tbuckley/cabot-search huggingface dataset:
Mural cells interact with macrophages in the dura mater to regulate CNS immune surveillance
Authors: Hyunjung Min, Shane M. O’Neil, Li Xu, E. Ashley Moseman, Joanne Kurtzberg, Anthony J. Filiano
Journal: The Journal of Experimental Medicine (2024)

The central nervous system (CNS) tightly regulates access of circulating immune cells. Immunosurveillance is therefore managed in the meninges at the borders of the CNS. Here, we demonstrated that mural cells, which include pericytes and smooth muscle cells, decreased coverage around blood vessels in the dura, the outermost layer of the meninges, and upregulated gene pathways involved in leukocyte migration in presymptomatic experimental autoimmune encephalomyelitis (EAE). Partially depleting mural cells promoted the trafficking of CNS antigen-specific T cells to the dura in a process that depended on resident antigen-presenting cells, thereby increasing susceptibility to passive EAE. Mechanistically, mural cells physically contacted macrophages in the dura and transferred cytoplasmic components, including processing bodies (RNA granules shown to reprogram transcriptomes), which were critical to suppress antigen-dependent T helper (TH) cell activation and TH17 differentiation. Our study revealed a mechanism by which mural cell-macrophage interactions regulate the trafficking of CNS antigen-specific T cells to the dura.
Abstract IA003: Molecular and imaging biomarkers of PARP inhibitors for small cell lung cancer
Authors: Benjamin H. Lok
Journal: Cancer Research (2024)

Abstract This presentation will briefly define the different types of biomarkers and subsequently will cover examples of response, predictive, and prognostic biomarkers from preclinical and clinical evidence for small cell lung cancer (SCLC). The talk will cover examples with translational relevance, including intrinsic molecular features associated with DNA damage repair and response to PARP inhibitors, with a focus on the SCLC-specific context. Additionally, it will delve into the use of positron emission tomography with a radiolabeled PARP inhibitor to assess pharmacodynamic response, and the utilization of liquid biopsy patient blood samples for interrogating the tumor methylome with prognostic associations. Future opportunities and directions both specific to the aforementioned examples and more generally will be discussed. Citation Format: Benjamin H. Lok. Molecular and imaging biomarkers of PARP inhibitors for small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA003.
A key to unlocking the door: water pressure method for endoscopic submucosal dissection of a superficial non-ampullary duodenal epithelial tumor with a history of multiple biopsies
Authors: Tao Dong, Lin Jing, Yaohui Wang, Jun Xiao
Journal: Endoscopy (2024)

Endoscopic resection of superficial non-ampullary duodenal epithelial tumors has been popular for its mini-invasiveness and comparable treatment outcome to surgery. However, the thin wall and narrow submucosal space of the duodenum make endoscopic treatment difficult [1]. Furthermore, preoperative biopsy remains common and could induce significant submucosal fibrosis. The underwater method has been reported to facilitate the resection, but sometimes a sufficient amount of saline cannot be maintained to soak the lesion [2] [3]. In this case, we emphasized the role of the water pressure method in assisting endoscopic submucosal dissection (ESD) for a superficial non-ampullary duodenal epithelial tumor with a history of multiple biopsies ([Video 1]).
Whole-genome Sequencing Reveals Autooctoploidy in Chinese Sturgeon and Its Evolutionary Trajectories
Authors: Binzhong Wang, Bin Wu, Xueqing Liu, Yacheng Hu, Yao Ming, Mingzhou Bai, Juanjuan Liu, Kan Xiao, Qingkai Zeng, Jing Yang, Hongqi Wang, Baifu Guo, Chun Tan, Zixuan Hu, Xun Zhao, Yanhong Li, Zhen Yue, Junpu Mei, Wei Jiang, Yuanjin Yang, Zhiyuan Li, Yong Gao, Lei Chen, Jianbo Jian, Hejun Du
Journal: Genomics Proteomics & Bioinformatics (2023)

