The predominant Quillaja Saponaria fraction, QS-18, is safe and effective when formulated in a liposomal murine cancer peptide vaccine.

Extracts of the Chilean soapbark tree, Quillaja Saponaria (QS) are the source of potent immune-stimulatory saponin compounds. This study compared the adjuvanticity and toxicity of QS-18 and QS-21, assessing the potential to substitute QS-18 in place of QS-21 for vaccine development. QS-18, the most abundant QS saponin fraction, has been largely overlooked due to safety concerns. We found that QS-18 spontaneously inserted into liposomes, thereby neutralizing hemolytic activity, and following administration did not induce local reactogenicity in a footpad swelling test in mice. With high-dose intramuscular administration, transient weight loss was minor, and QS-18 did not induce significantly more weight loss compared to a liposome vaccine adjuvant system lacking it. Two days after administration, no elevation of inflammatory cytokines was detected in murine serum. In a formulation including cobalt-porphyrin-phospholipid (CoPoP) for short peptide sequestration, QS-18 did not impact the formation of peptide nanoparticles. With immunization, QS-18 peptide particles induced higher levels of cancer neoepitope-specific and tumor-associated antigen-specific CD8+ T cells compared to QS-21 particles, without indication of greater toxicity based on mouse body weight. T cell receptor sequencing of antigen-specific CD8+ T cells showed that QS-18 induced significantly more T cell transcripts. In two murine cancer models, vaccination with QS-18 peptide particles induced a similar therapeutic effect as QS-21 particles, without indication of increased toxicity. Antigen-specific CD8+ T cells in the tumor microenvironment were found to express the exhaustion marker PD-1, pointing to the rationale for exploring combination therapy. Taken together, these data demonstrate that QS-18, when formulated in liposomes, can be a safe and effective adjuvant to induce tumor-inhibiting cellular responses in murine models with potential to facilitate or diminish costs of production for vaccine adjuvant systems. Further studies are warranted to assess liposomal QS-18 immunogic, reactogenic and toxicological profiles in mice and other animal species.

Reduced Monocular Luminance Promotes Fusion But Not Mixed Perception in Amblyopia.

Purpose: The purpose of this study was to understand how monocular luminance reduction affects binocular balance and examine whether it differentially influences fusion and mixed perception in amblyopia. Methods: Twenty-three normally sighted observers and 12 adults with amblyopia participated in this study. A novel binocular rivalry task was used to measure the phase duration of four perceptual responses (right- and left-tilts, fusion, and mixed perception) before and after a neutral density (ND) filter was applied at various levels to the dominant eye (DE) of controls and the fellow eye (FE) of patients with amblyopia. Phase durations were analyzed to assess whether the duration of fusion or mixed perception shifted after monocular luminance reduction. Moreover, we quantified ocular dominance and adjusted monocular contrast and luminance separately to investigate the relationship between changes in ocular dominance induced by the two manipulations. Results: In line with previous studies, binocular balance shifted in favor of the brighter eye in both normal adults and patients with amblyopia. As a function of the ND filter's density, the duration of fusion and mixed perception decreased in normal controls, whereas that of fusion but not mixed perception increased significantly in patients with amblyopia. In addition, changes in binocular balance from luminance reduction were more significant in more balanced amblyopes or normal observers. Furthermore, shifts in binocular balance after contrast and luminance modulation were correlated in both normal and amblyopic observers. Conclusions: The duration of fusion but not mixed perception increased in amblyopia after monocular luminance reduction in the FE. Moreover, our findings demonstrate that changes in ocular dominance from contrast-modulation and luminance-modulation are correlated in both normal and amblyopic observers.

Identification of Enhanced Vaccine Mimotopes for the p15E Murine Cancer Antigen.

