Citations

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.

ImportanceChronic hemodynamically significant aortic regurgitation (AR) is associated with excess risk of death, yet data for Asian patients are lacking, and whether Asian patients can abide by Western guidelines as to when aortic valve surgery should be performed is unknown.ObjectiveTo assess AR presentation and cutoffs of left ventricular ejection fraction (LVEF), LV end-systolic dimension index (LVESDi), and LV end-systolic volume index (LVESVi) that are associated with risk of death in Asian patients with AR.Design, Setting, and ParticipantsThis retrospective cohort study included consecutive patients with chronic, moderately severe to severe AR from 3 tertiary referral centers (2 in Japan and 1 in Taiwan) from June 11, 2008, through November 19, 2020, with follow-up through November 11, 2021.ExposuresAortic regurgitation severity, graded by a comprehensive integrated approach.Main Outcomes and MeasuresThe primary outcome was the association between volume-derived LVEF, LVESDi, and LVESVi and all-cause death (ACD). The secondary outcome was the association of these LV indexes with cardiovascular death (CVD). Clinical and echocardiographic data were analyzed retrospectively. A de novo disk-summation method was used to derive LV volumes and volume-derived LVEF.ResultsOf 1259 patients (mean [SD] age, 64 [17] years; 934 [74%] male), 515 (41%) were Japanese and 744 (59%) were Taiwanese. The median follow-up was 4.1 years (IQR, 1.56-7.24 years). The mean (SD) body surface area was 1.67 (0.21) m2; LVEF, 55% (11%); LVESDi, 24.7 (5.7) mm/m2; LVESVi, 50.1 (28.0) mL/m2; and indexed mid–ascending aorta size, 24.7 (5.5) mm/m2. Aortic valve surgery occurred in 483 patients (38%); 240 patients (19%) died during follow-up. Overall mean (SD) 8-year survival was 74% (2%). Separate multivariate models adjusted for covariates demonstrated independent associations of LVEF, LVESDi, and LVESVi with ACD (LVEF: hazard ratio [HR] per 10%, 0.80; 95% CI, 0.70-0.92; P = .002; LVESDi: HR, 1.04; 95% CI, 1.01-1.06; P = .002; LVESVi: HR per 10 mL/m2, 1.11; 95% CI, 1.05-1.17; P < .001) and CVD (LVEF: HR per 10%, 0.69; 95% CI, 0.56-0.85; P < .001; LVESDi: HR, 1.05; 95% CI, 1.01-1.09; P = .01; LVESVi per 10 mL/m2: HR, 1.15; 95% CI, 1.06-1.24; P < .001). In the total cohort, spline curves showed that mortality started to increase for an LVEF of 53% or less, LVESDi of 22 mm/m2 or greater, and LVESVi of 46 mL/m2 or greater for both ACD and CVD. Early surgery was beneficial in 3 strata of LVESDi (<20, 20 to <25, and ≥25 mm/m2) and 2 strata of LVESVi (<46 and ≥46 mL/m2).Conclusions and RelevanceThis multicenter cohort study of Asian patients with hemodynamically significant AR found cutoff values of LVEF, LVESDi, and LVESVi that were associated with increased risk of death. These findings suggest that Western guidelines seem applicable in Asian patients and, most importantly, that indexed LV parameters with a lower cutoff could be used in discriminating patients with excess mortality risk.

BACKGROUND: There are limited data regarding outcomes for patients with gastrointestinal (GI) primaries and brain metastases treated with stereotactic radiosurgery (SRS). OBJECTIVE: To examine clinical outcomes after SRS for patients with brain metastases from GI primaries and evaluate potential prognostic factors. METHODS: The International Radiosurgery Research Foundation centers were queried for patients with brain metastases from GI primaries managed with SRS. Primary outcomes were local control (LC) and overall survival (OS). Kaplan-Meier analysis was used for univariate analysis (UVA) of prognostic factors. Factors significant on UVA were evaluated with a Cox multivariate analysis proportional hazards model. Logistic regressions were used to examine correlations with RN. RESULTS: We identified 263 eligible patients with 543 brain metastases. Common primary sites were rectal (31.2%), colon (31.2%), and esophagus (25.5%) with a median age of 61.6 years (range: 37-91.4 years) and a median Karnofsky performance status (KPS) of 90% (range: 40%-100%). One-year and 2-year LC rates were 83.5% (95% CI: 78.9%-87.1%) and 73.0% (95% CI: 66.4%-78.5%), respectively. On UVA, age >65 years ( P = .001), dose <20 Gy ( P = .006) for single-fraction plans, KPS <90% ( P < .001), and planning target volume ≥2cc ( P = .007) were associated with inferior LC. All factors other than dose were significant on multivariate analysis ( P ≤ .002). One-year and 2-year OS rates were 68.0% (95% CI: 61.5%-73.6%) and 31.2% (95% CI: 24.6%-37.9%), respectively. Age > 65 years ( P = .006), KPS <90% ( P = .005), and extracranial metastases ( P = .05) were associated with inferior OS. CONCLUSION: SRS resulted in comparable LC with common primaries. Age and KPS were associated with both LC and OS with planning target volume and extracranial metastases correlating with LC and OS, respectively. These factors should be considered in GI cancer patient selection for SRS.

