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Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer immunotherapy and have enhanced the survival of patients with malignant tumors. However, the overall efficacy of ICIs remains unsatisfactory and is faced with two major concerns of resistance development and occurrence of immune-related adverse events (irAEs). Bispecific antibodies (bsAbs) have emerged as promising strategies with unique mechanisms of action to achieve a better efficacy and safety than monoclonal antibodies (mAbs) or even their combination. BsAbs along with other bispecific platforms such as bispecific fusion proteins, nanobodies, and CAR-T cells may help to avoid development of resistance and reduce irAEs caused by on-target/off-tumor binding effects of mAbs., Areas Covered: A literature search was performed using PubMed for English-language articles to provide a comprehensive overview of preclinical and clinical studies on bsAbs specified for both immune checkpoints and non-checkpoint molecules as a well-enhanced class of therapeutics., Expert Opinion: Identifying suitable targets and selecting effective engineering platforms enhance the potential of bsAbs to address the challenges associated with conventional therapies such as ICIs, positioning them as a promising class of therapeutics in the landscape of cancer immunotherapy.

Platelet-derived growth factors (PDGFs) ligands and their corresponding receptors, PDGF receptor (PDGFR)α and PDGFRβ, play a crucial role in controlling diverse biological functions, including cell growth, viability and migration. These growth factors bind to PDGFRs, which are receptor tyrosine kinases present on the surface of target cells. The interaction between PDGFs and PDGFRs induces receptor dimerization and subsequent activation through auto-phosphorylation, which in turn triggers a cascade of intracellular signaling pathways. PDGF/PDGFR signaling is essential for maintaining normal physiological functions, including tissue regeneration and growth. However, dysregulation of this signaling pathway leads to pathological conditions, including fibrosis, atherosclerosis, and cancer development in various organs. The pathological impact of PDGF/PDGFR signaling primarily stems from its capacity to promote excessive cell proliferation, enhanced migration, and increased extracellular matrix deposition, resulting in tissue overgrowth, scarring, and abnormal vessel formation. These processes are integral to the pathogenesis of fibrotic, neoplastic, and vascular disorders. Therefore, understanding these pathways is crucial for developing targeted treatments designed to inhibit PDGF/PDGFR signaling in these diseases. This review delves into the dual role of PDGF/PDGFR signaling in both physiological and pathophysiological contexts across different organs and provides insights into current pharmacological therapies designed to target the PDGF signaling pathway. INTRODUCTION Platelet-derived growth factors (PDGFs) are key signaling molecules that interact with specific cell to modulate various cellular responses. Upon binding to their receptors (PDGFRs), PDGFs initiate dimerization and tyrosine phosphorylation, which activates downstream signaling pathways. The PDGF signaling network comprises four ligands-PDGF-A, PDGF-B, PDGFC, and PDGF-D, that interact with two receptors, PDGFRα and PDGFRβ [1-6]. PDGFRα exhibits broader ligand specificity, binding to PDGF-A, PDGF-B, PDGF-C homodimers, and PDGFAB heterodimers, whereas PDGFRβ specifically binds to PDGFB and PDGF-D homodimers. Under both physiological and pathol.

Bronchopulmonary dysplasia (BPD) is the predominant chronic lung disease in preterm infants, linked with various adverse long-term outcomes. Multiple prenatal and postnatal risk factors can impede lung development, leading to BPD. Current management of BPD relies heavily on pharmacotherapies and alterations in ventilatory strategies. However, these interventions only mitigate BPD symptoms without addressing underlying alveolar, vascular, structural, and functional deficiencies. Given the retarded lung development in infants with BPD and the limitations of existing modalities, new therapeutic approaches are imperative. The induced differentiation of stem/progenitor cells and the spatiotemporal expression patterns of growth factors associated with lung developmental processes are critical for lung development reactivation in BPD, which focuses on stimulating pulmonary vasculogenesis and alveolarization. This review summarizes the process of lung development and offers a comprehensive overview of advancements in therapies designed to reinitiate lung development in BPD. Furthermore, we assessed the potential of these therapies for maintaining lung homeostasis and effectively restoring pulmonary structure and function through stem/progenitor cells and growth factors, which have been widely researched., (© 2024. The Author(s).)

By recruiting stem cells into scaffolds and differentiating them into osteoblasts, stem cells can be mobilized to directly repair bone defects, which avoids a series of disadvantages of exogenous stem cell implantation. In this study, a microsphere-composite hydrogel for the recruitment and osteogenic differentiation of stem cells was constructed. Methacrylic anhydride modified gelatin (GelMA) and heparin (HepMA), as well as nanohydroxyapatite (nHAP), were used to prepare microspheres followed by adsorbing platelet-derived growth factor BB (PDGF-BB) whose loading efficiency was 53.7 ± 2.2%. Then the microspheres were compounded to the GelMA hydrogel encapsulated with simvastatin (SIM) to obtain microsphere-composite hydrogel GHnH-P@GS. GHnH-P@GS hydrogel could slowly release SIM and PDGF-BB, and the extents of release within 7 days were 44.1 ± 2.0% and 32.8 ± 1.1%. The synergistic effect of small molecule drugs and growth factors not only induced the recruitment of rabbit bone marrow-derived mesenchymal stem cells, but also promoted the osteogenic differentiation of stem cells, which was confirmed by experiments of cell migration, alkaline phosphatase, and alizarin red staining. Collectively, the microsphere-composite hydrogel GHnH-P@GS has a certain reference significance for the design of scaffolds for alveolar bone repair and regeneration.

Growth-factor-induced cell signaling plays a crucial role in development; however, negative regulation of this signaling pathway is important for sustaining homeostasis and preventing diseases. SPROUTY2 (SPRY2) is a potent negative regulator of receptor tyrosine kinase (RTK) signaling that binds to GRB2 during RTK activation and inhibits the GRB2-SOS complex, which inhibits RAS activation and attenuates the downstream RAS/ERK signaling cascade. SPRY was formerly discovered in Drosophila but was later discovered in higher eukaryotes and was found to be connected to many developmental abnormalities. In several experimental scenarios, increased SPRY2 protein levels have been observed to be involved in both peripheral and central nervous system neuronal regeneration and degeneration. SPRY2 is a desirable pharmaceutical target for improving intracellular signaling activity, particularly in the RAS/ERK pathway, in targeted cells because of its increased expression under pathological conditions. However, the role of SPRY2 in brain-derived neurotrophic factor (BDNF) signaling, a major signaling pathway involved in nervous system development, has not been well studied yet. Recent research using a variety of small-animal models suggests that SPRY2 has substantial therapeutic promise for treating a range of neurological conditions. This is explained by its function as an intracellular ERK signaling pathway inhibitor, which is connected to a variety of neuronal activities. By modifying this route, SPRY2 may open the door to novel therapeutic approaches for these difficult-to-treat illnesses. This review integrates an in-depth analysis of the structure of SPRY2, the role of its major interactive partners in RTK signaling cascades, and their possible mechanisms of action. Furthermore, this review highlights the possible role of SPRY2 in neurodevelopmental disorders, as well as its future therapeutic implications.

Membrane ruffles are cell actin-based membrane protrusions that have distinct structural characteristics. Linear ruffles with columnar spike-like and veil-like structures assemble at the leading edge of cell membranes. Circular dorsal ruffles (CDRs) have no supporting columnar structures but their veil-like structures, connecting from end to end, present an enclosed ring-shaped circular outline. Membrane ruffles are involved in multiple cell functions such as cell motility, macropinocytosis, receptor internalization, fluid viscosity sensing in a two-dimensional culture environment, and protecting cells from death in response to physiologically compressive loads. Herein, we review the state-of-the-art knowledge on membrane ruffle structure and function, the growth factor-induced membrane ruffling process, and the growth factor-independent ruffling mode triggered by calcium and other stimulating factors, together with the respective underlying mechanisms. We also summarize the inhibitors used in ruffle formation studies and their specificity. In the last part, an overview is given of the various techniques in which the membrane ruffles have been visualized up to now.

