Ergothioneine Protects Against UV-Induced Oxidative Stress Through the PI3K/AKT/Nrf2 Signaling Pathway.

Background: Ergothioneine (EGT) is an antioxidant, which could be detected in human tissues, and human skin cells could utilize EGT and play an anti-oxidative role in keratinocytes. And in this study we are going to elucidate whether EGT could protect the skin from photoaging by Ultraviolet (UV) exposure in mice and its molecule pathway. Methods: Histological analysis was performed for evaluating the skin structure change. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured with biological assay for evaluating oxidative and antioxidative ability of skin exposed to UV light. And the level of marker molecules in mouse skin were detected by hydroxyproline (Hyp) assay, immunohistochemical analysis, Western blot, and quantitative real-time PCR (qRT-PCR). The markers of skin aging and cell death were tested by cell culture and treatment, Western blot and qRT-PCR. Results: EGT decreased the levels of inflammatory factors induced by UV exposure in mouse skin. MDA and SOD activity detection showed that EGT decreased MDA levels, increased SOD activity, and upregulated PI3K/Akt/Nrf2 signals in mouse skin exposed to UV, which further activated Nrf2 in the nucleus and enhanced the expression of Nrf2 target genes. In the cell model, we revealed that EGT could inhibit the increase in senescence-associated ß-galactosidase-positive cells and p16 and γ-H2A.X positive cells induced by etoposide and activate PI3K/Akt/Nrf2 signaling. Moreover, a PI3K inhibitor blocked EGT protection against etoposide-induced cell death. Conclusion: The study showed EGT may play an important protective role against cell damage or death through the PI3K/Akt/Nrf2 signaling pathway in skin.

Digital ray: enhancing cataractous fundus images using style transfer generative adversarial networks to improve retinopathy detection.

BACKGROUND/AIMS: The aim of this study was to develop and evaluate digital ray, based on preoperative and postoperative image pairs using style transfer generative adversarial networks (GANs), to enhance cataractous fundus images for improved retinopathy detection. METHODS: For eligible cataract patients, preoperative and postoperative colour fundus photographs (CFP) and ultra-wide field (UWF) images were captured. Then, both the original CycleGAN and a modified CycleGAN (C2ycleGAN) framework were adopted for image generation and quantitatively compared using Frechet Inception Distance (FID) and Kernel Inception Distance (KID). Additionally, CFP and UWF images from another cataract cohort were used to test model performances. Different panels of ophthalmologists evaluated the quality, authenticity and diagnostic efficacy of the generated images. RESULTS: A total of 959 CFP and 1009 UWF image pairs were included in model development. FID and KID indicated that images generated by C2ycleGAN presented significantly improved quality. Based on ophthalmologists' average ratings, the percentages of inadequate-quality images decreased from 32% to 18.8% for CFP, and from 18.7% to 14.7% for UWF. Only 24.8% and 13.8% of generated CFP and UWF images could be recognised as synthetic. The accuracy of retinopathy detection significantly increased from 78% to 91% for CFP and from 91% to 93% for UWF. For retinopathy subtype diagnosis, the accuracies also increased from 87%-94% to 91%-100% for CFP and from 87%-95% to 93%-97% for UWF. CONCLUSION: Digital ray could generate realistic postoperative CFP and UWF images with enhanced quality and accuracy for overall detection and subtype diagnosis of retinopathies, especially for CFP.\ TRIAL REGISTRATION NUMBER: This study was registered with ClinicalTrials.gov (NCT05491798).

IL-36 antagonism blunts the proliferation and migration of oral squamous cell carcinoma cells.

