tbuckley/cabot-search huggingface dataset:
Incretin‐based therapies for the management of cardiometabolic disease in the clinic: Past, present, and future
Authors: James P. Psaltis, Jessica A. Marathe, Mau T. Nguyen, Richard Le, Christina A. Bursill, Chinmay S. Marathe, Adam J. Nelson, Peter J. Psaltis
Journal: Medicinal Research Reviews (2024)

Among newer classes of drugs for type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are incretin-based agents that lower both blood sugar levels and promote weight loss. They do so by activating pancreatic GLP-1 receptors (GLP-1R) to promote glucose-dependent insulin release and inhibit glucagon secretion. They also act on receptors in the brain and gastrointestinal tract to suppress appetite, slow gastric emptying, and delay glucose absorption. Phase 3 clinical trials have shown that GLP-1 RAs improve cardiovascular outcomes in the setting of T2DM or overweight/obesity in people who have, or are at high risk of having atherosclerotic cardiovascular disease. This is largely driven by reductions in ischemic events, although emerging evidence also supports benefits in other cardiovascular conditions, such as heart failure with preserved ejection fraction. The success of GLP-1 RAs has also seen the evolution of other incretin therapies. Tirzepatide has emerged as a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA, with more striking effects on glycemic control and weight reduction than those achieved by isolated GLP-1R agonism alone. This consists of lowering glycated hemoglobin levels by more than 2% and weight loss exceeding 15% from baseline. Here, we review the pharmacological properties of GLP-1 RAs and tirzepatide and discuss their clinical effectiveness for T2DM and overweight/obesity, including their ability to reduce adverse cardiovascular outcomes. We also delve into the mechanistic basis for these cardioprotective effects and consider the next steps in implementing existing and future incretin-based therapies for the broader management of cardiometabolic disease.
Immunoglobulin class‐switch recombination: Mechanism, regulation, and related diseases
Authors: Jia‐Chen Liu, Ke Zhang, Xu Zhang, Fei Guan, Hu Zeng, Masato Kubo, Pamela Lee, Fabio Candotti, Louisa Katherine James, Niels Olsen Saraiva Camara, Kamel Benlagha, Jia‐Hui Lei, Huamei Forsman, Lu Yang, Wei Xiao, Zheng Liu, Chao‐Hong Liu
Journal: MedComm (2024)

Maturation of the secondary antibody repertoire requires class-switch recombination (CSR), which switches IgM to other immunoglobulins (Igs), and somatic hypermutation, which promotes the production of high-affinity antibodies. Following immune response or infection within the body, activation of T cell-dependent and T cell-independent antigens triggers the activation of activation-induced cytidine deaminase, initiating the CSR process. CSR has the capacity to modify the functional properties of antibodies, thereby contributing to the adaptive immune response in the organism. Ig CSR defects, characterized by an abnormal relative frequency of Ig isotypes, represent a rare form of primary immunodeficiency. Elucidating the molecular basis of Ig diversification is essential for a better understanding of diseases related to Ig CSR defects and could provide clues for clinical diagnosis and therapeutic approaches. Here, we review the most recent insights on the diversification of five Ig isotypes and choose several classic diseases, including hyper-IgM syndrome, Waldenström macroglobulinemia, hyper-IgD syndrome, selective IgA deficiency, hyper-IgE syndrome, multiple myeloma, and Burkitt lymphoma, to illustrate the mechanism of Ig CSR deficiency. The investigation into the underlying mechanism of Ig CSR holds significant potential for the advancement of increasingly precise diagnostic and therapeutic approaches.
An IL-7 fusion protein targeting EDA fibronectin upregulates TCF1 on CD8+ T-cells, preferentially accumulates to neoplastic lesions, and boosts PD-1 blockade
Authors: Cesare Di Nitto, Domenico Ravazza, Ettore Gilardoni, Thomas Look, Miaomiao Sun, Eleonora Prodi, Vlad Moisoiu, Christian Pellegrino, Markus G Manz, Emanuele Puca, Michael Weller, Tobias Weiss, Dario Neri, Roberto De Luca
Journal: Journal for ImmunoTherapy of Cancer (2024)

