tbuckley/cabot-search huggingface dataset:
WRN Helicase: Is There More to MSI-H than Immunotherapy?
Authors: Zev A. Wainberg
Journal: Cancer Discovery (2024)

In this issue, Picco and colleagues provide further evidence that WRN inhibitors are synthetically lethal in microsatellite instability-high (MSI-H) cancers and function by blocking the helicase domain of select WRN residues. They demonstrate that WRN inhibitors may be even more effective in a subset of MSI-high tumors with (TA)n repeat expansions, which represents a possible strategy in clinical development. See related article by Picco et al., p. 1457 (1).
HLA Awareness in tissue decellularization: A paradigm shift for enhanced biocompatibility, studied on the model of the human fascia lata graft
Authors: Julie Manon, Robin Evrard, Louis Maistriaux, Lies Fieve, Daela Xhema, Ugo Heller, Lucien Van Den Broeck, Julia Vettese, Jean Boisson, Thomas Schubert, Benoît Lengele, Catherine Behets, Olivier Cornu
Journal: Biomaterials (2024)

Last twenties, tissue engineering has rapidly advanced to address the shortage of organ donors. Decellularization techniques have been developed to mitigate immune rejection and alloresponse in transplantation. However, a clear definition of effective decellularization remains elusive. This study compares various decellularization protocols using the human fascia lata model. Morphological, structural and cytotoxicity/viability analyses indicated that all the five tested protocols were equivalent and met Crapo's criteria for successful decellularization. Interestingly, only the in vivo immunization test on rats revealed differences. Only one protocol exhibited Human Leucocyte Antigen (HLA) content below 1% residual threshold, the only criterion preventing rat immunization with an absence of rat anti-human IgG switch after one month (N=4 donors for each of the 7 groups, added by negative and positive controls, n=28). By respecting a refined set of criteria, i.e. lack of visible nuclear material, <50ng DNA/mg dry weight of extracellular matrix, and <1% residual HLA content, the potential for adverse host reactions can be drastically reduced. In conclusion, this study emphasizes the importance of considering not only nuclear components but also major histocompatibility complex in decellularization protocols and proposes new guidelines to promote safer clinical development and use of bioengineered scaffolds.
Clonal haematopoiesis is associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy
Authors: Fernando L. Scolari, Darshan Brahmbhatt, Sagi Abelson, Deacon Lee, Raymond H. Kim, Ali Pedarzadeh, Ali Sakhnini, Arnon Adler, Raymond H. Chan, John E. Dick, Harry Rakowski, Filio Billia
Journal: European Journal of Heart Failure (2024)

Abstract Aims The heterogeneous phenotype of hypertrophic cardiomyopathy (HCM) is still not fully understood. Clonal haematopoiesis (CH) is emerging as a cardiovascular risk factor potentially associated with adverse clinical events. The prevalence, phenotype and outcomes related to CH in HCM patients were evaluated. Methods and results Patients with HCM and available biospecimens from the Peter Munk Cardiac Centre Cardiovascular Biobank were subjected to targeted sequencing for 35 myeloid genes associated with CH. CH prevalence, clinical characteristics, morphological phenotypes assessed by echocardiogram and cardiac magnetic resonance and outcomes were assessed. All patients were evaluated for a 71‐plex cytokines/chemokines, troponin I and B‐type natriuretic peptide analysis. Major adverse cardiovascular events (MACE) were defined as appropriate implantable cardioverter‐defibrillator shock, stroke, cardiac arrest, orthotopic heart transplant and death. Among the 799 patients, CH was found in 183 (22.9%) HCM patients with sarcomeric germline mutations. HCM patients with CH were more symptomatic and with a higher burden of fibrosis than those without CH. CH was associated with MACE in those HCM patients with sarcomeric germline mutations (adjusted hazard ratio [HR] 6.89, 95% confidence interval [CI] 1.78–26.6; p = 0.005), with the highest risk among those that had DNMT3A , TET2 and ASXL1 mutations (adjusted HR 5.76, 95% CI 1.51–21.94; p = 0.010). Several cytokines (IL‐1ra, IL‐6, IL‐17F, TGFα, CCL21, CCL1, CCL8, and CCL17), and troponin I were upregulated in gene‐positive HCM patients with CH. Conclusions These results indicate that CH in patients with HCM is associated with worse clinical outcomes. In the absence of CH, gene‐positive patients with HCM have lower rates of MACE.
Optimization of Vascularized Intestinal Organoid Model
Authors: Zhang Wen, Mariabelen Orduno, Zixie Liang, Xiangyu Gong, Michael Mak
Journal: Advanced Healthcare Materials (2024)

