tbuckley/cabot-search huggingface dataset:
Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer’s disease
Authors: Hyo Jung Shin, In Soo Kim, Seung Gyu Choi, Kayoung Lee, Hyewon Park, Juhee Shin, Dayoung Kim, Jaewon Beom, Yoon Young Yi, Deepak Prasad Gupta, Gyun Jee Song, Won-Suk Chung, C. Justin Lee, Dong Woon Kim
Journal: Molecular Neurodegeneration (2024)

Abstract Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer’s disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16 ink4a ), a cell cycle factor related to aging. We found that p16 ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic- co -glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16 ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16 ink4a in microglia is a promising strategy for the treatment of Alzheimer’s disease.
Acidic/hypoxia dual-alleviated nanoregulators for enhanced treatment of tumor chemo-immunotherapy
Authors: Xiaoju Guo, Xiaoxiao Chen, Jiayi Ding, Feng Zhang, Shunyang Chen, Xin Hu, Shiji Fang, Lin Shen, Chenying Lu, Zhongwei Zhao, Jianfei Tu, Gaofeng Shu, Minjiang Chen, Jiansong Ji
Journal: Asian Journal of Pharmaceutical Sciences (2024)

Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.
Overcoming neutrophil-induced immunosuppression in postoperative cancer therapy: Combined sialic acid-modified liposomes with scaffold-based vaccines
Authors: Cong Li, Lihong Wang, Kexin Zhang, Zeyu Wang, Zhihang Li, Zehao Li, Lijiang Chen
Journal: Asian Journal of Pharmaceutical Sciences (2024)

Immunotherapy is a promising approach for preventing postoperative tumor recurrence and metastasis. However, inflammatory neutrophils, recruited to the postoperative tumor site, have been shown to exacerbate tumor regeneration and limit the efficacy of cancer vaccines. Consequently, addressing postoperative immunosuppression caused by neutrophils is crucial for improving treatment outcomes. This study presents a combined chemoimmunotherapeutic strategy that employs a biocompatible macroporous scaffold-based cancer vaccine (S-CV) and a sialic acid (SA)-modified, doxorubicin (DOX)-loaded liposomal platform (DOX@SAL). The S-CV contains whole tumor lysates as antigens and imiquimod (R837, Toll-like receptor 7 activator)-loaded PLGA nanoparticles as immune adjuvants for cancer, which enhance dendritic cell activation and cytotoxic T cell proliferation upon localized implantation. When administered intravenously, DOX@SAL specifically targets and delivers drugs to activated neutrophils in vivo, mitigating neutrophil infiltration and suppressing postoperative inflammatory responses. In vivo and vitro experiments have demonstrated that S-CV plus DOX@SAL, a combined chemo-immunotherapeutic strategy, has a remarkable potential to inhibit postoperative local tumor recurrence and distant tumor progression, with minimal systemic toxicity, providing a new concept for postoperative treatment of tumors.
CellViT: Vision Transformers for precise cell segmentation and classification
Authors: Fabian Hörst, Moritz Rempe, Lukas Heine, Constantin Seibold, Julius Keyl, Giulia Baldini, Selma Ugurel, Jens Siveke, Barbara Grünwald, Jan Egger, Jens Kleesiek
Journal: Medical Image Analysis (2024)

Nuclei detection and segmentation in hematoxylin and eosin-stained (H&E) tissue images are important clinical tasks and crucial for a wide range of applications. However, it is a challenging task due to nuclei variances in staining and size, overlapping boundaries, and nuclei clustering. While convolutional neural networks have been extensively used for this task, we explore the potential of Transformer-based networks in combination with large scale pre-training in this domain. Therefore, we introduce a new method for automated instance segmentation of cell nuclei in digitized tissue samples using a deep learning architecture based on Vision Transformer called CellViT. CellViT is trained and evaluated on the PanNuke dataset, which is one of the most challenging nuclei instance segmentation datasets, consisting of nearly 200,000 annotated nuclei into 5 clinically important classes in 19 tissue types. We demonstrate the superiority of large-scale in-domain and out-of-domain pre-trained Vision Transformers by leveraging the recently published Segment Anything Model and a ViT-encoder pre-trained on 104 million histological image patches - achieving state-of-the-art nuclei detection and instance segmentation performance on the PanNuke dataset with a mean panoptic quality of 0.50 and an F
Sodium–glucose cotransporter 2 inhibitors for transthyretin amyloid cardiomyopathy: Analyses of short‐term efficacy and safety
Authors: Frederick M. Lang, Sergio Teruya, Ariel Weinsaft, Margaret Cuomo, Alfonsina Mirabal Santos, Ani Nalbandian, Dimitrios Bampatsias, Mathew S. Maurer
Journal: European Journal of Heart Failure (2024)
The m6A modification mediated-lncRNA POU6F2-AS1 reprograms fatty acid metabolism and facilitates the growth of colorectal cancer via upregulation of FASN
Authors: Tao Jiang, Junwen Qi, Zhenyu Xue, Bowen Liu, Jianquan Liu, Qihang Hu, Yuqiu Li, Jing Ren, Hu Song, Yixin Xu, Teng Xu, Ruizhi Fan, Jun Song
Journal: Molecular Cancer (2024)

