tbuckley/cabot-search huggingface dataset:
Fatty acid conjugated EPI-X4 derivatives with increased activity and in vivo stability
Authors: Mirja Harms, André Haase, Armando Rodríguez-Alfonso, Jessica Löffler, Yasser Almeida-Hernández, Yasser B Ruiz-Blanco, Dan Albers, Andrea Gilg, Franziska von Bank, Fabian Zech, Rüdiger Groß, Moumita Datta, Janeni Jaikishan, Bastian Draphoen, Monica Habib, Ludger Ständker, Sebastian Wiese, Mika Lindén, Gordon Winter, Volker Rasche, Ambros J Beer, Hassan Jumaa, Ashraf H Abadi, Frank Kirchhoff, Maike Busch, Nicole Dünker, Elsa Sanchez-Garcia, Jan Münch
Journal: Journal of Controlled Release (2024)

Dysregulation of the CXCL12/CXCR4 axis is implicated in autoimmune, inflammatory, and oncogenic diseases, positioning CXCR4 as a pivotal therapeutic target. We evaluated optimized variants of the specific endogenous CXCR4 antagonist, EPI-X4, addressing existing challenges in stability and potency. Our structure-activity relationship study investigates the conjugation of EPI-X4 derivatives with long-chain fatty acids, enhancing serum albumin interaction and receptor affinity. Molecular dynamic simulations revealed that the lipid moieties stabilize the peptide-receptor interaction through hydrophobic contacts at the receptor's N-terminus, anchoring the lipopeptide within the CXCR4 binding pocket and maintaining essential receptor interactions. Accordingly, lipidation resulted in increased receptor affinities and antagonistic activities. Additionally, by interacting with human serum albumin lipidated EPI-X4 derivatives displayed sustained stability in human plasma and extended circulation times in vivo. Selected candidates showed significant therapeutic potential in human retinoblastoma cells in vitro and in ovo, with our lead derivative exhibiting higher efficacies compared to its non-lipidated counterpart. This study not only elucidates the optimization trajectory for EPI-X4 derivatives but also underscores the intricate interplay between stability and efficacy, crucial for delineating their translational potential in clinical applications.
Adverse events in men with advanced prostate cancer treated with androgen biosynthesis inhibitors and androgen receptor inhibitors
Authors: Kassem S Faraj, Mary Oerline, Samuel R Kaufman, Christopher Dall, Arnav Srivastava, Megan E V Caram, Vahakn B Shahinian, Brent K Hollenbeck
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background The use of androgen biosynthesis and second-generation androgen receptor inhibitors for advanced prostate cancer is increasing. Because these therapies alter the androgen pathway, they have been associated with cardiometabolic and neurocognitive toxicities. Although their safety profiles have been assessed in clinical trials, real-world data are limited. Methods A 20% sample of national Medicare claims was used to perform a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer treated with androgen biosynthesis (ie, abiraterone) and second-generation androgen receptor inhibitors between 2012 and 2019. Outcomes were assessed after the first fill of either class of drug for the 12-month period after starting therapy. The primary outcome was a hospital admission or emergency department visit for a cardiometabolic event. Secondary outcomes included neurocognitive events and fractures. Multivariable regression was used to assess the association between the class of drug and occurrence of an adverse event. Results There were 3488 (60%) men started on an androgen biosynthesis inhibitor and 2361 (40%) started on an androgen receptor inhibitor for the first time. Cardiometabolic adverse events were more common in men managed with androgen biosynthesis inhibitor (9.2% vs 7.5%, P = .027). No difference between androgen biosynthesis and androgen receptor inhibitors was observed for neurocognitive events (3.3% vs 3.4%, respectively; P = .71) or fractures (4.2% vs 3.6%, respectively; P = .26). Conclusions Men with advanced prostate cancer initiating an androgen biosynthesis inhibitor for the first time more commonly had cardiometabolic events than those started on androgen receptor inhibitors. Neurocognitive events and fractures did not differ by drug class.
The RNA binding protein Arid5a drives IL-17–dependent autoantibody-induced glomerulonephritis
Authors: Yang Li, Shachi P. Vyas, Isha Mehta, Nariaki Asada, Ipsita Dey, Tiffany C. Taylor, Rami Bechara, Nilesh Amatya, Felix E.Y. Aggor, Bianca M. Coleman, De-Dong Li, Kenta Yamamoto, Ogechukwu Ezenwa, Yeque Sun, Esta Sterneck, C. Joel McManus, Ulf Panzer, Partha S. Biswas, Ram Savan, Jishnu Das, Sarah L. Gaffen
Journal: The Journal of Experimental Medicine (2024)

