tbuckley/cabot-search huggingface dataset:
ROS-sensitive PD-L1 siRNA cationic selenide nanogels for self-inhibition of autophagy and prevention of immune escape
Authors: Jie Gao, Yonghua Zhai, Weihong Lu, Xianghe Jiang, Jingsheng Zhou, Lili Wu, Longhai Du, Chunqing Ou, Xinyi Zhang, Hanliang He, Jian Zhu, Zhengbiao Zhang, Meiyun Li, Yan Wu, Xiangqiang Pan
Journal: Bioactive Materials (2024)

In the field of cancer therapy, inhibiting autophagy has emerged as a promising strategy. However, pharmacological disruption of autophagy can lead to the upregulation of programmed death-ligand 1 (PD-L1), enabling tumor immune evasion. To address this issue, we developed innovative ROS-responsive cationic poly(ethylene imine) (PEI) nanogels using selenol chemistry-mediated multicomponent reaction (MCR) technology. This procedure involved simple mixing of low-molecular-weight PEI (LMW PEI), γ-selenobutylacetone (γ-SBL), and poly(ethylene glycol) methacrylate (PEGMA). Through high-throughput screening, we constructed a library of A
Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study
Authors: Patrick Derigs, Maria-Luisa Schubert, Peter Dreger, Anita Schmitt, Schayan Yousefian, Simon Haas, Caroline Röthemeier, Brigitte Neuber, Angela Hückelhoven-Krauss, Monika Brüggemann, Helga Bernhard, Guido Kobbe, Albrecht Lindemann, Mathias Rummel, Birgit Michels, Felix Korell, Anthony D. Ho, Carsten Müller-Tidow, Michael Schmitt
Journal: Leukemia (2024)

Abstract Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 10 6 to 200 × 10 6 CART/m 2 . In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.
Epigenetic modification of ferroptosis by non-coding RNAs in cancer drug resistance
Authors: Hongquan Wang, Joshua S. Fleishman, Sihang Cheng, Weixue Wang, Fan Wu, Yumin Wang, Yu Wang
Journal: Molecular Cancer (2024)

Abstract The development of drug resistance remains a major challenge in cancer treatment. Ferroptosis, a unique type of regulated cell death, plays a pivotal role in inhibiting tumour growth, presenting new opportunities in treating chemotherapeutic resistance. Accumulating studies indicate that epigenetic modifications by non-coding RNAs (ncRNA) can determine cancer cell vulnerability to ferroptosis. In this review, we first summarize the role of chemotherapeutic resistance in cancer growth/development. Then, we summarize the core molecular mechanisms of ferroptosis, its upstream epigenetic regulation, and its downstream effects on chemotherapeutic resistance. Finally, we review recent advances in understanding how ncRNAs regulate ferroptosis and from such modulate chemotherapeutic resistance. This review aims to enhance general understanding of the ncRNA-mediated epigenetic regulatory mechanisms which modulate ferroptosis, highlighting the ncRNA-ferroptosis axis as a key druggable target in overcoming chemotherapeutic resistance.
Genetic hallmarks and clinical implications of chromothripsis in childhood T-cell acute lymphoblastic leukemia
Authors: Agata Pastorczak, Zuzanna Urbanska, Borys Styka, Karolina Miarka-Walczyk, Lukasz Sedek, Kamila Wypyszczak, Anna Wakulinska, Zuzanna Nowicka, Tomasz Szczepański, Marcin Stańczak, Wojciech Fendler, Jerzy Kowalczyk, Wojciech Młynarski, Monika Lejman
Journal: Leukemia (2024)

