Background: The tet oncogene family member 2 (TET2) gene has been reported to be involved in DNA methylation and epigenetic regulation in acute myeloid leukemia (AML). Various studies have proven functional role of TET2 mutations in AML. We herein studied the frequency and genotype-phenotype correlation of TET2 gene in AML patients in Sindh, Pakistan. Patients and methods: The current study was carried out at Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan, in collaboration with National Institute of Blood Disease & Bone Marrow Transplant, Karachi, Pakistan, during the period from June 2019 to June 2020. A total of 130 patients diagnosed with AML were screened for TET2 mutations. Whole exome sequencing of 14 individuals was carried out to find the genetic variants in TET2 gene. The pathogenicity of the variants was predicted by SIFT, PolyPhen2, Mutation Taster and CADD Phred scores. The allele frequency of the variants was compared with global population using 1000 genomes project and Exome Aggregation Consortium (ExAC). Furthermore, exon 3 and exon 5 of the TET2 gene were sequenced by using Sanger sequencing. The findings were correlated with subtypes of AML and corresponding karyotypes. Results: Through the exome sequencing, 17 genetic variants (13 SNPs and four indels) were identified in 14 individuals. Of these, four variants that is, one frameshift deletion, one frameshift insertion and two nonsense variants were novel and not present in dbSNP151 database. Three novel variants were found in exon 3 including two frameshift variants that is, p.T395fs and G494fs, predicted as deleterious by CADD Phred scores, and one stop-gain variant (p.G898X) predicted as deleterious by Mutation Taster and CADD Phred scores. One novel non sense variant (p.Q1191X) was found in the exon 5 predicted as deleterious by SIFT, Mutation Taster and CADD Phred scores. Sanger sequencing analysis revealed one novel deletion at g105233851: del.TAGATAGA, and one novel SNP g;105233861 T>G identified in the TET2 gene. Majority of the exon 3 mutations were seen in the patients diagnosed with AML with maturation, and had a normal karyotype. Conclusion: TET2 mutations were identified in around 16% of the total patients of our study indicating other mechanisms being involved in pathophysiology of AML in this cohort. The TET2 mutations provide a prognostic value in determining AML classification.

Background & objective: Nerve Growth Factor (NGF) plays a key role in the pathophysiology of bronchial asthma through contributing to inflammation of airway, remodeling of airway and neural regulation. This systematic review aimed for the evaluation of mechanisms that contributed to asthma and its relevance to ICU settings. Methodology: The PRISMA 2020 guidelines were followed in this review. Studies that explored NGF expression, regulation and therapeutic targeting in asthma were sought using a comprehensive search of PubMed, Scopus and Google Scholar. Study design, population, NGF measure methods, key findings, and ICU relevance were focused on data extraction. The assessment of risk of any bias was done using Evident Project Risk of Bias Tool. GRADE assessment was used for certainty of evidence. Results: Of the 10 studies included, 6 were based on animal models, 3 were based on human observational studies and the remaining one was a systematic review. Asthma patients exhibited markedly higher NGF levels than control subjects (mean: 3.45 ± 0.76 pg/mL). Eosinophilic counts (r = 0.74, P < 0.01) and inflammatory cytokines correlated in positive with NGF. Airway inflammation decreased by 45.2% (P = 0.002), and airway remodeling by 32% (P = 0.004) via anti-NGF therapy. Similar results were observed by vitamin D supplementation that caused NGF downregulation by 41% (P = 0.003) via the Nrf2/HO-1 pathway. Risk of bias assessment showed that four studies were classified as low risk, five as moderate, and one as high. Conclusion: NGF was significantly stimulated in asthma and contributed to inflammation, reformation and neuroimmune interactions. The correlation of NGF with severe exacerbations and ICU outcomes suggested its potential as a biomarker for therapeutic target. However large scale and long-term evaluation of NGF against asthma was required. Future studies should validate the role of NGF in asthma management particularly in ICU settings. Abbreviations: NGF: Nerve Growth Factor, ICU: Intensive Care Unit, BALF: Bronchoalveolar Lavage Fluid, AHR: Airway Hyperresponsiveness, IL-6: Interleukin-6, IL-1β: Interleukin-1 Beta, CRP: C-Reactive Protein, TRPV1: Transient Receptor Potential Vanilloid 1, Nrf2: Nuclear factor erythroid 2-related factor 2, HO-1: Heme Oxygenase-1, ELISA: Enzyme-Linked Immunosorbent Assay, RT-qPCR: Reverse Transcription Quantitative Polymerase Chain Reaction, GRADE: Grading of Recommendations, Assessment, Development, and Evaluations, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, RSV: Respiratory Syncytial Virus, OVA: Ovalbumin, RhoA: Ras homolog family member A, PM: Particulate Matter Keywords: Nerve Growth Factor; Asthma; Airway Remodeling; Inflammation; Neuroimmunomodulation; Intensive Care Units; Critical Care; Biomarkers Citation: Bukhari AAS, Shaikh ARK, Salman W, Bhatti FA, Malik W, Minhas M, Muddasser A, Khaliq H. Pathophysiological role of nerve growth factor (NGF) in asthma: insights into airway inflammation, remodeling, and neural regulation in intensive care settings. Anaesth. pain intensive care 2025;29(3):681-689. DOI: 10.35975/apic.v29i3.2778 Received: February 03, 2025; Revised: February 28, 2025; Accepted: March 05, 2025