Early Therapeutic Intervention Research Articles

Complex Attention-Deficit Hyperactivity Disorder in a 4-Year-Old With Repaired Critical Congenital Heart Disease and Autism Spectrum Disorder.

Congenital heart disease (CHD) is a risk factor for developmental delay and for attention-deficit hyperactivity disorder (ADHD). The Cardiac Neurodevelopmental Outcome Collaborative has developed recommendations for ongoing monitoring of this at-risk population to be able to detect developmental, learning, and behavioral concerns, as they become apparent as a child ages. A 4-year-old boy with tetralogy of Fallot with a ventricular septal defect repaired in infancy was followed periodically in the cardiac neurodevelopmental follow-up clinic and diagnosed with autism spectrum disorder as well as additional developmental and medical issues. He received early childhood special education and therapeutic interventions as well as social skills training and applied behavior analysis. At age 4 years, Alex presented with symptoms of hyperactivity, inattention, impulsivity, and immediate safety concerns for elopement. The clinician diagnosed him with ADHD-combined type. He was recommended to start medication in addition to behavioral and developmental supports. Managing medications in a child with CHD and ADHD presents unique challenges, and medication decisions were carefully made in collaboration with the child's cardiologist. After some medication adjustments and ongoing behavioral therapy to address behaviors associated with ADHD and autism spectrum disorder, the child is doing well academically and socially. Attention-deficit hyperactivity disorder medications can be safely prescribed in patients with CHD. However, pharmacotherapy for co-occurring ADHD and CHD needs an additional level of oversight and collaboration between cardiology and prescribing clinicians. Behavioral therapies can be transdiagnostic and address challenges associated with autism and symptoms related to ADHD.

Targeting the JAK-STAT pathway in colorectal cancer: mechanisms, clinical implications, and therapeutic potential

Colorectal cancer (CRC) remains one of the most prevalent and fatal malignancies worldwide, consistently ranking among the top three in terms of incidence and mortality. Despite notable advancements in early detection and therapeutic interventions, survival outcomes for advanced-stage CRC are still dismal, largely due to issues such as drug resistance and metastasis. Recent research has increasingly implicated the JAK-STAT signaling pathway as a pivotal contributor to CRC pathogenesis. This evolutionarily conserved pathway plays a key role in transmitting extracellular signals to the nucleus, thereby modulating gene expression involved in numerous fundamental biological processes. In CRC, dysregulation of the JAK-STAT pathway is frequently observed and is strongly associated with tumor progression, including processes such as cellular proliferation, apoptosis, metastasis, immune evasion, and the sustenance of cancer stem cells. Given its integral role in CRC advancement, the JAK-STAT pathway has gained recognition as a viable therapeutic target. Extensive evidence from preclinical and clinical models supports the efficacy and safety of targeting components of the JAK-STAT pathway, presenting new therapeutic possibilities for patients with CRC, particularly in addressing drug resistance and enhancing treatment outcomes. This review offers a detailed exploration of the JAK-STAT pathway, focusing on its regulatory mechanisms in CRC-related malignancies. Moreover, it examines the association between JAK-STAT protein expression, clinical features, prognosis, and its therapeutic potential in CRC management.

Exploring neurofeedback as a therapeutic intervention for subjective cognitive decline.

This study addresses the pressing issue of subjective cognitive decline in aging populations by investigating neurofeedback (NFB) as a potential early therapeutic intervention. By evaluating the efficacy of individualised NFB training compared to standard protocols, tailored to each participant's EEG profile, it provides novel insights into personalised treatment approaches. The incorporation of innovative elements and rigorous analytical techniques contributes to advancing our understanding of NFB's modulatory effects on EEG frequencies and cognitive function in aging individuals. In the context of an aging population, concerns surrounding memory function become increasingly prevalent, particularly as individuals transition into middle age and beyond. This study investigated neurofeedback (NFB) as a potential early therapeutic intervention to address subjective cognitive decline (SCD) in aging populations. NFB, a biofeedback technique utilising a brain-computer interface, has demonstrated promise in the treatment of various neurological and psychological conditions. Here, we evaluated the efficacy of individualised NFB training, tailored to each participant's EEG profile, compared to a standard NFB training protocol aimed at increasing peak alpha frequency power, in enhancing cognitive function among individuals experiencing SCD. Our NFB protocol incorporated innovative elements, including the implementation of a criterion for learning success to ensure consistent achievement levels by the conclusion of the training sessions. Additionally, we introduced a non-learner group to account for individuals who do not demonstrate the expected proficiency in NFB regulation. Analysis of electroencephalographic (EEG) signals during NFB sessions, as well as before and after training, provides insights into the modulatory effects of NFB on EEG frequencies. Contrary to expectations, our rigorous analysis revealed that the ability of individuals with SCD to modulate EEG signal power and duration at specific frequencies was not exclusive to the intended frequency target. Furthermore, examination of EEG signals recorded using a high-density EEG showed no discernible alteration in signal power between pre- and post-NFB training sessions. Similarly, no significant effects were observed on questionnaire scores when comparing pre- and post-NFB training assessments.

