens. Comprehensive experiments validate the superiority of our methods.
PubMed: 38941859
DOI: 10.1016/j.media.2024.103248 -
Heart & Lung : the Journal of Critical... Jun 2024Progressive exercise intolerance is a hallmark of pulmonary hypertension (pH), severely impacting patients' independence and quality of life (QoL). Accumulating evidence... (Review)
Review
Respiratory, cardiovascular and musculoskeletal mechanisms involved in the pathophysiology of pulmonary hypertension: An updated systematic review of preclinical and clinical studies.
BACKGROUND
Progressive exercise intolerance is a hallmark of pulmonary hypertension (pH), severely impacting patients' independence and quality of life (QoL). Accumulating evidence over the last decade shows that combined abnormalities in peripheral reflexes and target organs contribute to disease progression and exercise intolerance.
OBJECTIVE
The aim of this study was to review the literature of the last decade on the contribution of the cardiovascular, respiratory, and musculoskeletal systems to pathophysiology and exercise intolerance in pH.
METHODS
A systematic literature search was conducted using specific terms in PubMed, SciELO, and the Cochrane Library databases for original pre-clinical or clinical studies published between 2013 and 2023. Studies followed randomized controlled/non-randomized controlled and pre-post designs.
RESULTS
The systematic review identified 25 articles reporting functional or structural changes in the respiratory, cardiovascular, and musculoskeletal systems in pH. Moreover, altered biomarkers in these systems, lower cardiac baroreflex, and heightened peripheral chemoreflex activity seemed to contribute to functional changes associated with poor prognosis and exercise intolerance in pH. Potential therapeutic strategies acutely explored involved manipulating the baroreflex and peripheral chemoreflex, improving cardiovascular autonomic control via cardiac vagal control, and targeting specific pathways such as GPER1, GDF-15, miR-126, and the JMJD1C gene.
CONCLUSION
Information published in the last 10 years advances the notion that pH pathophysiology involves functional and structural changes in the respiratory, cardiovascular, and musculoskeletal systems and their integration with peripheral reflexes. These findings suggest potential therapeutic targets, yet unexplored in clinical trials, that could assist in improving exercise tolerance and QoL in patients with pH.
PubMed: 38941771
DOI: 10.1016/j.hrtlng.2024.06.001 -
Journal of the Neurological Sciences Jun 2024Brain and cortical atrophy play crucial roles in supporting the clinical diagnosis of Alzheimer's disease (AD). This study hypothesized that the ratios of brain or...
BACKGROUND
Brain and cortical atrophy play crucial roles in supporting the clinical diagnosis of Alzheimer's disease (AD). This study hypothesized that the ratios of brain or cortical volume to subcortical gray matter structure volumes are potential imaging markers for cognitive alterations in AD dementia and amnestic mild cognitive impairment (aMCI).
METHODS
Seventy-seven subjects diagnosed with AD dementia or aMCI underwent baseline neuropsychological testing, 2-year follow-up cognitive assessments, and high-resolution T1-weighted MRI scans. Total brain/cortical volume and subcortical gray matter structure volumes were automatically segmented and measured. Univariate and multiple linear regression analyses were conducted to determine the associations between volumetric ratios and interval changes in cognitive scores.
RESULTS
The ratio of cortical volume to caudate volume showed the most significant association with changes in MoCA (B = 0.132, SE = 0.042, p = 0.002), MMSE (B = 0.140, SE = 0.040, p = 0.001), and CDR-SOB (B = -0.013, SE = 0.005, p = 0.007) scores over the 2-year follow-up period. These associations remained significant after adjusting for various covariates. Similar associations were observed for the ratios of cortical volume to putamen and globus pallidum volumes.
CONCLUSIONS
The cortex-to-caudate volume ratio is significantly associated with cognitive decline in AD dementia and aMCI. This ratio may serve as a useful biomarker for monitoring disease progression and predicting cognitive outcomes. Our findings highlight the importance of considering the relative atrophy of cortical and subcortical structures in understanding AD pathology.
PubMed: 38941706
DOI: 10.1016/j.jns.2024.123113 -
Scientific Reports Jun 2024Eukaryotic cells can synthesize formyl-methionine (fMet)-containing proteins not only in mitochondria but also in the cytosol to some extent. Our previous study revealed...
Eukaryotic cells can synthesize formyl-methionine (fMet)-containing proteins not only in mitochondria but also in the cytosol to some extent. Our previous study revealed substantial upregulation of N-terminal (Nt)-fMet-containing proteins in the cytosol of SW480 colorectal cancer cells. However, the functional and pathophysiological implications remain unclear. Here, we demonstrated that removal of the Nt-formyl moiety of Nt-fMet-containing proteins (via expressing Escherichia coli PDF peptide deformylase) resulted in a dramatic increase in the proliferation of SW480 colorectal cancer cells. This proliferation coincided with the acquisition of cancer stem cell features, including reduced cell size, enhanced self-renewal capacity, and elevated levels of the cancer stem cell surface marker CD24 and pluripotent transcription factor SOX2. Furthermore, deformylation of Nt-fMet-containing proteins promoted the tumorigenicity of SW480 colorectal cancer cells in an in vivo xenograft mouse model. Taken together, these findings suggest that cytosolic deformylation has a tumor-enhancing effect, highlighting its therapeutic potential for cancer treatment.
Topics: Humans; Neoplastic Stem Cells; Animals; Cytosol; Mice; Cell Line, Tumor; Cell Proliferation; Amidohydrolases; Colorectal Neoplasms; CD24 Antigen; SOXB1 Transcription Factors; Disease Progression; Methionine
PubMed: 38942903
DOI: 10.1038/s41598-024-65701-1