IL-36 is known to mediate inflammation and fibrosis. Nevertheless, IL-36 signalling axis has also been implicated in cancer, although understanding of exact contribution of IL-36 to cancer progression is very limited, partly due to existence of multiple IL-36 ligands with agonistic and antagonistic function. Here we explored the role of IL-36 in oral squamous cell carcinoma (OSCC). Firstly, we analyzed expression of IL-36 ligands and receptor and found that the expression of IL-36γ was significantly higher in head and neck cancer (HNSCC) than that of normal tissues, and that the high expression of IL-36γ predicted poor clinical outcomes. Secondly, we investigated the direct effect of IL-36γ on OSCC cells and found that IL-36γ stimulated proliferation of OSCC cells with high expression of IL-36R expression. Interestingly, IL-36γ also promoted migration of OSCC cells with low to high IL-36R expression. Critically, both proliferation and migration of OSCC cells induced by IL-36γ were abrogated by anti-IL-36R mAb. Fittingly, RNA sequence analysis revealed that IL-36γ regulated genes involved in cell cycle and cell division. In summary, our results showed that IL-36γ can be a tumor-promoting factor, and targeting of IL-36R signalling may be a beneficial targeted therapy for patients with abnormal IL-36 signalling.

Rapid Discovery of Substances with Anticancer Potential from Marine Fungi Based on a One Strain-Many Compounds Strategy and UPLC-QTOF-MS.

The secondary metabolites of marine fungi with rich chemical diversity and biological activity are an important and exciting target for natural product research. This study aimed to investigate the fungal community in Quanzhou Bay, Fujian, and identified 28 strains of marine fungi. A total of 28 strains of marine fungi were screened for small-scale fermentation by the OSMAC (One Strain-Many Compounds) strategy, and 77 EtOAc crude extracts were obtained and assayed for cancer cell inhibition rate. A total of six strains of marine fungi (P-WZ-2, P-WZ-3-2, P-WZ-4, P-WZ-5, P56, and P341) with significant changes in cancer cell inhibition induced by the OSMAC strategy were analysed by UPLC-QTOF-MS. The ACD/MS Structure ID Suite software was used to predict the possible structures with inhibitory effects on cancer cells. A total of 23 compounds were identified, of which 10 compounds have been reported to have potential anticancer activity or cytotoxicity. In this study, the OSMAC strategy was combined with an untargeted metabolomics approach based on UPLC-QTOF-MS to efficiently analyse the effect of changes in culture conditions on anticancer potentials and to rapidly find active substances that inhibit cancer cell growth.

DeepQuality improves infant retinopathy screening.

Image quality variation is a prominent cause of performance degradation for intelligent disease diagnostic models in clinical applications. Image quality issues are particularly prominent in infantile fundus photography due to poor patient cooperation, which poses a high risk of misdiagnosis. Here, we developed a deep learning-based image quality assessment and enhancement system (DeepQuality) for infantile fundus images to improve infant retinopathy screening. DeepQuality can accurately detect various quality defects concerning integrity, illumination, and clarity with area under the curve (AUC) values ranging from 0.933 to 0.995. It can also comprehensively score the overall quality of each fundus photograph. By analyzing 2,015,758 infantile fundus photographs from real-world settings using DeepQuality, we found that 58.3% of them had varying degrees of quality defects, and large variations were observed among different regions and categories of hospitals. Additionally, DeepQuality provides quality enhancement based on the results of quality assessment. After quality enhancement, the performance of retinopathy of prematurity (ROP) diagnosis of clinicians was significantly improved. Moreover, the integration of DeepQuality and AI diagnostic models can effectively improve the model performance for detecting ROP. This study may be an important reference for the future development of other image-based intelligent disease screening systems.

Systemic Risk Factors for Vitreous Hemorrhage Secondary to Polypoidal Choroidal Vasculopathy.