Deciphering sepsis: An observational bioinformatic analysis of gene expression in granulocytes from GEO dataset GSE123731.

Sepsis triggers severe inflammatory responses leading to organ dysfunction and demands early diagnostic and therapeutic intervention. This study identifies differentially expressed genes (DEGs) in sepsis patients using the Gene Expression Omnibus database to find potential diagnostic and therapeutic markers. We analyzed the dataset GSE123731 via GEO2R to detect DEGs, constructed protein-protein interaction networks, and performed transcription factor analyses using Cytoscape. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted using R and FunRich software. Key genes were validated by Quantitative Reverse Transcription Polymerase Chain and co-immunoprecipitation assays in granulocytes from sepsis patients. We identified 59 DEGs significantly involved in neutrophil degranulation and immune system activation. Cytokine signaling pathways were highlighted in Kyoto Encyclopedia of Genes and Genomes analysis. Co-immunoprecipitation assays confirmed interactions involving matrix metallopeptidase 8, matrix metallopeptidase 9, and arginase 1, supporting their roles as biomarkers. The identified DEGs and validated interactions reveal crucial molecular mechanisms in sepsis, offering new avenues for diagnostic and therapeutic strategies, potentially enhancing patient outcomes.

Return to Play Guidelines in Pediatric Concussion: A Systematic Review of Current Literature.

Pediatric concussions, particularly in youth sports, are a significant public health concern, with up to 18% of children experiencing one by age 17. Return-to-play (RTP) guidelines aim to protect athletes from the adverse effects of repeated injuries, but these protocols vary widely based on factors such as age, sport, and geography. This review synthesizes current literature on RTP guidelines for pediatric concussions to provide evidence-based recommendations. A systematic search of PubMed was conducted using Medical Subject Headings (MeSH) terms "return to play," "pediatric concussion," and "mild traumatic brain injury." Studies published between January 2000 and December 2023 were included if they focused on RTP protocols for children aged 5 to 17. After screening 60 articles, 45 were selected for review. Study quality was assessed using the Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool. RTP protocols showed significant variability influenced by age, gender, and sport type. Common themes included initial rest followed by a gradual return to activity. Female athletes generally required longer recovery periods. Multidisciplinary care and early therapeutic interventions, such as vestibular therapy, were associated with better outcomes and faster recovery. There is a need for standardized, evidence-based RTP guidelines to address inconsistencies in concussion management. Future research should focus on creating universally applicable protocols, with attention to gender, sport-specific factors, and early intervention to improve recovery outcomes for young athletes.

Autism Spectrum Disorder in Children: Early Signs and Therapeutic Interventions.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by challenges in communication, social interaction difficulties, and repetitive behaviors that can hinder a child's development. The growing prevalence of autism necessitates early detection and effective intervention strategies. This review summarizes the current knowledge of early indicators of ASD, including brain development markers and behavioral signs visible in infants. It investigates diagnostic processes, emphasizing the importance of timely detection at 18 to 24 months using established screening tools. We discuss a variety of therapeutic approaches, including behavioral interventions, educational strategies such as music therapy, and technological advancements such as speech-generating devices. Furthermore, we investigate pharmacological options for treating associated symptoms, emphasizing the lack of targeted medications for core ASD symptoms. Finally, we present evidence highlighting the positive effects of early intervention on developmental outcomes, advocating for individualized treatment plans to enhance the well-being of children with ASD. This comprehensive overview aims to inform ongoing ASD research and clinical practices.

Duct of Luschka leak: A postoperative complication of cholecystectomy.

Bile leakage is a serious early postoperative complication of cholecystectomy. A leak in the duct of Luschka, though rare, can cause significant patient morbidity after a cholecystectomy. Early recognition of this uncommon complication allows for early therapeutic intervention.