Mimotopes of short CD8+ T-cell epitopes generally comprise one or more mutated residues, and can increase the immunogenicity and function of peptide cancer vaccines. We recently developed a two-step approach to generate enhanced mimotopes using positional peptide microlibraries and herein applied this strategy to the broadly used H-2Kb-restricted murine leukemia p15E tumor rejection epitope. The wild-type p15E epitope (sequence: KSPWFTTL) was poorly immunogenic in mice, even when combined with a potent peptide nanoparticle vaccine system and did not delay p15E-expressing MC38 tumor growth. Following positional microlibrary functional screening of over 150 mimotope candidates, two were identified, both with mutations at residue 3 (p15E-P3C; "3C," and p15E-P3M; "3M") that better induced p15E-specific CD8+ T cells and led to tumor rejection. Although 3M was more immunogenic, 3C effectively delayed tumor growth in a therapeutic setting relative to the wild-type p15E. As 3C had less H-2Kb affinity relative to both p15E and 3M, 15 additional mimotope candidates (all that incorporated the 3C mutation) were assessed that maintained or improved predicted MHC-I affinity. Valine substitution at position 2 (3C2V, sequence: KVCWFTTL) led to improved p15E-specific immunogenicity, tumor rejection, and subsequent long-term antitumor immunity. 3C, 3M, and 3C2V mimotopes were more effective than p15E in controlling MC38 and B16-F10 tumors. T-cell receptor (TCR) sequencing revealed unique TCR transcripts for mimotopes, but there were no major differences in clonality. These results provide new p15E mimotopes for further vaccine use and illustrate considerations for MHC-I affinity, immunogenicity, and functional efficacy in mimotope design. SIGNIFICANCE: The MHC-I-restricted p15E tumor rejection epitope is expressed in multiple murine cancer lines and is used as a marker of antitumor cellular immunity, but has seen limited success as a vaccine immunogen. An in vivo screening approach based on a positional peptide microlibraries is used to identify enhanced p15E mimotopes bearing amino acid mutations that induce significantly improved functional immunogenicity relative to vaccination with the wild-type epitope.

Risk Prediction of Diabetes Progression Using Big Data Mining with Multifarious Physical Examination Indicators.

Purpose: The purpose of this study is to explore the independent-influencing factors from normal people to prediabetes and from prediabetes to diabetes and use different prediction models to build diabetes prediction models. Methods: The original data in this retrospective study are collected from the participants who took physical examinations in the Health Management Center of Peking University Shenzhen Hospital. Regression analysis is individually applied between the populations of normal and prediabetes, as well as the populations of prediabetes and diabetes, for feature selection. Afterward,the independent influencing factors mentioned above are used as predictive factors to construct a prediction model. Results: Selecting physical examination indicators for training different ML models through univariate and multivariate logistic regression, the study finds Age, PRO, TP, and ALT are four independent risk factors for normal people to develop prediabetes, and GLB and HDL.C are two independent protective factors, while logistic regression performs best on the testing set (Acc: 0.76, F-measure: 0.74, AUC: 0.78). We also find Age, Gender, BMI, SBP, U.GLU, PRO, ALT, and TG are independent risk factors for prediabetes people to diabetes, and AST is an independent protective factor, while logistic regression performs best on the testing set (Acc: 0.86, F-measure: 0.84, AUC: 0.74). Conclusion: The discussion of the clinical relationships between these indicators and diabetes supports the interpretability of our feature selection. Among four prediction models, the logistic regression model achieved the best performance on the testing set.

Adjuvanted nanoliposomes displaying six hemagglutinins and neuraminidases as an influenza virus vaccine.

Inclusion of defined quantities of the two major surface proteins of influenza virus, hemagglutinin (HA) and neuraminidase (NA), could benefit seasonal influenza vaccines. Recombinant HA and NA multimeric proteins derived from three influenza serotypes, H1N1, H3N2, and type B, are surface displayed on nanoliposomes co-loaded with immunostimulatory adjuvants, generating "hexaplex" particles that are used to immunize mice. Protective immune responses to hexaplex liposomes involve functional antibody elicitation against each included antigen, comparable to vaccination with monovalent antigen particles. When compared to contemporary recombinant or adjuvanted influenza virus vaccines, hexaplex liposomes perform favorably in many areas, including antibody production, T cell activation, protection from lethal virus challenge, and protection following passive sera transfer. Based on these results, hexaplex liposomes warrant further investigation as an adjuvanted recombinant influenza vaccine formulation.

