tbuckley/cabot-search huggingface dataset:
Patient-derived tumor cell clusters (PTC) guiding-neoadjuvant therapy of HER2-positive breast cancer: A prospective randomized phase II clinical trial.
Authors: Xingfei Yu, Xiaofan Wu, Chen Wang, Weiliang Feng, Yabing Zheng, Hongjian Yang
Journal: Journal of Clinical Oncology (2024)

581 Background: In a previous study, the patient-derived tumor-like cell clusters (PTC) were confirmed to be an accurate medicine effect-predicting model in vitro for clinical practice (1). We designed this prospective randomized phase II trial to research if this PTC-guiding strategy could improve the effect of neoadjuvant therapy in human epidermal growth factor receptor 2 (HER2) positive breast cancer (NCT05103293). Methods: We enrolled HER2-positive early breast cancer patients planning for neoadjuvant therapy to accept the PTC-guiding regimen as an experimental group or regimens of the physician's choice as a control group randomly. All eligible patients in the experimental group would receive medicine-sensitive testing by PTC then accepted the regimen with the highest PTC killing rate (30% as the lowest cut-off value) from the three candidate regimens (Cyclophosphamide combined with epirubicin -- Docetaxel combined with trastuzumab and pertuzumab, EC-THP, Docetaxel and carboplatin with trastuzumab and pertuzumab, TCbHP and Docetaxel with trastuzumab and pyrotinib, THPy). The primary endpoint is pathological complete response (pCR) in two groups using superiority odd ratio Fisher's exact test (one-sided alpha =0.05, power of 80%, and superiority margin at 0.1). The secondary endpoints are Miller-Payne (MP) grade 4~5 proportion, objective response rate (ORR), disease-free survival (DFS), and overall survival (OS). Results: Finally, 86 patients were enrolled in this study, 44 in the experimental and 42 in the control groups. The experimental group had 65.9% of pCR, significantly higher than 42.9% in the control group (Hazard ratio=0.388, P=0.033). The PTC-guiding treatment also considerably increased MP 4~5 proportion (79.5% vs. 59.4%, Hazard ratio=0.283, P=0.009) and objective response rate (90.9% vs 71.4%, Hazard ratio=0.250, P=0.027). After a two-year medium follow-up, the disease-free survival of the PTC-guiding treatment group was 84.1% higher than 71.4% of the control group without a significant difference (Log Rank, P=0.106). The two groups had similar overall survival (Log Rank, P=0.958). Furthermore, the PTC-guiding strategy significantly impacted pCR in univariate and multivariate regression analyses but not survival. Conclusions: In this trial, we concluded that the PTC-guiding neoadjuvant therapy could improve the effect, including pCR, MP score, and ORR in HER2-positive breast cancer. 1. Yin et al., Sci.Transl. 2020. Clinical trial information: NCT05103293 .
Paracrine Ovarian Cancer Cell‐Derived CSF1 Signaling Regulates Macrophage Migration Dynamics in a 3D Microfluidic Model that Recapitulates In Vivo Infiltration Patterns in Patient‐Derived Xenografts
Authors: Alexis L. Scott, Dorota E. Jazwinska, Diana G. Kulawiec, Ioannis K. Zervantonakis
Journal: Advanced Healthcare Materials (2024)

Abstract A high density of macrophages in the ovarian cancer microenvironment is associated with disease progression and poor outcomes. Understanding cancer‐macrophage interaction mechanisms that establish this pro‐tumorigenic microenvironment is critical for developing macrophage‐targeted therapies. Here, 3D microfluidic assays and patient‐derived xenografts are utilized to define the role of cancer‐derived colony stimulating factor 1 (CSF1) on macrophage infiltration dynamics toward ovarian cancer cells. It is demonstrated that multiple ovarian cancer models promote the infiltration of macrophages into a 3D extracellular matrix in vitro in a cell density‐dependent manner. Macrophages exhibit directional migration and increased migration speed under both direct interactions with cancer cells embedded within the matrix and paracrine crosstalk with cancer cells seeded in an independent microchannel. It is also found that platinum‐based chemotherapy increases macrophage recruitment and the levels of cancer cell‐derived CSF1. Targeting CSF1 signaling under baseline or chemotherapy‐treatment conditions reduces the number of infiltrated macrophages. It is further shown that results obtained with the 3D microfluidic model reflect the recruitment profiles of macrophages in patient‐derived xenografts in vivo. These findings highlight the role of CSF1 signaling in establishing macrophage‐rich ovarian cancer microenvironments, as well as the utility of microfluidic models in recapitulating 3D tumor ecosystems and dissecting cancer‐macrophage signaling.
Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases
Authors: Chiara Pedicone, Sarah A. Weitzman, Alan E. Renton, Alison M. Goate
Journal: Molecular Neurodegeneration (2024)