Comorbidity neural network model for personalised recommendations in cardiometabolic risk factor management: towards early precision medicine in routine clinical practice

Abstract Background and Aims Hypertension and hypercholesterolaemia often develop in tandem to confer a risk of cardiovascular disease that may be more than additive. The present study explored early comorbid therapeutic intervention, i.e., beyond individual disease silos, while minimising data bias to provide clinical decision support tools that are portable across clinics. Methods A neural network was created to reproduce UK national clinical guidelines with an accuracy higher than 95%. Relying on real-world evidence from the UK primary care Clinical Practice Research Datalink electronic health record resource, a transfer learning methodology was then applied to achieve recommended risk factor goal attainment after two years. Shapley values derived from game theory were used to define similar digital twin cohorts, and to evaluate individualised recommendations that deviated from national clinical guidelines by rejecting a no-benefit hypothesis retrospectively in a classical proportion test. The methodology was ported to an independent hold-out dataset with anonymized records from six primary care clinics in the South of England. Results The adult patient population (n=469,496, mean+SD age 61+11yr; M 56% vs F 44%; primary 84% vs secondary prevention 16%) included 101,255 diagnosed for hypertension and 112,180 for cholesterol management. While a majority of the 52,504 therapeutic decisions in a test set agree with single morbidity guidelines, for 4639 deviations from the guidance, a significant minority was identified for whom alternative therapy was recommended. Rejecting a no-clinical benefit hypothesis at the 95% confidence level in a retrospective analysis, 1367 decisions showed statistically significant better outcomes over guidelines, for example by escalating anti-hypertensive therapies for patients receiving statin therapy (1085) or by complementing anti-hypertensive therapy with a statin (158). Similar findings were obtained when tested in a hold-out dataset with 13,725 decisions for 6531 patients. Conclusions The results support the contention that machine learning can identify patient subgroups for whom comorbid intervention deviating from clinical guidelines may be appropriate. A novel aspect of the study is the demonstration of clinically portable and actionable application of machine learning in the context of comorbid cardiometabolic diseases. The results represent practical steps towards personalised precision medicine for cardiovascular comorbidity in routine clinical practice.

Liquid biopsy with plasma Epstein-Barr virus DNA characterizes biological relapse for the prediction of cancer recurrence in non-disseminated nasopharyngeal carcinoma

PurposeTo investigate whether a bounce in plasma Epstein-Barr virus (EBV) DNA during posttreatment surveillance of nasopharyngeal carcinoma (NPC) informs the risk of clinical recurrence and its implication for early therapeutic intervention. Methods950 non-disseminated NPC patients with completed remission in 3 months after treatment were retrospectively screened. Detectable EBV DNA with no evidence of clinical relapse during follow-up was deemed as DNA bounce. The diagnostic and prognostic performance of EBV DNA bounce was assessed for subsequent failures. ResultsTumor recurrence occurred in 6.6 %, 10.1 % and 65.8 % in the group with persistently negative EBV DNA, single positive test and ≥ 2 positive tests, respectively. EBV DNA bounce over twice was associated with worse disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) than the other two groups. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for the prediction of recurrence were 0.56, 0.95, 0.66, 0.93 and 0.90 using two positive tests, which were hence deemed as biological relapse. Serial cutoffs (EBV DNA 1 ≥ 40 copies/ml or EBV DNA 2 ≥100 copies/ml) further defined a high-risk subgroup with an eventual recurrence rate of 77.9 % and 3-year DFS of merely 20.5 %. Prophylactic medical intervention with capecitabine or S1 significantly improved the 3-year DFS when compared to those with observation. ConclusionsThe earliest two positive tests of EBV DNA represent a biomarker of biological relapse that allows early detection of clinical recurrence in EBV-related NPC. For high-risk biological relapse, preemptive intervention provides potential survival benefits.