Autoantibody-mediated glomerulonephritis (AGN) arises from dysregulated renal inflammation, with urgent need for improved treatments. IL-17 is implicated in AGN and drives pathology in a kidney-intrinsic manner via renal tubular epithelial cells (RTECs). Nonetheless, downstream signaling mechanisms provoking kidney pathology are poorly understood. A noncanonical RNA binding protein (RBP), Arid5a, was upregulated in human and mouse AGN. Arid5a-/- mice were refractory to AGN, with attenuated myeloid infiltration and impaired expression of IL-17-dependent cytokines and transcription factors (C/EBPβ, C/EBPδ). Transcriptome-wide RIP-Seq revealed that Arid5a inducibly interacts with conventional IL-17 target mRNAs, including CEBPB and CEBPD. Unexpectedly, many Arid5a RNA targets corresponded to translational regulation and RNA processing pathways, including rRNAs. Indeed, global protein synthesis was repressed in Arid5a-deficient cells, and C/EBPs were controlled at the level of protein rather than RNA accumulation. IL-17 prompted Arid5a nuclear export and association with 18S rRNA, a 40S ribosome constituent. Accordingly, IL-17-dependent renal autoimmunity is driven by Arid5a at the level of ribosome interactions and translation.
Bioactive nanocomposite hydrogel enhances postoperative immunotherapy and bone reconstruction for osteosarcoma treatment
Authors: Xiangyu Chu, Bobin Mi, Yuan Xiong, Ruinan Wang, Tuozhou Liu, Liangcong Hu, Chenchen Yan, Ruiyin Zeng, Jiali Lin, Hao Fu, Guohui Liu, Kunyu Zhang, Liming Bian
Journal: Biomaterials (2024)
Microenvironment Matters: In Vitro 3D Bone Marrow Niches Differentially Modulate Survival, Phenotype and Drug Responses of Acute Myeloid Leukemia (AML) Cells
Authors: Hoi Lam Cheung, Yu Hin Wong, Yuk Yin Li, Xingxing Yang, Lok Him Ko, Jessica Evangeline Tan Kabigting, Koon Chuen Chan, Anskar Yu Hung Leung, Barbara Pui Chan
Journal: Biomaterials (2024)
Biomedical applications of functional hydrogels: Innovative developments, relevant clinical trials and advanced products
Authors: Katrin Zöller, Dennis To, Andreas Bernkop-Schnürch
Journal: Biomaterials (2024)

Functional hydrogels are used for numerous biomedical applications such as tissue engineering, wound dressings, lubricants, contact lenses and advanced drug delivery systems. Most of them are based on synthetic or natural polymers forming a three-dimensional network that contains aqueous media. Among synthetic polymers, poly(meth)acrylates, polyethyleneglycols, poly(vinylalcohols), poly(vinylpyrrolidones), PLGA and poly(urethanes) are of high relevance, whereas natural polymers are mainly polysaccharides such as hyaluronic acid, alginate or chitosan and proteins such as albumin, collagen or elastin. In contrast to most synthetic polymers, natural polymers are biodegradable. Both synthetic and natural polymers are often chemically modified in order to improve or induce favorable properties and functions like high mechanical strength, stiffness, elasticity, high porosity, adhesive properties, in situ gelling properties, high water binding capacity or drug release controlling properties. Within this review we provide an overview about the broad spectrum of biomedical applications of functional hydrogels, summarize innovative approaches, discuss the concept of relevant functional hydrogels that are in clinical trials and highlight advanced products as examples for successful developments.
Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer
Authors: Weishi Cheng, Kai Kang, Ailin Zhao, Yijun Wu
Journal: Journal of Hematology & Oncology (2024)