Abstract A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of the human genome as direct (H1) and inverted (H2) haplotype clades. This inversion region demonstrates high linkage disequilibrium, but the frequency of each haplotype differs across ancestries. While the H1 haplotype exists in all populations and shows a normal pattern of genetic variability and recombination, the H2 haplotype is enriched in European ancestry populations, is less frequent in African ancestry populations, and nearly absent in East Asian ancestry populations. H1 is a known risk factor for several neurodegenerative diseases, and has been associated with many other traits, suggesting its importance in cellular phenotypes of the brain and entire body. Conversely, H2 is protective for these diseases, but is associated with predisposition to recurrent microdeletion syndromes and neurodevelopmental disorders such as autism. Many single nucleotide variants and copy number variants define H1/H2 haplotypes and sub-haplotypes, but identifying the causal variant(s) for specific diseases and phenotypes is complex due to the extended linkage equilibrium. In this review, we assess the current knowledge of this inversion region regarding genomic structure, gene expression, cellular phenotypes, and disease association. We discuss recent discoveries and challenges, evaluate gaps in knowledge, and highlight the importance of understanding the effect of the 17q21.31 haplotypes to promote advances in precision medicine and drug discovery for several diseases. Graphical Abstract
Digital “flipbooks” for enhanced visual assessment of simple and complex brain tumors
Authors: Nicholas S Cho, Viên Lam Le, Francesco Sanvito, Sonoko Oshima, Jayla Harper, Saewon Chun, Catalina Raymond, Albert Lai, Phioanh L Nghiemphu, Jingwen Yao, Richard Everson, Noriko Salamon, Timothy F Cloughesy, Benjamin M Ellingson
Journal: Neuro-Oncology (2024)

Abstract Typical longitudinal radiographic assessment of brain tumors relies on side-by-side qualitative visualization of serial magnetic resonance images (MRIs) aided by quantitative measurements of tumor size. However, when assessing slowly growing tumors and/or complex tumors, side-by-side visualization and quantification may be difficult or unreliable. Whole-brain, patient-specific “digital flipbooks” of longitudinal scans are a potential method to augment radiographic side-by-side reads in clinical settings by enhancing the visual perception of changes in tumor size, mass effect, and infiltration across multiple slices over time. In this approach, co-registered, consecutive MRI scans are displayed in a slide deck, where one slide displays multiple brain slices of a single timepoint in an array (eg, 3 × 5 “mosaic” view of slices). The flipbooks are viewed similarly to an animated flipbook of cartoons/photos so that subtle radiographic changes are visualized via perceived motion when scrolling through the slides. Importantly, flipbooks can be created easily with free, open-source software. This article describes the step-by-step methodology for creating flipbooks and discusses clinical scenarios for which flipbooks are particularly useful. Example flipbooks are provided in Supplementary Material.
Recent progress of nano-drugs in neutron capture therapy
Authors: Yi-Tong Zhou, Kai Cheng, Bo Liu, Yuan-Cheng Cao, Jin-Xuan Fan, Zhi-Gang Liu, Yuan-Di Zhao
Journal: Theranostics (2024)