Patterns of trajectories of glycated hemoglobin, fasting plasma glucose, and body mass index until the first clinic visit: the real-world history of type 2 diabetes using repeated health checkup data of Japanese workers

Abstract Background There is a lack of evidence regarding the trajectories of type 2 diabetes until the first clinic visit, including the untreated period after diagnosis. Objective We aimed to determine the real-world history of type 2 diabetes until the first clinic visit, including the untreated duration, and to assess the effective timing of the therapeutic intervention. Methods A total of 23,622 nondiabetic Japanese workers with a mean (SD) age of 38.8 (11.5) years were retrospectively followed from 2008 to 2022 for annual health checkups. The trajectories of glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body mass index (BMI) until the first clinic visit in diabetes individuals were determined. ROC analysis was performed to assess the contribution of each measure to the first visit. Results During a median follow-up of 12.0 years, 1,725 individuals developed type 2 diabetes, of whom 532 individuals visited clinics. HbA1c and FPG trajectories steeply rose in the year before the first clinic visit after their progressive upward trends. ROC analysis showed cutoff values for each measure. As the untreated duration increased, glycemia increased and BMI decreased among individuals who visited clinics. Conclusions To prevent the initial worsening of diabetes, early therapeutic intervention is necessary during the increasing trends before the steep rise in glycemia, regardless of the degree of obesity. HbA1c ≥6.5% (47.5 mmol/mol) and an HbA1c ≥0.2% (2.2 mmol/mol)/year increase may be an effective timing for therapeutic intervention.

Gene therapy for targeting a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death.

Dysfunction of the sodium-activated potassium channel KNa1.1 (encoded by KCNT1) is associated with a severe condition characterized by frequent seizures (up to hundreds per day) and is often fatal by age three years. We defined the early developmental onset of KNa1.1 channels in prenatal and neonatal brain tissue, establishing a timeline for pathophysiology and a window for therapeutic intervention. Using patch-clamp electrophysiology, we observed age-dependent increases in KNa1.1 K+ conductance. In neurons derived from a child with a gain-of-function KCNT1 pathogenic variant (p.R474H), we detected abnormal excitability and action potential afterhyperpolarization kinetics. In a clinical trial, two individuals with the p.R474H variant showed dramatic reductions in seizure occurrence and severity with a first-in-human antisense oligonucleotide (ASO) RNA therapy. ASO-treated p.R474H neurons in vitro exhibited normalized spiking and burst properties. Finally, we demonstrated the feasibility of ASO knockdown of KNa1.1 in mid-gestation human neurons, suggesting potential for early therapeutic intervention before the onset of epileptic encephalopathy.

Revisiting ELISA with in situ amplification of biomarkers to boost its sensitivity

The enzyme-linked immunosorbent assay (ELISA) stands as a pivotal instrument in diagnostics and biomedical research, widely used for the detection and quantification of specific proteins associated with diseases. Despite its critical role, ELISA's ability to identify low-concentration proteins remains a significant challenge, hindering its effectiveness in early diagnostics, an area of growing importance. This study introduces a novel approach termed nucleic acid-templated amplification (NATA) to enhance ELISA's sensitivity without significantly modifying the common practices of the present ELISA. Drawing inspiration from viral proliferation mechanisms, our approach integrates a cell-free protein synthesis step using DNA sequences that encode the target biomarkers. This approach enables an in situ 'amplification' of target proteins during ELISA, boosting their concentrations to detectable levels. Our results demonstrate a substantial enhancement in sensitivity, with ELISA now being able to detect protein biomarkers at femtomolar concentrations—approaching the sensitivity range typically reserved for PCR in nucleic acid analysis. This breakthrough not only broadens ELISA’s applicability in early disease diagnosis and monitoring therapeutic interventions but also marks a significant advancement in protein biomarker detection technology. With its modular design, our method also offers high versatility and sensitivity, offering an advanced approach for protein detection in clinical diagnostics and research.

Hydronephrosis in a Sigmoid Supernumerary Kidney

Supernumerary kidneys are a rare developmental anomaly, often discovered incidentally or during the investigation of complications such as infections or obstructive uropathy. This case report presents a 70-year-old male patient with a sigmoid supernumerary kidney complicated by hydronephrosis and a staghorn calculus. The patient, with a history of poorly controlled hypertension and type 2 diabetes mellitus, was admitted for febrile left lumbar pain and hemodynamic instability. Diagnostic imaging, including renal ultrasound and uro-CT, revealed a major hydronephrosis in the supernumerary kidney caused by an obstructive staghorn calculus, along with signs of advanced local infection and inflammation. This report highlights the critical role of imaging modalities, particularly uro-CT, in diagnosing renal anomalies and planning treatment. We also review the literature on the management of supernumerary kidneys, emphasizing the importance of early detection and appropriate therapeutic intervention to prevent further complications such as renal insufficiency and infection.

Advances in Blood Biomarkers and Diagnosis Approaches for Neurodegenerative Dementias and Related Diseases.