Abstract Background Long noncoding RNAs (lncRNAs) have emerged as key players in tumorigenesis and tumour progression. However, the biological functions and potential mechanisms of lncRNAs in colorectal cancer (CRC) are unclear. Methods The novel lncRNA POU6F2-AS1 was identified through bioinformatics analysis, and its expression in CRC patients was verified via qRT–PCR and FISH. In vitro and in vivo experiments, such as BODIPY staining, Oil Red O staining, triglyceride (TAG) assays, and liquid chromatography mass spectrometry (LC-MS) were subsequently performed with CRC specimens and cells to determine the clinical significance, and functional roles of POU6F2-AS1. Biotinylated RNA pull-down, RIP, Me-RIP, ChIP, and patient-derived organoid (PDO) culture assays were performed to confirm the underlying mechanism of POU6F2-AS1. Results The lncRNA POU6F2-AS1 is markedly upregulated in CRC and associated with adverse clinicopathological features and poor overall survival in CRC patients. Functionally, POU6F2-AS1 promotes the growth and lipogenesis of CRC cells both in vitro and in vivo. Mechanistically, METTL3-induced m 6 A modification is involved in the upregulation of POU6F2-AS1. Furthermore, upregulated POU6F2-AS1 could tether YBX1 to the FASN promoter to induce transcriptional activation, thus facilitating the growth and lipogenesis of CRC cells. Conclusions Our data revealed that the upregulation of POU6F2-AS1 plays a critical role in CRC fatty acid metabolism and might provide a novel promising biomarker and therapeutic target for CRC.
Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects
Authors: Yufei Wang, Alicia Buck, Brandon Piel, Luann Zerefa, Nithyassree Murugan, Christian D. Coherd, Andras G. Miklosi, Haraman Johal, Ricardo Nunes Bastos, Kun Huang, Miriam Ficial, Yasmin Nabil Laimon, Sabina Signoretti, Zhou Zhong, Song-My Hoang, Gabriella M. Kastrunes, Marion Grimaud, Atef Fayed, Hsien-Chi Yuan, Quang-De Nguyen, Tran Thai, Elena V. Ivanova, Cloud P. Paweletz, Ming-Ru Wu, Toni K. Choueiri, Jon O. Wee, Gordon J. Freeman, David A. Barbie, Wayne A. Marasco
Journal: Molecular Cancer (2024)

One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues. A Tet-On doxycycline-inducible CAIX expressing cell line was established to mimic various CAIX densities, providing coverage from CAIX-high skrc-59 tumor cells to CAIX-low MMNK-1 cholangiocytes. Assessing the killing of CAR-T cells, we demonstrated that low-affinity/high-avidity fine-tuned G9 CAR-T has a wider therapeutic window compared to high-affinity/high-avidity G250 that was used in the first anti-CAIX CAR-T clinical trial but displayed serious OTOT effects. To assess the therapeutic effect of G9 on patient samples, we generated ccRCC patient derived organotypic tumor spheroid (PDOTS) ex vivo cultures and demonstrated that G9 CAR-T cells exhibited superior efficacy, migration and cytokine release in these miniature tumors. Moreover, in an RCC orthotopic mouse model, G9 CAR-T cells showed enhanced tumor control compared to G250. In summary, G9 has successfully mitigated OTOT side effects and in doing so has made CAIX a druggable immunotherapeutic target.
Hierarchically Biomimetic Scaffolds with Anisotropic Micropores and Nanotopological Patterns to Promote Bone Regeneration via Geometric Modulation
Authors: Xin Wei, Jiaxin Chen, Hui‐Yuan Shen, Kai Jiang, Haohao Ren, Yao Liu, En Luo, Jin Zhang, Jia‐Zhuang Xu, Zhong‐Ming Li
Journal: Advanced Healthcare Materials (2024)