As a developing radiation treatment for tumors, neutron capture therapy (NCT) has less side effects and a higher efficacy than conventional radiation therapy.Drugs with specific isotopes are indispensable counterparts of NCT, as they are the indespensable part of the neutron capture reaction.Since the creation of the first and second generations of boron-containing reagents, NCT has significantly advanced.Notwithstanding, the extant NCT medications, predominantly comprised of small molecule boron medicines, have encountered challenges such monofunctionality, inadequate targeting of tumors, and hypermetabolism.There is an urgent need to promote the research and development of new types of NCT drugs.Bio-nanomaterials can be introduced into the realm of NCT, and nanotechnology can give conventional medications richer functionality and significant adaptability.This can complement the advantages of each other and is expected to develop more new drugs with less toxicity, low side effects, better tumor targeting, and high biocompatibility.In this review, we summarized the research progress of nano-drugs in NCT based on the different types and sources of isotopes used, and introduced the attempts and efforts made by relevant researchers in combining nanomaterials with NCT, hoping to provide pivotal references for promoting the development of the field of tumor radiotherapy.
Building consensus on the application of organoid-based drug sensitivity testing in cancer precision medicine and drug development
Authors: Dongxi Xiang, Aina He, Rong Zhou, Yonggang Wang, Xiuying Xiao, Ting Gong, Wenyan Kang, Xiaolin Lin, Xiaochen Wang, Lianxin Liu, Ye-Guang Chen, Shaorong Gao, Yingbin Liu
Journal: Theranostics (2024)

Patient-derived organoids (PDOs) have emerged as a promising platform for clinical and translational studies. A strong correlation exists between clinical outcomes and the use of PDOs to predict the efficacy of chemotherapy and/or radiotherapy. To standardize interpretation and enhance scientific communication in the field of cancer precision medicine, we revisit the concept of PDO-based drug sensitivity testing (DST). We present an expert consensus-driven approach for medication selection aimed at predicting patient responses. To further standardize PDO-based DST, we propose guidelines for clarification and characterization. Additionally, we identify several major challenges in clinical prediction when utilizing PDOs.
Platelet-targeted thromboprophylaxis with a human serum albumin fusion drug: Preventing thrombosis and reducing cardiac ischemia/reperfusion injurywithout bleeding complications
Authors: Yuyang Song, Laura A. Bienvenu, Viktoria Bongcaron, Shania A. Prijaya, Ana C. Maluenda, Aidan P. G. Walsh, James D. McFayden, Geoffrey A. Pietersz, Karlheinz Peter, Xiaowei Wang
Journal: Theranostics (2024)

Background: Myocardial infarction (MI) as a consequence of atherosclerosis-associated acute thrombosis is a leading cause of death and disability globally.Antiplatelet and anticoagulant drugs are standard therapies in preventing and treating MI.However, all clinically used drugs are associated with bleeding complications, which ultimately limits their use in patients with a high risk of bleeding.We have developed a new recombinant drug, targ-HSA-TAP, that combines targeting and specific inhibition of activated platelets as well as anticoagulation.This drug is designed and tested for a prolonged circulating half-life, enabling unique thromboprophylaxis without bleeding complications.Methods: Targ-HSA-TAP combines a single-chain antibody (scFv) that targets activated glycoprotein IIb/IIIa on activated platelets, human serum albumin (HSA) for prolonged circulation, and tick anticoagulant peptide (TAP) for coagulation FX inhibition.A non-binding scFv is employed as a non-targeting control (non-targ-HSA-TAP).Its efficacy was investigated in vivo using murine models of acute thrombosis and cardiac ischemia-reperfusion (I/R) injury.Results: Our experiments confirmed the targeting specificity of targ-HSA-TAP to activated platelets and demonstrated effective prevention of platelet aggregation and thrombus formation, as well as FXa inhibition in vitro.Thromboprophylactic administration of targ-HSA-TAP subcutaneously in mice prevented occlusion of the carotid artery after ferric chloride injury as compared to non-targ-HSA-TAP and PBS-control treated mice.By comparing the therapeutic outcomes between targ-TAP and targ-HSA-TAP, we demonstrate the significant improvements brought by the HSA fusion in extending the drug's half-life and enhancing its therapeutic window for up to 16 h post-administration.Importantly, tail bleeding time was not prolonged with targ-HSA-TAP in contrast to the clinically used anticoagulant enoxaparin.Furthermore, in a murine model of cardiac I/R injury, mice administered targ-HSA-TAP 10 h before injury demonstrated preserved cardiac function, with significantly higher ejection fraction and fractional shortening, as compared to the non-targ-HSA-TAP and PBS control groups.Advanced strain analysis revealed reduced myocardial deformation and histology confirmed a reduced infarct size in targ-HSA-TAP treated mice compared to control groups. Ivyspring International
Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury: Erratum
Authors: Jing-Yuan Cao, Bin Wang, Tao-Tao Tang, Yi Wen, Zuo-Lin Li, Song-Tao Feng, Min Wu, Dan Liu, Di Yin, Kun-Ling Ma, Ri-Ning Tang, Qiu-Li Wu, Hui-Yao Lan, Lin-Li Lv, Bi-Cheng Liu
Journal: Theranostics (2024)

