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Frontiers in Pharmacology 2024Diabetic retinopathy is a secondary microvascular complication of diabetes mellitus. This disease progresses from two stages, non-proliferative and proliferative...
Diabetic retinopathy is a secondary microvascular complication of diabetes mellitus. This disease progresses from two stages, non-proliferative and proliferative diabetic retinopathy, the latter characterized by retinal abnormal angiogenesis. Pharmacological management of retinal angiogenesis employs expensive and invasive intravitreal injections of biologic drugs (anti-vascular endothelial growth factor agents). To search small molecules able to act as anti-angiogenic agents, we focused our study on axitinib, which is a tyrosine kinase inhibitor and represents the second line treatment for renal cell carcinoma. Axitinib is an inhibitor of vascular endothelial growth factor receptors, and among the others tyrosine kinase inhibitors (sunitinib and sorafenib) is the most selective towards vascular endothelial growth factor receptors 1 and 2. Besides the well-known anti-angiogenic and immune-modulatory functions, we hereby explored the polypharmacological profile of axitinib, through a bioinformatic/molecular modeling approach and models of diabetic retinopathy. We showed the anti-angiogenic activity of axitinib in two different models of diabetic retinopathy, by challenging retinal endothelial cells with high glucose concentration (fluctuating and non-fluctuating). We found that axitinib, along with inhibition of vascular endothelial growth factor receptors 1 (1.82 ± 0.10; 0.54 ± 0.13, phosphorylated protein levels in fluctuating high glucose axitinib 1 µM, respectively) and vascular endothelial growth factor receptors 2 (2.38 ± 0.21; 0.98 ± 0.20, phosphorylated protein levels in fluctuating high glucose axitinib 1 µM, respectively), was able to significantly reduce ( < 0.05) the expression of Nrf2 (1.43 ± 0.04; 0.85 ± 0.01, protein levels in fluctuating high glucose axitinib 1 µM, respectively) in retinal endothelial cells exposed to high glucose, through predicted Keap1 interaction and activation of melanocortin receptor 1. Furthermore, axitinib treatment significantly ( < 0.05) decreased reactive oxygen species production (0.90 ± 0.10; 0.44 ± 0.06, fluorescence units in high glucose axitinib 1 µM, respectively) and inhibited ERK pathway (1.64 ± 0.09; 0.73 ± 0.06, phosphorylated protein levels in fluctuating high glucose axitinib 1 µM, respectively) in HRECs exposed to high glucose. The obtained results about the emerging polypharmacological profile support the hypothesis that axitinib could be a valid candidate to handle diabetic retinopathy, with ancillary mechanisms of action.
PubMed: 38953109
DOI: 10.3389/fphar.2024.1415846 -
Epilepsy & Behavior Reports 2024Functional neurological disorder (FND) is a common neurologic disorder associated with many comorbid symptoms including fatigue, pain, headache, and orthostasis. These... (Review)
Review
Functional neurological disorder (FND) is a common neurologic disorder associated with many comorbid symptoms including fatigue, pain, headache, and orthostasis. These concurrent symptoms lead patients to accumulate multiple diagnoses comorbid with FND, including fibromyalgia, chronic fatigue syndrome, postural orthostatic tachycardia syndrome, persistent post-concussive symptoms, and chronic pain. The role of physical activity and exercise has not been evaluated in FND populations, though has been studied in certain comorbid conditions. In this traditional narrative literature review, we highlight some existing literature on physical activity in FND, then look to comorbid disorders to highlight the therapeutic potential of physical activity. We then consider abnormalities in the autonomic nervous system (ANS) as a potential pathophysiological explanation for symptoms in FND and comorbid disorders and postulate how physical activity and exercise may provide benefit via autonomic regulation.
PubMed: 38953100
DOI: 10.1016/j.ebr.2024.100682 -
Research and Practice in Thrombosis and... May 2024Implantation of a left ventricular assist device (LVAD) is a crucial therapeutic option for selected end-stage heart failure patients. However, major bleeding (MB)...
BACKGROUND
Implantation of a left ventricular assist device (LVAD) is a crucial therapeutic option for selected end-stage heart failure patients. However, major bleeding (MB) complications postimplantation are a significant concern.
OBJECTIVES
We evaluated current risk scores' predictive accuracy for MB in LVAD recipients.
METHODS
We conducted an observational, single-center study of LVAD recipients (HeartWare or HeartMate-3, November 2010-December 2022) in the Netherlands. The primary outcome was the first post-LVAD MB (according to the International Society on Thrombosis and Haemostasis [ISTH] and Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS], and INTERMACS combined with intracranial bleeding [INTERMACS+] criteria). Mortality prior to MB was considered a competing event. Discrimination (C-statistic) and calibration were evaluated for the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score, Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke score, Anticoagulation and Risk Factors in Atrial Fibrillation score, Outpatient Bleeding Risk Index, venous thromboembolism score, atrial fibrillation score, and Utah Bleeding Risk Score (UBRS).
