tbuckley/cabot-search huggingface dataset:
Force versus Response: Methods for Activating and Characterizing Mechanosensitive Ion Channels and GPCRs
Authors: Renate M. A. Roeterink, Xevi Casadevall i Solvas, David J. Collins, Daniel J. Scott
Journal: Advanced Healthcare Materials (2024)

Abstract Mechanotransduction is the process whereby cells convert mechanical signals into electrochemical responses, where mechanosensitive proteins mediate this interaction. To characterize these critical proteins, numerous techniques have been developed that apply forces and measure the subsequent cellular responses. While these approaches have given insight into specific aspects of many such proteins, subsequent validation and cross‐comparison between techniques remain difficult given significant variations in reported activation thresholds and responses for the same protein across different studies. Accurately determining mechanosensitivity responses for various proteins, however, is essential for understanding mechanotransduction and potential physiological implications, including therapeutics. This critical review provides an assessment of current and emerging approaches used for mechanosensitive ion channel and G‐Coupled Receptors (GPCRs) stimulation and measurement, with a specific focus on the ability to quantitatively measure mechanosensitive responses.
Targeting the LMP1‐ALIX axis in EBV<sup>+</sup> nasopharyngeal carcinoma inhibits immunosuppressive small extracellular vesicle secretion and boosts anti‐tumor immunity
Authors: Fajian He, Yan Gong, Gan Tao, Jianguo Zhang, Qiuji Wu, Yushuang Tan, Yajie Cheng, Chunsheng Wang, Jinru Yang, Linzhi Han, Zhihao Wang, Yanping Gao, Jingyi He, Rui Bai, Peikai Sun, Xiaoyan Yu, Yajuan Zhou, Conghua Xie
Journal: Cancer Communications (2024)

Abstract Background Immunotherapy has revolutionized the therapeutical regimen for nasopharyngeal carcinoma (NPC), yet its response rate remains insufficient. Programmed death‐ligand 1 (PD‐L1) on small extracellular vesicles (sEVs) mediates local and peripheral immunosuppression in tumors, and the mechanism of PD‐L1 loading into these vesicles is garnering increasing attention. Latent membrane protein 1 (LMP1), a key viral oncoprotein expressed in Epstein‐Barr virus (EBV)‐positive NPC, contributes to remodeling the tumor microenvironment. However, the precise mechanisms by which LMP1 modulates tumor immunity in NPC remain unclear. Here, we aimed to investigate the roles and regulatory mechanisms of LMP1 and sEV PD‐L1 in NPC immune evasion. Methods We analyzed the impact of LMP1 on tumor‐infiltrating lymphocyte abundance in NPC tissues and humanized tumor‐bearing mouse models using multiplex immunofluorescence (mIF) and flow cytometry, respectively. Transmission electron microscopy and nanoparticle tracking analysis were employed to characterize sEVs. Immunoprecipitation‐mass spectrometry was utilized to identify proteins interacting with LMP1. The regulatory effects of sEVs on tumor microenvironment were assessed by monitoring CD8 + T cell proliferation and interferon‐γ (IFN‐γ) expression via flow cytometry. Furthermore, the expression patterns of LMP1 and downstream regulators in NPC were analyzed using mIF and survival analysis. Results High LMP1 expression in NPC patient specimens and mouse models was associated with restricted infiltration of CD8 + T cells. Additionally, LMP1 promoted sEV PD‐L1 secretion, leading to inhibition of CD8 + T cell viability and IFN‐γ expression in vitro. Mechanistically, LMP1 recruited apoptosis‐linked gene 2‐interacting protein X (ALIX) through its intracellular domain and bound PD‐L1 through its transmembrane domain, thereby facilitating the loading of PD‐L1 into ALIX‐dependent sEVs. Disruption of ALIX diminished LMP1‐induced sEV PD‐L1 secretion and enhanced the anti‐tumor immunity of CD8 + T cells both in vitro and in vivo. Moreover, increased expression levels of LMP1 and ALIX were positively correlated with enhanced immunosuppressive features and worse prognostic outcomes in NPC patients. Conclusion Our findings uncovered the mechanism by which LMP1 interacts with ALIX and PD‐L1 to form a trimolecular complex, facilitating PD‐L1 loading into ALIX‐dependent sEV secretion pathway, ultimately inhibiting the anti‐tumor immune response in NPC. This highlights a novel target and prognostic marker for NPC immunotherapy.
Electrode Droplet Microarray (eDMA): An Impedance Platform for Label‐Free Parallel Monitoring of Cellular Drug Response in Nanoliter Droplets
Authors: Meijun Zhou, Joaquin E. Urrutia Gomez, Nikolaj K. Mandsberg, Sida Liu, Sabine Schmidt, Matthias Meier, Pavel A. Levkin, Heinz‐Georg Jahnke, Anna Popova
Journal: Advanced Healthcare Materials (2024)