Abstract Vasculature is crucial for maintaining organ homeostasis and metabolism. Although 3D organoids can mimic organ structures and patterns, they still lack vascular systems, limiting the recapitulation of physiological complexities. Although vascularization of organoids has been demonstrated by mixing Matrigel in fibrin, how the mixed gel niche affects endothelial cells (ECs) and organoids remains unclear. Existing protocols rely on fibroblasts to promote vascular network formation. This study explores how varying the ratio of Matrigel in fibrin‐Matrigel co‐gel affects vascular network formation and intestinal organoid growth. A fine‐tuned hydrogel is developed by adding aprotinin and 15% Matrigel in fibrin. Medium for co‐culturing ECs and organoids is modified with basic fibroblast growth factor (bFGF) and heparin. In combination with fine‐tuned hydrogel and modified medium, vascular network formation and organoid vascularization are successfully generated in the absence of fibroblast. Furthermore, structural cues and pore architectures are critical for angiogenesis and vascularization. By incorporating engineered thick collagen fiber bundles into the system, vascular network formation is guided by bundle architectures, enhancing interactions between vascular networks and organoids. The results demonstrate an optimized system that advances tissue and organoid vascularization by combining fiber bundles with fine‐tuned hydrogel and modified medium.
Probing the Topological Effects on Stability Enhancement and Therapeutic Performance of Protein Bioconjugates: Tadpole, Macrocycle versus Figure‐of‐Eight
Authors: Yajie Liu, Xibao Tian, Fan Zhang, Wen‐Bin Zhang
Journal: Advanced Healthcare Materials (2024)

Chemical topology provides a unique dimension for making therapeutic protein bioconjugates with native structure and intact function, yet the effects of topology remain elusive. Herein, the design, synthesis, and characterization of therapeutic protein bioconjugates in three topologies (i.e., tadpole, macrocycle, and figure-of-eight), are reported. The interferon α2b (IFN) and albumin binding domain (ABD) are selected as the model proteins for bioconjugation and proof-of-concept. The biosynthesis of these topological isoforms is accomplished via direct expression in cells using SpyTag-SpyCatcher chemistry and/or split-intein-mediated ligation for topology diversification. The corresponding topologies are proven with combined techniques of LC-MS, SDS-PAGE, and controlled proteolytic digestion. While the properties of these topological isoforms are similar in most cases, the figure-of-eight-shaped bioconjugate, f8-IFN-ABD, exhibits the best thermal stability and anti-aggregation properties along with prolonged half-life and enhanced tumor retention relative to the tadpole-shaped control, tadp-IFN-ABD, and the macrocyclic control, c-IFN-ABD, showcasing considerable topological effects. The work expands the topological diversity of proteins and demonstrates the potential advantages of leveraging chemical topology for functional benefits beyond multi-function integration in protein therapeutics.
Advance of Near‐Infrared Emissive Carbon Dots in Diagnosis and Therapy: Synthesis, Luminescence, and Application
Authors: Jing Hu, Ziliang Zheng, Yongzhen Yang, Lin Chen, Weiwei Kang
Journal: Advanced Healthcare Materials (2024)

Abstract Carbon dots (CDs) with good optical properties, biocompatibility, easy functionalization, and small size have attracted more and more attention and laid a good foundation for their applications in the biomedicine field. CDs emitted in near‐infrared regions (NIR‐CDs) can achieve high penetration depth imaging and produce high cytotoxic substance for disease treatment. Therefore, NIR‐CDs are promising materials to realize high‐quality imaging‐guided diagnostic and therapeutic integration. This review first introduces the current mainstream synthesis methods of NIR‐CDs by “top–down” and “bottom–up”. Second, the luminescence modes of NIR‐CDs are introduced, and the luminescence mechanisms based on carbon core state, surface state, molecular state, and crosslinking enhanced emission are summarized. Third, the applications and principles of NIR‐CDs in imaging, drug delivery, and non‐invasive therapeutics are introduced from a view of diagnosis and therapy. Finally, their prospects and challenges in biomedical and biotechnological applications are outlined.
Neuronal double-stranded DNA accumulation induced by DNase II deficiency drives tau phosphorylation and neurodegeneration
Authors: Ling-Jie Li, Xiao-Ying Sun, Ya-Ru Huang, Shuai Lu, Yu-Ming Xu, Jing Yang, Xi-Xiu Xie, Jie Zhu, Xiao-Yun Niu, Dan Wang, Shi-Yu Liang, Xiao-Yu Du, Sheng-Jie Hou, Xiao-Lin Yu, Rui-Tian Liu
Journal: Translational Neurodegeneration (2024)