Injectable ultrasound-powered bone-adhesive nanocomposite hydrogel for electrically accelerated irregular bone defect healing.

The treatment of critical-size bone defects with irregular shapes remains a major challenge in the field of orthopedics. Bone implants with adaptability to complex morphological bone defects, bone-adhesive properties, and potent osteogenic capacity are necessary. Here, a shape-adaptive, highly bone-adhesive, and ultrasound-powered injectable nanocomposite hydrogel is developed via dynamic covalent crosslinking of amine-modified piezoelectric nanoparticles and biopolymer hydrogel networks for electrically accelerated bone healing. Depending on the inorganic-organic interaction between the amino-modified piezoelectric nanoparticles and the bio-adhesive hydrogel network, the bone adhesive strength of the prepared hydrogel exhibited an approximately 3-fold increase. In response to ultrasound radiation, the nanocomposite hydrogel could generate a controllable electrical output (-41.16 to 61.82 mV) to enhance the osteogenic effect in vitro and in vivo significantly. Rat critical-size calvarial defect repair validates accelerated bone healing. In addition, bioinformatics analysis reveals that the ultrasound-responsive nanocomposite hydrogel enhanced the osteogenic differentiation of bone mesenchymal stem cells by increasing calcium ion influx and up-regulating the PI3K/AKT and MEK/ERK signaling pathways. Overall, the present work reveals a novel wireless ultrasound-powered bone-adhesive nanocomposite hydrogel that broadens the therapeutic horizons for irregular bone defects.

SARS-CoV-2 Protein Nanoparticle Vaccines Formed In Situ From Lyophilized Lipids.

The receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) glycoprotein is an appealing immunogen, but associated vaccine approaches must overcome the hapten-like nature of the compact protein and adapt to emerging variants with evolving RBD sequences. Here, a vaccine manufacturing methodology is proposed comprising a sterile-filtered freeze-dried lipid cake formulation that can be reconstituted with liquid proteins to instantaneously form liposome-displayed protein nanoparticles. Mannitol is used as a bulking agent and a small amount of Tween-80 surfactant is required to achieve reconstituted submicron particles that do not precipitate prior to usage. The lipid particles include an E. coli-derived monophosphoryl lipid A (EcML) for immunogenicity, and cobalt porphyrin-phospholipid (CoPoP) for antigen display. Reconstitution of the lipid cake with aqueous protein results in rapid conversion of the RBD into intact liposome-bound format prior to injection. Protein particles can readily be formed with sequent-divergent RBD proteins derived from the ancestral or Omicron strains. Immunization of mice elicits antibodies that neutralize respective viral strains. When K18-hACE2 transgenic mice are immunized and challenged with ancestral SARS-CoV-2 or the Omicron BA.5 variant, both liquid liposomes displaying the RBD and rapid reconstituted particles protect mice from infection, as measured by the viral load in the lungs and nasal turbinates.

Jacalin-related lectin 45 (OsJRL45) isolated from 'sea rice 86' enhances rice salt tolerance at the seedling and reproductive stages.