Anti-PD-1 antibodies have revolutionized cancer immunotherapy due to their ability to induce long-lasting complete remissions in a proportion of patients. Current research efforts are attempting to identify biomarkers and suitable combination partners to predict or further improve the activity of immune checkpoint inhibitors. Antibody-cytokine fusions are a class of pharmaceuticals that showed the potential to boost the anticancer properties of other immunotherapies. Extradomain A-fibronectin (EDA-FN), which is expressed in most solid and hematological tumors but is virtually undetectable in healthy adult tissues, is an attractive target for the delivery of cytokine at the site of the disease.
ALOX5 contributes to glioma progression by promoting 5-HETE-mediated immunosuppressive M2 polarization and PD-L1 expression of glioma-associated microglia/macrophages
Authors: Tao Chen, Jiangang Liu, Chenci Wang, Zhengwei Wang, Jiayi Zhou, Jiani Lin, Jie Mao, Tingzheng Pan, Jianwei Wang, Hongchao Xu, Xiaosheng He, Dinglan Wu, Zhuohao Liu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Oxylipin metabolism plays an essential role in glioma progression and immune modulation in the tumor microenvironment. Lipid metabolic reprogramming has been linked to macrophage remodeling, while the understanding of oxylipins and their catalyzed enzymes lipoxygenases in the regulation of glioma-associated microglia/macrophages (GAMs) remains largely unexplored.
Modified Titanium Implants Satisfy the Demands of Diabetic Osseointegration via Sequential Regulation of Macrophages and Mesenchymal Stem Cells
Authors: Bo Ma, Fangye Chen, Xin Liu, Yang Zhang, Shuangquan Gou, Qianxiang Meng, Peng Liu, Kaiyong Cai
Journal: Advanced Healthcare Materials (2024)

Abstract The application of titanium (Ti) implants for patients with diabetes mellitus (DM) is still facing a significant challenge due to obstacles such as hyperglycemia, reactive oxygen species (ROS), and chronic inflammation, which hinders osseointegration. To address this issue, a Ti implant with dual functions of regulating polarization of macrophages and facilitating osseointergration is developed via hydrothermal reaction and hydrogel coating. The reactive oxygen species (ROS) and glucose (Glu) responsive hydrogel coating can locally deliver adenosine (ADO) in the early stage of implantation. The controlled release of ADO regulated the phenotype of macrophages, restored oxidative balance, and enhanced mitochondrial function during the early stages of implantation. Subsequently, strontium (Sr) ions will be released to promote osteogenic differentiation and proliferation of mesenchymal stem cells (MSCs), as the hydrogel coating degraded. It eventually leads to bone reconstruction during the late stages, aligning with the biological cascade of bone healing. The modified Ti implants showed effective osteogenesis for bone defects in DM patients, shedding light on the design and biological mechanisms of surface modification. This research offers promising potential for improving the treatment of bone‐related complications in diabetic patients.
Light‐Controlled Electric Stimulation with Organic Electrolytic Photocapacitors Achieves Complex Neuronal Network Activation: Semi‐Chronic Study in Cortical Cell Culture and Rat Model
Authors: Marta Nowakowska, Marie Jakešová, Tony Schmidt, Aleksandar Opančar, Mathias Polz, Robert Reimer, Julia Fuchs, Silke Patz, Daniel Ziesel, Susanne Scheruebel, Karin Kornmueller, Theresa Rienmüller, Vedran Đerek, Eric D. Głowacki, Rainer Schindl, Muammer Üçal
Journal: Advanced Healthcare Materials (2024)