Structural engineering is an appealing means to modulate osteogenesis without the intervention of exogenous cells or therapeutic agents. In this work, a novel 3D scaffold with anisotropic micropores and nanotopographical patterns is developed. Scaffolds with oriented pores are fabricated via the selective extraction of water-soluble polyethylene oxide from its poly(ε-caprolactone) co-continuous mixture and uniaxial stretching. The plate apatite-like lamellae are subsequently hatched on the pore walls through surface-induced epitaxial crystallization. Such a unique geometric architecture yields a synergistic effect on the osteogenic capability. The prepared scaffold leads to a 19.2% and 128.0% increase in the alkaline phosphatase activity of rat bone mesenchymal stem cells compared to that of the scaffolds with only oriented pores and only nanotopographical patterns, respectively. It also induces the greatest upregulation of osteogenic-related gene expression in vitro. The cranial defect repair results demonstrate that the prepared scaffold effectively promotes new bone regeneration, as indicated by a 350% increase in collagen I expression in vivo compared to the isotropic porous scaffold without surface nanotopology after implantation for 14 weeks. Overall, this work provides geometric motifs for the transduction of biophysical cues in 3D porous scaffolds, which is a promising option for tissue engineering applications.
Robust Gradient Hydrogel‐Loaded Nanofiber Fleshy Artificial Skin Via A Coupled Microfluidic Electrospinning‐Reactive Coating Strategy
Authors: Qing Li, Rong Chen, Tingting Cui, Yuting Bai, Jie Hu, Jiafei Yu, Gefei Wang, Su Chen
Journal: Advanced Healthcare Materials (2024)

Skin regeneration attracts tremendous interest due to the important role of skin for human protection and beauty. Thus, methods allowing artificial skin to be carried out in a controllable fashion are potentially important for wound healing, which involves an intersection of materials, medicine, biology, and other disciplines. Herein, aiming at a new general methodology for fleshy materials, a new hydrogel-loaded hydrophobic-hydrophilic nanofiber fleshy artificial skin is designed and fabricated. The gradient hydrogel-loaded nanofiber artificial skin integrates both advantages of nanofiber and hydrogel, exhibiting fleshy feature (comparability to real skin in terms of appearance, texture, and function), excellent air permeability, compatibility, and good mechanical and antibacterial property. Interestingly, the efficient transport channels are formed throughout the hydrogel-loaded nanofiber structure, which is beneficial for water absorption and transfer. These advantages enable the establishment of a moist and favorable microenvironment; thus, greatly accelerating wound healing process. This work couples microfluidic electrospinning with reactive coating technique, which is in favor of material design and fabrication with controllable and uniform structures. The hydrogel-loaded nanofiber fleshy artificial skin shows comparability to real skin in terms of beauty, texture, and function, which would definitely provide new opportunities for the further optimization and upgrading of artificial skin.
Favorable outcome of non‐myeloablative allogeneic <scp>transplantation</scp> in adult patients with severe sickle cell disease: A single center experience of 200 patients
Authors: Moussab Damlaj, Bader Alahmari, Ahmed Alaskar, Ayman Alhejazi, Husam Alsadi, Mazin Ahmed, Tahani Alanazi, Rasha Ahmed, Amani Alharbi, Inaam Shehabeddine, Afnan Alzaidi, Suha Alkhuraisat, Isam Mahassnah, Hamza Alquraan, Maybelle Ballili, Mohsen Alzahrani
Journal: American Journal of Hematology (2024)

Abstract Allogeneic hematopoietic stem cell transplant (HSCT) for adults with severe sickle cell disease (SCD) is potentially curative but not commonly utilized therapy due to complications such as graft failure (GF) and organ toxicity. Herein, we are reporting our long‐term outcome data of non‐myeloablative (NMA) HSCT in adults with severe SCD with emphasis on factors predicting event free survival (EFS). Adults with severe SCD undergoing NMA match‐related donor allogeneic HSCT from 2015 to 2021 with at least 12 months of follow‐up were included. A total of 200 patients were included with a median age of 26 years (14–43) and 56% were male. The median infused CD34 dose was 13.7 (5.07–25.8), respectively. Median absolute neutrophil count engraftment was 19 (13–39) days with 51% of patients receiving GCSF to expedite recovery. A total of 17 patients experienced GF; 3 as primary and 14 as secondary within a median time of 204 days (40–905). A 76% successfully discontinued sirolimus at the last follow‐up. Median follow‐up for the cohort is 29.2 (2.1–71.4) months. Estimated 3‐year EFS and OS were 88.2% (81.9–92.5) and 94.6% (89.2–97.3). At multivariable analysis, minor ABC incompatibility hazard ratio (HR) 4 (1.3–12.1; 0.014) and allo‐antibody against non‐ABO donor antigens HR 4.3 (1.3–14.1; 0.016) were significant for EFS. No clonal evolution or myeloid malignancies were seen. This largest single‐center report of NMA HSCT in adults with severe SCD further delineated its feasibility, potential toxicities, and fertility outcomes. GF remains a major impediment and appears dependent on ABO matching and non‐ABO antibodies.
The H<sub>2</sub>O<sub>2</sub> Self‐Sufficient 3D Printed β‐TCP Scaffolds with Synergistic Anti‐Tumor Effect and Reinforced Osseointegration
Authors: Qing Wang, Chingyen Chiu, Hang Zhang, Xuan Wang, Yanzheng Chen, Xiang Li, Jinsong Pan
Journal: Advanced Healthcare Materials (2024)

