Citations

Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer’s disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell–specific Lrp1 -KO mice ( smLrp1 –/– ) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1 –/– mice but not in the APOE3 smLrp1 –/– mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1 –/– mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1 –/– mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype–dependent manner.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22–1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04–1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35–1.73, p < 0.001), microvascular (HR = 2.37, 95%–CI, 1.87–2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41–4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29–2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54–3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

Screening for colorectal cancer (CRC) is effective in reducing CRC related mortality. Current screening methods include endoscopy based and biomarker based approaches. This guideline is a joint official statement of the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society of Digestive Endoscopy (APSDE), developed in response to the increasing use of, and accumulating supportive evidence for the role of, non-invasive biomarkers for the diagnosis of CRC and its precursor lesions. A systematic review of 678 publications and a two stage Delphi consensus process involving 16 clinicians in various disciplines was undertaken to develop 32 evidence based and expert opinion based recommendations for the use of faecal immunochemical tests, faecal based tumour biomarkers or microbial biomarkers, and blood based tumour biomarkers for the detection of CRC and adenoma. Comprehensive up-to-date guidance is provided on indications, patient selection and strengths and limitations of each screening tool. Future research to inform clinical applications are discussed alongside objective measurement of research priorities. This joint APAGE–APSDE practice guideline is intended to provide an up-to-date guide to assist clinicians worldwide in utilising non-invasive biomarkers for CRC screening; it has particular salience for clinicians in the Asia-Pacific region.

Abstract Background: Spatial molecular analysis can provide functional characteristics of cellular components and their interactions present in the tumor immune microenvironment (TME), thus improving our understanding of the cancer ecosystem at a systemic level. We investigated the spatial and functional characteristics of the tumor, stroma, and immune cells, and their roles in the TME in facilitating cancer development, progression, and metastasis in pancreatic cancer. Methods: We performed spatial profiles of multiple regional TMEs of 13 pancreatic cancers (7 pancreatic adenocarcinoma, 3 pancreatic neuroendocrine, and 3 acinar cell carcinomas) using NanoString GeoMX at the whole transcriptome level (18,676 genes). We collected a total of 23 tissue samples containing matched primary tumors, adjacent normal pancreatic tissue, or normal/metastatic lymph node. Tumor, stroma, and immune cells are stained by PanCK, αSMA, and CD45 markers, respectively. We selected 234 regions of interest (ROIs) in the tumor core, border, adjacent normal pancreas, and lymph node to investigate spatial patterns of different cells and their cellular interactions in neighborhoods from paired primary and metastatic tumors. Results: TMEs in different ROIs are spatially correlated within a tumor but showed distinct phenotypes across tumors and tumor types. Each cell type in the ROIs has a unique role to drive cancer evolution in TMEs. Diverse types of cancer-associated fibroblasts (CAFs) are present in primary and metastatic TME, while CAFs in tumor border and metastatic lymph nodes showed mainly enriched with antigen-presenting CAF (apCAF) subtypes with higher extracellular matrix (ECM) and collagen fibrils components. Similarly, we found diverse functional phenotypes of the immune cell in TMEs. The immune response signaling pathway is activated in the stroma-infiltrated immune cells, but, in fact, not in the tumor-infiltrated immune cells. Instead, higher dysfunctional T cell and growth factors are present in the stroma-infiltrated immune cells from primary and metastatic tumors, but not in stromal immune normal pancreatic and lymph node tissues. The tumor-infiltrated immune cells showed suppressive immune activities by increasing TGFβ receptor signaling. We also discovered CCL5-driven metastatic patterns in TMEs from primary tumors and metastatic lymph nodes. Lastly, we concluded that these functional phenotypes of cells in TMEs are preserved in a certain pancreatic cancer type, suggesting the origin and evolution of different pancreatic tumors could be driven by diverse cellular and functional phenotypes of cells in TMEs. Conclusion: Our comprehensive analysis results demonstrate that the spatial analysis could provide insights into the spatial patterns that drive cancer evolution in pancreatic TMEs, thus helping understand the cellular microenvironment governing pancreatic cancer metastasis. Citation Format: Changjin Hong, Jean R. Clemenceau, Rondell P. Graham, Tae Hyun Hwang. Spatial transcriptomic landscape of primary and lymph node metastatic pancreatic cancer [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 2362.