Abstract Neurostimulation employing photoactive organic semiconductors offers an appealing alternative to conventional techniques, enabling targeted action and wireless control through light. In this study, organic electrolytic photocapacitors (OEPC) are employed to investigate the effects of light‐controlled electric stimulation on neuronal networks in vitro and in vivo. The interactions between the devices and biological systems are characterized. Stimulation of primary rat cortical neurons results in an elevated expression of c‐Fos within a mature neuronal network. OEPC implantation for three weeks and subsequent stimulation of the somatosensory cortex leads to an increase of c‐Fos in neurons at the stimulation site and in connected brain regions (entorhinal cortex, hippocampus), both in the ipsi‐ and contralateral hemispheres. Reactivity of glial and immune cells after semi‐chronic implantation of OEPC in the rat brain is comparable to that of surgical controls, indicating minimal foreign body response. Device functionality is further substantiated through retained charging dynamics following explantation. OEPC‐based, light‐controlled electric stimulation has a significant impact on neural responsiveness. The absence of detrimental effects on both the brain and device encourages further use of OEPC as cortical implants. These findings highlight its potential as a novel mode of neurostimulation and instigate further exploration into applications in fundamental neuroscience.
Tribovoltaic Effect Strengthened Microwave Catalytic Antibacterial Composite Hydrogel
Authors: Qiyao Zheng, Xiangmei Liu, Congyang Mao, Hanpeng Liu, Liguo Jin, Chaofeng Wang, Shengli Zhu, Yufeng Zheng, Zhaoyang Li, Hui Jiang, Zhenduo Cui, Yu Zhang, Paul K Chu, Shuilin Wu
Journal: Advanced Healthcare Materials (2024)

Abstract Microwave (MW) therapy is an emerging therapy with high efficiency and deep penetration to combat the crisis of bacterial resistance. However, as the energy of MW is too low to induce electron transition, the mechanism of MW catalytic effect remains ambiguous. Herein, a cerium‐based metal–organic framework (MOF) is fabricated and used in MW therapy. The MW‐catalytic performance of CeTCPP is largely dependent on the ions in the liquid environment, and the electron transition is achieved through a “tribovoltaic effect” between water molecules and CeTCPP. By this way, CeTCPP can generate reactive oxygen species (ROS) in saline under pulsed MW irradiation, showing 99.9995 ± 0.0002% antibacterial ratio against Staphylococcus aureus ( S. aureus ) upon two cycles of MW irradiation. Bacterial metabolomics further demonstrates that the diffusion of ROS into bacteria led to the bacterial metabolic disorders. The bacteria are finally killed due to “amino acid starvation”. In order to improve the applicability of CeTCPP, It is incorporated into alginate‐based hydrogel, which maintains good MW catalytic antibacterial efficiency and also good biocompatibility. Therefore, this work provides a comprehensive instruction of using CeTCPP in MW therapy, from mechanism to application. This work also provides new perspectives for the design of antibacterial composite hydrogel.
The Cost of Inflammatory Bowel Disease Care – How to Make it Sustainable
Authors: Johan Burisch, Jennifer Claytor, Inmaculada Hernandez, Jason Ken Hou, Gilaad G. Kaplan
Journal: Clinical Gastroenterology and Hepatology (2024)

The rising global prevalence of inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, underscores the need to examine current and future IBD care costs. Direct health care expenses, including ambulatory visits, hospitalizations, and medications, are substantial, averaging $9,000 to $12,000 per person annually in high-income regions. However, these estimates do not fully account for factors such as disease severity, accessibility, and variability in health care infrastructure among regions. Indirect costs, predominantly stemming from loss in productivity due to absenteeism, presenteeism, and other intangible costs, further contribute to the financial burden of IBD. Despite efforts to quantify indirect costs, many aspects remain poorly understood, leading to an underestimation of their actual impact. Challenges to achieving cost sustainability include disparities in access, treatment affordability, and the absence of standardized cost-effective care guidelines. Strategies for making IBD care sustainable include early implementation of biologic therapies, focusing on cost-effectiveness in settings with limited resources, and promoting the uptake of biosimilars to reduce direct costs. Multidisciplinary care teams leveraging technology and patient-reported outcomes also hold promise in reducing both direct and indirect costs associated with IBD. Addressing the increasing financial burden of IBD requires a comprehensive approach that tackles disparities, enhances access to cost-effective therapeutics, and promotes collaborative efforts across health care systems. Embracing innovative strategies can pave the way for personalized, cost-effective care accessible to all individuals with IBD, ensuring better outcomes and sustainability.
Dupilumab response onset, maintenance, and durability in patients with severe CRSwNP
Authors: Claus Bachert, Asif H. Khan, Wytske J. Fokkens, Claire Hopkins, Philippe Gevaert, Joseph K. Han, Peter W. Hellings, Stella E. Lee, Jérôme Msihid, Scott Nash, Harry Sacks, Juby A. Jacob-Nara, Yamo Deniz, Paul J. Rowe
Journal: Journal of Allergy and Clinical Immunology (2024)
DNA liquid biopsy-based prediction of cancer-associated venous thromboembolism
Authors: Justin Jee, A. Rose Brannon, Rohan Singh, Andriy Derkach, Christopher Fong, Adrian Lee, Lauren Gray, Karl Pichotta, Anisha Luthra, Monica Diosdado, Mohammad Haque, Jiannan Guo, Jennifer Hernandez, Kavita Garg, Clare Wilhelm, Maria E. Arcila, Nick Pavlakis, Stephen Clarke, Sohrab P. Shah, Pedram Razavi, Jorge S. Reis-Filho, Marc Ladanyi, Nikolaus Schultz, Jeffrey Zwicker, Michael F. Berger, Bob T. Li, Simon Mantha
Journal: Nature Medicine (2024)