Tumor recurrence and massive bone defects are two critical challenges for postoperative treatment of oral and maxillofacial tumor, posing serious threats to the health of patients. Herein, in order to eliminate residual tumor cells and promote osteogenesis simultaneously, the hydrogen peroxide (H
Characterising user engagement with mHealth for chronic disease self-management and impact on machine learning performance
Authors: Christopher Duckworth, Bethany Cliffe, Brian Pickering, Ben Ainsworth, Alison Blythin, Adam Kirk, Thomas M. A. Wilkinson, Michael J. Boniface
Journal: npj Digital Medicine (2024)

Abstract Mobile Health (mHealth) has the potential to be transformative in the management of chronic conditions. Machine learning can leverage self-reported data collected with apps to predict periods of increased health risk, alert users, and signpost interventions. Despite this, mHealth must balance the treatment burden of frequent self-reporting and predictive performance and safety. Here we report how user engagement with a widely used and clinically validated mHealth app, myCOPD (designed for the self-management of Chronic Obstructive Pulmonary Disease), directly impacts the performance of a machine learning model predicting an acute worsening of condition (i.e., exacerbations). We classify how users typically engage with myCOPD, finding that 60.3% of users engage frequently, however, less frequent users can show transitional engagement (18.4%), becoming more engaged immediately ( &lt; 21 days) before exacerbating. Machine learning performed better for users who engaged the most, however, this performance decrease can be mostly offset for less frequent users who engage more near exacerbation. We conduct interviews and focus groups with myCOPD users, highlighting digital diaries and disease acuity as key factors for engagement. Users of mHealth can feel overburdened when self-reporting data necessary for predictive modelling and confidence of recognising exacerbations is a significant barrier to accurate self-reported data. We demonstrate that users of mHealth should be encouraged to engage when they notice changes to their condition (rather than clinically defined symptoms) to achieve data that is still predictive for machine learning, while reducing the likelihood of disengagement through desensitisation.
Relative Energy Deficiency in Sport (REDs): Endocrine Manifestations, Pathophysiology and Treatments
Authors: Angeliki M Angelidi, Konstantinos Stefanakis, Sharon H Chou, Laura Valenzuela-Vallejo, Konstantina Dipla, Chrysoula Boutari, Konstantinos Ntoskas, Panagiotis Tokmakidis, Alexander Kokkinos, Dimitrios G Goulis, Helen A Papadaki, Christos S Mantzoros
Journal: Endocrine Reviews (2024)

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on nonpharmacological, behavioral, and lifestyle modifications that target its underlying cause-energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance.
Five-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study
Authors: Xiu Juan Zhang, Yuzhou Zhang, Benjamin H.K. Yip, Ka Wai Kam, Fangyao Tang, Xiangtian Ling, Mandy P.H. Ng, Alvin L. Young, Pei-Chang Wu, Clement C. Tham, Li Jia Chen, Chi Pui Pang, Jason C. Yam
Journal: Ophthalmology (2024)
Tumor immune escape by autotaxin: keeping eosinophils at bay
Authors: Elisa Matas-Rico, Wouter H. Moolenaar
Journal: Trends in cancer (2024)

Secreted autotaxin (ATX) promotes tumor progression by producing the pleiotropic lipid mediator lysophosphatidic acid (LPA). In a recent Nature Cancer paper, Bhattacharyya et al. show that ATX/LPA signaling suppresses CCL11-driven infiltration of eosinophils into the pancreatic tumor microenvironment to facilitate tumor progression, thus revealing a new ATX-mediated immune escape mechanism and highlighting the antitumor potential of eosinophils.
Does Overgrading on Targeted Biopsy of Magnetic Resonance Imaging-visible Lesions in Prostate Cancer Lead to Overtreatment?
Authors: Michael Baboudjian, Romain Diamand, Alessandro Uleri, Jean-Baptiste Beauval, Alae Touzani, Jean-Baptiste Roche, Vito Lacetera, Thierry Roumeguère, Giuseppe Simone, Daniel Benamran, Alexandre Fourcade, Bastien Gondran-Tellier, Gaelle Fiard, Alexandre Peltier, Guillaume Ploussard
Journal: European Urology (2024)
Systemic and Tumor-directed Therapy for Oligorecurrent Metastatic Prostate Cancer (SATURN): Primary Endpoint Results from a Phase 2 Clinical Trial
Authors: John Nikitas, Matthew Rettig, John Shen, Robert Reiter, Alan Lee, Michael L. Steinberg, Luca F. Valle, Ankush Sachdeva, Tahmineh Romero, Jeremie Calais, Johannes Czernin, Nicholas G. Nickols, Amar U. Kishan
Journal: European Urology (2024)