Spinal cord injury (SCI) is a severe clinical disease usually accompanied by activated glial scar, neuronal axon rupture, and disabled motor function. To mimic the microenvironment of the SCI injury site, a hydrogel system with a comparable mechanical property to the spinal cord is desirable. Therefore, a novel elastic bovine serum albumin (BSA) hydrogel is fabricated with excellent adhesive, injectable, and biocompatible properties. The hydrogel is used to deliver paclitaxel (PTX) together with basic fibroblast growth factor (bFGF) to inhibit glial scar formation as well as promote axon regeneration and motor function for SCI repair. Due to the specific interaction of BSA with both drugs, bFGF, and PTX can be controllably released from the hydrogel system to achieve an effective concentration at the wound site during the SCI regeneration process. Moreover, benefiting from the combination of PTX and bFGF, this bFGF/PTX@BSA system significantly aided axon repair by promoting the elongation of axons across the glial scar with reduced reactive astrocyte secretion. In addition, remarkable anti-apoptosis of nerve cells is evident with the bFGF/PTX@BSA system. Subsequently, this multi-functionalized drug system significantly improved the motor function of the rats after SCI. These results reveal that bFGF/PTX@BSA is an ideal functionalized material for nerve repair in SCI., (© 2024 Wiley‐VCH GmbH.)

Objectives: Tracheal regeneration is challenging owing to its unique anatomy and low blood supply. Most tracheal regeneration applications require scaffolds. Herein, we developed bio-three-dimensional-printed scaffold-free artificial tracheas., Methods: We fabricated bio-three-dimensional-printed artificial tracheas. Their anterior surface comprised hyaline cartilage differentiated from mesenchymal stem cells, and their posterior surface comprised smooth muscle. Human bone marrow-derived mesenchymal stem cells were cultured and differentiated into chondrocytes using fibroblast growth factor-2 and transforming growth factor-beta-3. Initially, horseshoe-shaped spheroids were printed to cover the anterior surface of the artificial trachea, followed by the application of human bronchial smooth muscle cells for the posterior surface. After a 3-week maturing process, the artificial trachea was subjected to histological and immunohistochemical analyses., Results: The anterior surface of the artificial trachea comprised well-differentiated hyaline cartilage from human bone marrow-derived mesenchymal stem cells. Immunohistochemistry revealed that the smooth muscle expressed α-smooth muscle actin and smooth muscle myosin heavy chain 11., Conclusions: A bio-three-dimensional-printed scaffold-free artificial trachea comprising different tissues at the front and back was successfully fabricated., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Growth factor holds great promise for bone regeneration, and spatiotemporal control of their expressing through site-specific reactions is crucial but challenging for on-demand therapy. In this study, we present the development of a novel unnatural amino acids (UAAs)-triggered therapeutic switch (UATS) system, composed of an orthogonal aminoacyl-tRNA-synthase (aaRS)-tRNA pair and a bone morphogenetic protein 2 (BMP2) gene harboring premature stop codon, which enable in situ and on-demand initiation of the expression of BMP2. The resulting UATS system allowed specifically control of base expressing on the BMP2 mRNA that switched to the BMP2 protein with complete structure and function to facilitate bone regeneration. Our investigations showed that the UATS system exhibits remarkable attributes of rapid, sensitive, reversible, and sustained BMP2 expression both in vitro and in vivo settings. Moreover, the implantation of microencapsulated cells with UATS system is applied to a mouse femur defect model, demonstrating high effciency in controlled expressing of BMP2 protein and substantial repair of bone defect following oral administration of UAAs. Therefore, our findings underscore the great potential of UATS system for on-demand awakening of functional growth factor, thus offering promising prospects in the realm of regenerative medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation in the United States, but the actual roles that eosinophils play in CRSwNP remain largely unclear., Objective: To reveal the roles and heterogeneity of eosinophils in nasal polyp (NP) tissue, we performed single cell RNA sequencing (scRNA-Seq) analysis of NP tissue., Methods: Sinonasal tissues (NP and control sinus tissue) and patient matched peripheral blood (PB) samples were obtained from 5 control patients and 5 patients with CRSwNP. Eosinophils were enriched before processing for scRNA-Seq. The gene expression profiles in eosinophils were determined by microwell-based scRNA-Seq technology (BD Rhapsody platform). We predicted the overall function of NP eosinophils by Gene Ontology (geneontology.org) enrichment and pathway analyses and confirmed expression of selected genes by flow cytometry., Results: After filtering out contaminating cells, we detected 5,542 eosinophils from control PB, 3,883 eosinophils from CRSwNP PB, 101 eosinophils from control sinus tissues (not included in further analyses), and 9,727 eosinophils from NPs by scRNA-Seq. We found that 204 genes were downregulated and 354 genes upregulated in NP eosinophils compared to all PB eosinophils (>1.5-fold, P adj  < .05). Upregulated genes in NP eosinophils were associated with activation, cytokine-mediated signaling, growth factor activity, NF-κB signaling, and antiapoptotic molecules. NP eosinophils displayed 4 clusters revealing potential heterogeneity of eosinophils in NP tissue., Conclusions: Elevated eosinophils in NP tissue appear to exist in several subtypes that may play important pathogenic roles in CRSwNP, in part by controlling inflammation and hyperproliferation of other cells., Competing Interests: Disclosure statement Supported in part by Regeneron Pharmaceuticals, the National Institutes of Health (grants P01AI145818, R01AI137174, and U19AI136443), and a grant from the Ernest S. Bazley Foundation. Disclosure of potential conflict of interest: W. W. Stevens has served on advisory boards for GlaxoSmithKline, Regeneron, and Melinta Therapeutics. A. T. Petershas served on advisory boards for Sanofi-Genzyme/Regeneron, Optinose, AstraZeneca, Novartis, and GSK; and has received research support from Optinose and Sanofi/Regeneron. L. C. Grammer reports personal fees from Astellas Pharmaceuticals. K. C. Welch reports consultant fees from Baxter, OptiNose, and Acclarent. D. B. Conley reports consulting fees from Medtronic and Sanofi/Regeneron. R. P. Schleimer reports personal fees from Intersect ENT, Merck, GlaxoSmithKline, Sanofi, AstraZeneca/Medimmune, Genentech, Actobio Therapeutics, Lyra Therapeutics, Astellas Pharma, and Otsuka; and has royalty rights to Siglec-8 and Siglec-8 ligand–related patents licensed by Johns Hopkins to Allakos. R. C. Kern reports consulting fees from Lyra Therapeutics, Medtronic, GSK, Genentech and Sanofi/Regeneron. B. S. Bochner has received remuneration for serving on scientific advisory board of Allakos and owns stock in Allakos; has served as consultant for GSK, Third Harmonic Bio, Lupagen, Acelyrin, and Sanofi/Regeneron; receives publication-related royalty payments from Elsevier and UpToDate; is coinventor of existing Siglec-8–related patents and thus may be entitled to a share of royalties received by Johns Hopkins University during development and potential sales of such products; and is a cofounder of Allakos, which makes him subject to certain restrictions under university policy (terms of this arrangement are being managed by Johns Hopkins University and Northwestern University in accordance with their conflict-of-interest policies). B. K. Tan reports personal fees from Sanofi/Regeneron/Genzyme and GSK. A. Kato has served on advisory board for AstraZeneca; reports gift for his research from Lyra Therapeutics; and has received research grants from Regeneron and AstraZeneca. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Bone tissue engineering using biodegradable porous scaffolds is a promising approach for restoring oral and maxillofacial bone defects. Recently, attempts have been made to incorporate proteins such as growth factors to create bioactive scaffolds that can engage cells to promote tissue formation. Collagen-based scaffolds containing bone morphogenetic protein-2 (BMP2) have been studied for bone formation. However, controlling the initial burst of BMP2 remains difficult. Here we designed a functional chimeric protein composed of BMP2 and a collagen-binding domain (CBD), specifically the A3 domain of von Willebrand factor, to sustain BMP2 release from collagen-based scaffolds. Based on the results of computer-based structural prediction, we prepared a chimeric protein consisting of CBD and BMP2 in this order with a peptide tag for affinity purification. The chimeric protein had a collagen-binding capacity and enhanced osteogenic differentiation of human mesenchymal stem cells. These results are consistent with insights from in silico structural prediction.