Cancer-associated venous thromboembolism (VTE) is a major source of oncologic cost, morbidity and mortality. Identifying high-risk patients for prophylactic anticoagulation is challenging and adds to clinician burden. Circulating tumor DNA (ctDNA) sequencing assays ('liquid biopsies') are widely implemented, but their utility for VTE prognostication is unknown. Here we analyzed three plasma sequencing cohorts: a pan-cancer discovery cohort of 4,141 patients with non-small cell lung cancer (NSCLC) or breast, pancreatic and other cancers; a prospective validation cohort consisting of 1,426 patients with the same cancer types; and an international generalizability cohort of 463 patients with advanced NSCLC. ctDNA detection was associated with VTE independent of clinical and radiographic features. A machine learning model trained on liquid biopsy data outperformed previous risk scores (discovery, validation and generalizability c-indices 0.74, 0.73 and 0.67, respectively, versus 0.57, 0.61 and 0.54 for the Khorana score). In real-world data, anticoagulation was associated with lower VTE rates if ctDNA was detected (n = 2,522, adjusted hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.30–0.81); ctDNA− patients (n = 1,619) did not benefit from anticoagulation (adjusted HR = 0.89, 95% CI: 0.40–2.0). These results provide preliminary evidence that liquid biopsies may improve VTE risk stratification in addition to clinical parameters. Interventional, randomized prospective studies are needed to confirm the clinical utility of liquid biopsies for guiding anticoagulation in patients with cancer. An analysis of three multi-cancer cohorts shows that the detection of ctDNA using liquid biopsies has the potential to improve the risk prediction of cancer-associated venous thromboembolism.
Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD
Authors: Jonathan E. Knikman, Qinglian Zhai, Carin A. T. C. Lunenburg, Linda M. Henricks, Stefan Böhringer, Maaike van der Lee, Femke M. de Man, Steven M. Offer, Shikshya Shrestha, Geert-Jan Creemers, Arnold Baars, Vincent O. Dezentjé, Alexander L. T. Imholz, Frank J. F. Jeurissen, Johanna E. A. Portielje, Rob L. H. Jansen, Paul Hamberg, Helga J. Droogendijk, Miriam Koopman, Peter Nieboer, Marlène H. W. van de Poel, Caroline M. P. W. Mandigers, Ron H. N. van Schaik, Hans Gelderblom, Ron H. J. Mathijssen, Jan H. M. Schellens, Annemieke Cats, Henk-Jan Guchelaar, Jesse J. Swen
Journal: Genome Medicine (2024)

Abstract Background The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD ( DPYD *2A/rs3918290, c.1236G &gt; A/rs75017182, c.2846A &gt; T/rs67376798 and c.1679 T &gt; G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD , that may contribute to fluoropyrimidine toxicity. Methods Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD . In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD . Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS. Results Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C &gt; T, c.1913 T &gt; C, c.1925 T &gt; C, c.506delC, c.731A &gt; C, c.1740 + 1G &gt; T, c.763 − 2A &gt; G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41–11.3, P = 0.388) increased risk of severe toxicity compared to matched controls ( N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance ( P ≤ 5 × 10 −8 ), however, five variants were suggestive of association ( P &lt; 5 × 10 −6 ) with severe toxicity. Conclusions Results from DPYD exon sequencing and GWAS analysis did not identify additional genetic variants associated with severe toxicity, which suggests that testing for single markers at a population level currently has limited clinical value. Identifying additional variants on an individual level is still promising to explain fluoropyrimidine-related severe toxicity. In addition, studies with larger samples sizes, in more diverse cohorts are needed to identify potential clinically relevant genetic variants related to severe fluoropyrimidine toxicity.
Central regulation of feeding and body weight by ciliary GPR75
Authors: Yiao Jiang, Yu Xun, Zhao Zhang
Journal: Journal of Clinical Investigation (2024)