RESULTS
One hundred four patients were included (median age, 64 years; female, 20.2%; HeartWare, 90.4%; HeartMate-3, 9.6%). The cumulative MB incidence was 75.7% (95% CI 65.5%-85.9%) by ISTH and INTERMACS+ criteria and 67.0% (95% CI 56.0%-78.0%) per INTERMACS criteria over a median event-free follow-up time of 1916 days (range, 59-4521). All scores had poor discriminative ability on their intended prediction timeframe. Cumulative area under the receiving operator characteristic curve ranged from 0.49 (95% CI 0.35-0.63, venous thromboembolism-BLEED) to 0.56 (95% CI 0.47-0.65, UBRS) according to ISTH and INTERMACS+ criteria and from 0.48 (95% CI 0.40-0.56, Anticoagulation and Risk Factors in Atrial Fibrillation) to 0.56 (95% CI 0.47-0.65, UBRS) per INTERMACS criteria. All models showed poor calibration, largely underestimating MB risk.
CONCLUSION
Current bleeding risk scores exhibit inadequate predictive accuracy for LVAD recipients. There is a need for an accurate risk score to identify LVAD patients at high risk of MB who may benefit from patient-tailored antithrombotic therapy.
PubMed: 38953051
DOI: 10.1016/j.rpth.2024.102437 -
Leukemia Research Reports 2024Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome...
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark mutation transforming to AML characterized by a previously unreported fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors.
PubMed: 38952949
DOI: 10.1016/j.lrr.2024.100465 -
Open Access Emergency Medicine : OAEM 2024Hyperkalemia is a prevalent electrolyte disorder related to elevated serum potassium levels, resulting in diverse abnormal electrocardiographic findings and associated...
INTRODUCTION
Hyperkalemia is a prevalent electrolyte disorder related to elevated serum potassium levels, resulting in diverse abnormal electrocardiographic findings and associated clinical signs and symptoms, often necessitating specific treatment. However, in some patients, these abnormal findings may not be present on the electrocardiogram even in elevated serum potassium levels. This study aims to identify electrocardiographic abnormalities related to the severity of hyperkalemia and the clinical outcomes in an emergency department in southwestern Colombia.
METHODOLOGY
This is a retrospective cross-sectional descriptive study. We described the electrocardiographic findings, clinical characteristics, treatment, and outcomes related to the degrees of hyperkalemia. The potential association between the severity of hyperkalemia and electrocardiographic findings was evaluated.
RESULTS
A total of 494 patients were included. The median of the potassium level was 6.6 mEq/L. Abnormal electrocardiographic findings were reported in 61.5% of the cases. Mild and severe hyperkalemia groups reported abnormalities in 59.9% and 61.2%, respectively. The most common electrocardiography abnormalities were the peaked T wave 36.2%, followed by wide QRS 83 (16.8%). Only 1.4% of patients had adverse outcomes. The abnormal findings were registered in 61.5%. Mortality was 11.9%. The peaked T wave was the most common finding across different levels of hyperkalemia severity.
CONCLUSION
High serum potassium levels are related with abnormal ECG. However, patients with different degrees of hyperkalemia could not describe abnormal ECG findings. In a high proportion of patients with renal chronic disease and hyperkalemia, the abnormalities in the ECG could be minimal or absent.
PubMed: 38952854
DOI: 10.2147/OAEM.S455159 -
IScience Jun 2024The development of antifungal drugs requires novel molecular targets due to limited treatment options and drug resistance. Through chemical screening and establishment...
The development of antifungal drugs requires novel molecular targets due to limited treatment options and drug resistance. Through chemical screening and establishment of a novel genetic technique to repress gene expression in , the primary causal fungus of dermatophytosis, we demonstrated that fungal Cdc42 and Rac GTPases are promising antifungal drug targets. Chemical inhibitors of these GTPases impair hyphal formation, which is crucial for growth and virulence in . Conditional repression of Cdc24, a guanine nucleotide exchange factor for Cdc42 and Rac, led to hyphal growth defects, abnormal cell morphology, and cell death. EHop-016 inhibited the promotion of the guanine nucleotide exchange reaction in Cdc42 and Rac by Cdc24 as well as germination and growth on the nail fragments of and improved animal survival in an invertebrate infection model of . Our results provide a novel antifungal therapeutic target and a potential lead compound.
PubMed: 38952678
DOI: 10.1016/j.isci.2024.110139 -
Frontiers in Oncology 2024Levels of the Wnt pathway components are abnormally altered in gastric cancer cells, leading to malignant cell proliferation, invasion and metastasis, poor prognosis and... (Review)
Review
Levels of the Wnt pathway components are abnormally altered in gastric cancer cells, leading to malignant cell proliferation, invasion and metastasis, poor prognosis and chemoresistance. Therefore, it is important to understand the mechanism of Wnt signaling pathway in gastric cancer. We systematically reviewed the molecular mechanisms of the Wnt pathway in gastric cancer development; and summarize the progression and the challenges of research on molecular agents of the Wnt pathway.