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 Background: While immune checkpoint inhibitors (ICI) extend survival for patients suffering from a variety of cancers, most gastric cancer (GC) patients do not respond to ICI. There is a critical need to identify novel biomarkers that guide the use of ICI or strategies to improve outcomes for GC patients. We aim to gain a deeper understanding of the GC tumor microenvironment (TME) to refine the use of ICI using spatial transcriptomes from ICI-treated gastric tumors. Method: We collected 12 pre-ICI treatment gastric tumor samples from five responders and seven nonresponders and performed spatial profiling to investigate spatial heterogeneity, functions, and phenotypes of tumor and neighboring stromal and immune cells to identify features associated with ICI response. We used pan-cytokeratin (pan-CK) to mark epithelial cells, CD45 for immune cells, and smooth muscle actin (SMA) for fibroblasts. We generated gene expression profiles of each cell type within regions of interest (ROI) with a NanoString GeoMx Cancer Transcriptome Atlas panel, comprised of 1,800 genes. A total of 58 ROIs were analyzed from responders and 62 ROIs from nonresponders. Results: We measured the spatial heterogeneity of each cell type in ROIs within and across tumors. We found the tumor, immune, and fibroblasts from nonresponders are transcriptionally more heterogeneous, compared to those from responders. This might indicate a higher degree of intratumor transcriptional heterogeneity is linked to ICI resistance. We found that nonresponse was associated with higher expression of VEGFA and VEGFB in tumor cells and higher ACTA2 in fibroblasts, not in other cell types. These findings are intriguing when considering our other finding that increased endothelial cell and fibroblast proportions in the TME are associated with ICI nonresponse. We also found that the TME of nonresponders had fewer M1 and more M2 macrophages, and there were more T cells that overexpressed gene programs consistent with dysfunction and exhaustion. These findings indicate that ICI-resistant TMEs are densely surrounded by immune-suppressive cellular components which might reduce ICI efficacy and result in ICI resistance. Finally, we performed cell-cell interaction and identified ligand-receptor interactions that are stronger in nonresponders, including CXCL12-CXCR4, CD74-MIF, and LGALS9-LRP1 ligand-receptor interactions. The predicted ligand-receptor interactions are present in cell-type-specific manners, indicating the functional role of each cell type in facilitating ICI response. Conclusion: We investigated how tumor and neighboring stromal and immune cells interact within GC TME to mediate ICI response, which demonstrate that spatial analysis could be used to identify novel biomarkers that predict response to ICI, and new therapies to enhance ICI efficacy in GC patients. Citation Format: Sunho Park, Changjing Hong, Jae-Ho Cheong, Sam C. Wang, Matthew R. Porembka, In-Ho Kim, Sung Hak Lee, Tae Hyun Hwang. Spatial architecture and cellular interactions of tumor immune microenvironment to discover biomarkers and predict immune checkpoint inhibitor response in gastric cancer [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 2262.

Background and Aims: We present findings from the inaugural American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable, which was convened to evaluate the evidence for physical activity as a means of preventing or modifying the course of NAFLD. Approach and Results: A scoping review was conducted to map the scientific literature and identify key concepts, research gaps, and evidence available to inform clinical practice, policymaking, and research. The scientific evidence demonstrated regular physical activity is associated with decreased risk of NAFLD development. Low physical activity is associated with a greater risk for disease progression and extrahepatic cancer. During routine health care visits, all patients with NAFLD should be screened for and counseled about physical activity benefits, including reduction in liver fat and improvement in body composition, fitness, and quality of life. While most physical activity benefits occur without clinically significant weight loss, evidence remains limited regarding the association between physical activity and liver fibrosis. At least 150 min/wk of moderate or 75 min/wk of vigorous-intensity physical activity are recommended for all patients with NAFLD. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. Conclusions: The panel found consistent and compelling evidence that regular physical activity plays an important role in preventing NAFLD and improving intermediate clinical outcomes. Health care, fitness, and public health professionals are strongly encouraged to disseminate the information in this report. Future research should prioritize determining optimal strategies for promoting physical activity among individuals at risk and in those already diagnosed with NAFLD.

AbstractINTRODUCTIONAt the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias.METHODSThe meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry.RESULTSDuring the 4‐day meeting, presenters illuminated aspects of the cross‐talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]).DISCUSSIONThis manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.

Abstract Objective Flares of autoimmune rheumatic diseases (AIRDs) following COVID-19 vaccination are a particular concern in vaccine-hesitant individuals. Therefore, we investigated the incidence, predictors and patterns of flares following vaccination in individuals living with AIRDs, using global COVID-19 Vaccination in Autoimmune Diseases (COVAD) surveys. Methods The COVAD surveys were used to extract data on flare demographics, comorbidities, COVID-19 history, and vaccination details for patients with AIRDs. Flares following vaccination were identified as patient-reported (a), increased immunosuppression (b), clinical exacerbations (c) and worsening of PROMIS scores (d). We studied flare characteristics and used regression models to differentiate flares among various AIRDs. Results Of 15 165 total responses, the incidence of flares in 3453 patients with AIRDs was 11.3%, 14.8%, 9.5% and 26.7% by definitions a–d, respectively. There was moderate agreement between patient-reported and immunosuppression-defined flares (K = 0.403, P = 0.022). Arthritis (61.6%) and fatigue (58.8%) were the most commonly reported symptoms. Self-reported flares were associated with higher comorbidities (P = 0.013), mental health disorders (MHDs) (P &lt; 0.001) and autoimmune disease multimorbidity (AIDm) (P &lt; 0.001). In regression analysis, the presence of AIDm [odds ratio (OR) = 1.4; 95% CI: 1.1, 1.7; P = 0.003), or a MHD (OR = 1.7; 95% CI: 1.1, 2.6; P = 0.007), or being a Moderna vaccine recipient (OR = 1.5; 95% CI: 1.09, 2.2; P = 0.014) were predictors of flares. Use of MMF (OR = 0.5; 95% CI: 0.3, 0.8; P = 0.009) and glucocorticoids (OR = 0.6; 95% CI: 0.5, 0.8; P = 0.003) were protective. A higher frequency of patients with AIRDs reported overall active disease post-vaccination compared with before vaccination (OR = 1.3; 95% CI: 1.1, 1.5; P &lt; 0.001). Conclusion Flares occur in nearly 1 in 10 individuals with AIRDs after COVID vaccination; people with comorbidities (especially AIDm), MHDs and those receiving the Moderna vaccine are particularly vulnerable. Future avenues include exploring flare profiles and optimizing vaccine strategies for this group.