Neurodegenerative dementias and related diseases, such as Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease have no fundamental cure yet. Degenerative proteins begin to accumulate before the onset of the symptoms of these diseases, and the early detection of these symptoms can lead to early therapeutic intervention. Therefore, early and simpler diagnostic methods are required. This review focuses on blood biomarkers, which are less expensive and easier to use than cerebrospinal fluid biomarkers and diagnostic imaging. A variety of approaches exist for establishing diagnostic methods for neurodegenerative dementias using blood biomarkers, such as disease differentiation using a single molecule, methods that combine multiple biomarkers, studies that search for important markers by comprehensively analyzing many molecules, and methods that combine other data. Finally, we discuss the future prospects for blood biomarker research based on the characteristics of each approach.

Unveiling new chapters in medullary thyroid carcinoma therapy: advances in molecular genetics and targeted treatment strategies.

Medullary Thyroid Carcinoma (MTC), a neuroendocrine malignancy that arises from the calcitonin-secreting parafollicular C-cells of the thyroid, constitutes a minor yet impactful fraction of thyroid malignancies. Distinguished by its propensity for aggressive growth and a pronounced tendency for metastasis, MTC poses formidable obstacles to the early diagnosis and therapeutic intervention. The molecular genetics of MTC, particularly the role of the RET gene and the RAS gene family, have been extensively studied, offering insights into the pathogenesis of the disease and revealing potential therapeutic targets. This comprehensive review synthesizes the latest advancements in the molecular genetics of MTC, the evolution of precision therapies, and the identification of novel biomarkers. We also discuss the implications of these findings for clinical practice and the future direction of MTC research.

Acute optogenetic induction of the prodromal endophenotype of CA1 hyperactivity causes schizophrenia-related deficits in cognition and salience attribution.

Hyperactivity of the human anterior hippocampus has been reported to spread from its CA1 subfield to the subiculum around the onset of first-episode psychosis and could be a cellular target for early therapeutic intervention in the schizophrenia prodrome. However, to what extent CA1 hyperactivity actually causes schizophrenia-related symptoms remains unknown. Here, we mimic this endophenotype by direct optogenetic activation of excitatory cells in the homologous mouse region, ventral CA1 (vCA1) and assess its consequence in multiple schizophrenia-related behavioural tests. We find that hyperactivity of vCA1 causes hyperlocomotion and impairments of spatial and object-related short-term habituation (spatial novelty-preference and novel-object recognition memory) and spatial working memory, whereas social interaction, spatial exploration, and anxiety remain unaltered. Stimulation of the ventral subiculum, in contrast, only increased locomotion and exploration. In conclusion, CA1 hyperactivity may be a direct driver of prodromal cognitive symptoms and of aberrant salience assignment leading to psychosis.

Randomized Controlled Trial to Assess the Feasibility of a Novel Clinical Decision Support System Based on the Automatic Generation of Alerts through Remote Patient Monitoring

Background/Objectives: Early identification of complications in chronic and infectious diseases can reduce clinical deterioration, lead to early therapeutic interventions and lower morbidity and mortality rates. Here, we aimed to assess the feasibility of a novel clinical decision support system (CDSS) based on the automatic generation of alerts through remote patient monitoring and to identify the patient profile associated with the likelihood of severe medical alerts. Methods: A prospective, multicenter, open-label, randomized controlled trial was conducted. Patients with COVID-19 in home isolation were randomly assigned in a 1:1 ratio to receive either conventional primary care telephone follow-up plus access to a mobile app for self-reporting of symptoms (control group) or conventional primary care telephone follow-up plus access to the mobile app for self-reporting of symptoms and wearable devices for real-time telemonitoring of vital signs (case group). Results: A total of 342 patients were randomized, of whom 247 were included in the per-protocol analysis (103 cases and 144 controls). The case group received a more exhaustive follow-up, with a higher number of alerts (61,827 vs. 1825; p < 0.05) but without overloading healthcare professionals thanks to automatic alert management through artificial intelligence. Baseline factors independently associated with the likelihood of a severe alert were having asthma (OR: 1.74, 95% CI: 1.22–2.48, p = 0.002) and taking corticosteroids (OR: 2.28, 95% CI: 1.24–4.2, p = 0.008). Conclusions: The CDSS could be successfully implemented and enabled real-time telemonitoring of patients’ clinical status, providing valuable information to physicians and public health agencies.