BACKGROUND: Rice (Oryza sativa L.) is one of the most widely cultivated grain crops in the world that meets the caloric needs of more than half the world's population. Salt stress seriously affects rice production and threatens food security. Therefore, mining salt tolerance genes in salt-tolerant germplasm and elucidating their molecular mechanisms in rice are necessary for the breeding of salt tolerant cultivars. RESULTS: In this study, a salt stress-responsive jacalin-related lectin (JRL) family gene, OsJRL45, was identified in the salt-tolerant rice variety 'sea rice 86' (SR86). OsJRL45 showed high expression level in leaves, and the corresponding protein mainly localized to the endoplasmic reticulum. The knockout mutant and overexpression lines of OsJRL45 revealed that OsJRL45 positively regulates the salt tolerance of rice plants at all growth stages. Compared with the wild type (WT), the OsJRL45 overexpression lines showed greater salt tolerance at the reproductive stage, and significantly higher seed setting rate and 1,000-grain weight. Moreover, OsJRL45 expression significantly improved the salt-resistant ability and yield of a salt-sensitive indica cultivar, L6-23. Furthermore, OsJRL45 enhanced the antioxidant capacity of rice plants and facilitated the maintenance of Na+-K+ homeostasis under salt stress conditions. Five proteins associated with OsJRL45 were screened by transcriptome and interaction network analysis, of which one, the transmembrane transporter Os10g0210500 affects the salt tolerance of rice by regulating ion transport-, salt stress-, and hormone-responsive proteins. CONCLUSIONS: The OsJRL45 gene isolated from SR86 positively regulated the salt tolerance of rice plants at all growth stages, and significantly increased the yield of salt-sensitive rice cultivar under NaCl treatment. OsJRL45 increased the activity of antioxidant enzyme of rice and regulated Na+/K+ dynamic equilibrium under salinity conditions. Our data suggest that OsJRL45 may improve the salt tolerance of rice by mediating the expression of ion transport-, salt stress response-, and hormone response-related genes.

Vaccine approaches for antigen capture by liposomes.

INTRODUCTION: Liposomes have been used as carriers for vaccine adjuvants and antigens due to their inherent biocompatibility and versatility as delivery vehicles. Two vial admixture of protein antigens with liposome-formulated immunostimulatory adjuvants has become a broadly used clinical vaccine preparation approach. Compared to freely soluble antigens, liposome-associated forms can enhance antigen delivery to antigen-presenting cells and co-deliver antigens with adjuvants, leading to improved vaccine efficacy. AREAS COVERED: Several antigen-capture strategies for liposomal vaccines have been developed for proteins, peptides, and nucleic acids. Specific antigen delivery methodologies are discussed, including electrostatic adsorption, encapsulation inside the liposome aqueous core, and covalent and non-covalent antigen capture. EXPERT OPINION: Several commercial vaccines include active lipid components, highlighting an increasingly prominent role of liposomes and lipid nanoparticles in vaccine development. Utilizing liposomes to associate antigens offers potential advantages, including antigen and adjuvant dose-sparing, co-delivery of antigen and adjuvant to immune cells, and enhanced immunogenicity. Antigen capture by liposomes has demonstrated feasibility in clinical testing. New antigen-capture techniques have been developed and appear to be of interest for vaccine development.

Understanding CaCl2 induces surface gelatinization to promote cold plasma modified maize starch: Structure-effect relations.

To investigate the influence of surface gelatinization on cold plasma (CP) modification of starch, this study used CaCl2 to modify maize starch by surface gelatinization, further combined with CP treatment and characterized its multi-scale structure and physicochemical properties. The results revealed that starch surface gelatinization causes roughness and fragmentation on the granule surface, and CP undergoes etching effects. The synergistic modification promotes starch degradation, as evidenced by molecular weight decrease and short-chain ratio increase. Although the growth rings, FT-IR patterns, and crystal types of starch remained unchanged, the synergistic modification induced a reduction in the short-range orderliness and crystallinity of starch, thus causing a decrease in the pasting properties and contributing to its solubility. Notably, the CP treatment improved the RDS and SDS contents of the gelatinized starch due to more active sites on the granule surface after gelatinization, and this finding may provide insight into the deep processing of starch.

Corrigendum: Improved single-cell genome amplification by a high-efficiency phi29 DNA polymerase.

[This corrects the article DOI: 10.3389/fbioe.2023.1233856.].

Low-light image enhancement based on Retinex-Net with color restoration.