Abstract Background Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer’s disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified. Methods The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test. Results The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits. Conclusions DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders. Graphical Abstract Scheme depicting the possible mechanism by which DNase II deficiency induces cognitive impairment in mice. DNase II deficiency induces tau phosphorylation by regulating kinases CDK5 and CaMKII as well as phosphatase PP2A through accumulation of undigested damaged DNA in the cytoplasm of neurons. Then phosphorylated tau induces synaptic loss, neuroinflammation, and neuronal apoptosis, eventually rendering cognitive impairment in mice.
Reply letter
Authors: Carla G. S. Saad, Ana Cristina Medeiros‐Ribeiro, Clarissa Q. Pimentel, Eloisa Bonfa
Journal: Arthritis & Rheumatology (2024)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Long‐term follow‐up of anti‐infliximab antibodies in radiographic axial spondyloarthritis patients: a marker of drug survival and tapering: comment on the article by Clarissa et al
Authors: Jin‐Xian Huang, Guo‐Wen Zhang
Journal: Arthritis & Rheumatology (2024)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
LX1 Targets Androgen Receptor Variants and AKR1C3 to overcome Therapy Resistance in Advanced Prostate Cancer
Authors: Shu Ning, Cameron M. Armstrong, Enming Xing, Amy R. Leslie, Richard Y. Gao, Masuda Sharifi, Zachary A. Schaaf, Wei Lou, Xiangrui Han, Desiree H. Xu, Rui Yang, Jeffrey Cheng, Shabber Mohammed, Nicholas Mitsiades, Chengfei Liu, Alan P. Lombard, Chun-Yi Wu, Xiaolin Cheng, Pui-Kai Li, Allen C. Gao
Journal: Cancer Research (2024)

The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for new therapeutic strategies targeting key resistant drivers, such as AR variants like AR-V7, and steroidogenic enzymes, such as aldo-keto reductase 1C3 (AKR1C3), to overcome drug resistance and improve outcomes for patients with advanced prostate cancer. Here, we have designed, synthesized, and characterized a novel class of LX compounds targeting both the AR/AR variants and AKR1C3 pathways. Molecular docking and in vitro studies demonstrated that LX compounds bind to the AKR1C3 active sites and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and to inhibit their target gene signaling. LX1 inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. In addition, LX1 inhibited the growth of cells resistant to antiandrogens including enzalutamide (Enza), abiraterone, apalutamide, and darolutamide in vitro. A synergistic effect was observed when LX1 was combined with antiandrogens and taxanes, indicating the potential for this combination in treating resistant prostate cancer. Treatment with LX1 significantly decreased tumor volume, serum PSA levels, as well as reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 was found to overcome resistance to Enza treatment, and its combination with Enza further suppressed tumor growth in both the CWR22Rv1 xenograft and LuCaP35CR patient-derived xenograft models. Collectively, the dual effect of LX1 in reducing AR signaling and intratumoral testosterone, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer. Significance: LX1 simultaneously targets androgen receptor variants and the steroidogenic enzyme AKR1C3, offering a promising approach to combat drug resistance and enhancing therapeutic efficacy in conjunction with standard treatments for advanced prostate cancer.
Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma
Authors: Meng Jiao, Christopher J. Pirozzi, Chen Yu, Xuhui Bao, Mengjie Hu, Dong Pan, Sejiro Littleton, Nathan Reynolds, Daniel R. Saban, Fang Li, Chuan-Yuan Li
Journal: Cancer Research (2024)

Abstract Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of the currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-O-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson’s disease, in glioma treatment. Analysis of The Cancer Genome Atlas data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in patients with glioma. Significance: Inhibition of catechol-O-methyltransferase, a well-established drug target in Parkinson’s disease, interferes with mitochondrial electron transport and induces mitochondrial double-stranded RNA leakage, activating type I interferon signaling and sensitizing glioma to radiotherapy.
Integrative Modeling of Signaling Network Dynamics Identifies Cell Type-selective Therapeutic Strategies for FGFR4-driven Cancers
Authors: Sungyoung Shin, Nicole J. Chew, Milad Ghomlaghi, Anderly C. Chüeh, Yunhui Jeong, Lan K. Nguyen, Roger J. Daly
Journal: Cancer Research (2024)

