Citations

Background/Objectives: Immortality and anti-aging research is accelerating, with implications across medicine. This narrative review explores the biological principles, translational innovations, and ethical considerations at the intersection of aging and plastic surgery, reframed for a broad clinical audience. Methods: A narrative review of the literature from PubMed, clinical trials, and translational studies was conducted, with emphasis on regenerative medicine, stem cells, tissue engineering, gene editing, and longevity pharmacologics within the field of plastic and reconstructive surgery. Results: Key themes include (1) the biology of aging and epigenetic reprogramming, (2) esthetic and regenerative innovations with broader clinical significance, (3) emerging genetic and pharmacologic longevity strategies, (4) ethical and regulatory challenges, and (5) future directions such as nanotechnology, artificial intelligence, and digital immortality. Conclusions: Immortality remains an aspirational frontier, but innovations in regenerative science and longevity research offer opportunities for improving healthspans. Medicine as a whole must balance innovation with ethics, equity, and safety in translating these discoveries to patient care.

Abstract Targetable drivers governing to 5-fluorouracil and cisplatin (5FU+CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Accordingly, we established 5FU+CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 was demonstrated to confer chemoresistance and self-renewal in an RNA editing-dependent manner. WES-seq coupled with RNA-seq identified enrichment of hyperedited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3’UTR of stearoyl-CoA desaturase (SCD1) increased binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogated chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveiled a novel actionable target to circumvent chemoresistance. Citation Format: Jia Jian Loh, Tin Lok Wong, Shixun Lu, Helen HN Yan, Hoi Cheong Siu, Ren Xi, Dessy Chan, Max JF Kam, Lei Zhou, Man Tong, John A. Copland, Leilei Chen, Jingping Yun, Suet Yi Leung, Stephanie Ma. ADAR1-mediated RNA editing of SCD1 links lipid metabolism to gastric cancer drug resistance and self-renewal [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1755.

Abstract Posterior Fossa Group A (PFA) ependymomas are pediatric brain tumors with extremely poor survival outcomes. As protein-coding mutations in PFA are exceedingly rare, the underlying etiology of these tumors remains elusive. Elevated CpG island methylation and depletion of H3K27me3 have been described in PFA, leading to the hypothesis that PFA may be driven by a dysregulated epigenetic state. In this study, we sought to determine how three-dimensional (3D) genome features (such as DNA loops, domains, and compartments) differ between pediatric brain tumors. We performed Hi-C sequencing on a collection of 64 patient specimens and patient-derived primary cultures that collectively span multiple subgroups of ependymoma, medulloblastoma, high-grade glioma, and non-neoplastic brain. For certain samples, we further performed RNA-seq, histone modification ChIP-seq, or whole-genome bisulfite sequencing to allow multiomic data integration. Overall, the 3D genome organization of PFA samples appeared distinct from other tumor types. We identified and defined TULIPs: a subset of type B compartments, separated by genomic distances greater than 10 Mbp, that exhibit a striking fivefold increase in reciprocal interaction strength. These TULIPs recurred at the same genomic positions across the vast majority of PFA samples with minimal representation among other tumor or non-tumor samples. TULIPs displayed enrichment for heterochromatic features such as H3K9me3 and late replication timing and were depleted of euchromatic features such as H3K27ac and protein-coding genes. By using immuno-fluorescence for H3K9me3 and oligo-FISH to label TULIP regions, we demonstrated that TULIP regions are more compact in PFA than other tumors. Finally, by applying inhibitors of H3K9 lysine methylation to PFA cultures we showed that TULIPs become more diffuse and cell viability is reduced. Altogether, this work defines TULIPs as highly recurrent epigenetic features of PFA tumors.

AbstractBackgroundHis bundle pacing (HBP) is a physiological pacing strategy to preserve the electrical synchrony of ventricular conduction and left ventricular (LV) function. Left bundle branch pacing (LBBP) has emerged as an alternative physiological pacing technique.ObjectiveTo evaluate cardiac electrical and mechanical synchrony comparing LBBP and HBP in patients with permanent atrial fibrillation (AF).MethodsConsecutive patients with symptomatic bradycardia and AF were enrolled from January to June of 2019. The cardiac electrical and mechanical synchrony in different pacing mode were evaluated at baseline and after implantation.ResultsBoth HBP and LBBP were performed in 20 patients. LBBP significantly widened the QRS duration compared with the intrinsic conduction (113.2 ± 14.5 vs. 96.5 ± 16.2 ms; p = .01), while HBP did not (104.5 ± 22.3 vs. 96.5 ± 16.2 ms; p = .12). Both LBBP and HBP patients had similar LV myocardial strain measurements for the mechanical synchrony evaluation without significant change compared with baseline. There was no significant difference in right ventricular synchrony measurement between LBBP and HBP. Compared to HBP, LBBP had less interventricular synchrony (IMVD, 14.7 ± 9.2 vs. 3.1 ± 12.7 ms, p < .01; Ts‐LV‐RV, 37.9 ± 10.7 vs. 18.5 ± 10.8 ms, p < .001).ConclusionsAlthough LBBP's a physiological pacing mode can achieve a similar cardiac electrical and mechanical synchronization when compared to HBP, LBBP results in modest delay in RV activation, and the clinical implication remains to be studied.