INTRODUCTION: It remains unclear whether systemic factors are associated with an increased risk of vitreous hemorrhage (VH) secondary to polypoidal choroidal vasculopathy (PCV), and there is no method to predict the possibility of VH occurrence in patients with PCV. This study aimed to investigate and visualize systemic risk factors for VH in patients with PCV. METHODS: Data on the sex, age, history of systematic diseases, best-corrected visual acuity, intraocular pressure, and laboratory data of patients with PCV were collected from the medical record system. Univariate and multivariate binary logistic regression analyses were applied to investigate independent risk factors for VH in patients with PCV. Receiver operating characteristic analysis and nomograms were used to visualize the independent risk factors. RESULTS: The patient population comprised 115 patients with VH secondary to PCV and 181 patients with PCV without VH. Binary logistic regression analyses showed that higher white blood cell count [WBC; odds ratios (OR) 1.247], higher aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT; OR 2.339), and longer activated partial thromboplastin time (APTT; OR 1.196) were independent risk factors of VH in patients with PCV. Integrated application of APTT, AST/ALT, and WBC as markers showed the best performance for distinguishing patients with VH, with an area under the curve of 0.723. The nomogram was created for doctors to calculate the possibility of VH in a patient with PCV. CONCLUSIONS: Higher WBC, higher AST/ALT, and longer APTT are independent serum risk factors of VH secondary to PCV, which may shed light on VH prevention in patients with PCV.

Anti-inflammatory therapeutic biomarkers identified of human bone marrow mesenchymal stem cell therapy on aging mice by serum proteomics and peptidomics study.

Aging is accompanied by deterioration in physical condition, and creates high risks of diseases. Stem cell therapy exhibited promising potential in delaying aging. However, the unelucidated therapeutic mechanism limits future clinical application. Herein, to systematically understand the response to stem cell transfusion at the molecular level, we performed quantitative serum proteomic and peptidomics analyses in the 24-month-old aging mice model with or without mesenchymal stem cell (MSC) treatment. As a result, a total of 560 proteins and 2131 endogenous peptides were identified, among which, 6 proteins and 9 endogenous peptides derived from 6 precursor proteins were finally identified as therapeutic biomarkers after MSC transfusion on aging mice both by untargeted label-free quantification and targeted parallel reaction monitoring (PRM) quantification. Amazingly, the biological function of these differential proteins was mainly related to inflammation, which is not only the important hallmark of aging, but also the main cause of inducing aging. The reduction of these inflammatory protein content after MSC treatment further suggests the anti-inflammatory effect of MSC therapy reported elsewhere. Therefore, our study provides new evidence for the anti-inflammatory effect of MSC therapy for anti-aging and offers abundant data to support deeper investigations of the therapeutic mechanism of MSC in delaying aging.

A food poisoning caused by ST7 Staphylococcal aureus harboring sea gene in Hainan province, China.

ST7 Staphylococcus aureus is highly prevalent in humans, pigs, as well as food in China; however, staphylococcal food poisoning (SFP) caused by this ST type has rarely been reported. On May 13, 2017, an SFP outbreak caused by ST7 S. aureus strains occurred in two campuses of a kindergarten in Hainan Province, China. We investigated the genomic characteristics and phylogenetic analysis of ST7 SFP strains combined with the 91 ST7 food-borne strains from 12 provinces in China by performing whole-genome sequencing (WGS). There was clear phylogenetic clustering of seven SFP isolates. Six antibiotic genes including blaZ, ANT (4')-Ib, tetK, lnuA, norA, and lmrS were present in all SFP strains and also showed a higher prevalence rate in 91 food-borne strains. A multiple resistance plasmid pDC53285 was present in SFP strain DC53285. Among 27 enterotoxin genes, only sea and selx were found in all SFP strains. A ФSa3int prophage containing type A immune evasion cluster (sea, scn, sak, and chp) was identified in SFP strain. In conclusion, we concluded that this SFP event was caused by the contamination of cakes with ST7 S. aureus. This study indicated the potential risk of new emergencing ST7 clone for SFP.

Prevalence and associated factors of depressive and anxiety symptoms among healthcare workers in the post-pandemic era of COVID-19 at a tertiary hospital in Shenzhen, China: A cross-sectional study.