[This corrects the article DOI: 10.7150/thno.54550.].
Theranostic digital twins: Concept, framework and roadmap towards personalized radiopharmaceutical therapies
Authors: Hamid Abdollahi, Fereshteh Yousefirizi, Isaac Shiri, Julia Brosch-Lenz, Elahe Mollaheydar, Ali Fele-Paranj, Kuangyu Shi, Habib Zaidi, Ian Alberts, Madjid Soltani, Carlos Uribe, Babak Saboury, Arman Rahmim
Journal: Theranostics (2024)

Radiopharmaceutical therapy (RPT) is a rapidly developing field of nuclear medicine, with several RPTs already well established in the treatment of several different types of cancers.However, the current approaches to RPTs often follow a somewhat inflexible "one size fits all" paradigm, where patients are administered the same amount of radioactivity per cycle regardless of their individual characteristics and features.This approach fails to consider inter-patient variations in radiopharmacokinetics, radiation biology, and immunological factors, which can significantly impact treatment outcomes.To address this limitation, we propose the development of theranostic digital twins (TDTs) to personalize RPTs based on actual patient data.Our proposed roadmap outlines the steps needed to create and refine TDTs that can optimize radiation dose to tumors while minimizing toxicity to organs at risk.The TDT models incorporate physiologically-based radiopharmacokinetic (PBRPK) models, which are additionally linked to a radiobiological optimizer and an immunological modulator, taking into account factors that influence RPT response.By using TDT models, we envisage the ability to perform virtual clinical trials, selecting therapies towards improved treatment outcomes while minimizing risks associated with secondary effects.This framework could empower practitioners to ultimately develop tailored RPT solutions for subgroups and individual patients, thus improving the precision, accuracy, and efficacy of treatments while minimizing risks to patients.By incorporating TDT models into RPTs, we can pave the way for a new era of precision medicine in cancer treatment.
Well-defined alginate oligosaccharides ameliorate joint pain and inflammation in a mouse model of gouty arthritis
Authors: Chengyu Yin, Qianqian Lyu, Zishan Dong, Boyu Liu, Keke Zhang, Zhende Liu, Qing Yu, Peiyi Li, Zhuoqun Wei, Yan Tai, Chuan Wang, Jianqiao Fang, Weizhi Liu, Boyi Liu
Journal: Theranostics (2024)

Background: Gouty arthritis causes severe pain and inflammation.Alginate oligosaccharides (AOSs) are natural products derived from alginate and have anti-inflammatory properties.We explored the potential effects of AOSs with different degrees of polymerization (Dp) on gouty arthritis and associated mechanisms. Methods:We established a mouse model of gouty arthritis by injecting monosodium urate (MSU) into ankle joint.Nocifensive behavior, gait and ankle swelling were used to study AOS's effects.Biochemical assays, in vivo imaging, live cell Ca 2+ imaging, electrophysiology, RNA-sequencing, etc. were used for mechanism exploration.Results: AOS2 (Dp=2), AOS3 (Dp=3) and AOS4 (Dp=4) all inhibited ankle swelling, whereas AOS2&3 produced the most obvious analgesia on model mice.AOS3, which was picked for further evaluation, produced dose-dependent ameliorative effects on model mice.AOS3 reversed gait impairments but did not alter locomotor activity.AOS3 inhibited NLRP3 inflammasome activation and inflammatory cytokine up-regulation in ankle joint.AOS3 ameliorated MSU-induced oxidative stress and reactive oxygen species (ROS) production both in vivo and in vitro and reversed the impaired mitochondrial bioenergetics.AOS3 activated the Nrf2 pathway and promoted Nrf2 disassociation from Keap1-bound complex and Nrf2 nuclear translocation, thus facilitating antioxidant gene expression via Nrf2-dependent mechanism.Nrf2 gene deficiency abolished AOS3's ameliorative effects on pain, inflammation and oxidative stress in ankle joints of model mice.AOS3 reduced TRPV1 functional enhancement in DRG neurons and constrained neuroactive peptide release.Conclusions: AOS3 ameliorates gouty arthritis via activating Nrf2-dependent antioxidant signaling, resulting in suppression of ROS-mediated NLRP3 inflammasome activation and TRPV1 enhancement.AOS3 may be novel therapeutics for gouty arthritis.
Ultrasound and neuroinflammation: immune modulation via the heat shock response
Authors: Graham M. Seasons, Carly Pellow, Hedwich F. Kuipers, G. Bruce Pike
Journal: Theranostics (2024)