SummaryBackgroundPrevious studies have demonstrated an association between nonselective beta‐blockers (NSBBs) and lower risk of hepatocellular carcinoma (HCC) in cirrhosis. However, there has been no population‐based study investigating the risk of HCC among cirrhotic patients treated using carvedilol.AimsTo determine the risk of HCC among cirrhotic patients with NSBBs including carvedilol.MethodsThis retrospective cohort study utilised the Cerner Health Facts database in the United States from 2000 to 2017. Kaplan‐Meier estimate, Cox proportional hazards regression, and propensity score matching (PSM) were used to test the HCC risk among the carvedilol, nadolol, and propranolol groups compared with no beta‐blocker group.ResultsThe final cohort comprised 107 428 eligible patients. The 100‐month cumulative HCC incidence of NSBBs was significantly lower than the no beta‐blocker group (carvedilol (11.24%) vs no beta‐blocker (15.69%), nadolol (27.55%) vs no beta‐blocker (32.11%), and propranolol (26.17%) vs no beta‐blocker (28.84%) (P values < 0.0001). NSBBs were associated with a significantly lower risk of HCC (Hazard ratio: carvedilol 0.61 (95% CI 0.51‐0.73), nadolol 0.74 (95% CI 0.63‐0.87), propranolol 0.75 (95% CI 0.66‐0.84) after PSM in the multivariate cox analysis. In subgroup analysis, NSBBs reduced the risk of HCC in cirrhosis with complications and non‐alcoholic cirrhosis.ConclusionsNSBBs, including carvedilol, were associated with a significantly decreased risk of HCC in patients with cirrhosis when compared with no beta‐blocker regardless of complications status. Future randomised‐controlled studies comparing the incidence of HCC among NSBBs should elucidate which NSBB would be the best option to prevent HCC in cirrhosis.

Vascular permeability factor/vascular endothelial growth factor A (VEGF) is a central regulator of angiogenesis and potently promotes vascular permeability. VEGF plays a key role in the pathologies of heart disease, stroke, and cancer. Therefore, understanding the molecular regulation of VEGF signaling is an important pursuit. Rho GTPase proteins play various roles in vasculogenesis and angiogenesis. While the functions of RhoA and RhoB in these processes have been well defined, little is known about the role of RhoC in VEGF-mediated signaling in endothelial cells and vascular development. Here, we describe how RhoC modulates VEGF signaling to regulate endothelial cell proliferation, migration and permeability. We found VEGF stimulation activates RhoC in human umbilical vein endothelial cells (HUVECs), which was completely blocked after VEGF receptor 2 (VEGFR-2) knockdown indicating that VEGF activates RhoC through VEGFR-2 signaling. Interestingly, RhoC knockdown delayed the degradation of VEGFR-2 compared to control siRNA treated HUVECs, thus implicating RhoC in VEGFR-2 trafficking. In light of our results suggesting VEGF activates RhoC through VEGFR-2, we sought to determine whether RhoC regulates vascular permeability through the VEGFR-2/phospholipase Cγ (PLCγ) /Ca 2+ /eNOS cascade. We found RhoC knockdown in VEGF-stimulated HUVECs significantly increased PLC-γ1 phosphorylation at tyrosine 783, promoted basal and VEGF-stimulated eNOS phophorylation at serine 1177, and increased calcium flux compared with control siRNA transfected HUVECs. Taken together, our findings suggest RhoC negatively regulates VEGF-induced vascular permeability. We confirmed this finding through a VEGF-inducible zebrafish model of vascular permeability by observing significantly greater vascular permeability in RhoC morpholino (MO)-injected zebrafish than control MO-injected zebrafish. Furthermore, we showed that RhoC promotes endothelial cell proliferation and negatively regulates endothelial cell migration. Our data suggests a scenario in which RhoC promotes proliferation by upregulating -catenin in a Wnt signaling-independent manner, which in turn, promotes Cyclin D1 expression and subsequently drives cell cycle progression.