Introduction: β-TCP ceramics are bone replacement materials that have recently been tested as a drug delivery system that can potentially be applied to endogenous substances like growth factors found in blood platelets to facilitate positive attributes., Methods: In this work, we used flow chamber loading to load β-TCP dowels with blood suspensions of platelet-rich plasma (PRP), platelet-poor plasma (PPP), or buffy coat (BC) character. PRP and BC platelet counts were adjusted to the same level by dilution. Concentrations of TGF-β1, PDGF-AB, and IGF-1 from dowel-surrounding culture medium were subsequently determined using ELISA over 5 days. The influence of alginate was additionally tested to modify the release., Results: Concentrations of TGF-β1 and PDGF-AB increased and conclusively showed a release from platelets in PRP and BC compared to PPP. The alginate coating reduced the PDGF-AB release but did not reduce TGF-β1 and instead even increased TGF-β1 in the BC samples. IGF-1 concentrations were highest in PPP, suggesting circulating levels rather than platelet release as the driving factor. Alginate samples tended to have lower IGF-1 concentrations, but the difference was not shown to be significant., Discussion: The release of growth factors from different blood suspensions was successfully demonstrated for β-TCP as a drug delivery system with release patterns that correspond to PRP activation after Ca 2+ -triggered activation. The release pattern was partially modified by alginate coating., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Waldmann, Bohner, Baghnavi, Riedel and Seidenstuecker.)

Fibroblast growth factor1 is a powerful signaling molecule that plays a critical role in injury repair of diverse tissue by stimulating cell growth and angiogenesis. FGF1 has significant role in the cell fate and regulating inflammation with short half-life and poor in vivo stability. The encapsulation of the growth factor in the hydrogel led to peptide protect from the degradation and/or immune recognition and enable controlled drug delivery over a longer period of time. The aim of this study is to develop and evaluate a hydrogel carrier with adjustable release rate while maintaining bioactivity of FGF1. Here we describe an optimal ratio of sodium alginate and polyacrylic acid without additional cross linker containing optimum amount of FGF1 with the potential of sustained release to be used as a therapeutic agent. The carrier was characterized by FTIR, contact angle and swelling ratio. The activity of FGF1 after release from the hydrogel was confirmed by ELISA and Western blot. Further assessment of genes related to inflammation were evaluated by RTPCR. This hydrogel is able to deliver growth factors by restricting the essential proteins within the matrix to prevent rapid proteolysis and explosive release and is therefore widely applicable., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The cutaneous lymphatic system regulates tissue inflammation, fluid balance and immunological responses. Lymphangiogenesis or lymphatic dysfunction may lead to lymphedema, immune deficiency, chronic inflammation etc. Tissue regeneration and healing depend on angiogenesis and lymphangiogenesis during wound healing. Tissue oedema and chronic inflammation can slow wound healing due to impaired lymphangiogenesis or lymphatic dysfunction. For example, impaired lymphangiogenesis or lymphatic dysfunction has been detected in nonhealing wounds such as diabetic ulcers, venous ulcers and bedsores. This review summarizes the structure and function of the cutaneous lymphatic vessel system and lymphangiogenesis in wounds. Furthermore, we review wound lymphangiogenesis processes and remodelling, especially the influence of the inflammatory phase. Finally, we outline how to control lymphangiogenesis to promote wound healing, assess the possibility of targeting lymphangiogenesis as a novel treatment strategy for chronic wounds and provide an analysis of the possible problems that need to be addressed., (© The Author(s) 2024. Published by Oxford University Press.)

Three-dimensional (3D) bioprinting has emerged as a promising strategy for fabricating complex tissue analogs with intricate architectures, such as vascular networks. Achieving this necessitates bioink formulations that possess highly printable properties and provide a cell-friendly microenvironment mimicking the native extracellular matrix. Rapid advancements in printing techniques continue to expand the capabilities of researchers, enabling them to overcome existing biological barriers. This review offers a comprehensive examination of ultraviolet-based 3D bioprinting, renowned for its exceptional precision compared to other techniques, and explores its applications in inducing angiogenesis across diverse tissue models related to hypoxia. The high-precision and rapid photocuring capabilities of 3D bioprinting are essential for accurately replicating the intricate complexity of vascular networks and extending the diffusion limits for nutrients and gases. Addressing the lack of vascular structure is crucial in hypoxia-related diseases, as it can significantly improve oxygen delivery and overall tissue health. Consequently, high-resolution 3D bioprinting facilitates the creation of vascular structures within three-dimensional engineered tissues, offering a potential solution for addressing hypoxia-related diseases. Emphasis is placed on fundamental components essential for successful 3D bioprinting, including cell types, bioink compositions, and growth factors highlighted in recent studies. The insights provided in this review underscore the promising prospects of leveraging 3D printing technologies for addressing hypoxia-related diseases through the stimulation of angiogenesis, complementing the therapeutic efficacy of cell therapy., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Implants have become the first treatment option in the anterior esthetic region. Buccal bone loss is the sequalae of tooth extraction compromising osseointegration and cosmetic goals. The present case report is of a 47-year-old female who requested to have her fractured central incisor replaced with fixed restoration supported by an implant; the tooth had already undergone a root canal and lacked a sufficient structure for crown prosthesis placement. This case report evaluates the efficacy of the socket shield technique (SST) combined with a coating of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) on the implant surface to achieve optimal biomechanical stability and esthetics., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kawadkar et al.)

Mesenchymal stromal cells (MSCs) have the potential to be used as autologous or allogenic cell therapy in several diseases due to their beneficial secretome and capacity for immunomodulation and differentiation. However, clinical trials using MSCs require a large number of cells. As an alternative to traditional culture flasks, suspension bioreactors provide a scalable platform to produce clinically relevant quantities of cells. When cultured in bioreactors, anchorage-dependent cells like MSCs require the addition of microcarriers, which provide a surface for cell attachment while in suspension. The best performing microcarriers are typically coated in animal derived proteins, which increases cellular attachment and proliferation but present issues from a regulatory perspective. To overcome this issue, a recombinant fusion protein was generated linking basic fibroblast growth factor (bFGF) to a cellulose-specific carbohydrate binding module (CBM) and used to functionalize the surface of cellulose microcarriers for the expansion of human umbilical MSCs in suspension bioreactors. The fusion protein was shown to support the growth of MSCs when used as a soluble growth factor in the absence of cellulose, readily bound to cellulose microcarriers in a dose-dependent manner, and ultimately improved the expansion of MSCs when grown in bioreactors using cellulose microcarriers. The use of CBM fusion proteins offers a simple method for the surface immobilization of growth factors to animal component-free substrates such as cellulose, which can be used alongside bioreactors to increase growth factor lifespan, decrease culture medium cost, and increase cell production in the manufacturing of therapeutic cells.