The order Acipenseriformes, which includes sturgeons and paddlefishes, represents "living fossils" with complex genomes that are good models for understanding whole-genome duplication (WGD) and ploidy evolution in fishes. Here, we sequenced and assembled the first high-quality chromosome-level genome for the complex octoploid Acipenser sinensis (Chinese sturgeon), a critically endangered species that also represents a poorly understood ploidy group in Acipenseriformes. Our results show that A. sinensis is a complex autooctoploid species containing four kinds of octovalents (8n), a hexavalent (6n), two tetravalents (4n), and a divalent (2n). An analysis taking into account delayed rediploidization reveals that the octoploid genome composition of Chinese sturgeon results from two rounds of homologous WGDs, and further provides insights into the timing of its ploidy evolution. This study provides the first octoploid genome resource of Acipenseriformes for understanding ploidy compositions and evolutionary trajectories of polyploid fishes.
Endoscopic ultrasound-guided transduodenal ERCP for hepatico-jejunostomy stricture
Authors: Jun Liang Teh, Shannon M Chan, Hon Chi Yip, Anthony Yuen Bun Teoh
Journal: Endoscopy (2024)

A 75-year-old man was referred for management of a hepaticojejunostomy (HJS) stricture following HJS performed for a bile duct injury during cholecystectomy 3 months prior. A short-type double-balloon enteroscopy (DBE) was attempted but was unsuccessful due to inability to reach the HJS. Endoscopic ultrasound (EUS)-guided transduodenal endoscopic retrograde cholangiopancreatography (ERCP) for management of the HJS stricture was planned [1].
Efficacy and effectiveness of antipsychotics in schizophrenia: network meta-analyses combining evidence from randomised controlled trials and real-world data
Authors: Orestis Efthimiou, Heidi Taipale, Joaquim Radua, Johannes Schneider-Thoma, Justo Pinzón-Espinosa, Maria Ortuño, Christiaan H Vinkers, Ellenor Mittendorfer-Rutz, Narcís Cardoner, Antti Tanskanen, Paolo Fusar-Poli, Andrea Cipriani, Eduard Vieta, Stefan Leucht, Jari Tiihonen, Jurjen J Luykx
Journal: The Lancet Psychiatry (2024)
Abstract IA014: BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair
Authors: Pei Xin Lim, Maria Jasin
Journal: Cancer Research (2024)