Chromothripsis (cth) is a form of genomic instability leading to massive de novo structural chromosome rearrangements in a one-time catastrophic event. It can cause cancer-promoting alterations, such as loss of sequences for tumor-suppressor genes, formation of oncogenic fusions, and oncogene amplifications. We investigated the genetic background and clinical significance of cth in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. For this purpose, whole-genome copy number alterations were analyzed in 173 children with newly diagnosed T-ALL using high-density microarrays. Cth was identified in 10 T-ALL samples (5.78%). In six of them, cth occurred in a constitutional background of Nijmegen breakage syndrome (n = 5) or Li-Fraumeni syndrome (n = 1). Cth generated alterations, including deletions of CDKN2A/B (n = 4) and EZH2 (n = 4), amplifications of CDK6 (n = 2), and NUP214::ABL1 and TFG::GPR128 fusions. Cth-positive leukemias exhibited deletions involving the tumor-suppressor genes RB1 (n = 3), TP53 (n = 1) and MED12 (n = 2). Cth-positive T-ALL patients had a lower probability of 5-year overall survival (OS) [0.56 vs. 0.81; hazard ratio (HR) = 4.14 (1.42–12.02) p = 0.017] as did 5-year event-free survival [0.45 vs. 0.74; HR = 3.91 (1.52–10.08); p = 0.012]. Chromothripsis is an infrequent genomic phenomenon in pediatric T-ALL but is significantly associated with cancer-predisposing syndromes and may associate with inferior prognosis.
Global burden of thyroid cancer from 1990 to 2021: a systematic analysis from the Global Burden of Disease Study 2021
Authors: Tianjiao Zhou, Xiaoting Wang, Jingyu Zhang, Enhui Zhou, Chen Xu, Ying Shen, Jianyin Zou, Wen Lu, Kaiming Su, Weijun Huang, Hongliang Yi, Shankai Yin
Journal: Journal of Hematology & Oncology (2024)

Thyroid cancer (TC) is a significant global healthcare burden. However, the lack of comprehensive data has impeded our understanding of its global impact. We aimed to examine the burden of TC and its trends at the global, regional, and national levels using data stratified by sociodemographic index (SDI), sex, and age. Data on TC, including incidence, mortality, and disability-adjusted life-years (DALYs) from 1990 to 2021, were obtained from the Global Burden of Disease Study 2021. Estimated annual percentage changes (EAPCs) were calculated to assess the incidence rate, mortality, and DALYs trends. The incidence, mortality, and DALYs of TC in 2021 were 249,538 (95% uncertainty interval: 223,290–274,638), 44,799 (39,925–48,541), and 646,741 (599,119–717,357), respectively. The age-standardized incidence rate (ASIR) in 2021 was 2.914 (2.607–3.213), with an EAPC of 1.25 (1.14–1.37) compared to 1990. In 2021, the age-standardized death rate (ASDR) was 0.53 (0.47–0.575) and age-standardized DALYs rate was 14.571 (12.783–16.115). Compared with 1990, the EAPCs of ASDR and age-standardized DALYs rate showed decreasing trends, at − 0.24 (− 0.27 to − 0.21) and − 0.14 (− 0.17 to − 0.11), respectively. Low SDI regions showed the highest ASDR and age-standardized DALYs rate, at 0.642 (0.516–0.799) and 17.976 (14.18–23.06), respectively. Low-middle SDI regions had the highest EAPCs for ASDR and age-standardized DALYs rate, at 0.74 (0.71–0.78) and 0.67 (0.63–0.7), respectively. Females exhibited decreasing trend in ASDR and age-standardized DALYs rate, with EAPCs of − 0.58 (− 0.61 to − 0.55) and − 0.45 (− 0.47 to − 0.42), respectively. In contrast, males showed an increasing trend in ASDR and age-standardized DALYs rate, with EAPCs of 0.41 (0.35–0.46) for both. In high-income regions, most countries with decreased annual changes in deaths experience increasing age-related deaths. Over the past few decades, a notable increase in TC incidence and decreased mortality has been observed globally. Regions characterized by lower SDI, male sex, and an aging population exhibited no improvement in TC mortality. Effective resource allocation, meticulous control of risk factors, and tailored interventions are crucial for addressing these issues.
The prognostic impact of psychiatric intervention on alcohol-associated liver disease: The UK Biobank cohort study
Authors: Keungmo Yang, Sunghwan Kim, Hyun Yang, Sheng-Min Wang, Bumseok Jeong, Hyun Kook Lim, Si Hyun Bae
Journal: Clinical and Molecular Hepatology (2024)