Background: Healthcare workers were at high risk of psychological problems during the COVID-19 pandemic, but it remains not well-investigated in the post-pandemic era of COVID-19, with regular epidemic prevention and control embedded in burdened healthcare work. This study aimed to investigate the prevalence and potential risk factors of the symptoms of depression and anxiety among healthcare workers at a tertiary hospital in Shenzhen. Method: Our cross-sectional study was conducted among 21- to 64-year-old healthcare workers in December 2021 at a tertiary hospital in Shenzhen, using a simple random sampling strategy. A wide range of socio-demographic characteristics, individual information, and psychological condition of the subjects were extracted. Healthcare workers' psychological conditions were tested with the Center for Epidemiologic Studies Depression (CESD-10), General Anxiety Disorder (GAD-7), Insomnia Severity Index (ISI), Work-Family Conflict Scale (WFCS), 10-item Connor-Davidson Resilience Scale (CD-RISC-10), and 17-item of Maslach's Burnout Inventory-Human Services Survey (MBI-HSS-17). Data were collected based on these questionnaires. Descriptive statistics were used to assess the difference between healthcare workers with depressive and anxiety symptoms among different groups. Hierarchical logistic regression analyses were conducted to investigate the association between focused variables and mental health outcomes. Results: A total of 245 healthcare workers were enrolled. The proportion of depressive symptoms, anxiety symptoms and their co-occurrence were 34.7, 59.6, and 33.1%, respectively. Logistic regression showed that for the three outcomes, no history of receiving psychological help and self-rated good or higher health were protective factors, whereas more severe insomnia and job burnout were risk factors. Junior or lower job title and higher psychological resilience were related to a lower prevalence of depressive symptoms, while relatively longer working hours and larger work-family conflict were positively associated with the anxiety symptoms. Psychological resilience was inversely associated with the co-occurrence of depressive and anxiety symptoms. Conclusions: Our study revealed a high proportion of psychological problems and proved that several similar factors which were significant during the pandemic were also associated with the symptoms of depression and anxiety among healthcare workers in the post-pandemic era of COVID-19. These results provide scientific evidence for psychological interventions for healthcare workers.

iPSCs-derived mesenchymal stromal cells mitigate anxiety and neuroinflammation in aging female mice.

Perimenopause is a natural transition to menopause, when hormone disturbance can result in both short-term mental disorders, such as anxiety, and long-term neuroinflammation due to blood-brain barrier (BBB) impairment, which may lead to more serious neurological disorders later on, such as dementia. Effective treatments may prevent both short-term and long-term neurological sequela, which formed the aim of this study. In aged female C57BL/6 mice (16-18 months of age), mesenchymal stromal cells (MSCs) differentiated from human-induced pluripotent stem cells (iPSCs), were administered via tail vein injection. Mice showed increased blood estrogen levels, alleviated anxiety and neuroinflammation, and improved BBB integrity. Interestingly, transplanted MSCs were located close to ovarian sympathetic nerves and decreased ovarian norepinephrine levels, which in turn increased ovarian estrogen secretion. Moreover, the administration of anastrozole, an inhibitor of estrogen synthesis, diminished the therapeutic effects of MSCs in vivo, suggesting the effect to be estrogen-dependent. In vitro study confirmed the impact of MSCs on sympathetic nerves via mitochondria exchange. In conclusion, iPSC-derived MSCs may provide a novel option to manage perimenopause-related hormonal dysregulation and neurological disorders during the female aging process.

Effects of the Implementation of an Emergency Surgical Pattern in Patients with Rhegmatogenous Retinal Detachment: A Retrospective Observational Study.