Aim: To evaluate the effect of concentrated growth factor (CGF) on regeneration of facial nerve after crush injury., Materials and Methods: Fourteen rats were randomized into two groups. The control group (CG) (n = 7) received a crush injury to the right facial nerve. The CGF group (CGFG) (n = 7) received a crush injury to the right facial nerve and concentrated growth factor prepared from their own blood thereafter. Left facial nerves were used for functional comparison. Nerve function was evaluated using whisker movements and electromyography. Histologic properties were evaluated using hematoxylin and eosin and Masson-trichrome staining, and immunohistochemical properties were evaluated using Neurofilament-H and Anti-Tau degeneration markers., Results: In the CGFG, whisker functions began to recover earlier and recovered more quickly compared with the CG. The CG showed significantly prolonged latency and reduced amplitudes in the first week compared with the CGFG (p < 0.05). Recordings of 4th-week latency and amplitudes were similar to the preoperative period in the CGFG (p > 0.05), whereas recordings of the same week were significantly worse in the CG (p < 0.05). Edema and fibrosis were also more pronounced in the CG compared with the CGFG. Neurofilament-H and Anti-Tau were at significantly high levels in the CG (p < 0.05)., Conclusion: Concentrated growth factor promotes recovery in facial crush injury and may prove a cost-effective, practical, and effective treatment choice in peripheral nerve injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Recently, low human epidermal growth factor receptor 2 (HER2) protein expression has been proposed as a predictive biomarker for response to the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in metastatic breast cancer. HER2 expression in non-small cell lung cancer (NSCLC) patients has never been carefully measured, and little is known about the frequency of cases with unamplified but detectable levels of the protein. Although some HER2-targeted therapies have been studied in NSCLC patients, they have been restricted to those with genomic ERBB2 gene alterations, which only represent relatively rare cases of NSCLC. Still, emerging investigations of T-DXd in NSCLC have shown promise in patients with unamplified HER2. Taken together, we hypothesize that there may be many cases of NSCLC with levels of HER2 protein expression comparable with levels seen in breast cancer that benefit from T-DXd. Here, we used a previously validated, analytic, quantitative immunofluorescence (QIF) assay that is more sensitive than legacy clinical HER2 immunohistochemistry assays. We measured HER2 protein levels in NSCLC cases to determine the proportion of cases with detectable HER2 expression. Using cell line calibration microarrays alongside our QIF method enabled us to convert HER2 signal into units of attomoles per mm 2 . We found that over 63% of the 741 analyzed NSCLC cases exhibited HER2 expression above the limit of detection, with more than 17% of them exceeding the lower limit of quantification. Although the threshold for response to T-DXd in breast cancer is still unknown, many cases of NSCLC have expression in a range comparable to breast cancer cases with immunohistochemistry scores of 1+ or 2+. Our assay could potentially select NSCLC cases with a detectable target (ie, HER2) that might benefit from HER2 antibody-drug conjugates, irrespective of ERBB2 genomic alterations., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

The growth factor Neuregulin-1 (NRG1) has pleiotropic roles in proliferation and differentiation of the stem cell niche in different tissues. It has been implicated in gut, brain and muscle development and repair. Six isoform classes of NRG1 and over 28 protein isoforms have been previously described. Here we report a new class of NRG1, designated NRG1-VII to denote that these NRG1 isoforms arise from a myeloid-specific transcriptional start site (TSS) previously uncharacterized. Long-read sequencing was used to identify eight high-confidence NRG1-VII transcripts. These transcripts presented major structural differences from one another, through the use of cassette exons and alternative stop codons. Expression of NRG1-VII was confirmed in primary human monocytes and tissue resident macrophages and induced pluripotent stem cell-derived macrophages (iPSC-derived macrophages). Isoform switching via cassette exon usage and alternate polyadenylation was apparent during monocyte maturation and macrophage differentiation. NRG1-VII is the major class expressed by the myeloid lineage, including tissue-resident macrophages. Analysis of public gene expression data indicates that monocytes and macrophages are a primary source of NRG1. The size and structure of class VII isoforms suggests that they may be more diffusible through tissues than other NRG1 classes. However, the specific roles of class VII variants in tissue homeostasis and repair have not yet been determined., (© 2024. The Author(s).)

In the field of oral and maxillofacial surgery, extensive oral soft-tissue injuries occur repeatedly in clinical practice; however, effective restorative materials are lacking. In this study, a biodegradable waterborne polyurethane patch featuring a mucosa bionic bilayer structure is presented. This patch consists of a porous scaffold layer that faces the lesion, incorporating a polydopamine coating to achieve sustained release of epidermal growth factors (EGFs) for mucosal defect reconstruction. Additionally, there is a dense barrier layer toward the oral cavity loaded with silver nanoparticles, which prevents bacteria from entering the wound and simultaneously acts as a physical barrier. This patch can sustainably release EGF in vitro for 2 weeks, thereby facilitating the proliferation and migration of HaCaT and L929 cells, while effectively killing common oral cavity bacteria. In a rabbit buccal mucosal full-thickness defect model, the patch demonstrates better efficacy than the clinical benchmark, decellularized extracellular matrix (dECM). It effectively reduces wound inflammation and significantly upregulates gene expression associated with epithelialization by activating the EGF/epidermal growth factor receptor (EGFR) pathway. These mechanisms promote the proliferation, differentiation, and migration of epithelial/keratinocyte cells, ultimately expediting mucosal defect healing and wound closure.

Skin wounds heal faster during stem cell differentiation. Cold plasma reportedly enhances cell proliferation and differentiation and enhances the efficacy of stem cell therapy. However, the exact mechanism of action involved remains unknown. Therefore, this study aimed to evaluate the effect of a combination therapy involving the transplantation of mouse mesenchymal stem cells (mMSCs) into mice with wounds followed by their activation using no-ozone cold plasma (NCP). Balb/c mMSCs were transplanted into BALB/c mice and treated with NCP for 5 min. The animals were divided into four groups based on treatments received: no treatment (Wound), mMSCs only (mMSC), NCP only (NCP), and both mMSC and NCP (mMSC + NCP). NCP treatment was administered six times over two weeks, and tissue samples were prepared by sacrificing the mice in the 1st and 2nd weeks. The wound healing efficacy was assessed using morphological, histological, and molecular approaches including wound healing length measurements, hematoxylin and eosin staining, Masson trichrome staining, immunofluorescence staining, immunohistochemistry, and real-time polymerase chain reaction. The wound healing effect was better in the mMSC + NCP group than that in the groups treated with either. Tracking the injected mMSCs in mice also revealed that the mMSC + NCP group had a greater survival rate. Furthermore, upon wound healing, the mMSC + NCP group exhibited elevated levels of growth factors, like platelet-derived growth factor, transforming growth factor-beta, and vascular endothelial growth factor. These results suggest that NCP stimulated transplanted mMSCs, resulting in faster wound healing. Therefore, further studies are warranted in preclinical and clinical studies to confirm this effect., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gyoo Cheon Kim reports a relationship with Pusan National University that includes: funding grants. Gyoo Cheon Kim has patent #2016M3A9C6918283 pending to Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean government. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/Objectives: Various biological response modifiers play important roles in the immunopathogenesis of chronic hepatitis C (CHC). While serum levels of cytokines and growth factors change with the disease severity and treatment responses, the impact of concomitant liver steatosis on systemic inflammatory response is largely unknown. The aim of this study was to analyze the characteristics and kinetics of serum profiles of interleukins and growth factors in CHC patients with steatotic liver disease (SLD). Methods: Serum concentrations of 12 cytokines (IL-5, IL-13, IL-2, IL-6, IL-9, IL-10, IFN-γ, TNF-α, IL-17A, IL-17F, IL-4 and IL-22) and 6 growth factors (Angiopoietin-2, EGF, EPO, HGF, SCF, VEGF) were analyzed in 56 CHC patients at four time points (baseline, week 4, week 8 and SVR12) with bead-based flow cytometry assay. Results: At baseline, patients with SLD had significantly lower IL-9, IL-10, IL-13 and IL-22 and higher serum concentrations of EGF, VEGF and ANG. In a subgroup of patients with advanced liver fibrosis, SLD was linked with lower serum concentrations of IL-4, IL-5, IL-9, IL-10, IL-13 and IL-22 and higher concentrations of HGH and VEGF. Distinct cytokine kinetics during DAA treatment was observed, and SLD was identified as the main source of variation for IL-5, IL-9, IL-10, IL-13, IL-17A, IL-22, EGF, VEGF and ANG. Patients with SLD at SVR12 had significantly higher VEGF and HGF serum concentrations. Conclusions: SLD is associated with distinct cytokine and growth factor profiles and kinetics during CHC treatment, which might be associated with disease severity and the capacity for liver regeneration and contribute to fibrosis persistence.