Background/Aims: Alcohol-associated liver disease (ALD) is a public health concern. ALD patients often have psychiatric comorbidities, but the effects of psychiatric interventions on ALD are not well-established. This study explores the prognostic impact of psychiatric intervention on ALD within UK Biobank cohort.Methods: This population-based study included 2,417 ALD patients from the UK Biobank cohort. Psychiatric intervention was defined by a consultation with psychiatrists during hospitalization or a history of medication related to alcohol use disorder and psychiatric comorbidities. Survival analysis was conducted, incorporating propensity score matching (PSM), to precisely assess the impact of psychiatric intervention.Results: Among 2,417 ALD patients, those with F10 (mental disorders due to alcohol) codes had poorer survival outcomes. Psychiatric intervention significantly improved the outcomes of both all-cause and liver-related mortality and reduced the incidence of liver cirrhosis. In subgroup or 2-year landmark analyses, psychiatric intervention consistently showed a survival benefit in ALD patients. In the multivariate analysis, psychiatric intervention was identified as a favorable prognostic factor (hazard ratio, 0.780; &lt;i&gt;P&lt;/i&gt;=0.002 after PSM).Conclusions: This study demonstrates the favorable effect of psychiatric intervention in ALD patients with psychiatric comorbidities. These findings emphasize the importance of integrated management for ALD patients to address both their medical and psychiatric aspects. Therefore, we suggest the potential benefits of early psychiatric interventions in improving survival outcomes in ALD.
Reply to correspondence on “Severity of microvascular invasion does matter in hepatocellular carcinoma prognosis”
Authors: Abdelrahman M Attia, Hasmik Adetyan, Ju Dong Yang
Journal: Clinical and Molecular Hepatology (2024)

Reply to correspondence on "Severity of microvascular invasion does matter in hepatocellular carcinoma prognosis: Editorial on "Classification of microvascular invasion of hepatocellular carcinoma: correlation with prognosis and magnetic resonance imaging"
Enthesitis on Chip – A Model for Studying Acute and Chronic Inflammation of the Enthesis and its Pharmacological Treatment
Authors: Francesca Giacomini, Hoon Suk Rho, Maria Eischen‐Loges, Zeinab Tahmasebi Birgani, Clemens van Blitterswijk, Martijn van Griensven, Stefan Giselbrecht, Pamela Habibović, Roman Truckenmüller
Journal: Advanced Healthcare Materials (2024)

Abstract Enthesitis, the inflammation of the enthesis, which is the point of attachment of tendons and ligaments to bones, is a common musculoskeletal disease. The inflammation often originates from the fibrocartilage region of the enthesis as a consequence of mechanical overuse or ‐load and consequently tissue damage. During enthesitis, waves of inflammatory cytokines propagate in(to) the fibrocartilage, resulting in detrimental, heterotopic bone formation. Understanding of human enthesitis and its treatment options is limited, also because of lacking in vitro model systems that can closely mimic the pathophysiology of the enthesis and can be used to develop therapies. In this study, an enthes(it)is‐on‐chip model is developed. On opposite sides of a porous culture membrane separating the chip's two microfluidic compartments, human mesenchymal stromal cells are selectively differentiated into tenocytes and fibrochondrocytes. By introducing an inflammatory cytokine cocktail into the fibrochondrocyte compartment, key aspects of acute and chronic enthesitis, measured as increased expression of inflammatory markers, can be recapitulated. Upon inducing chronic inflammatory conditions, hydroxyapatite deposition, enhanced osteogenic marker expression and reduced secretion of tissue‐related extracellular matrix components are observed. Adding the anti‐inflammatory drug celecoxib to the fibrochondrocyte compartment mitigates the inflammatory state, demonstrating the potential of the enthesitis‐on‐chip model for drug testing.
Docetaxel‐Encapsulated Catalytic Pt/Au Nanotubes for Synergistic Chemo‐Photothermal Therapy of Triple‐Negative Breast Cancer
Authors: Haiyan Yang, Qian Zhang, Liwei Dai, Yazi Wang, Guangrong Zheng, Xinyue Zhang, Di Zheng, Xiaojuan Ji, Yutao Sang, Zhihong Nie
Journal: Advanced Healthcare Materials (2024)

The combination of photothermal therapy with chemotherapy has emerged as a promising therapeutic modality for addressing triple-negative breast cancer (TNBC). This manuscript describes a novel hybrid nanoplatform comprising ultrathin catalytic platinum/gold (Pt/Au) nanotubes encapsulated with docetaxel and phase-change materials (PCMs) for the photoacoustic imaging-guided synergistic chemo-photothermal therapy of TNBC. Upon irradiation of near-infrared laser, the photothermal heating of nanotubes converts solid-state PCM into liquid, triggering the controlled release of the encapsulated docetaxel. The thin Pt layer within nanotubes enhances the nanotube's thermal stability, thus prolonging the photothermal ablation of tumors. Furthermore, platinum effectively mitigates tumor hypoxia by catalyzing the decomposition of hydrogen peroxides to generate oxygen in the tumor microenvironment, thus improving the efficiency of chemotherapy. It is demonstrated that the drug-loaded nanotubes achieve significant tumor inhibition rates of 75.4% in vivo on 4T1 tumor-bearing mice, significantly surpassing control groups. These nanotubes also notably extend survival, attributable to the synergistic effects of prolonged photothermal therapy facilitated by platinum and oxygenation-enhanced chemotherapy. This combination leverages the unique properties of the Pt/Au NTs-DTX/PCM nanoplatform, optimizing therapeutic outcomes. It is envisioned that this nanoplatform may find important applications in managing superficial malignant solid tumors in general.
A novel shark VNAR antibody-based immunotoxin targeting TROP-2 for cancer therapy
Authors: Xiaozhi Xi, Yanqing Wang, Guiqi An, Shitao Feng, Qiumei Zhu, Zhongqiu Wu, Jin Chen, Zhicheng Zuo, Qiang Wang, Ming-Wei Wang, Yuchao Gu
Journal: Acta Pharmaceutica Sinica B (2024)