Biomarkers of acute kidney injury: a concise review of current literature

Abstract Background Acute kidney injury (AKI), a medical condition associated with increased hospitalization rates which requires interdisciplinary management, is a major health concern because of the burden it places on the health systems of different countries. Biomarkers represent the focus of recent years in furthering the early diagnosis of AKI, providing new opportunities for correct prophylaxis or early therapeutic intervention so that the evolution of patients with this pathology is favorable and the risk of life-threatening complications is negligible. Methods We performed an extensive literature search on PubMed and ScienceDirect databases, using keywords related to bio-markers for AKI. We searched for acute kidney injury (AKI), cystatin C (CYS-C), galectin-3 (GAL-3), kidney injury molecule-1 (KIM-1), neutrophil-gelatinase-associated lipocalin (NGAL), interleukin-8 (IL-8), and liver-type fatty acid-binding protein (L-FABP). We included a high number of papers, with an emphasis on more recent publications. Results Studies that analyzed the biomarkers for AKI show that CYS-C, GAL-3, KIM-1, NGAL, IL-8, calprotectin, and proteinuria were noted as potential biomarkers for early diagnosis of AKI. Conclusions Biomarkers represent the focus of recent years in furthering an early diagnosis of AKI, providing new opportunities for correct prophylaxis or early therapeutic intervention.

Alterations in peripheral T-cell and B-cell subsets in the ankylosing spondylitis patients with gut inflammation.

This study investigates changes in immune cell subsets in peripheral blood of ankylosing spondylitis (AS) patients with colitis or terminal ileitis. It aims to explore the connection between changes in lymphocyte subsets and gut inflammation, providing insights for early detection. Overall, 50 AS patients undergoing colonoscopy were enrolled. Flow cytometry was employed to analyze lymphocyte subsets, including T and B cells, in peripheral blood. Disease activity was assessed using CRP, ESR, BASDAI, ASDAS-CRP, and ASDAS-ESR. Compared to AS patients without gut inflammation, those with colorectal inflammation showed a significant increase in total T cells (p < .05), an increase in exhausted CD4+ T cells (p < .05), and a decrease in Th2 cells and total Tc cells (p < .05). Notably, in AS patients with terminal ileitis, there was an increase in total B cells and classic switched B cells (p < .05), with a decrease in double-positive T cells (p < .05). However, no significant differences were observed in the distribution of Tfh-cell subpopulations (Tfh1, Tfh2, Tfh17) and Tc-cell subpopulations (Tc1, Tc2, Tc17) between AS patients with either colorectal inflammation or terminal ileitis (p > .05). We explored the relationship between disease activity scores, ESR, CRP, and lymphocyte subsets, but found no statistically significant correlation between them. Distinct immune patterns may exist in AS with different types of intestinal inflammation. Colitis in AS is primarily characterized by a significant increase in exhausted CD4+ T cells, along with a decrease in Th2 cells. In contrast, terminal ileum inflammation in AS is marked by an increase in total B cells and classic switched B cells. These findings offer new insights for early detection and therapeutic intervention.

CDKN1A promotes Cis-induced AKI by inducing cytoplasmic ROS production and ferroptosis

Background and objectiveThis study focuses on investigating the role of CDKN1A in cisplatin-induced AKI (acute kidney injury, AKI) and its potential as a biomarker for early diagnosis and therapeutic intervention by integrating bioinformatics analysis, machine learning, and experimental validation. MethodsWe analyzed the GSE85957 dataset to find genes that changed between control and cisplatin-treated rats. Using bioinformatics and machine learning, we found 13 important genes related to ferroptosis and the P53 pathway. The key gene, CDKN1A, was identified using various algorithms. We then tested how reducing CDKN1A in human kidney cells affected cell health, ROS, and iron levels. We also checked how CDKN1A changes the levels of proteins linked to ferroptosis using Q-PCR and Western Blot. ResultsCDKN1A was found to negatively regulate the G1/S phase transition and was associated with ferroptosis in p53 signaling. Experiments in human renal tubular epithelial cells (HK-2) and rat NRK-52E cells showed that CDKN1A knockdown mitigated cisplatin-induced cell injury by reducing oxidative stress and ferroptosis. ConclusionOur integrated approach identified CDKN1A as a biomarker for cisplatin-induced AKI. Its regulation could be key in AKI pathogenesis, offering new therapeutic insights and aiding in early diagnosis and intervention.