Bile acid-induced hepatotoxicity is inevitable in Cholestasis pathogenesis and L-Glutamine (L-Gln) has been reported to prevent total parenteral nutrition (TPN)-induced cholestasis in premature neonates. While mechanisms remain unknown, we hypothesize that bile acids impair growth factor (GF) function in hepatocytes which L-glutamine prevents through NAPDH oxidase (NOX) modulation. Glycochenodeoxycholic acid (GCDC, 0-100 µM) when added to primary hepatocyte cultures significantly (p < 0.01) decreased the FBS-induced BrdU incorporation, however inhibition of Fibroblast Growth factor (FGF)- or Hepatocyte growth factor (HGF)-induced DNA synthesis was more pronounced (p < 0.001). L-Gln markedly attenuated GCDC-mediated inhibition of DNA synthesis in both FBS and GF-treated cells. GCDC significantly increased the NADPH oxidase activity and NOX-1 protein expression that were markedly reduced by L-Gln and protein kinase c (PKC) inhibitor, LY-333531. Apocynin (APCN) and diphenyliodonium (DPI) significantly blocked the GCDC-mediated inhibition of GF-induced DNA synthesis. This study demonstrates that bile acid-induced hepatotoxicity involves dysfunction of certain growth factors via protein kinase c (PKC)- mediated NOX modulation which can be corrected, at least partly, by L-glutamine.

Autologous or allogeneic bone tissue grafts remain the mainstay of treatment for clinical bone defects. However, the risk of infection and donor scarcity in bone grafting pose challenges to the process. Therefore, the development of excellent biomaterial grafts is of great clinical importance for the repair of bone defects. In this study, we used gas-assisted microfluidics to construct double-cross-linked hydrogel microspheres with good biological function based on the ionic cross-linking of Cu 2+ with alginate and photo-cross-linking of gelatin methacryloylamide (GelMA) by loading vascular endothelial growth factor (VEGF) and His-tagged bone morphogenetic protein-2 (BMP2) (AGMP@VEGF&BMP2). The Cu 2+ component in the microspheres showed good antibacterial and drug-release behavior, whereas VEGF and BMP2 effectively promoted angiogenesis and bone tissue repair. In in vitro and in vivo experiments, the dual cross-linked hydrogel microspheres showed good biological function and biocompatibility. These results demonstrate that AGMP@VEGF&BMP2 microspheres could be used as a bone defect graft substitute to promote effective healing of bone defects and may be applied to other tissue engineering studies., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships. This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. We have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Titanium and titanium alloys are widely favored materials for orthopedic implants due to their exceptional mechanical properties and biological inertness. The additional benefit of sustained local release of bioactive substances further promotes bone tissue formation, thereby augmenting the osseointegration capacity of titanium implants and attracting increasing attention in bone tissue engineering. Among these bioactive substances, growth factors have shown remarkable osteogenic and angiogenic induction capabilities. Consequently, researchers have developed various physical, chemical, and biological loading techniques to incorporate growth factors into titanium implants, ensuring controlled release kinetics. In contrast to conventional treatment modalities, the localized release of growth factors from functionalized titanium implants not only enhances osseointegration but also reduces the risk of complications. This review provides a comprehensive examination of the types and mechanisms of growth factors, along with a detailed exploration of the methodologies used to load growth factors onto the surface of titanium implants. Moreover, it highlights recent advancements in the application of growth factors to the surface of titanium implants (Scheme 1). Finally, the review discusses current limitations and future prospects for growth factor-functionalized titanium implants. In summary, this paper presents cutting-edge design strategies aimed at enhancing the bone regenerative capacity of growth factor-functionalized titanium implants-a significant advancement in the field of enhanced bone regeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Most tympanic membrane (TM) perforations heal spontaneously, but 10%-20% remain chronic and might lead to impaired hearing and recurrent middle ear infections. Alpha1-antitrypsin (AAT) is a circulating tissue-protective protein that is elevated under inflammatory conditions and is currently indicated for genetic AAT deficiency. Recently, AAT has been shown to promote tissue remodeling and inflammatory resolution., Objective: This study aimed to examine the effects of local clinical-grade AAT treatment on tissue repair in a mouse model of acute traumatic TM perforation., Methods: Wild-type mice underwent unilateral TM perforation and were either left untreated or treated locally with human AAT (9 × 10 -3  mL at 20 mg/mL on days 0, 1, and 2; n = 15/group). The perforations were evaluated macroscopically on a serial basis. Mice were sacrificed on various days post-injury, and TMs were excised for gene analysis by RT-PCR., Results: There were no adverse reactions in hAAT-treated ears throughout the study period. Compared with untreated animals, TM closure occurred earlier in the treated group (days until full closure, median: 4 and 9, respectively). According to gene expression analysis, VEGF, TGFβ, and collagen-5A1 were induced earlier in AAT-treated mice (day 4-5 compared with day 9). Additionally, IL-10 expression levels were higher and IL-6 levels were lower in treated versus untreated mice., Conclusion: A local tissue environment rich in AAT promotes early tissue repair in a perforated TM model both macroscopically and molecularly. Studies are underway to examine TM functionality and recombinant AAT formulations for micro-dosing in the format of a single local application., Level of Evidence: NA Laryngoscope, 134:3802-3806, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Bioactive hydrogels are currently receiving significant attention. In this study, silk fibroin tyramine-modified gelatin hydrogels (SF-TG) with varying degrees of tyramine root substitution were explored. The physicochemical property and biocompatibility of low degree of substitution tyramine-modified gelatin hydrogel (SF-LTG) and high degree of substitution tyramine-modified gelatin hydrogel (SF-HTG) were compared. The results showed that SF-LTG possessed better mechanical property and higher biocompatibility. Thus, SF-LTG was selected as a bioactive matrix and loaded with basic fibroblast growth factor (bFGF); subsequently, curcumin-coupled chitosan rods (CCCRs-EGF) enriched with epidermal growth factor (EGF) were added to obtain SF-LTG-bFGF@CCCRs-EGF hydrogels. The results showed that SF-LTG-bFGF@CCCRs-EGF retained the basic structural and mechanical properties of the SF-LTG matrix gel material and underwent multiple loading and orderly release with different activities while displaying antioxidant, anti-inflammatory, antimicrobial, and pro-cellular proliferation activities and orderly regulation of activity during wound healing. Therefore, the SF-LTG-bFGF@CCCRs-EGF hydrogel is of great value in healing complex wounds., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Following nerve injury, growth factors (GFs) are transiently upregulated in injured neurons, proliferating Schwann cells, and denervated muscle and skin. They act on these same cells and tissues to promote nerve regeneration and end-organ reinnervation. Consequently, much attention has been focused on developing GF-based therapeutics. A major barrier to clinical translation of GFs is their short half-life. To provide sustained GF treatment to the affected nerve, muscle, and skin in a safe and practical manner, engineered drug delivery systems are needed. This review highlights recent advancements in GF-based therapeutics and discusses the remaining hurdles for clinical translation., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Growth differentiation factor 15 (GDF-15) is a multifunctional cytokine that belongs to the transforming growth factor-beta (TGF-β) superfamily. GDF-15 is involved in immune tolerance and is elevated in several acute and chronic stress conditions, often correlating with disease severity and patient prognosis in cancer172 and metabolic and cardiovascular disorders. Despite these clinical associations, the molecular mechanisms orchestrating its effects remain to be elucidated. The effects of GDF-15 are pleiotropic but cell-specific and dependent on the microenvironment. While GDF-15 expression can be stimulated by inflammatory mediators, its predominant effects were reported as anti-inflammatory and pro-fibrotic. The role of GDF-15 in the macrophage system has been increasingly investigated in recent years. Macrophages produce high levels of GDF-15 during oxidative and lysosomal stress, which can lead to fibrogenesis and angiogenesis at the tissue level. At the same time, macrophages can respond to GDF-15 by switching their phenotype to a tolerogenic one. Several GDF-15-based therapies are under development, including GDF-15 analogs/mimetics and GDF-15-targeting monoclonal antibodies. In this review, we summarize the major physiological and pathological contexts in which GDF-15 interacts with macrophages. We also discuss the major challenges and future perspectives in the therapeutic translation of GDF-15.