Low-light images often suffer from a variety of degradation problems such as loss of detail, color distortions, and prominent noise. In this paper, the Retinex-Net model and loss function with color restoration are proposed to reduce color distortion in low-light image enhancement. The model trains the decom-net and color recovery-net to achieve decomposition of low-light images and color restoration of reflected images, respectively. First, a convolutional neural network and the designed loss functions are used in the decom-net to decompose the low-light image pair into an optimal reflection image and illumination image as the input of the network, and the reflection image after normal light decomposition is taken as the label. Then, an end-to-end color recovery network with a simplified model and time complexity is learned and combined with the color recovery loss function to obtain the correction reflection map with higher perception quality, and gamma correction is applied to the decomposed illumination image. Finally, the corrected reflection image and the illumination image are synthesized to get the enhanced image. The experimental results show that the proposed network model has lower brightness-order-error (LOE) and natural image quality evaluator (NIQE) values, and the average LOE and NIQE values of the low-light dataset images can be reduced to 942 and 6.42, respectively, which significantly improves image quality compared with other low-light enhancement methods. Generally, our proposed method can effectively improve image illuminance and restore color information in the end-to-end learning process of low-light images.

HS-GC-IMS Analysis of Volatile Organic Compounds in Different Varieties and Harvesting Times of Rhizoma gastrodiae (Tian Ma) in Yunnan Province.

Headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) coupled with principal component analysis (PCA) was used to investigate the differences in volatile organic compounds (VOCs) in four different varieties of Yunnan Huang Tian Ma (containing both winter and spring harvesting times), Yunnan Hong Tian Ma, Yunnan Wu Tian Ma, and Yunnan Lv Tian Ma. The results showed that the flavor substances of different varieties and different harvesting times of Rhizoma gastrodiae were mainly composed of aldehydes, alcohols, ketones, heterocycles, esters, acids, alkenes, hydrocarbons, amines, phenols, ethers, and nitrile. Among them, the contents of the aldehydes, alcohols, ketones, and heterocyclic compounds are significantly higher than those of other substances. The results of cluster analysis and fingerprint similarity analysis based on principal component analysis and Euclidean distance showed that there were some differences between different varieties of Yunnan Rhizoma gastrodiae and different harvesting times. Among them, Yunnan Lv Tian Ma and Wu Tian Ma contained the richest volatile components. Winter may be the best harvesting season for Tian Ma. At the same time, we speculate that the special odor contained in Tian Ma should be related to the aldehydes it is rich in, especially benzene acetaldehyde, Benzaldehyde, Heptanal, Hexanal, Pentanal, and butanal, which are aldehydes that contain a strong and special odor and are formed by the combination of these aldehydes.

Improved single-cell genome amplification by a high-efficiency phi29 DNA polymerase.

Single-cell genomic whole genome amplification (WGA) is a crucial step in single-cell sequencing, yet its low amplification efficiency, incomplete and uneven genome amplification still hinder the throughput and efficiency of single-cell sequencing workflows. Here we introduce a process called Improved Single-cell Genome Amplification (iSGA), in which the whole single-cell sequencing cycle is completed in a high-efficient and high-coverage manner, through phi29 DNA polymerase engineering and process engineering. By establishing a disulfide bond of F137C-A377C, the amplification ability of the enzyme was improved to that of single-cell. By further protein engineering and process engineering, a supreme enzyme named HotJa Phi29 DNA Polymerase was developed and showed significantly better coverage (99.75%) at a higher temperature (40°C). High single-cell genome amplification ability and high coverage (93.59%) were also achieved for commercial probiotic samples. iSGA is more efficient and robust than the wild-type phi29 DNA polymerase, and it is 2.03-fold more efficient and 10.89-fold cheaper than the commercial Thermo Scientific EquiPhi29 DNA Polymerase. These advantages promise its broad applications in large-scale single-cell sequencing.

Interaction between two overall neutral charged microscopically patterned surfaces.