Abstract Tumor suppressor BRCA2 functions in multiple pathways. The role of BRCA2 in homologous recombination, also termed homology-directed repair (HDR), is particularly well known. We also showed that it has a key role in the protection of stalled replication forks from the MRE11 nuclease. Moreover, BRCA2 also suppresses the formation of single-stranded gaps during replication. We have attempted to delineate the relative contributions of these three pathways to the maintenance of genome integrity and chemotherapy response using separation of function alleles. First, we report that mouse and human cells require a RAD51 filament stabilization motif in BRCA2 for both fork protection and gap suppression but not HDR. In mice, loss of fork protection and gap suppression do not compromise genome instability or shorten tumor latency. By contrast, HDR deficiency increases spontaneous and replication stress-induced chromosome aberrations and tumor predisposition. Unlike with HDR, fork protection and gap suppression defects are also observed in Brca2 heterozygous cells from mice, likely due to reduced RAD51 stabilization at stalled forks and gaps. Sensitivity to the PARP inhibitor olaparib is greatest for HDR-deficient cells, although fork protection/gap suppression-defective cells show a weak sensitivity. Gaps arise from PRIMPOL activity, which is associated with sensitivity to 5-hydroxymethyl-2’-deoxyuridine (hmdU) and DNPH1 inhibition due to the formation of SMUG1-generated abasic sites and is exacerbated by poly(ADP-ribose) polymerase inhibition. In summary, this work demonstrates that HDR deficiency has the major role in generating sensitivity to chemotherapeutics, although gap suppression deficiency may be targeted by specific agents. Citation Format: Pei Xin Lim, Maria Jasin. BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA014.
An inoculation site-retained mRNA vaccine induces robust immune responses against SARS-CoV-2 variants
Authors: Lei Huang, Fanfan Zhao, Muye He, Yi Fang, Xiaoping Ma, Shuaiyao Lu, Entao Li, Hui Xiao, Hanfei Zhu, Xueli Wang, Siyuan Tang, Bo Yu, Jie Wang, Dong Zhao, Chao Wang, Hangwen Li, Yuwei Gao, Xiaozhong Peng, Haifa Shen
Journal: Journal of Controlled Release (2024)
Plasma cell-free DNA hydroxymethylation profiling reveals anti-PD-1 treatment response and resistance biology in non-small cell lung cancer
Authors: Gulfem D Guler, Yuhong Ning, Ceyda Coruh, Giuliana P Mognol, Tierney Phillips, Maryam Nabiyouni, Kyle Hazen, Aaron Scott, Wayne Volkmuth, Samuel Levy
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Treatment with immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) can yield durable antitumor responses, yet not all patients respond to ICIs. Current approaches to select patients who may benefit from anti-PD-1 treatment are insufficient. 5-hydroxymethylation (5hmC) analysis of plasma-derived cell-free DNA (cfDNA) presents a novel non-invasive approach for identification of therapy response biomarkers which can tackle challenges associated with tumor biopsies such as tumor heterogeneity and serial sample collection. Methods 151 blood samples were collected from 31 patients with non-small cell lung cancer (NSCLC) before therapy started and at multiple time points while on therapy. Blood samples were processed to obtain plasma-derived cfDNA, followed by enrichment of 5hmC-containing cfDNA fragments through biotinylation via a two-step chemistry and binding to streptavidin coated beads. 5hmC-enriched cfDNA and whole genome libraries were prepared in parallel and sequenced to obtain whole hydroxymethylome and whole genome plasma profiles, respectively. Results Comparison of on-treatment time point to matched pretreatment samples from same patients revealed that anti-PD-1 treatment induced distinct changes in plasma cfDNA 5hmC profiles of responding patients, as judged by Response evaluation criteria in solid tumors, relative to non-responders. In responders, 5hmC accumulated over genes involved in immune activation such as inteferon (IFN)-γ and IFN-α response, inflammatory response and tumor necrosis factor (TNF)-α signaling, whereas in non-responders 5hmC increased over epithelial to mesenchymal transition genes. Molecular response to anti-PD-1 treatment, as measured by 5hmC changes in plasma cfDNA profiles were observed early on, starting with the first cycle of treatment. Comparison of pretreatment plasma samples revealed that anti-PD-1 treatment response and resistance associated genes can be captured by 5hmC profiling of plasma-derived cfDNA. Furthermore, 5hmC profiling of pretreatment plasma samples was able to distinguish responders from non-responders using T cell-inflamed gene expression profile, which was previously identified by tissue RNA analysis. Conclusions These results demonstrate that 5hmC profiling can identify response and resistance associated biological pathways in plasma-derived cfDNA, offering a novel approach for non-invasive prediction and monitoring of immunotherapy response in NSCLC.
TCCIA: a comprehensive resource for exploring CircRNA in cancer immunotherapy
Authors: Shixiang Wang, Yi Xiong, Yihao Zhang, Haitao Wang, Minjun Chen, Jianfeng Li, Peng Luo, Yung-Hung Luo, Markus Hecht, Benjamin Frey, Udo Gaipl, Xuejun Li, Qi Zhao, Hu Ma, Jian-Guo Zhou
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immunotherapies targeting immune checkpoints have gained increasing attention in cancer treatment, emphasizing the need for predictive biomarkers. Circular RNAs (circRNAs) have emerged as critical regulators of tumor immunity, particularly in the PD-1/PD-L1 pathway, and have shown potential in predicting immunotherapy efficacy. Yet, the detailed roles of circRNAs in cancer immunotherapy are not fully understood. While existing databases focus on either circRNA profiles or immunotherapy cohorts, there is currently no platform that enables the exploration of the intricate interplay between circRNAs and anti-tumor immunotherapy. A comprehensive resource combining circRNA profiles, immunotherapy responses, and clinical outcomes is essential to advance our understanding of circRNA-mediated tumor-immune interactions and to develop effective biomarkers.
Experience of patients considering or using checkpoint inhibitors in cancer treatment: a systematic review of qualitative research
Authors: Raphael Yip, Gaston Arnolda, Klay Lamprell, Bróna Nic Giolla Easpaig, Renuka Chittajallu, Geoff Delaney, Ian Olver, Winston Liauw, Jeffrey Braithwaite
Journal: Journal for ImmunoTherapy of Cancer (2024)