Abstract Label‐free real‐time monitoring of cellular behavior using impedance spectroscopy is important for drug development and toxicological assessments. Parallelization and miniaturization of such experiments are essential for increasing throughput and enabling experiments with low abundant stem or primary cells. Traditional methods are not miniaturized and require large volumes of reagents and number of cells, limiting their suitability for cost effective high‐throughput screening of cells of limited availability. Here, the fabrication, optimization, and application of a bioelectrical signaling monitoring system – electrode droplet microarray (eDMA) are demonstrated. The eDMA platform is based on preparation of a hydrophilic‐superhydrophobic patterns covering an array of individually addressable microelectrodes, which confines cells to individual microelectrodes, allowing for parallel, real‐time, and label‐free detection of cellular responses to drug treatments in nanoliter droplets. The real‐time monitoring of cytotoxic effect of an anticancer drug is demonstrated over 48 h with real‐time calculation of the half‐inhibitory concentration (IC50) values through impedance spectroscopy. This demonstrates eDMA's ability to dynamically assess responses to various drugs in parallel at any given time point, which is crucial for functional personalized oncology. Specifically, the platform can be employed for monitoring anticancer drug toxicity using limited patient samples, where the miniaturization provided by eDMA is essential.
The future of genetic medicines delivered via targeted lipid nanoparticles to leukocytes
Authors: Dana Tarab-Ravski, Lior Stotsky-Oterin, Aviad Elisha, Govinda Reddy Kundoor, Srinivas Ramishetti, Inbal Hazan-Halevy, Heinrich Haas, Dan Peer
Journal: Journal of Controlled Release (2024)
Periodontitis impacts on thrombotic diseases: from clinical aspect to future therapeutic approaches
Authors: Jinting Ge, Xuanzhi Zhu, Chengxin Weng, Ding Yuan, Jichun Zhao, Lei Zhao, Tiehao Wang, Yafei Wu
Journal: International Journal of Oral Science (2024)

Periodontitis is a chronic inflammatory disease initiated by biofilm microorganisms and mediated by host immune imbalance. Uncontrolled periodontal infections are the leading cause of tooth loss in adults. Thrombotic diseases can lead to partial or complete obstruction of blood flow in the circulatory system, manifesting as organ or tissue ischemia and necrosis in patients with arterial thrombosis, and local edema, pain and circulatory instability in patients with venous thrombosis, which may lead to mortality or fatality in severe case. Recent studies found that periodontitis might enhance thrombosis through bacterial transmission or systemic inflammation by affecting platelet-immune cell interactions, as well as the coagulation, and periodontal therapy could have a prophylactic effect on patients with thrombotic diseases. In this review, we summarized clinical findings on the association between periodontitis and thrombotic diseases and discussed several novel prothrombotic periodontitis-related agents, and presented a perspective to emphasize the necessity of oral health management for people at high risk of thrombosis.
Multifunctional nanoparticles potentiate in-situ tumor vaccines via reversing insufficient Photothermal therapy by disrupting tumor vasculature
Authors: Lili Zhao, Yiran Liu, Fangfei Jin, Kaiyuan Hu, Miao Lv, Yuehua Zhou, Weijun Zhao, Yiqiao Hu, Jinhui Wu, Yong Yang, Wenguang Wang
Journal: Journal of Controlled Release (2024)
Human OX40L–CAR-T <sub>regs</sub> target activated antigen-presenting cells and control T cell alloreactivity
Authors: Xianliang Rui, Francesca Alvarez Calderon, Holly Wobma, Ulrike Gerdemann, Alexandre Albanese, Lorenzo Cagnin, Connor McGuckin, Katherine A. Michaelis, Kisa Naqvi, Bruce R. Blazar, Victor Tkachev, Leslie S. Kean
Journal: Science Translational Medicine (2024)