Abstract Cancer immunotherapies, represented by immune checkpoint inhibitors (ICIs), have reshaped the treatment paradigm for both advanced non-small cell lung cancer and small cell lung cancer. Programmed death receptor-1/programmed death receptor ligand-1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are some of the most common and promising targets in ICIs. Compared to ICI monotherapy, which occasionally demonstrates treatment resistance and limited efficacy, the dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 operates at different stages of T cell activation with synergistically enhancing immune responses against cancer cells. This emerging dual therapy heralds a new direction for cancer immunotherapy, which, however, may increase the risk of drug-related adverse reactions while improving efficacy. Previous clinical trials have explored combination therapy strategy of anti-PD-1/PD-L1 and anti-CTLA-4 agents in lung cancer, yet its efficacy remains to be unclear with the inevitable incidence of immune-related adverse events. The recent advent of bispecific antibodies has made this sort of dual targeting more feasible, aiming to alleviate toxicity without compromising efficacy. Thus, this review highlights the role of dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in treating lung cancer, and further elucidates its pre-clinical mechanisms and current advancements in clinical trials. Besides, we also provide novel insights into the potential combinations of dual blockade therapies with other strategies to optimize the future treatment mode for lung cancer.
Analogies for modeling belief dynamics
Authors: Henrik Olsson, Mirta Galesic
Journal: Trends in Cognitive Sciences (2024)

Belief dynamics has an important role in shaping our responses to natural and societal phenomena, ranging from climate change and pandemics to immigration and conflicts. Researchers often base their models of belief dynamics on analogies to other systems and processes, such as epidemics or ferromagnetism. Similar to other analogies, analogies for belief dynamics can help scientists notice and study properties of belief systems that they would not have noticed otherwise (conceptual mileage). However, forgetting the origins of an analogy may lead to some less appropriate inferences about belief dynamics (conceptual baggage). Here, we review various analogies for modeling belief dynamics, discuss their mileage and baggage, and offer recommendations for using analogies in model development.
Metabolic Evaluation and Recurrence Prevention for Urinary Stone Patients: An EAU Guidelines Update
Authors: Andreas Skolarikos, Bhaskar Somani, Andreas Neisius, Helene Jung, Alec Petřík, Thomas Tailly, Niall Davis, Lazaros Tzelves, Rob Geraghty, Riccardo Lombardo, Carla Bezuidenhout, Giovanni Gambaro
Journal: European Urology (2024)
Correction: HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases
Authors: Anna Calliari, Lillian M. Daughrity, Ellen A. Albagli, Paula Castellanos Otero, Mei Yue, Karen Jansen-West, Naeyma N. Islam, Thomas Caulfield, Bailey Rawlinson, Michael DeTure, Casey Cook, Neill R. Graff-Radford, Gregory S. Day, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Keith A. Josephs, Björn Oskarsson, Aaron D. Gitler, Dennis W. Dickson, Tania F. Gendron, Mercedes Prudencio, Michael E. Ward, Yong-Jie Zhang, Leonard Petrucelli
Journal: Molecular Neurodegeneration (2024)
Precise targeting of lipid metabolism in the era of immuno-oncology and the latest advances in nano-based drug delivery systems for cancer therapy
Authors: Hongyan Zhang, Yujie Li, Jingyi Huang, Limei Shen, Yang Xiong
Journal: Acta Pharmaceutica Sinica B (2024)

Over the past decade, research has increasingly identified unique dysregulations in lipid metabolism within the tumor microenvironment (TME). Lipids, diverse biomolecules, not only constitute biological membranes but also function as signaling molecules and energy sources. Enhanced synthesis or uptake of lipids in the TME significantly promotes tumorigenesis and proliferation. Moreover, lipids secreted into the TME influence tumor-resident immune cells (TRICs), thereby aiding tumor survival against chemotherapy and immunotherapy. This review aims to highlight recent advancements in understanding lipid metabolism in both tumor cells and TRICs, with a particular emphasis on exogenous lipid uptake and endogenous lipid
Development of a bacteria-nanosapper for the active delivery of ZIF-8 particles containing therapeutic genes for cancer immune therapy
Authors: Yiting Qiao, Miao Luo, Yufei Wang, Haoxiang Qi, Menglan Wang, Yunxin Pei, Mengqing Sun, Zhengguo Zhang, Jiacheng Huang, Pengyu Gong, Shusen Zheng, Jianxiang Chen
Journal: Acta Pharmaceutica Sinica B (2024)

Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment (TME). Some bacteria exhibit spontaneous chemotaxis toward the anaerobic and immune-suppressive TME, which makes them ideal natural vehicles for cancer gene therapy. Here, we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2 (Il2) expression plasmid onto the surface of VNP20009, an attenuated Salmonella typhimurium strain with well-documented anti-cancer activity, and constructed a TME-targeted Il2 delivery system named Il2/ZIF-8@Salmonella. Both in vitro and in vivo experiments demonstrated that Il2/ZIF-8@Salmonella maintained the tumor-targeting feature of bacteria, and could be effectively phagocytosed by intratumoral macrophages, thus leading to the expression and secretion of IL2 in TME. The detailed analysis of tumor immune microenvironment (TIME) showed that one dose of combinatorial Il2/ZIF-8@Salmonella achieved synergistic actions on a potent remodeling of TIME, marked by the activation of cytotoxic T cells and M1-polarization of macrophages in TME, thus leading to significant anti-tumor effects in melanoma, orthotopic hepatocellular carcinoma, and pulmonary metastasis models. More importantly, Il2/ZIF-8@Salmonella exhibited high safety to major organs and hematopoietic systems. Taken together, we report a novel plasmid/ZIF-8@Salmonella system that simultaneously achieves effective TME-targeted delivery of therapeutic gene, as well as synergistic re-activation of TIME.
High-performance Mg–Zn alloy achieved by the ultrafine grain and nanoparticle design
Authors: Wenhui Wang, Xiyue Zhang, Anke Zhang, Han Yu, Xinbao Kang, Cheng Wang, Yang Song, Jiahua Ni, Mikhail L Zheludkevich, Xiaonong Zhang
Journal: Bioactive Materials (2024)

Improving the comprehensive performance of low alloyed Mg is a significant challenge for biomedical applications. This paper developed a high-performance Mg-Zn alloy with uniform ultrafine grains and nano-precipitates through a straightforward, high-temperature reciprocating equal channel angle extrusion (ECAP) process and researched the microstructure, mechanical property, degradation behaviour, and biocompatibility of the developed alloy. Results showed that the lean Mg-2Zn alloy successfully refined grain to about 1 μm and produced plenty of nano-particles with uniform distribution, providing high comprehensive mechanical properties (YS: 235 MPa, UTS: 267 MPa, EL: 15.6 %). Additionally, Zn-riched nano-particles in the matrix could decrease the Zn aggregation at the corrosion layer-matrix interface and form a dense oxide film, achieving a low degradation rate (0.13 mm/year
Expert gaze as a usability indicator of medical AI decision support systems: a preliminary study
Authors: Nora Castner, Lubaina Arsiwala-Scheppach, Sarah Mertens, Joachim Krois, Enkeleda Thaqi, Enkelejda Kasneci, Siegfried Wahl, Falk Schwendicke
Journal: npj Digital Medicine (2024)

Abstract Given the current state of medical artificial intelligence (AI) and perceptions towards it, collaborative systems are becoming the preferred choice for clinical workflows. This work aims to address expert interaction with medical AI support systems to gain insight towards how these systems can be better designed with the user in mind. As eye tracking metrics have been shown to be robust indicators of usability, we employ them for evaluating the usability and user interaction with medical AI support systems. We use expert gaze to assess experts’ interaction with an AI software for caries detection in bitewing x-ray images. We compared standard viewing of bitewing images without AI support versus viewing where AI support could be freely toggled on and off. We found that experts turned the AI on for roughly 25% of the total inspection task, and generally turned it on halfway through the course of the inspection. Gaze behavior showed that when supported by AI, more attention was dedicated to user interface elements related to the AI support, with more frequent transitions from the image itself to these elements. When considering that expert visual strategy is already optimized for fast and effective image inspection, such interruptions in attention can lead to increased time needed for the overall assessment. Gaze analysis provided valuable insights into an AI’s usability for medical image inspection. Further analyses of these tools and how to delineate metrical measures of usability should be developed.
Efficiently directing differentiation and homing of mesenchymal stem cells to boost cartilage repair in osteoarthritis via a nanoparticle and peptide dual-engineering strategy
Authors: Cuixi Wu, Zhenwen Huang, Jianmao Chen, Nan Li, Yu Cai, Jieli Chen, Guangfeng Ruan, Weiyu Han, Changhai Ding, Yao Lu
Journal: Biomaterials (2024)
Deceased donor kidney function and branched chain amino acid metabolism during ex vivo normothermic perfusion
Authors: Armin Ahmadi, Jacquelyn Yu, Jennifer E. Loza, Brian C. Howard, Ivonne Palma, Naeem Goussous, Junichiro Sageshima, Baback Roshanravan, Richard V. Perez
Journal: Kidney International (2024)