Background: To analyze the effects of the implementation of emergency surgical patterns in patients with rhegmatogenous retinal detachment (RRD) and provide evidence for promoting emergency surgical patterns for RRD. Methods: We reviewed the electronic medical records of 346 patients (348 eyes) who underwent surgical repair of RRD at the Zhongshan Ophthalmic Center in Southern China. A total of 140 patients (140 eyes) in the routine inpatient surgery group were collected at the fundus disease department between January 2019 and December 2019, and 206 patients (208 eyes) in the emergency surgery group were collected at the ophthalmic emergency department between January 2021 and December 2021. Demographics, best-corrected visual acuity (BCVA) expressed as the logarithm of the minimum angle of resolution (logMAR), the status of the macula before surgery, time to presentation, treatment interval, and postoperative BCVA measured at least three months follow-up were compared. Results: The preoperative BCVA (logMAR) of the emergency surgery group and the inpatient surgery group were 1.0 (0.4-1.7) and 1.4 (0.7-1.7), respectively, with significant differences between groups (P < 0.001). However, patients had a shorter time to presentation (7 days vs. 21 days, P < 0.001), shorter treatment interval (2 days vs. 12 days, P < 0.01), and significantly better postoperative BCVA (logMAR 0.5 vs. logMAR 1.0, P < 0.001) in the emergency surgery group than in the inpatient surgery group. There was no significant difference in primary anatomical success between the two groups (P=0.802). The median follow-up for the emergency surgery group and the inpatient surgery group were 6.08 months and 6.2 months, respectively, with no significant differences (P > 0.05). Conclusions: Patients who underwent emergency surgical patterns of RRD had better visual outcomes after surgery than patients with routine inpatient surgery, which might be attributed to a shorter duration, shorter treatment interval, and the preoperative status of the macula in the emergency surgery pattern. Emergency surgical patterns for RRD should be considered to achieve better surgical outcomes in suitable patients.

Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing.

Male reproductive system ageing is closely associated with deficiency in testosterone production due to loss of functional Leydig cells, which are differentiated from stem Leydig cells (SLCs). However, the relationship between SLC differentiation and ageing remains unknown. In addition, active lipid metabolism during SLC differentiation in the reproductive system requires transportation and processing of substrates among multiple organelles, e.g., mitochondria and endoplasmic reticulum (ER), highlighting the importance of interorganelle contact. Here, we show that SLC differentiation potential declines with disordered intracellular homeostasis during SLC senescence. Mechanistically, loss of the intermediate filament Nestin results in lower differentiation capacity by separating mitochondria-ER contacts (MERCs) during SLC senescence. Furthermore, pharmacological intervention by melatonin restores Nestin-dependent MERCs, reverses SLC differentiation capacity and alleviates male reproductive system ageing. These findings not only explain SLC senescence from a cytoskeleton-dependent MERCs regulation mechanism, but also suggest a promising therapy targeting SLC differentiation for age-related reproductive system diseases.

The accelerated aging skin in rhino-like SHJHhr mice.

SHJHhr mice line is rhino-like mice with a nonsense Hairless (Hr) mutant, which shows the characteristic of shedding hair and wrinkled skin with increasing age. Through histological analysis and aging indexes detection, SHJHhr mice show an increased thickness skin with degraded hair follicle and dermal cysts and disorganized collagen fibres, as well as decreased level of Hyp. Meanwhile, the aging markers p16 and p21 are significantly higher in SHJHhr mouse skin than ICR mouse skin at same age. Moreover, the data of MDA and SOD show a higher oxidative stress in SHJHhr mouse skin, and the levels of Nrf2 and its targets are significantly downregulated, which suggests SHJHhr mice have a faster aging skin and its reason maybe poor antioxidative protection. Overall, this study shows SHJHhr mice with an accelerated aging skin, which suggests the role of Hr gene in skin aging.

Multiscale Hierarchical Architecture-Based Bioactive Scaffolds for Versatile Tissue Engineering.

Artificial construction from tendon to bone remains a formidable challenge in tissue engineering owing to their structural complexity. In this work, bioinspired calcium silicate nanowires and alginate composite hydrogels are utilized as building blocks to construct multiscale hierarchical bioactive scaffolds for versatile tissue engineering from tendon to bone. By integrating 3D printing technology and mechanical stretch post-treatment in a confined condition, the obtained composite hydrogels possess bioinspired reinforcement architectures from nano- to submicron- to microscale with significantly enhanced mechanical properties. The biochemical and topographical cues of the composite hydrogel scaffolds provide much more efficient microenvironment to the rabbit bone mesenchymal stem cells and rabbit tendon stem cells, leading to ordered alignment and improved differentiation. The composite hydrogels markedly promote in vivo tissue regeneration from bone to tendon, especially fibrocartilage transitional tissue. Therefore, such calcium silicate nanowires/alginate composite hydrogels with multiscale hierarchical structures have potential application for tissue regeneration from tendon to bone. This work provides an innovative strategy to construct multiscale hierarchical architecture-based scaffolds for tendon/bone engineering.

