Robust Gradient Hydrogel-Loaded Nanofiber Fleshy Artificial Skin Via A Coupled Microfluidic Electrospinning-Reactive Coating Strategy.

Skin regeneration attracts tremendous interest due to the important role of skin for human protection and beauty. Thus, methods allowing artificial skin to be carried out in a controllable fashion are potentially important for wound healing, which involves an intersection of materials, medicine, biology, and other disciplines. Herein, aiming at a new general methodology for fleshy materials, a new hydrogel-loaded hydrophobic-hydrophilic nanofiber fleshy artificial skin is designed and fabricated. The gradient hydrogel-loaded nanofiber artificial skin integrates both advantages of nanofiber and hydrogel, exhibiting fleshy feature (comparability to real skin in terms of appearance, texture, and function), excellent air permeability, compatibility, and good mechanical and antibacterial property. Interestingly, the efficient transport channels are formed throughout the hydrogel-loaded nanofiber structure, which is beneficial for water absorption and transfer. These advantages enable the establishment of a moist and favorable microenvironment; thus, greatly accelerating wound healing process. This work couples microfluidic electrospinning with reactive coating technique, which is in favor of material design and fabrication with controllable and uniform structures. The hydrogel-loaded nanofiber fleshy artificial skin shows comparability to real skin in terms of beauty, texture, and function, which would definitely provide new opportunities for the further optimization and upgrading of artificial skin.

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors.

VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 µM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

Prognostic characteristics of a six-gene signature based on ssGSEA in sarcoma.

BACKGROUND: Sarcoma is a rare malignant tumor originating of the interstitial or connective tissue with a poor prognosis. Next-generation sequencing technology offers new opportunities for accurate diagnosis and treatment of sarcomas. There is an urgent need for new gene signature to predict prognosis and evaluate treatment outcomes. METHODS: We used transcriptome data from the Cancer Genome Atlas (TCGA) database and single sample gene set enrichment analysis (ssGSEA) to explore the cancer hallmarks most associated with prognosis in sarcoma patients. Then, weighted gene coexpression network analysis, univariate COX regression analysis and random forest algorithm were used to construct prognostic gene characteristics. Finally, the prognostic value of gene markers was validated in the TCGA and Integrated Gene Expression (GEO) (GSE17118) datasets, respectively. RESULTS: MYC targets V1 and V2 are the main cancer hallmarks affecting the overall survival (OS) of sarcoma patients. A six-gene signature including VEGFA, HMGB3, FASN, RCC1, NETO2 and BIRC5 were constructed. Kaplan-Meier analysis suggested that higher risk scores based on the six-gene signature associated with poorer OS (P < 0.001). The receiver Operating characteristic curve showed that the risk score based on the six-gene signature was a good predictor of sarcoma, with an area under the curve (AUC) greater than 0.73. In addition, the prognostic value of the six-gene signature was validated in GSE17118 with an AUC greater than 0.72. CONCLUSION: This six-gene signature is an independent prognostic factor in patients with sarcoma and is expected to be a potential therapeutic target for sarcoma.

Development of a 3 MV coaxial peaking capacitor for large-scale electromagnetic pulse simulator.

Coaxial peaking capacitor is a key component in high-altitude electromagnetic pulse (EMP) simulators with fast front pulse output. It poses significant technical and engineering challenges in limiting radiation field amplitude and test space. This paper presents the design and testing of a 180 pF, 3 MV coaxial peaking capacitor with improved insulation performance. In the insulation design, the length of the dielectric film is extended to reduce the background electric field on the flashover path. The electric field threshold obtained from image diagnosis is used as a reference. During capacitor testing, the insulation characteristics are diagnosed using both direct and indirect methods. The voltage measured by a D-dot probe, the output waveform of the Marx generator in the primary source, and the radiation field waveform are analyzed to understand the flashover characteristics of the capacitor and to improve the reliability of the test results. The experimental results demonstrate that the peaking capacitor can operate stably at 3.0 MV. If flashover occurring on the dropping edge of the pulse is permitted, the operating voltage can be greater than 3.7 MV without significantly affecting the radiation field waveform. The analysis on the surface flashover morphology of the peaking capacitor reveals that the flashover mainly occurs at the dropping edge of the capacitor's waveform, indicating that the damage to the film is not serious. This research significantly increases the working voltage of coaxial peaking capacitors and contributes to the development of high-altitude EMP simulation technology.

Bispecific antibodies in cancer therapy: Target selection and regulatory requirements.

In recent years, the development of bispecific antibodies (bsAbs) has been rapid, with many new structures and target combinations being created. The boom in bsAbs has led to the successive issuance of industry guidance for their development in the US and China. However, there is a high degree of similarity in target selection, which could affect the development of diversity in bsAbs. This review presents a classification of various bsAbs for cancer therapy based on structure and target selection and examines the advantages of bsAbs over monoclonal antibodies (mAbs). Through database research, we have identified the preferences of available bsAbs combinations, suggesting rational target selection options and warning of potential wastage of medical resources. We have also compared the US and Chinese guidelines for bsAbs in order to provide a reference for their development.

HE@PCL/PCE Gel-Nanofiber Dressing with Robust Self-Adhesion toward High Wound-Healing Rate via Microfluidic Electrospinning Technology.