Increasing numbers of patients with cancer are considering or undergoing immunotherapy, however, little is known about patients’ perspectives on this treatment. We undertook a systematic review for use by clinicians and researchers, consolidating published qualitative research studies on patient experience of checkpoint inhibitor therapy. A search of Medline, Embase, and PsycINFO was carried out for publications in English to 30 June 2022. Publications were selected if they reported a qualitative study of patient experience with checkpoint inhibitor therapy for cancer, either by patients or their families or carers. Quality was appraised using the Johanna Briggs Institute quality assessment tool for qualitative studies. A thematic synthesis was conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standard was followed. We identified 17 eligible studies published between 2017 and 2022, 9 using mixed methods, and 8 solely using qualitative methods. Most studies reported on the experiences of patients with advanced stage melanoma and were using the earliest approved checkpoint inhibitors for cancer therapy. Studies met most formal quality criteria but varied in the extent of their qualitative explorations of data; some mixed methods studies had limited reporting of qualitative results. Through thematic synthesis, we categorized study findings into four domains: (1) treatment decision-making; (2) success with immunotherapy; (3) treatment-related adverse events (AEs); and (4) quality of life on immunotherapy. Our review identified several areas with potential for improving the care system. These include, for example: routinely linking patients to peers who have experienced this therapy; improving the capacity of patients and carers to identify and report AEs faster; and supporting patients and carers to live with changed circumstances after successful treatment. Most studies focused on patients who had successful treatment, effectively excluding those who do not respond or who discontinue due to serious side effects; future research targets are suggested.
Reconstruction of unreported subgroup survival data with PD-L1-low expression in advanced/metastatic triple-negative breast cancer using innovative KMSubtraction workflow
Authors: Yan Li, Xueyan Liang, Huijuan Li, Xiaoyu Chen
Journal: Journal for ImmunoTherapy of Cancer (2024)

Among patients with advanced/metastatic triple-negative breast cancer (TNBC) with high/positive programmed death-ligand 1 (PD-L1) expression, a superior survival outcome has been demonstrated with immune checkpoint inhibitors (ICIs). However, it remains unclear whether ICIs are beneficial for patients with low PD-L1 levels. Here, we derived survival data for subgroups with low PD-L1-expressing and conducted a pooled analysis. After a systematic search of Embase, PubMed, MEDLINE, and CENTRAL from inception until May 18, 2023, randomized controlled trials (RCTs) reporting progression-free survival (PFS), overall survival (OS), or duration of response (DOR) for metastatic TNBC treated with ICI-based regimens were included. Kaplan-Meier curves were extracted for the intention-to-treat population and high PD-L1 subgroups. KMSubtraction was used when survival curves were not provided for subgroups with low PD-L1 expression. A pooled analysis of survival data was then conducted. A total of 3022 patients were included in four RCTs: Impassion130, Impassion131, KEYNOTE-119, and KEYNOTE-355. Unreported low PD-L1-expressing subgroups were identified, including PD-L1 immune cell (IC)<1%, combined positive score (CPS)<1, and 1≤CPS<10. Compared with chemotherapy, ICI-chemotherapy combinations did not significantly differ in OS, PFS, or DOR in the Impassion PD-L1<1%, KEYNOTE-355 PD-L1 CPS<1, and KEYNOTE-355 1≤CPS<10 subgroups. In the KEYNOTE-119 CPS<1 subgroup, the risk of tumor progression was increased with pembrolizumab (HR, 2.23; 95% CI, 1.62 to 3.08; p<0.001), as well as in the 1≤CPS<10 subgroup (HR, 1.64; 95% CI, 1.22 to 2.20; p<0.001). A pooled analysis using a scoring system found no significant difference in OS and PFS among the subgroups with an IC of <1% between immunochemotherapy and chemotherapy. OS (HR, 1.07; 95% CI, 0.91 to 1.26), PFS (HR, 0.96; 95% CI, 0.84 to 1.10), and DOR were also not significantly different in pooled analysis of first-line trials for those with low PD-L1 expression. ICI-based regimens are not associated with a survival benefit versus chemotherapy in subgroups of advanced/metastatic TNBC that express low PD-L1 levels.
Supramolecular Assembly Based on Calix(4)arene and Aggregation‐Induced Emission Photosensitizer for Phototherapy of Drug‐Resistant Bacteria and Skin Flap Transplantation
Authors: Rui‐Peng Wang, Wenbin Liu, Xiaoxuan Wang, Guogang Shan, Tuozhou Liu, Fengrui Xu, Honglian Dai, Chunxuan Qi, Hai‐Tao Feng, Ben Zhong Tang
Journal: Advanced Healthcare Materials (2024)