FG7142 combined with restraint stress induces anxiogenic-like effects via downregulation gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine 1A receptors expression in the hippocampus.

OBJECTIVES: The existing anxiety animal models are susceptible to interference, and no single animal anxiety model can predict the future anxiolytic potential and profile of new putative anxiolytics. Therefore, to find a better anxiety animal model, we used FG7142, a nonselective benzodiazepine inverse agonist. This anxiety animal model was established by intraperitoneal injection of FG7142 combined with restraint stress. METHODS: Adult male C57BL/6J mice (18-20 g) were randomly classified into five groups (n = 10 per group), namely the control, restraint stress, restraint stress + 10 mg/kg FG7142, restraint stress + 20 mg/kg FG7142, restraint stress +30 mg/kg FG7142. The impact on behavior was explored by elevated plus maze, and marble burying test, followed by immunohistochemistry and quantitative real-time PCR enabled the elucidation of the possible mechanism. RESULTS: Compared with the control group and restraint stress group, intraperitoneal injection of FG7142 combined with restraint stress model group was found to induce anxiogenic-like behavior in elevated plus maze and marble burying test. Moreover, relative to the control group, significantly increased expression of c-fos in the hippocampus and amygdala in the model group was evident, whereas the expression of gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine receptor 1A mRNA was significantly decreased in the hippocampus. CONCLUSIONS: These results indicated that FG7142 combined with restraint stress is sufficient to induce anxiety, and its mechanism is associated with downregulation of hippocampal gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine 1A receptors.

Structural and functional insights into a novel pre-clinical-stage antibody targeting IL-17A for treatment of autoimmune diseases.

The pro-inflammatory cytokine interleukin-17A (IL-17A) is a key driver of multiple inflammatory and immune disorders. Therapeutic antibodies targeting IL-17A have been proven effective in treating patients with these diseases; however, large variations in clinical outcomes have been observed with different antibodies. In this study, we developed HB0017, a novel monoclonal antibody that targets human IL-17A. HB0017 specifically and strongly bound to human, cynomolgus monkey, and mouse IL-17A at the physiological interface with the IL-17A receptor. In human and monkey cells, HB0017 potently antagonized the functions of IL-17A through competitive binding. HB0017 functioned equivalently to that of clinically approved antibodies in terms of therapeutic efficacy for inflammatory disorders and psoriasis in a mouse model. The results indicate that HB0017 may be an alternative biological therapy for treating patients with inflammation and autoimmune diseases.

Nestin promotes pulmonary fibrosis via facilitating recycling of TGF-ß receptor I.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is characterised by aberrant proliferation of activated myofibroblasts and pathological remodelling of the extracellular matrix. Previous studies have revealed that the intermediate filament protein nestin plays key roles in tissue regeneration and wound healing in different organs. Whether nestin plays a critical role in the pathogenesis of IPF needs to be clarified. METHODS: Nestin expression in lung tissues from bleomycin-treated mice and IPF patients was determined. Transfection with nestin short hairpin RNA vectors in vitro that regulated transcription growth factor (TGF)-ß/Smad signalling was conducted. Biotinylation assays to observe plasma membrane TßRI, TßRI endocytosis and TßRI recycling after nestin knockdown were performed. Adeno-associated virus serotype (AAV)6-mediated nestin knockdown was assessed in vivo. RESULTS: We found that nestin expression was increased in a murine pulmonary fibrosis model and IPF patients, and that the upregulated protein primarily localised in lung α-smooth muscle actin-positive myofibroblasts. Mechanistically, we determined that nestin knockdown inhibited TGF-ß signalling by suppressing recycling of TßRI to the cell surface and that Rab11 was required for the ability of nestin to promote TßRI recycling. In vivo, we found that intratracheal administration of AAV6-mediated nestin knockdown significantly alleviated pulmonary fibrosis in multiple experimental mice models. CONCLUSION: Our findings reveal a pro-fibrotic function of nestin partially through facilitating Rab11-dependent recycling of TßRI and shed new light on pulmonary fibrosis treatment.