Regulatory T cells (T regs ) make major contributions to immune homeostasis. Because T reg dysfunction can lead to both allo- and autoimmunity, there is interest in correcting these disorders through T reg adoptive transfer. Two of the central challenges in clinically deploying T reg cellular therapies are ensuring phenotypic stability and maximizing potency. Here, we describe an approach to address both issues through the creation of OX40 ligand (OX40L)–specific chimeric antigen receptor (CAR)–T regs under the control of a synthetic forkhead box P3 ( FOXP3 ) promoter. The creation of these CAR-T regs enabled selective T reg stimulation by engagement of OX40L, a key activation antigen in alloimmunity, including both graft-versus-host disease and solid organ transplant rejection, and autoimmunity, including rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus. We demonstrated that OX40L–CAR-T regs were robustly activated in the presence of OX40L-expressing cells, leading to up-regulation of T reg suppressive proteins without induction of proinflammatory cytokine production. Compared with control T regs , OX40L–CAR-T regs more potently suppressed alloreactive T cell proliferation in vitro and were directly inhibitory toward activated monocyte-derived dendritic cells (DCs). We identified trogocytosis as one of the central mechanisms by which these CAR-T regs effectively decrease extracellular display of OX40L, resulting in decreased DC stimulatory capacity. OX40L–CAR-T regs demonstrated an enhanced ability to control xenogeneic graft-versus-host disease compared with control T regs without abolishing the graft-versus-leukemia effect. These results suggest that OX40L–CAR-T regs may have wide applicability as a potent cellular therapy to control both allo- and autoimmune diseases.
Intraoperative evaluation of tumor margins using a TROP2 near-infrared imaging probe to enable human breast-conserving surgery
Authors: Weiling Chen, Yongqu Zhang, Lixin Zhang, Xiangjie Luo, Xia Yang, Yuanyuan Zhu, Guimei Wang, Wenhe Huang, Deliang Zhang, Yunzhu Zeng, Ronghui Li, Cuiping Guo, Jiazheng Wang, Zhao Wu, Na Liu, Guojun Zhang
Journal: Science Translational Medicine (2024)

Intraoperative surgical margin assessment remains a challenge during breast-conserving surgery. Here, we report a combined strategy of immuno–positron emission tomography (PET) for preoperative detection of breast cancer and guided assessment of margins in breast-conserving surgery through second near-infrared (NIR-II) fluorescence imaging of trophoblastic cell surface antigen 2 (TROP2). We demonstrated that the intensity of PET signals in the tumors was nearly five times higher than in normal breast tissue with a zirconium-89 tracer conjugated to sacituzumab govitecan (SG) in a mouse spontaneous breast cancer model, enabling the identification of tumors. We further generated a NIR-II probe of indocyanine green conjugated to SG (ICG-SG) and developed a rapid incubation imaging method for intraoperative margin assessment in a relevant time window for the operation workflow. The ICG-SG NIR-II fluorescence image guidance was first verified to remove tumors completely and accurately in mouse breast cancer models. Moreover, the rapid incubation imaging method was applied to distinguish benign and malignant breast lesions in samples from 26 patients with breast cancer. Therefore, we have developed both nuclide and optical probes targeting TROP2 for rapid and precise identification of tumor margins during breast-conserving surgery in humans.
Follistatin drives neuropathic pain in mice through IGF1R signaling in nociceptive neurons
Authors: Bao-Chun Jiang, Yue-Juan Ling, Meng-Lin Xu, Jun Gu, Xiao-Bo Wu, Wei-Lin Sha, Tian Tian, Xue-Hui Bai, Nan Li, Chang-Yu Jiang, Ouyang Chen, Ling-Jie Ma, Zhi-Jun Zhang, Yi-Bin Qin, Meixuan Zhu, Hong-Jie Yuan, Long-Jun Wu, Ru-Rong Ji, Yong-Jing Gao
Journal: Science Translational Medicine (2024)