Background : Tooth infraocclusion is a process in which a completely or partially erupted tooth gradually moves away from the occlusal plane. Submerged teeth can lead to serious complications. Treating teeth with infraocclusion is very challenging. One of the procedures allowing for the replacement of a missing tooth is autotransplantation. The aim of this paper is to review the literature on teeth autotransplantation, supported by a case report involving the autotransplantation of a third mandibular molar into the site of an extracted infraoccluded first mandibular molar, as well as the utilization of advanced platelet-rich fibrin (A-PRF) alongside autogenous dentin grafts for bone tissue regeneration. Methods : A severely infraoccluded first permanent right mandibular molar was extracted and then ground to obtain the dentin graft. A-PRF clots (collected from the patient's peripheral blood) were added to the autogenous dentin graft, to create the A-PRF membrane. An atraumatic extraction of the lower left third molar was performed and then it was transplanted into the socket of tooth no. 46. Immediately after transplantation, tooth no. 38 was stabilized with orthodontic bracket splints for 3 months. The patient attended regular follow-up visits within 12 months. Results : After one year, the patient did not report any pain. In the clinical examination, the tooth and surrounding tissues did not show any signs of infection. However, radiographically, cervical inflammatory resorption, unchanged pulp canal dimensions, absent root growth, periapical radiolucency, and lack of apical and marginal healing were observed. Reconstruction of the bone defect was obtained and the alveolar ridge of the mandible was preserved. Due to poor stability of the tooth and severe resorption, the tooth needed to be extracted. Conclusions : This study is designed to critically evaluate the efficacy of autotransplantation, the application of growth factors, and the integration of autogenous dentin grafts in remedying dental deficiencies resulting from reinclusion. We aim to point out the possible causes of treatment failure.

Impaired insulin and growth factor functions are thought to drive many alterations in neurodegenerative diseases like dementia and seem to contribute to oxidative stress and inflammatory responses. Recent studies revealed that nasal growth factor therapy could induce neuronal and oligodendroglia protection in rodent brain damage induction models. Impairment of several growth factors signaling was reported in neurodegenerative diseases. So, in the present study, we examined the effects of intranasal co-treatment of insulin and a pool of growth factor-rich serum (GFRS) which separated from activated platelets on memory, and behavioral defects induced by intracerebroventricular streptozotocin (icv-STZ) rat model also investigated changes in the hippocampal oxidative-nitrosative state and histology. We found that icv-STZ injection (3 mg/kg bilaterally) impairs spatial learning and memory in Morris Water Maze, leads to anxiogenic-like behavior in the open field arena, and induces oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia death in the hippocampus. GFRS (1µl/kg, each other day, 9 doses) and regular insulin (4 U/40 µl, daily, 18 doses) treatments improved learning, memory, and anxiogenic behaviors. The present study showed that co-treatment (GFRS + insulin with respective dose) has more robust protection against hippocampal oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia survival in comparison with the single therapy. Memory and behavioral improvements in the co-treatment of insulin and GFRS could be attributed to their effects on neuronal/oligodendroglia survival and reduction of neuroinflammation in the hippocampus., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate whether there is a correlation between the inflammatory state and the pathogenesis and clinical features of sudden hearing loss (SHL) by studying the expression of inflammation-related cytokines in the peripheral blood of patients with SHL., Methods: In this work, we analyzed the cytokine profiles of 48 analytes in 38 patients with SHL compared to 38 healthy donors using a multiplex immunoassay. This study used appropriate statistical methods to screen for inflammatory cytokines associated with the pathogenesis of SHL, to analyze their network correlation, and to analyze the relationship between clinical features of SHL and inflammatory cytokines., Results: Several cytokines, including CTACK, Eotaxin, HGF, INF-α2, IFN-β, IL-1β, IL-1ra, IL-2Rα, IL-4, IL-7, IL-8, IL-9, IL-10, IL-12(p40), IL-13, MIG, β-NGF, SCF, and TNF-α, exhibited significantly higher levels in the peripheral blood of the SHL group compared to the control group. An inflammatory network composed of multiple cytokines, including IL-1β, is a risk factor for the development of SHL., Conclusion: This study identified several inflammatory cytokines with elevated expression, which may be linked with the onset of SHL. The results of this study also provide a basis for the theoretical hypothesis of inflammation in SHL., Level of Evidence: 3 Laryngoscope, 134:3293-3301, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Background/aim: The purpose of the current study was to compare the vascular endothelial growth factor-A (VEGF-A) levels in the aqueous humor of patients with primary open angle glaucoma (POAG) and non-glaucomatous eyes and reveal any potential statistically significant correlations., Patients and Methods: This was an observational cross-sectional study. Aqueous humor samples (50-100 μl) were collected under aseptic conditions, from the anterior chamber at the start of glaucoma or cataract surgery. The levels of VEGF-A were measured using a multiplex bead-based immunoassay., Results: Aqueous humor samples were obtained from 76 participants: 39 with POAG and 36 with age-related cataracts as controls. VEGF-A levels were significantly elevated in the POAG group (166.37±110.04 pg/ml, p=0.011) compared to the control group (119.02±49.09 pg/ml). The receiver operating characteristic (ROC) analysis showed that VEGF-A had significant prognostic ability for POAG (AUC=0.67; p=0.006). An optimal cut-off for VEGF-A was found to be 148.5 pg/ml with a sensitivity of 54%, specificity of 81.1%, positive prognostic value (PPV) of 75% and negative prognostic value (NPV) of 62.5%. Logistic regression analysis showed that after adjusting for sex and age, patients with VEGF-A higher than 148.5 pg/ml had almost 10 times greater likelihood for POAG., Conclusion: VEGF-A is elevated in patients with POAG and can potentially have a prognostic ability for these patients., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This study is focused on fractionation of insulin-like growth factor I (IGF-I) and transforming growth factor-β2 (TGF-β2) using a new electro-based membrane process calledelectrodialysis with filtration membranes (EDFM). Before EDFM, different pretreatments were tested, and four pH conditions (4.25, 3.85, 3.45, and 3.05) were used during EDFM. It was demonstrated that a 1:1 dilution of defatted colostrum with deionized water to decrease mineral content followed by the preconcentration of GFs by UF is necessary and allow for these compounds to migrate to the recovery compartment during EDFM. MS analyses confirmed the migration, in low quantity, of only α-lactalbumin (α-la) and β-lactoglobulin (β-lg) from serocolostrum to the recovery compartment during EDFM. Consequently, the ratio of GFs to total protein in recovery compartment compared to that of feed serocolostrum solution was 60× higher at pH value 3.05, the optimal pH favoring the migration of IGF-I and TGF-β2. Finally, these optimal conditions were tested on acid whey to also demonstrate the feasibility of the proposed process on one of the main by-products of the cheese industry; the ratio of GFs to total protein was 2.7× higher in recovery compartment than in feed acid whey solution, and only α-la migrated. The technology of GF enrichment for different dairy solutions by combining ultrafiltration and electrodialysis technologies was proposed for the first time.

A pterygium is a wedge-shaped fibrovascular growth of the conjunctiva membrane that extends onto the cornea, which is the outer layer of the eye. It is also known as surfer's eye. Growth of a pterygium can also occur on the either side of the eye, attaching firmly to the sclera. Pterygia are one of the world's most common ocular diseases. However, the pathogenesis remains unsolved to date. As the pathogenesis of pterygium is closely related to finding the ideal treatment, a clear understanding of the pathogenesis will lead to better treatment and lower the recurrence rate, which is notably high and more difficult to treat than a primary pterygium. Massive studies have recently been conducted to determine the exact causes and mechanism of pterygia. We evaluated the pathogenetic factors ultraviolet radiation, viral infection, tumor suppressor genes p53, growth factors, oxidative stress, apoptosis and neuropeptides in the progression of the disease. The heightened expression of TRPV1 suggests its potential contribution in the occurrence of pterygium, promoting its inflammation and modulating sensory responses in ocular tissues. Subsequently, the developmental mechanism of pterygium, along with its correlation with dry eye disease is proposed to facilitate the identification of pathogenetic factors for pterygia, contributing to the advancement of understanding in this area and may lead to improved surgical outcomes., Competing Interests: Declaration of competing interest The author reports no conflicts of interest in this work. The authors declare that they have no competing financial interests exist., (Copyright © 2024. Published by Elsevier Ltd.)