A Novel Bispecific Antibody Targeting PD-L1 and VEGF With Combined Anti-Tumor Activities.

Therapeutic monoclonal antibodies (mAbs) blocking immune checkpoints have been mainly used as monotherapy. Recently, combination therapy targeting multiple immune checkpoints has recently been explored to increase anti-cancer efficacy. Particularly, a single molecule targeting more than one checkpoints has been investigated. As dual blocking of PD-1/PD-L1 and VEGF/VEGFR has demonstrated synergism in anti-tumor activities, we developed a novel bispecific antibody, termed HB0025, which is formed via fusing the domain 2 of vascular endothelial growth factor receptor 1 (VEGFR1D2) and anti-PD-L1 mAb by using mAb-Trap technology. HB0025 almost completely retains the binding affinities and the biological activities in-vitro when compared with the parent anti-PD-L1 mAb or VEGFR1D2 fusion protein. Preclinical data demonstrated that HB0025 was more effective in inhibiting cancer growth than anti PD-L1 mAb or VEGFR1D2 fusion protein. Thus, our bispecific antibody may bring about greater clinical benefits and broader indications.

3D printed hydrogel/PCL core/shell fiber scaffolds with NIR-triggered drug release for cancer therapy and wound healing.

Hydrogel based scaffolds with the ability of on-demand drug delivery gained increasing interests for localized cancer therapy and tissue engineering application. However, most drug-loaded hydrogels are generally not suitable for long-term drug delivery, because of the uncontrolled diffusion of drugs from the swollen hydrogels. Therefore, in this study, a core/shell fiber scaffold was fabricated by coating a homogeneous layer of polycaprolactone (PCL) on the 3D printed alginate-gelatin hydrogel scaffolds. The PCL coatings could reduce the free diffusion of drugs from the core gels. Subsequently, polydopamine (PDA) was coated on the Gel/PCL core/shell scaffolds, endowing the scaffolds with great photothermal effects. Thus, near-infrared (NIR) laser triggered on-demand drug release was realized in this system due to the thermally induced sol-gel transition of the core gels. The released drugs (doxorubicin) and photothermal therapy could effectively prohibit or ablate tumor in vitro and in vivo. Additionally, the Gel/PCL/PDA core/shell scaffold could serve as platform for promoting wound healing. Therefore, the reported Gel/PCL/PDA core/shell scaffolds have the potential for application in localized cancer therapy and tissue regeneration. Especially for those cancer patients suffering surgical resection, the scaffolds could be implanted in the resection site to kill the residual or recurrent cancer cells, as well as to repair the tissue defects caused by surgery. STATEMENT OF SIGNIFICANCE: This paper reported a facile strategy to realize stimuli-triggered on demand drug release in vitro and in vivo. Polycaprolactone (PCL) and polydopamine were sequentially deposited on the surface of 3D printed drug-loaded alginate/gelatin scaffold. PCL encapsulation could effectively reduce the free diffusion of drugs from the core hydrogel, achieving sustained drug release. Polydopamine with good photothermal effects endowed the scaffold with stimuli-triggered drug release in response to near-infrared (NIR) laser irradiation. This scaffold could be applied for localized cancer therapy and tissue regeneration. Especially for those cancer patients suffering surgical resection, the scaffolds could be implanted in the resection site to kill the residual or recurrent cancer cells, as well as to repair the tissue defects caused by surgery.