The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histological progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution towards an IDHwt-like phenotype

Comparative study between transde

Background: This study evaluated the efficacy of transdermal nicotine (TDN) delivery system (15 mg/16 h) or transdermal melatonin (TDM) delivery system (7 mg) 2 h preoperatively for acute postoperative pain after laparoscopic cholecystectomy compared to placebo group (C). Methods: Sixty female non-smoker patients, aged 18–50 years and ASA I and II undergoing elective laparoscopic cholecystectomy under general anesthesia were included in this randomized controlled double-blind study. Patients were randomly divided into 3 groups 20 each, and C group patients received transdermal placebo patch, TDN group (15 mg/16 h) and TDM group (7 mg/8 h). Assessment of postoperative pain, sedation, hemodynamic variables such as HR and MAP, postoperative monitoring of arterial SpO2 and side effects (e.g. nausea, vomiting, pruritus, respiratory depression and hemodynamic instability) were done 30 min, 1, 2, 6 and 12 h postoperatively. Postoperative Patient’s and Surgeons’ satisfaction, Intraoperative bleeding and plasma cortisol (μg/dl) 2 h postoperatively were also assessed. Results: There was a significant reduction in the VAS score, total pethidine requirements (mg) and significantly higher patient’s satisfaction in TDN and TDM groups when compared with the C group postoperatively. The sedation score and surgeons’ satisfaction were significantly higher associated with a significant decrease in MAP and Intraoperative bleeding in TDM group compared to C and TDN groups postoperatively. Significant nausea and vomiting in TDN group and significant sedation in TDM group were recorded. Conclusion: The use of preoperative TDN (15 mg/16 h) or TDM (7 mg/8 h) was an effective and a safe adjuvant for acute pain after surgery

Single-cell nanobiopsy enables multigenerational longitudinal transcriptomics of cancer cells

Single-cell RNA sequencing has revolutionized our understanding of cellular heterogeneity, but routine methods require cell lysis and fail to probe the dynamic trajectories responsible for cellular state transitions, which can only be inferred. Here, we present a nanobiopsy platform that enables injection of exogenous molecules and multigenerational longitudinal cytoplasmic sampling from a single cell and its progeny. The technique is based on scanning ion conductance microscopy (SICM) and, as proof-of-concept, was applied to longitudinally profile the transcriptome of single glioblastoma (GBM) brain tumor cells in vitro over 72hrs. The GBM cells were biopsied before and after exposure to chemotherapy and radiotherapy, and our results suggest that treatment either induces or selects for more transcriptionally stable cells. We envision the nanobiopsy will contribute to the new emerging field that will transform standard single-cell transcriptomics from a static analysis into a dynamic and temporal assay