We study the interaction between heterogeneously charged surfaces in an electrolyte solution by employing classical Density Functional Theory (cDFT) and Monte Carlo simulations. We observe a consistent behavior between cDFT and Monte Carlo simulations regarding force curves and two-dimensional density profiles. Armed with the validated cDFT, we explore the system's behavior under parameters that are challenging to simulate directly. Our findings include the impacts of domain size, domain charge, domain charge configuration, and bulk electrolyte concentration on the osmotic pressure. Remarkably, the force curve is more sensitive to the domain size for an asymmetric configuration than a symmetry configuration; the bulk concentration weakly influences the force curve independent of the system configurations.

Tanshinone IIA promotes vascular normalization and boosts Sorafenib's anti-hepatoma activity via modulating the PI3K-AKT pathway.

Introduction: Angiogenesis is an essential feature of liver cancer. Tumor hypoxia results from abnormal vessel architecture. Numerous studies have sufficiently demonstrated that Tanshinone IIA (Tan IIA) can increase blood flow and enhance microcirculation. The objectives of this study are to: 1 assess the impact of Tan IIA on tumor angiogenesis and architecture, 2 determine the impact of Tan IIA on tumor hypoxia and susceptibility to Sorafenib, and 3 clarify the relevant mechanisms. Methods: CCK8 and flow cytometry measured cell proliferation and apoptosis, respectively. Tube creation assay was used to investigate medication effects on angiogenesis and structure. Drug effects on tumor development, metastasis, and hypoxic tumor microenvironment are assessed in an orthotopic xenograft model of liver tumors. Protein expression was measured by Western blotting and immunohistochemistry. Results: Our results demonstrated that Tan IIA could not reduce tumor proliferation or enhance Sorafenib's anti-tumor effect in vitro. Nevertheless, it can prevent Sorafenib from demolishing the typical vascular structure and aid sorafenib in blocking the recruitment of vascular endothelial cells by liver cancer cells. Although Tan IIA cannot inhibit tumor growth in vivo, it can significantly boost Sorafenib's inhibitory effect on liver cancer, alleviate tumor microenvironment hypoxia, and minimize lung metastasis. This effect may be achieved by reducing HIF-1α and HIF-2α expression via the PI3K-AKT signal pathway. Discussion: Our results reveal the mechanism of Tan IIA in normalizing tumor blood vessels, provide innovative concepts and approaches to overcome chemotherapy resistance, and provide a theoretical basis for the clinical transformation and usage of Tan IIA.

Yak Milk: Nutritional Value, Functional Activity, and Current Applications.

The yak is a special species that inhabits the Qinghai-Tibet Plateau and its surrounding areas. Its unique habitat gives yak milk certain distinct characteristics compared to regular cow milk. Yak milk not only has a high nutritional value but also holds potential benefits for human health. In recent years, there has been increasing research attention on yak milk. Studies have found that the bioactive components in yak milk have various functional properties, including antioxidant, anticancer, antibacterial, blood pressure-lowering, anti-fatigue, and constipation-relieving effects. However, more evidence is needed to confirm these functions in the human body. Therefore, by reviewing the current research status on the nutrition and functionality of yak milk, we aim to reveal its enormous potential as a source of nutritional and functional substances. This article primarily analyzed the nutritional composition of yak milk and the functional effects of its bioactive components, categorically elucidated the mechanisms behind its functional activities, and provided a brief introduction to related yak milk products. Our objective is to deepen people's understanding of yak milk and provide some references for its further development and utilization.