The hygroscopicity of PM 2.5 particles plays an important role in PM 2.5 haze in Northeast Asian countries by influencing particle growth and chemical composition. New particle formation (NPF) and atmospheric volatile organic compounds (VOCs) are factors that influence particle hygroscopicity. However, the lack of real-time hygroscopicity measurements has deterred the understanding of their effects on particle hygroscopicity. In this study, two intensive monitoring campaigns were conducted during the summer of 2021 and spring of 2022 using real-time aerosol instruments, including a humidified tandem differential mobility analyzer (HTDMA), in Seosan, Republic of Korea. The hygroscopicity parameter κ was calculated from the real-time HTDMA measurement data (κ Gf ). The diurnal variations in κ Gf exhibited strong inverse linear correlations with the total concentration of VOCs (C TVOC ) during the two campaigns. The higher atmospheric C TVOC in summer increased the growth rate of the particle diameter from 10 to 40 nm (6 nm/h) compared with that in spring (2.7 nm/h), resulting in a faster change in κ Gf for 40-nm particles in summer than in spring because of the increase in organic matter in the chemical compositions of particles. In addition, NPF events introduced additional tiny fresh particles into the atmosphere, which reduced the κ Gf of 40-nm particles and increased the intensity of the less hygroscopic peaks (κ Gf  < 0.1) of κ-probability density functions (κ-PDF) in NPF days. However, 100-nm particles exhibited fewer changes in κ Gf than 40-nm particles, resulting in additional dominant hygroscopic peaks (κ ∼ 0.2) of κ-PDFs in both NPF and non-NPF days. When κ Gf values measured in Seosan were compared with those in other Northeast Asian countries in the literature, the κ values for 40-nm particles were lower than those (κ > 0.2) measured in Beijing and Guangzhou, but those for 100-nm particles were close to those measured in the two cities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Microorganisms, physical factors such as temperature or mechanical injury, and chemical factors such as free monomers from composite resin are the main causes of dental pulp diseases. Current clinical treatment methods for pulp diseases include the root canal therapy, vital pulp therapy and regenerative endodontic therapy. Regenerative endodontic therapy serves the purpose of inducing the regeneration of new functional pulp tissues through autologous revascularization or pulp tissue engineering. This article first discusses the current clinical methods and reviews strategies as well as the research outcomes regarding the pulp regeneration. Then the in vivo models, the prospects and challenges for regenerative endodontic therapy were further discussed., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

Poloxamer-based hydrogels show promise to stabilise and sustain the delivery of growth factors in tissue engineering applications, such as following spinal cord injury. Typically, growth factors such as neurotrophin-3 (NT-3) degrade rapidly in solution. Similarly, poloxamer hydrogels also degrade readily and are, therefore, only capable of sustaining the release of a payload over a small number of days. In this study, we focused on optimising a hydrogel formulation, incorporating both poloxamer 188 and 407, for the sustained delivery of bioactive NT-3. Hyaluronic acid blended into the hydrogels significantly reduced the degradation of the gel. We identified an optimal hydrogel composition consisting of 20 % w/w poloxamer 407, 5 % w/w poloxamer 188, 0.6 % w/w NaCl, and 1.5 % w/w hyaluronic acid. Heparin was chemically bound to the poloxamer chains to enhance interactions between the hydrogel and the growth factor. The unmodified and heparin-modified hydrogels exhibited sustained release of NT-3 for 28 days while preserving the bioactivity of NT-3. Moreover, these hydrogels demonstrated excellent cytocompatibility and had properties suitable for injection into the intrathecal space, underscoring their suitability as a growth factor delivery system. The findings presented here contribute valuable insights to the development of effective delivery strategies for therapeutic growth factors for tissue engineering approaches, including the treatment of spinal cord injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Mammalian melanin is produced in melanocytes and accumulated in melanosomes. Melanogenesis is supported by many factors derived from the surrounding tissue environment, such as the epidermis, dermis, and subcutaneous tissue, in addition to numerous melanogenesis-related genes. The roles of these genes have been fully investigated and the molecular analysis has been performed. Moreover, the role of paracrine factors derived from epidermis has also been studied. However, the role of dermis has not been fully studied. Thus, in this review, dermis-derived factors including soluble and insoluble components were overviewed and discussed in normal and abnormal circumstances. Dermal factors play an important role in the regulation of melanogenesis in the normal and abnormal mammalian skin.

Chronic odontogenic maxillary sinusitis (COMS), a prolonged inflammation of the maxillary sinus lasting over 12 weeks, is often a result of periapical lesions, marginal periodontitis, and complications like oro-antral communication (OAC) and fistula (OAF). OAC, commonly emerging post-teeth extraction in the lateral maxilla, lacks documented treatments using advanced platelet-rich fibrin (A-PRF). This study evaluates A-PRF's efficacy in treating COMS and immediately sealing extensive OAC. A case of a 28-year-old male with COMS linked to a periapical lesion and supernumerary molars is presented. Treatment involved extracting specific teeth while preserving adjacent ones and using A-PRF for immediate OAC closure. A-PRF, enriched with growth factors, was pivotal in healing, showcasing enhanced tissue regeneration, pain reduction, and faster recovery. The findings suggest A-PRF as an effective adjunct in treating extensive OAC and COMS, proposing its inclusion in standard treatment protocols. This study underscores A-PRF's potential in improving outcomes for patients with COMS and related complications.

Limited data regarding elevation of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in mobilized donors with G-CSF is available. We extended these findings by examining serum NT-proBNP in a cohort study including 35 healthy donors and 69 patients who received G-CSF for CD34+ mobilization as well as 54 patients who did not receive G-CSF but who underwent collection of CD3+ cells for chimeric antigen receptor (CAR) T-cell manufacturing. No donor in the three cohorts experienced significant cardiac adverse events. NT-proBNP levels were measured before and after G-CSF administration and after finishing apheresis procedure. NT-proBNP increase was observed in mobilized healthy donors after G-CSF administration, but was not observed in mobilized or non-mobilized patients. Only in the cohort of healthy donors, pairwise comparisons using Wilcoxon signed ranks test showed a significant increase between the mean serum NT-proBNP level after G-CSF administration and the mean serum NT-proBNP level measured before G-CSF administration (231.09 ± 156.15 pg/mL vs. 58.88 ± 26.84 pg/mL; P < .01). No correlation was observed between NT-proBNP increase and G-CSF dose (r s = 0.09; n = 32; P = .6) and no other variables contributing to predict serum NT-proBNP increase were detected. In conclusion, we observed a statistically, although not clinically, significant increase of NT-proBNP in healthy donors who received G-CSF as CD34+ cell mobilization., Competing Interests: Declaration of competing interest No conflicts of interest exist., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In pet clinics, the number of cases using trauma drugs accounts for >10% of the total number of cases, and most wounds are healing by second intention. The prolongation of wound healing time causes inconvenience and burden to pets and pet owners. Therefore, how to reduce wound healing time and achieve maximum recovery of tissue function and aesthetics is one of the focuses of veterinary clinical practice. Wound suppuration caused by Staphylococcus aureus and Pseudomonas aeruginosa is the main cause of delaying wound healing. Clinically, available antimicrobial treatments are almost exhausted due to the production of large numbers of resistant bacteria. At present, there are no bacteria resistant to traditional Chinese medicine (TCM), which makes TCM have the potential to become an effective drug for the treatment of bacterial infections, so the use of TCM in the treatment of traumatic infections has broad prospects. Based on the characteristics of infection syndrome, three different prescriptions were formulated in our laboratory, and the most effective prescription and dosage form was screened and named Lianrong Healing Cream (LRHC). The results showed that LRHC regulated the expression of fibroblast growth factor-2 (FGF-2), epidermal growth factor-1 (EGF-1), transforming growth factor-β (TGF-β) and vascular endothelial growth factor-1 (VEGF-1) genes in wound tissues and fibroblasts, thereby accelerating wound healing and repairing wound appearance and function. The results of this study may be help to develop TCM formulation for traumatic infections., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The precise delivery of growth factors (GFs) in regenerative medicine is crucial for effective tissue regeneration and wound repair. However, challenges in achieving controlled release, such as limited half-life, potential overdosing risks, and delivery control complexities, currently hinder their clinical implementation. Despite the plethora of studies endeavoring to accomplish effective loading and gradual release of GFs through diverse delivery methods, the nuanced control of spatial and temporal delivery still needs to be elucidated. In response to this pressing clinical imperative, our review predominantly focuses on explaining the prevalent strategies employed for spatiotemporal delivery of GFs over the past five years. This review will systematically summarize critical aspects of spatiotemporal GFs delivery, including judicious bio-scaffold selection, innovative loading techniques, optimization of GFs activity retention, and stimulating responsive release mechanisms. It aims to identify the persisting challenges in spatiotemporal GFs delivery strategies and offer an insightful outlook on their future development. The ultimate objective is to provide an invaluable reference for advancing regenerative medicine and tissue engineering applications., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Refractory wounds present complex and serious clinical dilemmas in plastic and reconstructive surgeries. Currently, there are no standard guidelines for the treatment of refractory wounds. To observe the clinical effects of ultraviolet (UV) therapy combined with autologous platelet-rich plasma (PRP) on chronic refractory wounds. Between January 2021 and December 2022, 60 inpatients with chronic refractory wounds were enrolled. Twenty patients were assigned to each of control groups 1 and 2 and treatment group according to whether they received PRP or UV treatment. All the patients underwent thorough debridement. Control group 2 received UV radiation. The treatment group underwent UV radiation combined with PRP gel covering the wound. Control group 1 underwent routine dressing changes after surgery, followed by skin grafting or skin key transfer if needed. One month later, we observed the wound healing in the two groups. After 2-4 PRP gel treatments, the wounds of patients in the treatment group healed. The healing time was 25.25 ± 4.93 days, and the dressings were changed 4.15 ± 3.30 times, both of which were better outcomes than in both control groups. In the treatment group, epidermal growth factor (EGF), insulin-like growth factor (IGF), platelet-derived growth factor (PGF), and transforming growth factor β (TGF-β) were slightly higher, and the concentration of vascular endothelial growth factor (VEGF) was significantly higher than in the control group (p < 0.05). PRP combined with UV therapy significantly increased the concentration of wound growth factors, accelerated wound healing, shortened treatment time, reduced treatment costs, and alleviated pain in patients., (© 2024 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