PubMed: 38952556
DOI: 10.3389/fonc.2024.1410513 -
Frontiers in Aging Neuroscience 2024Studying the spatiotemporal patterns of amyloid accumulation in the brain over time is crucial in understanding Alzheimer's disease (AD). Positron Emission Tomography...
INTRODUCTION
Studying the spatiotemporal patterns of amyloid accumulation in the brain over time is crucial in understanding Alzheimer's disease (AD). Positron Emission Tomography (PET) imaging plays a pivotal role because it allows for the visualization and quantification of abnormal amyloid beta (Aβ) load in the living brain, providing a powerful tool for tracking disease progression and evaluating the efficacy of anti-amyloid therapies. Generative artificial intelligence (AI) can learn complex data distributions and generate realistic synthetic images. In this study, we demonstrate for the first time the potential of Generative Adversarial Networks (GANs) to build a low-dimensional representation space that effectively describes brain amyloid load and its dynamics.
METHODS
Using a cohort of 1,259 subjects with AV45 PET images from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we develop a 3D GAN model to project images into a latent representation space and generate back synthetic images. Then, we build a progression model on the representation space based on non-parametric ordinary differential equations to study brain amyloid evolution.
RESULTS
We found that global SUVR can be accurately predicted with a linear regression model only from the latent representation space ( = 0.08 ± 0.01). We generated synthetic PET trajectories and illustrated predicted Aβ change in four years compared with actual progression.
DISCUSSION
Generative AI can generate rich representations for statistical prediction and progression modeling and simulate evolution in synthetic patients, providing an invaluable tool for understanding AD, assisting in diagnosis, and designing clinical trials. The aim of this study was to illustrate the huge potential that generative AI has in brain amyloid imaging and to encourage its advancement by providing use cases and ideas for future research tracks.
PubMed: 38952479
DOI: 10.3389/fnagi.2024.1410844 -
Biological Psychiatry Global Open... Jul 2024Psychological treatments for persecutory delusions, particularly cognitive behavioral therapy for psychosis, are efficacious; however, mechanistic theories explaining... (Review)
Review
Psychological treatments for persecutory delusions, particularly cognitive behavioral therapy for psychosis, are efficacious; however, mechanistic theories explaining why they work rarely bridge to the level of cognitive neuroscience. Predictive coding, a general brain processing theory rooted in cognitive and computational neuroscience, has increasing experimental support for explaining symptoms of psychosis, including the formation and maintenance of delusions. Here, we describe recent advances in cognitive behavioral therapy for psychosis-based psychotherapy for persecutory delusions, which targets specific psychological processes at the computational level of information processing. We outline how Bayesian learning models employed in predictive coding are superior to simple associative learning models for understanding the impact of cognitive behavioral interventions at the algorithmic level. We review hierarchical predictive coding as an account of belief updating rooted in prediction error signaling. We examine how this process is abnormal in psychotic disorders, garnering noisy sensory data that is made sense of through the development of overly strong delusional priors. We argue that effective cognitive behavioral therapy for psychosis systematically targets the way sensory data are selected, experienced, and interpreted, thus allowing for the strengthening of alternative beliefs. Finally, future directions based on these arguments are discussed.
PubMed: 38952435
DOI: 10.1016/j.bpsgos.2024.100333 -
Clinical, Cosmetic and Investigational... 2024Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that influences structures of ectodermal origin, such as teeth, hair, and sweat glands. Compared with...
INTRODUCTION
Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that influences structures of ectodermal origin, such as teeth, hair, and sweat glands. Compared with autosomal recessive and dominant modes of inheritance, the X-linked HED (XLHED) characterized by Hypodontia/Oligodontia teeth, Absent/sparse hair, Anhidrosis/hypohidrosis, and characteristic facial features, is the most frequent and its primary cause is the mutation of ectodysplasin A (EDA) gene. This research aimed to expound the clinical and molecular features of a Chinese male with XLHED and to summarize and compare several previous findings.
METHODS
Genomic DNA was obtained from the peripheral blood of the proband and his family members, then Sanger sequencing was used to perform a mutational analysis of . Real-time quantitative PCR and Western blotting were used to detect EDA expression. The transcriptional activity of NF-κB was detected using a luciferase assay.
RESULTS
The probandwith XLHED was identified a novel mutation, c.1119G>C(p.M373I), that affected the molecular analysis of transmembrane protein exon8 mutations, inherited from the mother. He showed a severe multiple-tooth loss, with over 20 permanent teeth missing and sparse hair and eyebrows, dry, thin, and itching skin. Furthermore, his sweating function was abnormal to a certain extent.
DISCUSSION
The functional study showed that this novel mutant led to a significant decrease in the EDA expression level and transcriptional activity of NF-κB. Our findings extend the range of mutations in XLHED patients, which provides the basis and idea for further exploring the pathogenesis of XLHED.
PubMed: 38952411
DOI: 10.2147/CCID.S451125