Photodynamic therapy as a burgeoning and non-invasive theranostic technique has drawn great attention in the field of antibacterial treatment but often encounters undesired phototoxicity of photosensitizers during systemic circulation. Herein, a supramolecular substitution strategy is proposed for phototherapy of drug-resistant bacteria and skin flap repair by using macrocyclic p-sulfonatocalix(4)arene (SC4A) as a host, and two cationic aggregation-induced emission luminogens (AIEgens), namely TPE-QAS and TPE-2QAS, bearing quaternary ammonium group(s) as guests. Through host-guest assembly, the obtained complex exhibits obvious blue fluorescence in the solution due to the restriction of free motion of AIEgens and drastically inhibits efficient type I ROS generation. Then, upon the addition of another guest 4,4'-benzidine dihydrochloride, TPE-QAS can be competitively replaced from the cavity of SC4A to restore its pristine ROS efficiency and photoactivity in aqueous solution. The dissociative TPE-QAS shows a high bacterial binding ability with an efficient treatment for methicillin-resistant Staphylococcus aureus (MRSA) in dark and light irradiation. Meanwhile, it also exhibits an improved survival rate for MRSA-infected skin flap transplantation and largely accelerates the healing process. Thus, such cascaded host-guest assembly is an ideal platform for phototheranostics research.
Intratumoral administration of the immunologic adjuvant AS01<sub>B</sub>in combination with autologous CD1c (BDCA-1)<sup>+</sup>/CD141 (BDCA-3)<sup>+</sup>myeloid dendritic cells plus ipilimumab and intravenous nivolumab in patients with refractory advanced melanoma
Authors: Jens Tijtgat, Xenia Geeraerts, Anais Boisson, Latoya Stevens, Manon Vounckx, Iris Dirven, Julia Katharina Schwarze, Steven Raeymaeckers, Ramses Forsyth, Ivan Van Riet, Sandra Tuyaerts, Karen Willard-Gallo, Bart Neyns
Journal: Journal for ImmunoTherapy of Cancer (2024)

Patients with advanced melanoma who progress after treatment with immune checkpoint-inhibitors (ICI) and BRAF-/MEK-inhibitors (if BRAF V600 mutated) have no remaining effective treatment options. The presence of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment correlates with pre-existing immune recognition and responsiveness to immune checkpoint blockade. The synthetic saponin-based immune adjuvant AS01B enhances adaptive immunity through the involvement of myDC. In this first-in-human phase I clinical trial, patients with metastatic melanoma refractory to ICI and BRAF-/MEK inhibitors (when indicated) were recruited. Patients received an intravenous administration of low-dose nivolumab (10 mg, every 2 weeks) plus an intratumoral (IT) administration of 10 mg ipilimumab and 50 µg (0.5 mL) AS01B (every 2 weeks). All myDC, isolated from blood, were injected on day 2 into the same metastatic lesion. Tumor biopsies and blood samples were collected at baseline and repeatedly on treatment. Multiplex immunohistochemistry (mIHC) was performed on biopsy sections to characterize and quantify the IT and peritumoral immune cell composition. Study treatment was feasible and well tolerated without the occurrence of unexpected adverse events in all eight patients. Four patients (50%) obtained a complete response (CR) in the injected lesions. Of these, two patients obtained an overall CR, and one patient a partial response. All responses are ongoing after more than 1 year of follow-up. One additional patient had a stable disease as best response. The disease control rate was 50%. Median progression-free survival and overall survival were 24.1 and 41.9 weeks, respectively. Baseline tumor biopsies from patients who responded to treatment had features of T-cell exclusion. During treatment, there was an increased T-cell infiltration, with a reduced mean distance between T cells and tumor cells. Peripheral blood immune cell composition did not significantly change during study treatment. Combining an intratumoral injection of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myDC with repeated IT administration of ipilimumab and AS01B and systemic low-dose nivolumab is safe, feasible with promising early results, worthy of further clinical investigation. ClinicalTrials.gov identifier NCT03707808.