It has been reported that the effective inhibition of vascular endothelial growth factor (VEGF) can prevent the progression of ovarian hyperstimulation syndrome (OHSS). The present study aimed to investigate the mechanism underlying the effect of vitamin D 3 (VD3) on OHSS in mouse models and granulosa cells. The effects of VD3 administration (16 and 24 IU) on ovarian permeability were determined using Evans blue. In addition, ovarian pathology, corpus luteum count, inflammatory responses, and hormone and VEGFA levels were assessed using pathological sections and ELISA. Molecular docking predicted that pentraxin 3 (PTX3) could be a potential target of VD3, and therefore, the effects of human chorionic gonadotropin (hCG) and VD3 as well as PTX3 overexpression on the production and secretion of VEGFA in granulosa cells were also investigated using western blotting and immunofluorescence. Twenty-four IU VD3 significantly reversed the increase in ovarian weight and permeability in mice with OHSS. Additionally, VD3 diminished congestion and the number of corpus luteum in the ovaries and reduced the secretion levels of inflammatory factors and those of estrogen and progesterone. Notably, VD3 downregulated VEGFA and CD31 in ovarian tissues, while the expression levels of PTX3 varied among different groups. Furthermore, VD3 restored the hCG-induced enhanced VEGFA and PTX3 expression levels in granulosa cells, whereas PTX3 overexpression abrogated the VD3-mediated inhibition of VEGFA production and secretion. The present study demonstrated that VD3 could inhibit the release of VEGFA through PTX3, thus supporting the beneficial effects of VD3 administration on ameliorating OHSS symptoms., (© 2024. The Author(s).)

Tamoxifen, a selective estrogen receptor modulator (SERM), is commonly used as an adjuvant drug therapy for estrogen-receptor-positive breast cancers. Though effective at reducing the rate of cancer recurrence, patients often report unwanted cognitive and affective side effects. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We, therefore, used long-term ad lib consumption of medicated food pellets to model chronic tamoxifen exposure in a clinically relevant way. Adult female Long-Evans Hooded rats consumed tamoxifen-medicated food pellets for approximately 12 weeks, while control animals received standard chow. At the conclusion of the experiment, blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography-tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain-derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. These findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients.

Macrophages play a role in nephrolithiasis, offering the possibility of developing macrophage-mediated preventive therapies. To establish a system for screening drugs that could prevent the formation of kidney stones, we aimed to develop a model using human induced pluripotent stem cell (iPSC)-derived macrophages to study phagocytosis of calcium oxalate monohydrate (COM) crystals. Human iPSCs (201B7) were cultured. CD14+ monocytes were recovered using a stepwise process that involved the use of growth factors and cytokines. These cells were then allowed to differentiate into M1 and M2 macrophages. The macrophages were co-cultured with COM crystals and used in the phagocytosis experiments. Live cell imaging and polarized light observation via super-resolution microscopy were used to visualize phagocytosis. Localization of phagocytosed COM crystals was observed using transmission electron microscopy. Intracellular fluorescence intensity was measured using imaging cytometry to quantify phagocytosis. Human iPSCs successfully differentiated into M1 and M2 macrophages. M1 macrophages adhered to the culture plate and moved COM crystals from the periphery to cell center over time, whereas M2 macrophages did not adhere to the culture plate and actively phagocytosed the surrounding COM crystals. Fluorescence assessment over a 24-h period showed that M2 macrophages exhibited higher intracellular fluorescence intensity (5.65-times higher than that of M1 macrophages at 4.5 h) and maintained this advantage for 18 h. This study revealed that human iPSC-derived macrophages have the ability to phagocytose COM crystals, presenting a new approach for studying urinary stone formation and highlighting the potential of iPSC-derived macrophages as a tool to screen nephrolithiasis-related drugs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Immunosuppressive pathways in the tumor microenvironment (TME) are inextricably linked to tumor progression. Mono-therapeutics of immune checkpoint inhibitors (ICIs, e.g. antibodies against programmed cell death protein-1/programmed cell death ligand-1, PD-1/PD-L1) is prone to immune escape while combination therapeutics tends to cause high toxicity and side effects. Therefore, using multi-functional molecules to target multiple pathways simultaneously is becoming a new strategy for cancer therapies. Here, we developed a trifunctional fusion protein, DR30206, composed of Bevacizumab (an antibody against VEGF), and a variable domain of heavy chain of heavy chain antibody (VHH) against PD-L1 and the extracellular domain (ECD) protein of TGF-β receptor II (TGF-β RII), which are fused to the N- and C-terminus of Bevacizumab, respectively. The original intention of DR30206 design was to enhance the immune responses pairs by targeting PD-L1 while inhibiting VEGF and TGF-β in the TME. Our data demonstrated that DR30206 exhibits high antigen-binding affinities and efficient blocking capabilities, the principal drivers of efficacy in antibody therapy. Furthermore, the capability of eliciting antibody-dependent cellular cytotoxicity (ADCC) and mixed lymphocyte reaction (MLR) provides a greater possibility to enhance the immune response. Finally, in vivo experiments showed that the antitumor activity of DR30206 was superior to those of monoclonal antibody of PD-L1 or VEGF, PD-L1 and TGF-β bispecific antibody or the combination inhibition of PD-L1 and VEGF. Our findings suggest there is a great potential for DR30206 to become a therapeutic for the treatment of multiple cancer types, especially lung cancer, colon adenocarcinoma and breast carcinoma., Competing Interests: Declaration of competing interest Wenlu Fan, Yonglu Chen, Zhenxing Zhou, Wenwen Duan, Chengcheng Yang, Shimei Sheng, Yongwei Wang, Xinru Wei, Ying Liu and Yanshan Huang are employed by Zhejiang Doer Biologics Corporation, Ltd. Yanshan Huang is a shareholder of Zhejiang Doer Biologics Corporation, Ltd., (Copyright © 2024 Elsevier B.V. All rights reserved.)