Abstract Background In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR‐Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR‐Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence‐based findings and recommendation from the full document. Methods ICAR‐Allergic Rhinitis 2023 employed established evidence‐based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work. Results ICAR‐Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost. Conclusion The ICAR‐Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment.

Abstract Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome‐wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage‐PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta‐Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross‐phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (G corr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (G corr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). Conclusions We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

AbstractBackgroundAs gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited.ObjectiveThe objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.MethodsWe conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.ResultsWe collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ‐1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.ConclusionsWithin the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD‐linked variants; (2) provide harmonized and quality‐controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene‐targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

AbstractClinical trials of novel salvage therapies have encouraging outcomes for relapsed/refractory transplant‐eligible classic Hodgkin lymphoma (R/R cHL) but comparison with conventional chemotherapy is lacking. Herein, we report the final analysis of a multicenter retrospective cohort of R/R cHL assessing outcomes by type of salvage therapy before autologous stem cell transplant (ASCT). R/R cHL patients who underwent ASCT at 14 institutions across the United States were included. Outcomes were compared among patients receiving conventional chemotherapy, brentuximab vedotin (BV) + chemotherapy, BV alone, and a checkpoint inhibitor (CPI)‐based regimens before ASCT. Study endpoints included event‐free survival (EFS), progression‐free survival (PFS), and overall survival (OS). All endpoints are defined from relapse. Of 936 patients, 728 received conventional chemotherapy, 73 received BV + chemotherapy, 70 received BV alone, and 65 received CPI‐based regimens prior to ASCT. When adjusted for time to relapse, pre‐ASCT response and use of BV maintenance, patients receiving CPI‐based regimens had superior 2‐year EFS compared to conventional chemotherapy, BV + chemotherapy, and BV alone (79.7, 49.6, 62.3, and 36.9%, respectively, p < .0001). Among 649 patients transplanted after 1 line of salvage therapy, CPI‐based regimens were associated with superior 2‐year PFS compared to conventional chemotherapy (98% vs. 68.8%, hazard ratio: 0.1, 95% confidence interval: 0.03–0.5, p < .0001). OS did not differ by pre‐ASCT salvage regimen. In this large multicenter retrospective study, CPI‐based regimens improved EFS and PFS compared to other salvage regimens independent of pre‐ASCT response. These data support earlier sequencing of CPI‐based regimens in R/R cHL in the pre‐ASCT setting.

Abstract Structural changes on the surface of the class I Ag binding domain resulting from point mutations localized inside the Ag binding cleft of the H-2Kb and Kf glycoproteins were revealed using mAb. Both the loss and gain of antibody binding sites found among naturally occurring K glycoproteins resulted from single amino acid substitutions at a variety of different positions buried within the Ag binding groove. Each of the amino acid replacements analyzed represented naturally occurring diversity known to exist among the functional class I Ag-presenting molecules of the mouse. The binding of the affected mAb was not significantly altered in Kb molecules expressed by transfected T2 cells. Because T2 cells have been shown to express Kb molecules that are either largely devoid of bound peptides or bind a vastly different set of low affinity peptides, it is unlikely that the detected structural changes were caused by alterations in the spectrum of peptides bound by the class I variant glycoproteins. Similarly, a class I point mutant, Kb-97R, that also has been shown previously to bind a very different set of peptides in comparison to the parental Kb molecule also displays normal antibody binding properties. We conclude from these studies that structural diversity within the Ag binding cleft indirectly influences the external surface of the Ag-presenting domain of the class I H chain. Significantly, this surface is the interface between the T cell receptor and MHC molecules and may make contributions to the fine specificity of allorecognition.

Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic–lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic–lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic–lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.