Current kidney perfusion protocols are not optimized for addressing the ex vivo physiological and metabolic needs of the kidney. Ex vivo normothermic perfusion may be utilized to distinguish high-risk kidneys to determine suitability for transplantation. Here, we assessed the association of tissue metabolic changes with changes in a kidney injury biomarker and functional parameters in eight deceased donor kidneys deemed unsuitable for transplantation during a 12-hour ex vivo normothermic perfusion. The kidneys were grouped into good and poor performers based on blood flow and urine output. The mean age of the deceased kidney donors was 43 years with an average cold ischemia time of 37 hours. Urine output and creatinine clearance progressively increased and peaked at six hours post-perfusion among good performers. Poor performers had 71 ng/ml greater (95% confidence interval 1.5, 140) urinary neutrophil gelatinase-associated lipocalin at six hours compared to good performers corresponding to peak functional differences. Organ performance was distinguished by tissue metabolic differences in branched chain amino acid metabolism and that their tissue levels negatively correlated with urine output among all kidneys at six hours. Tissue lipid profiling showed poor performers were highlighted by the accumulation of membrane structure components including glycerolipids and sphingolipids at early perfusion time points. Thus, we showed that six hours is needed for kidney function recovery during ex vivo normothermic perfusion and that branched chain amino acid metabolism may be a major determinant of organ function and resilience.
Advances in Meniscus Tissue Engineering: Towards Bridging the Gaps from Bench to Bedside
Authors: Yixin Bian, Xuejie Cai, Runze Zhou, Zehui Lv, Yiming Xu, Yingjie Wang, Han Wang, Wei Zhu, Hanyang Sun, Xiuli Zhao, Bin Feng, Xisheng Weng
Journal: Biomaterials (2024)

Meniscus is vital for maintaining the anatomical and functional integrity of knee. Injuries to meniscus, commonly caused by trauma or degenerative processes, can result in knee joint dysfunction and secondary osteoarthritis, while current conservative and surgical interventions for meniscus injuries bear suboptimal outcomes. In the past decade, there has been a significant focus on advancing meniscus tissue engineering, encompassing isolated scaffold strategies, biological augmentation, physical stimulus, and meniscus organoids, to improve the prognosis of meniscus injuries. Despite noteworthy promising preclinical results, translational gaps and inconsistencies in the therapeutic efficiency between preclinical and clinical studies exist. This review comprehensively outlines the developments in meniscus tissue engineering over the past decade (Scheme 1). Reasons for the discordant results between preclinical and clinical trials, as well as potential strategies to expedite the translation of bench-to-bedside approaches are analyzed and discussed.
EVolution in ALS diagnosis: molecular markers in extracellular vesicles
Authors: Philippe Codron, Stéphanie Millecamps, Philippe Corcia
Journal: Trends in Molecular Medicine (2024)

The identification of biomarkers for amyotrophic lateral sclerosis (ALS) is a central issue in disease research. In a recent article, Chatterjee et al. show that blood extracellular vesicles (EVs) with high levels of transactive response DNA-binding protein 43 (TDP-43) accurately discriminate patients with ALS from controls and correlate with disease severity, providing a promising biomarker for early diagnosis and monitoring.
Disseminated Coccidioidomycosis
Authors: Atif S Siddiqui, Jawairia Shakil
Journal: New England Journal of Medicine (2024)

A 60-year-old man presented with a 4-month history of hemoptysis and painful lumps on his neck. CT of the neck showed supraclavicular abscesses, and CT of the chest showed a cavitary lesion in the left upper lobe.