TROP-2, a tumor-associated antigen, has been implicated in the progression of various epithelial tumors. Due to its favorable expression profile, TROP-2 has emerged as a promising target for antibody–drug conjugates (ADCs) based anti-tumor therapies. Although ADCs have shown efficacy in cancer treatment, their application in solid tumors is hindered by their high molecular weight, poor tumor penetration, and release of cytotoxic molecules. Therefore, a recombinant immunotoxin was developed based on a shark-derived variable domain of immunoglobulin new antigen receptor (VNAR) antibody. VNARs are only one-tenth the size of IgG antibodies and possess remarkable tissue penetration capabilities and high stability. In this study, a shark VNAR phage display library was created, leading to the identification of shark VNAR-5G8 that targets TROP-2. VNAR-5G8 exhibited a high affinity and cellular internalization ability towards cells expressing high levels of TROP-2. Epitope analysis revealed that VNAR-5G8 recognizes a hidden epitope consisting of CRD and TY-1 on TROP-2. Subsequently, VNAR-5G8 was fused with a truncated form of Pseudomonas exotoxin (PE38) to create the recombinant immunotoxin (5G8-PE38), which exhibited significant anti-tumor activity in vitro and in vivo. Overall, this study highlights the promise of 5G8-PE38 as a valuable candidate for cancer therapy.
On the role of antibody affinity and avidity in the <scp>IgE</scp>‐mediated allergic response
Authors: Martin F. Bachmann, Pascal S. Krenger, Mona O. Mohsen, Matthias F. Kramer, Sviatlana Starchenka, Piers Whitehead, Monique Vogel, Matthew D. Heath
Journal: Allergy (2024)

Abstract Type I hypersensitivity, also known as classical allergy, is mediated via allergen‐specific IgE antibodies bound to type I FcR (FcεRI) on the surface of mast cells and basophils upon cross‐linking by allergens. This IgE‐mediated cellular activation may be blocked by allergen‐specific IgG through multiple mechanisms, including direct neutralization of the allergen or engagement of the inhibitory receptor FcγRIIb which blocks IgE signal transduction. In addition, co‐engagement of FcεRI and FcγRIIb by IgE‐IgG‐allergen immune complexes causes down regulation of receptor‐bound IgE, resulting in desensitization of the cells. Both, activation of FcεRI by allergen‐specific IgE and engagement of FcγRIIb by allergen‐specific IgG are driven by allergen‐binding. Here we delineate the distinct roles of antibody affinity versus avidity in driving these processes and discuss the role of IgG subclasses in inhibiting basophil and mast cell activation.
Laparoscopic hepatectomy versus microwave ablation For multifocal 3-5cm hepatocellular carcinoma: a Multi-center, Real-world Study
Authors: Zhen Wang, Chuan Pang, Qiong Meng, De-zhi Zhang, Zhi-xian Hong, Guang-bin He, Hong Yang, Bang-de Xiang, Xiao Li, Tian-an Jiang, Kai Li, Zhe Tang, Fei Huang, Man Lu, Xiao-ling Yu, Zhi-gang Cheng, Fang-yi Liu, Zhi-yu Han, Jian-ping Dou, Song-song Wu, Jie Yu, Ping Liang
Journal: International Journal of Surgery (2024)