Neuropathic pain is a debilitating chronic condition that lacks effective treatment. The role of cytokine- and chemokine-mediated neuroinflammation in its pathogenesis has been well documented. Follistatin (FST) is a secreted protein known to antagonize the biological activity of cytokines in the transforming growth factor–β (TGF-β) superfamily. The involvement of FST in neuropathic pain and the underlying mechanism remain largely unknown. Here, we report that FST was up-regulated in A-fiber sensory neurons after spinal nerve ligation (SNL) in mice. Inhibition or deletion of FST alleviated neuropathic pain and reduced the nociceptive neuron hyperexcitability induced by SNL. Conversely, intrathecal or intraplantar injection of recombinant FST, or overexpression of FST in the dorsal root ganglion (DRG) neurons, induced pain hypersensitivity. Furthermore, exogenous FST increased neuronal excitability in nociceptive neurons. The biolayer interferometry (BLI) assay and coimmunoprecipitation (co-IP) demonstrated direct binding of FST to the insulin-like growth factor–1 receptor (IGF1R), and IGF1R inhibition reduced FST-induced activation of extracellular signal–regulated kinase (ERK) and protein kinase B (AKT), as well as neuronal hyperexcitability. Further co-IP analysis revealed that the N-terminal domain of FST exhibits the highest affinity for IGF1R, and blocking this interaction with a peptide derived from FST attenuated Nav1.7-mediated neuronal hyperexcitability and neuropathic pain after SNL. In addition, FST enhanced neuronal excitability in human DRG neurons through IGF1R. Collectively, our findings suggest that FST, released from A-fiber neurons, enhances Nav1.7-mediated hyperexcitability of nociceptive neurons by binding to IGF1R, making it a potential target for neuropathic pain treatment.
High-fidelity PAMless base editing of hematopoietic stem cells to treat chronic granulomatous disease
Authors: Vera Bzhilyanskaya, Linyuan Ma, Siyuan Liu, Lauren R. Fox, Madelynn N. Whittaker, Ronald J. Meis, Uimook Choi, Amanda Lawson, Michelle Ma, Narda Theobald, Sandra Burkett, Colin L. Sweeney, Cicera R. Lazzarotto, Shengdar Q. Tsai, Justin B. Lack, Xiaolin Wu, Gary A. Dahl, Harry L. Malech, Benjamin P. Kleinstiver, Suk See De Ravin
Journal: Science Translational Medicine (2024)

X-linked chronic granulomatous disease (X-CGD) is an inborn error of immunity (IEI) resulting from genetic mutations in the cytochrome b-245 beta chain ( CYBB ) gene. The applicability of base editors (BEs) to correct mutations that cause X-CGD is constrained by the requirement of Cas enzymes to recognize specific protospacer adjacent motifs (PAMs). Our recently engineered PAMless Cas enzyme, SpRY, can overcome the PAM limitation. However, the efficiency, specificity, and applicability of SpRY-based BEs to correct mutations in human hematopoietic stem and progenitor cells (HSPCs) have not been thoroughly examined. Here, we demonstrated that the adenine BE ABE8e-SpRY can access a range of target sites in HSPCs to correct mutations causative of X-CGD. For the prototypical X-CGD mutation CYBB c.676C&gt;T, ABE8e-SpRY achieved up to 70% correction, reaching efficiencies greater than three-and-one-half times higher than previous CRISPR nuclease and donor template approaches. We profiled potential off-target DNA edits, transcriptome-wide RNA edits, and chromosomal perturbations in base-edited HSPCs, which together revealed minimal off-target or bystander edits. Edited alleles persisted after transplantation of the base-edited HSPCs into immunodeficient mice. Together, these investigational new drug–enabling studies demonstrated efficient and precise correction of an X-CGD mutation with PAMless BEs, supporting a first-in-human clinical trial (NCT06325709) and providing a potential blueprint for treatment of other IEI mutations.
Melatonin receptor 1A variants as genetic cause of idiopathic osteoporosis
Authors: Brygida Bisikirska, Rossella Labella, Alvaro Cuesta-Dominguez, Na Luo, Jessica De Angelis, Ioanna Mosialou, Chyuan-Sheng Lin, David Beck, Sneh Lata, Peter Timothy Shyu, Donald J. McMahon, Edward Guo, Jacob Hagen, Wendy K. Chung, Elizabeth Shane, Adi Cohen, Stavroula Kousteni
Journal: Science Translational Medicine (2024)

Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A ( MTNR1A ) with a potential pathogenic outcome. A rare MTNR1A variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an MTNR1A variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [ MTNR1A c.184+1G&gt;T ( MTNR1A c. 184+1G&gt;T )] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that MTNR1A mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the MTNR1A variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant.
Exhaled Breath Analysis: from Laboratory Test to Wearable Sensing
Authors: Wenzheng Heng, Shukun Yin, Yonglin Chen, Wei Gao
Journal: IEEE Reviews in Biomedical Engineering (2024)

Breath analysis and monitoring have emerged as pivotal components in both clinical research and daily health management, particularly in addressing the global health challenges posed by respiratory and metabolic disorders. The advancement of breath analysis strategies necessitates a multidisciplinary approach, seamlessly integrating expertise from medicine, biology, engineering, and materials science. Recent innovations in laboratory methodologies and wearable sensing technologies have ushered in an era of precise, real-time, and in situ breath analysis and monitoring. This comprehensive review elucidates the physical and chemical aspects of breath analysis, encompassing respiratory parameters and both volatile and non-volatile constituents. It emphasizes their physiological and clinical significance, while also exploring cutting-edge laboratory testing techniques and state-of-the-art wearable devices. Furthermore, the review delves into the application of sophisticated data processing technologies in the burgeoning field of breathomics and examines the potential of breath control in human-machine interaction paradigms. Additionally, it provides insights into the challenges of translating innovative laboratory and wearable concepts into mainstream clinical and daily practice. Continued innovation and interdisciplinary collaboration will drive progress in breath analysis, potentially revolutionizing personalized medicine through entirely non-invasive breath methodology.
Prioritising primary care patients with unexpected weight loss for cancer investigation: diagnostic accuracy study (update)
Authors: Brian D Nicholson, Pradeep Virdee, Paul Aveyard, Sarah J Price, F D Richard Hobbs, Constantinos Koshiaris, Willie Hamilton
Journal: BMJ (2024)

To quantify the predictive value of unexpected weight loss for cancer according to patient's age, sex, smoking status, and concurrent clinical features (symptoms, signs, and abnormal blood test results).
Ephrin A1 Stimulates CCL2 Secretion to Facilitate Pre-metastatic Niche Formation and Promote Gastric Cancer Liver Metastasis
Authors: Yun Cui, Yongxia Chang, Xixi Ma, Meng Sun, Yuliang Huang, Feng Yang, Shuang Li, Wei Zhuo, Wei Liu, Bo Yang, Aifu Lin, Guangshuo Ou, Yuehong Yang, Shanshan Xie, Tianhua Zhou
Journal: Cancer Research (2024)

Abstract The liver is a primary target for distal metastasis of gastric cancer (GC). The hepatic pre-metastatic niche (PMN) facilitates crucial communications between primary tumor and liver, thereby playing an essential role in hepatic metastasis. Identification of the molecular mechanisms driving PMN formation in GC could facilitate development of strategies to prevent and treat liver metastasis. Here, we uncovered a role for ephrin A1 (EFNA1) signaling in development of the PMN. EFNA1 overexpression in GC cells significantly increased CCL2 secretion through the Hippo-YAP pathway. Secreted CCL2 activated hepatic stellate cells (HStCs) within the hepatic PMN via the WNT/β-catenin pathway. Inhibition of CCL2 significantly suppressed HStC activation and reduced liver metastasis triggered by EFNA1 signaling in GC cells. Moreover, high CCL2 expression correlated with poor survival in GC patients. Overall, these findings reveal that EFNA1 signaling in GC cells upregulates CCL2, which activates HStCs to engender establishment of a hepatic pre-metastatic niche that supports liver metastasis.