Oncogenic FGFR4 signaling represents a potential therapeutic target in various cancer types, including triple-negative breast cancer and hepatocellular carcinoma. However, resistance to FGFR4 single-agent therapy remains a major challenge, emphasizing the need for effective combinatorial treatments. Our study sought to develop a comprehensive computational model of FGFR4 signaling and to provide network-level insights into resistance mechanisms driven by signaling dynamics. An integrated approach, combining computational network modeling with experimental validation, uncovered potent AKT reactivation following FGFR4 targeting in triple-negative breast cancer cells. Analyzing the effects of cotargeting specific network nodes by systematically simulating the model predicted synergy of cotargeting FGFR4 and AKT or specific ErbB kinases, which was subsequently confirmed through experimental validation; however, cotargeting FGFR4 and PI3K was not synergistic. Protein expression data from hundreds of cancer cell lines was incorporated to adapt the model to diverse cellular contexts. This revealed that although AKT rebound was common, it was not a general phenomenon. For example, ERK reactivation occurred in certain cell types, including an FGFR4-driven hepatocellular carcinoma cell line, in which there is a synergistic effect of cotargeting FGFR4 and MEK but not AKT. In summary, this study offers key insights into drug-induced network remodeling and the role of protein expression heterogeneity in targeted therapy responses. These findings underscore the utility of computational network modeling for designing cell type-selective combination therapies and enhancing precision cancer treatment. Significance: Computational predictive modeling of signaling networks can decipher mechanisms of cancer cell resistance to targeted therapies and enable identification of more effective cancer type-specific combination treatment strategies.
Ribonucleotide reductase small subunit M2 promotes the proliferation of esophageal squamous cell carcinoma cells via HuR-mediated mRNA stabilization
Authors: Jing Zhang, Qiong Wu, Yifei Xie, Feng Li, Huifang Wei, Yanan Jiang, Yan Qiao, Yinhua Li, Yanan Sun, Han Huang, Mengmeng Ge, Dengyun Zhao, Zigang Dong, Kangdong Liu
Journal: Acta Pharmaceutica Sinica B (2024)

Esophageal squamous cell carcinoma (ESCC), a malignancy of the digestive system, is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets. Dysregulated ribonucleotide reductase (RNR) expression has been confirmed to be causally linked to tumorigenesis. This study demonstrated that ribonucleotide reductase small subunit M2 (RRM2) is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes. Mechanistically, HuR promotes
Submucosal steroid pre-injection strategy to prevent oesophageal stricture after circumferential endoscopic submucosal dissection
Authors: Ke Zhan, Pengfei Wang, Wei-hui Liu, Yang Bai, Daorong Chen, Ling Sun, Min Qiao, Jianhua Dai, Xusheng Nie, Xin Yang
Journal: Gut (2024)
Radiofrequency-responsive black phosphorus nanogel crosslinked with cisplatin for precise synergy in multi-modal tumor therapies
Authors: Can Hong, Yiming Liu, Dingwen Shi, Chao Liu, Shidong Zou, Mengqin Guo, Xingyu Chen, Chuansheng Zheng, Yanbing Zhao, Xiangliang Yang
Journal: Journal of Controlled Release (2024)
Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening
Authors: Chao Huang, Yang Jin, Panpan Fu, Kongying Hu, Mengxue Wang, Wenjing Zai, Ting Hua, Xinluo Song, Jianyu Ye, Yiqing Zhang, Gan Luo, Haiyu Wang, Jiangxia Liu, Jieliang Chen, Xuwen Li, Zhenghong Yuan
Journal: Acta Pharmaceutica Sinica B (2024)

Due to the limitations of current anti-HBV therapies, the HBV core (HBc or HBcAg) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound
The METRIC-framework for assessing data quality for trustworthy AI in medicine: a systematic review
Authors: Daniel Schwabe, Katinka Becker, Martin Seyferth, Andreas Klaß, Tobias Schaeffter
Journal: npj Digital Medicine (2024)

The adoption of machine learning (ML) and, more specifically, deep learning (DL) applications into all major areas of our lives is underway. The development of trustworthy AI is especially important in medicine due to the large implications for patients' lives. While trustworthiness concerns various aspects including ethical, transparency and safety requirements, we focus on the importance of data quality (training/test) in DL. Since data quality dictates the behaviour of ML products, evaluating data quality will play a key part in the regulatory approval of medical ML products. We perform a systematic review following PRISMA guidelines using the databases Web of Science, PubMed and ACM Digital Library. We identify 5408 studies, out of which 120 records fulfil our eligibility criteria. From this literature, we synthesise the existing knowledge on data quality frameworks and combine it with the perspective of ML applications in medicine. As a result, we propose the METRIC-framework, a specialised data quality framework for medical training data comprising 15 awareness dimensions, along which developers of medical ML applications should investigate the content of a dataset. This knowledge helps to reduce biases as a major source of unfairness, increase robustness, facilitate interpretability and thus lays the foundation for trustworthy AI in medicine. The METRIC-framework may serve as a base for systematically assessing training datasets, establishing reference datasets, and designing test datasets which has the potential to accelerate the approval of medical ML products.