Background: Researches comparing laparoscopic liver resection (LLR) with microwave ablation (MWA) for 3–5 cm multifocal hepatocellular carcinoma (MFHCC) are rare. Materials and methods: From 2008 to 2019, 666 intrahepatic tumours in 289 patients from 12 tertiary medical centres in China were included in this retrospective study. Propensity score matching (PSM) was performed to balance variables between the two treatment groups over time frames 2008–2019 and 2013–2019 to observe the potential impact of advancements in intervention techniques on overall survival (OS), disease-free progression (DFS) of patients. complications, hospitalization, and cost were compared. Results: Among 289 patients, the median age was 59 years [interquartile range (IQR) 52–66]. 2008–2019, after PSM, the median OS was 97.4 months in the LLR group and 75.2 months (95% CI 47.8–102.6) in the MWA group during a follow-up period of 39.0 months. The 1-year, 3-year and 5-year OS rates in the two groups were 91.8%, 72.6%, 60.7% and 96.5%, 72.8%, 62.5% [hazard ratio (HR) 1.03, 95% CI 0.62–1.69, P =0.920]; The corresponding DFS rates were 75.9%, 57.2%, 46.9%, and 53.1%, 17.5%, 6.2% (HR 0.35, 95% CI 0.23–0.54, P &lt;0.001). 2013–2019, the median OS time was not reached in either group during the 34.0 months of follow-up, the 1-year, 3-year and 5-year OS rates in the two groups were 90.2%, 67.6%, 56.7% and 96.5%, 76.7%, 69.7% (HR 1.54, 95% CI 0.79–3.01, P =0.210); The corresponding DFS rates were 69.6%, 53.9%, 43.3%, and 70.4%, 32.1%, 16.5% (HR 0.68, 95% CI 0.41–1.11, P =0.120). The incidence of major complications was similar in both groups (all P &gt; 0.05). MWA had shorter intervention times, hospitalization, and lower costs. Conclusions: For resectable MFHCC patients, LLR is preferable due to its lower recurrence rate. For patients who do not qualify for LLR, advances in ablation technology have promoted MWA as a promising alternative.
Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis.
Authors: Sinéad Ryan, Louise Crowe, Sofía N Almeida Cruz, Matthew D Galbraith, Carol O'Brien, Juliet A Hammer, Ronan Bergin, Shauna K Kellett, Gary E Markey, Taylor M Benson, Olga Fagan, Joaquin M Espinosa, Niall Conlon, Claire L Donohoe, Susan McKiernan, Andrew E Hogan, Eóin N McNamee, Glenn T Furuta, Calies Menard-Katcher, Joanne C Masterson
Journal: Journal of Allergy and Clinical Immunology (2024)

Investigating the contributory role that epithelial cell metabolism plays in allergic inflammation is a key factor to understanding what influences dysfunction and the pathogenesis of the allergic disease eosinophilic esophagitis (EoE). We previously highlighted that the absence of hypoxia signaling through hypoxia-inducible factor (HIF)-1α in EoE contributes to esophageal epithelial dysfunction. However, metabolic regulation by HIF-1α has not been explored in esophageal allergy.
CT-based fully automated artificial intelligence model to predict extrapancreatic perineural invasion in pancreatic ductal adenocarcinoma
Authors: Jieyu Yu, Chengwei Chen, Mingzhi Lu, Xu Fang, Jing Li, Mengmeng Zhu, Na Li, Xiaohan Yuan, Yaxing Han, Li Wang, Jianping Lu, Chengwei Shao, Yun Bian
Journal: International Journal of Surgery (2024)

Background: Extrapancreatic perineural invasion (EPNI) increases the risk of postoperative recurrence in pancreatic ductal adenocarcinoma (PDAC). This study aimed to develop and validate a computed tomography (CT)-based, fully automated preoperative artificial intelligence (AI) model to predict EPNI in patients with PDAC. Methods: The authors retrospectively enrolled 1065 patients from two Shanghai hospitals between June 2014 and April 2023. Patients were split into training ( n =497), internal validation ( n =212), internal test ( n =180), and external test ( n =176) sets. The AI model used perivascular space and tumor contact for EPNI detection. The authors evaluated the AI model’s performance based on its discrimination. Kaplan–Meier curves, log-rank tests, and Cox regression were used for survival analysis. Results: The AI model demonstrated superior diagnostic performance for EPNI with 1-pixel expansion. The area under the curve in the training, validation, internal test, and external test sets were 0.87, 0.88, 0.82, and 0.83, respectively. The log-rank test revealed a significantly longer survival in the AI-predicted EPNI-negative group than the AI-predicted EPNI-positive group in the training, validation, and internal test sets ( P &lt;0.05). Moreover, the AI model exhibited exceptional prognostic stratification in early PDAC and improved assessment of neoadjuvant therapy’s effectiveness. Conclusion: The AI model presents a robust modality for EPNI diagnosis, risk stratification, and neoadjuvant treatment guidance in PDAC, and can be applied to guide personalized precision therapy.