Current pharmacological therapeutic approaches targeting chronic inflammation exhibit transient efficacy, often with adverse effects, limiting their widespread use -especially in the context of neuroinflammation.Effective interventions require the consideration of homeostatic function, pathway dysregulation, and pleiotropic effects when evaluating therapeutic targets.Signalling molecules have multiple functions dependent on the immune context, and this complexity results in therapeutics targeting a single signalling molecule often failing in clinical translation.Additionally, the administration of non-physiologic levels of neurotrophic or anti-inflammatory factors can alter endogenous signalling, resulting in unanticipated effects.Exacerbating these challenges, the central nervous system (CNS) is isolated by the blood brain barrier (BBB), restricting the infiltration of many pharmaceutical compounds into the brain tissue.Consequently, there has been marked interest in therapeutic techniques capable of modulating the immune response in a pleiotropic manner; ultrasound remains on this frontier.While ultrasound has been used therapeutically in peripheral tissues -accelerating healing in wounds, bone fractures, and reducing inflammation -it is only recently that it has been applied to the CNS.The transcranial application of low intensity pulsed ultrasound (LIPUS) has successfully mitigated neuroinflammation in vivo, in models of neurodegenerative disease across a broad spectrum of ultrasound parameters.To date, the underlying biological effects and signalling pathways modulated by ultrasound are poorly understood, with a diverse array of reported molecules implicated.The distributed nature of the beneficial response to LIPUS implies the involvement of an, as yet, undetermined upstream signalling pathway, homologous to the protective effect of febrile range hyperthermia in chronic inflammation.As such, we review the heat shock response (HSR), a protective signalling pathway activated by thermal and mechanical stress, as the possible upstream regulator of the anti-inflammatory effects of ultrasound.
PRL1 and PRL3 promote macropinocytosis via its lipid phosphatase activity
Authors: Zu Ye, Chee Ping Ng, Haidong Liu, Qimei Bao, Shengfeng Xu, Dan Zu, Yanhua He, Yixing Huang, Abdul Qader Omer Al-Aidaroos, Ke Guo, Jie Li, Lai Ping Yaw, Qiancheng Xiong, Min Thura, Weihui Zheng, Fenghui Guan, Xiangdong Cheng, Yin Shi, Qi Zeng
Journal: Theranostics (2024)

PRL1 and PRL3, members of the protein tyrosine phosphatase family, have been associated with cancer metastasis and poor prognosis.Despite extensive research on their protein phosphatase activity, their potential role as lipid phosphatases remains elusive.Methods: We conducted comprehensive investigations to elucidate the lipid phosphatase activity of PRL1 and PRL3 using a combination of cellular assays, biochemical analyses, and protein interactome profiling.Functional studies were performed to delineate the impact of PRL1/3 on macropinocytosis and its implications in cancer biology.Results: Our study has identified PRL1 and PRL3 as lipid phosphatases that interact with phosphoinositide (PIP) lipids, converting PI(3,4)P2 and PI(3,5)P2 into PI(3)P on the cellular membranes.These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis, facilitating nutrient extraction, cell migration, and invasion, thereby contributing to tumor development.These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis.Additionally, we found a correlation between PRL1/3 expression and glioma development, suggesting their involvement in glioma progression.Conclusions: Combining with the knowledge that PRLs have been identified to be involved in mTOR, EGFR and autophagy, here we concluded the physiological role of PRL1/3 in orchestrating the nutrient sensing, absorbing and recycling via regulating macropinocytosis through its lipid phosphatase activity.This mechanism could be exploited by tumor cells facing a nutrient-depleted microenvironment, highlighting the potential therapeutic significance of targeting PRL1/3-mediated macropinocytosis in cancer treatment.