The Potential of Natural Oils to Improve Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder that includes ulcerative colitis (UC) and Crohn's disease (CD), the exact cause of which is still unknown. Numerous studies have confirmed that diet is one of the major environmental factors associated with IBD, as it can regulate the gut microbiota and reduce inflammation and oxidative stress. Since the consumption of oil is essential in the diet, improving IBD through oil has potential. In this article, we first briefly reviewed the current treatment methods for IBD and introduce the role of natural oils in improving inflammatory diseases. We then focused on the recent discovery of the role of natural oils in the prevention and treatment of IBD and summarized their main mechanisms of action. The results showed that the anti-inflammatory activity of oils derived from different plants and animals has been validated in various experimental animal models. These oils are capable of improving the intestinal homeostasis in IBD animal models through multiple mechanisms, including modulation of the gut microbiota, protection of the intestinal barrier, reduction in colonic inflammation, improvement in oxidative stress levels in the intestine, and regulation of immune homeostasis. Therefore, dietary or topical use of natural oils may have potential therapeutic effects on IBD. However, currently, only a few clinical trials support the aforementioned conclusions. This review emphasized the positive effects of natural oils on IBD and encouraged more clinical trials to provide more reliable evidence on the improvement of human IBD by natural oils as functional substances.

Transcatheter arterial chemoembolization plus apatinib with or without camrelizumab for unresectable hepatocellular carcinoma: a multicenter retrospective cohort study.

BACKGROUND: The evidence of transcatheter arterial chemoembolization (TACE) plus tyrosine kinase inhibitor and immune checkpoint inhibitor in unresectable hepatocellular carcinoma (HCC) was limited. This study aimed to evaluate the role of TACE plus apatinib (TACE + A) and TACE combined with apatinib plus camrelizumab (TACE + AC) in patients with unresectable HCC. METHODS: This study retrospectively reviewed patients with unresectable HCC who received TACE + A or TACE + AC in 20 centers of China from January 1, 2019 to June 31, 2021. Propensity score matching (PSM) at 1:1 was performed to reduce bias. Treatment-related adverse events (TRAEs), overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were collected. RESULTS: A total of 960 eligible patients with HCC were included in the final analysis. After PSM, there were 449 patients in each group, and the baseline characteristics were balanced between two groups. At data cutoff, the median follow-up time was 16.3 (range: 11.9-21.4) months. After PSM, the TACE + AC group showed longer median OS (24.5 vs 18.0 months, p < 0.001) and PFS (10.8 vs 7.7 months, p < 0.001) than the TACE + A group; the ORR (49.9% vs 42.5%, p = 0.002) and DCR (88.4% vs 84.0%, p = 0.003) of the TACE + AC group were also higher than those in the TACE + A group. Fever, pain, hypertension and hand-foot syndrome were the more common TRAEs in two groups. CONCLUSIONS: Both TACE plus apatinib and TACE combined with apatinib plus camrelizumab were feasible in patients with unresectable HCC, with manageable safety profiles. Moreover, TACE combined with apatinib plus camrelizumab showed additional benefit.

Assessing urban flooding risk in response to climate change and urbanization based on shared socio-economic pathways.

Global climate change and rapid urbanization, mainly driven by anthropogenic activities, lead to urban flood vulnerability and uncertainty in sustainable stormwater management. This study projected the temporal and spatial variation in urban flood susceptibility during the period 2020-2050 on the basis of shared socioeconomic pathways (SSPs). A case study in Guangdong-Hong Kong-Macao Greater Bay Area (GBA) was conducted for verifying the feasibility and applicability of this approach. GBA is predicted to encounter the increase in extreme precipitation with high intensity and frequency, along with rapid expansion of constructed areas, resulting in exacerbating of urban flood susceptibility. The areas with medium and high flood susceptibility will be expected to increase continuously from 2020 to 2050, by 9.5 %, 12.0 %, and 14.4 % under SSP1-2.6, SSP2-4.5, and SSP5-8.5 scenarios, respectively. In terms of the assessment of spatial-temporal flooding pattern, the areas with high flood susceptibility are overlapped with that in the populated urban center in GBA, surrounding the existing risk areas, which is consistent with the tendency of construction land expansion. The approach in the present study will provide comprehensive insights into the reliable and accurate assessment of urban flooding susceptibility in response to climate change and urbanization.