Variants of the G protein-coupled receptor 75 (GPR75) are associated with a lower BMI in large-scale human exome-sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Using random germline mutagenesis in mice, we identified a missense allele (Thinner) of Gpr75 that resulted in a lean phenotype and verified the decreased body weight and fat weight in Gpr75-knockout (Gpr75-/-) mice. Gpr75-/- mice displayed reduced food intake under high-fat diet (HFD) feeding, and pair-feeding normalized their body weight. The endogenous GPR75 protein was exclusively expressed in the brains of 3xFlag-tagged Gpr75-knockin (3xFlag-Gpr75) mice, with consistent expression across different brain regions. GPR75 interacted with Gαq to activate various signaling pathways after HFD feeding. Additionally, GPR75 was localized in the primary cilia of hypothalamic cells, whereas the Thinner mutation (L144P) and human GPR75 variants in individuals with a lower BMI failed to localize in the cilia. Loss of GPR75 selectively inhibited weight gain in HFD-fed mice but failed to suppress the development of obesity in leptin ob-mutant (Lepob-mutant) mice and adenylate cyclase 3-mutant (Adcy3-mutant) mice on a chow diet. Our data reveal that GPR75 is a ciliary protein expressed in the brain and plays an important role in regulating food intake.
SegVir: Reconstruction of complete segmented RNA viral genomes from metatranscriptomes
Authors: Xubo Tang, Jiayu Shang, Guowei Chen, Kei Hang Katie Chan, Mang Shi, Yanni Sun
Journal: Molecular Biology and Evolution (2024)

Segmented RNA viruses are a complex group of RNA viruses with multisegment genomes. Reconstructing complete segmented viruses is crucial for advancing our understanding of viral diversity, evolution, and public health impact. Using metatranscriptomic data to identify known and novel segmented viruses has sped up the survey of segmented viruses in various ecosystems. However, the high genetic diversity and the difficulty in binning complete segmented genomes present significant challenges in segmented virus reconstruction. Current virus detection tools are primarily used to identify nonsegmented viral genomes. This study presents SegVir, a novel tool designed to identify segmented RNA viruses and reconstruct their complete genomes from complex metatranscriptomes. SegVir leverages both close and remote homology searches to accurately detect conserved and divergent viral segments. Additionally, we introduce a new method that can evaluate the genome completeness and conservation based on gene content. Our evaluations on simulated datasets demonstrate SegVir's superior sensitivity and precision compared to existing tools. Moreover, in experiments using real data, we identified some virus segments missing in the NCBI database, underscoring SegVir's potential to enhance viral metagenome analysis. The source code and supporting data of SegVir are available via https://github.com/HubertTang/SegVir.
Developing fibrin-based biomaterials/scaffolds in tissue engineering
Authors: Songjie Li, Xin Dan, Han Chen, Tong Li, Bo Liu, Yikun Ju, Yang Li, Lanjie Lei, Xing Fan
Journal: Bioactive Materials (2024)

Tissue engineering technology has advanced rapidly in recent years, offering opportunities to construct biologically active tissues or organ substitutes to repair or even enhance the functions of diseased tissues and organs. Tissue-engineered scaffolds rebuild the extracellular microenvironment by mimicking the extracellular matrix. Fibrin-based scaffolds possess numerous advantages, including hemostasis, high biocompatibility, and good degradability. Fibrin scaffolds provide an initial matrix that facilitates cell migration, differentiation, proliferation, and adhesion, and also play a critical role in cell-matrix interactions. Fibrin scaffolds are now widely recognized as a key component in tissue engineering, where they can facilitate tissue and organ defect repair. This review introduces the properties of fibrin, including its composition, structure, and biology. In addition, the modification and cross-linking modes of fibrin are discussed, along with various forms commonly used in tissue engineering. We also describe the biofunctionalization of fibrin. This review provides a detailed overview of the use and applications of fibrin in skin, bone, and nervous tissues, and provides novel insights into future research directions for clinical treatment.