Hydrogels have attracted increasing attention in the biomedical field due to their similarity in structure and composition to natural extracellular matrices. However, they have been greatly limited by their low mechanical strength and self-adhesion for further application. Here, a gel-nanofiber material is designed for wound healing, which synergistically combines the benefits of hydrogels and nanofibers and can overcome the bottleneck of poor mechanical strength and self-adhesion in hydrogels and inadequate healing environment created by nanofibers. First, a nanofiber scaffold composed of polycaprolactone/poly(citric acid)-ε-lysine (PCL/PCE) nanofibers is fabricated via a new strategy of microfluidic electrospinning, which could provide a base for hyaluronic acid-polylysine (HE) gel growth on nanofibers. The prepared HE@PCL/PCE gel-nanofiber possesses high tensile strength (24.15 ± 1.67 MPa), excellent air permeability (656 m3/m2 h kPa), outstanding self-adhesion property, and positive hydrophilicity. More importantly, the prepared gel-nanofiber dressing shows good cytocompatibility and antibacterial properties, achieving a high wound-healing rate (92.48%) and 4.685 mm granulation growth thickness within 12 days. This material may open a promising avenue for accelerating wound healing and tissue regeneration, providing potential applications in clinical medicine.

Subphenotyping heterogeneous patients with chronic critical illness to guide individualised fluid balance treatment using machine learning: a retrospective cohort study.

Background: The great heterogeneity of patients with chronic critical illness (CCI) leads to difficulty for intensive care unit (ICU) management. Identifying subphenotypes could assist in individualized care, which has not yet been explored. In this study, we aim to identify the subphenotypes of patients with CCI and reveal the heterogeneous treatment effect of fluid balance for them. Methods: In this retrospective study, we defined CCI as an ICU length of stay over 14 days and coexists with persistent organ dysfunction (cardiovascular Sequential Organ Failure Assessment (SOFA) score ≥1 or score in any other organ system ≥2) at Day 14. Data from five electronic healthcare record datasets covering geographically distinct populations (the US, Europe, and China) were studied. These five datasets include (1) subset of Derivation (MIMIC-IV v1.0, US) cohort (2008-2019); (2) subset Derivation (MIMIC-III v1.4 'CareVue', US) cohort (2001-2008); (3) Validation I (eICU-CRD, US) cohort (2014-2015); (4) Validation II (AmsterdamUMCdb/AUMC, Euro) cohort (2003-2016); (5) Validation III (Jinling, CN) cohort (2017-2021). Patients who meet the criteria of CCI in their first ICU admission period were included in this study. Patients with age over 89 or under 18 years old were excluded. Three unsupervised clustering algorithms were employed independently for phenotypes derivation and validation. Extreme Gradient Boosting (XGBoost) was used for phenotype classifier construction. A parametric G-formula model was applied to estimate the cumulative risk under different daily fluid management strategies in different subphenotypes of ICU mortality. Findings: We identified four subphenotypes as Phenotype A, B, C, and D in a total of 8145 patients from three countries. Phenotype A is the mildest and youngest subgroup; Phenotype B is the most common group, of whom patients showed the oldest age, significant acid-base abnormality, and low white blood cell count; Patients with Phenotype C have hypernatremia, hyperchloremia, and hypercatabolic status; and in Phenotype D, patients accompany with the most severe multiple organ failure. An easy-to-use classifier showed good effectiveness. Phenotype characteristics showed robustness across all cohorts. The beneficial fluid balance threshold intervals of subphenotypes were different. Interpretation: We identified four novel phenotypes that revealed the different patterns and significant heterogeneous treatment effects of fluid therapy within patients with CCI. A prospective study is needed to validate our findings, which could inform clinical practice and guide future research on individualized care. Funding: This study was funded by 333 High Level Talents Training Project of Jiangsu Province (BRA2019011), General Program of Medical Research from the Jiangsu Commission of Health (M2020052), and Key Research and Development Program of Jiangsu Province (BE2022823).

Blood Stream Microbiota Dysbiosis Establishing New Research Standards in Cardio-Metabolic Diseases, A Meta-Analysis Study.

AIMS: Scientists have recently discovered a link between the circulating microbiome and homeostasis, as well as the pathogenesis of a number of metabolic diseases. It has been demonstrated that low-grade chronic inflammation is one of the primary mechanisms that has long been implicated in the risk of cardio-metabolic disease (CMDs) and its progression. Currently, the dysbiosis of circulating bacteria is considered as a key regulator for chronic inflammation in CMDs, which is why we have conducted this systemic review focused on circulating bacterial dysbiosis. METHODS: A systemic review of clinical and research-based studies was conducted via PubMed, Scopus, Medline, and Web of Science. Literature was considered for risk of bias and patterns of intervention effects. A randomized effect model was used to evaluate the dysbiosis of circulating microbiota and clinical outcomes. We conducted a meta-analysis considering the circulating bacteria in both healthy people and people with cardio-metabolic disorders, in reports published mainly from 2008 to 2022, according to the PRISMA guidelines. RESULTS: We searched 627 studies and, after completing the risk of bias and selection, 31 studies comprising of 11,132 human samples were considered. This meta-analysis found that dysbiosis of phyla Proteobacteria, Firmicutes, and Bacteroidetes was associated with metabolic diseases. CONCLUSIONS: In most instances, metabolic diseases are linked to higher diversity and elevated bacterial DNA levels. Bacteroides abundance was higher in healthy people than with metabolic disorders. However, more rigorous studies are required to determine the role of bacterial dysbiosis in cardio-metabolic diseases. Understanding the relationship between dysbiosis and cardio-metabolic diseases, we can use the bacteria as therapeutics for the reversal of dysbiosis and targets for therapeutics use in cardio-metabolic diseases. In the future, circulating bacterial signatures can be used as biomarkers for the early detection of metabolic diseases.

Self-Healing Supramolecular Hydrogels with Antibacterial Abilities for Wound Healing.

Wound healing due to skin defects is a growing clinical concern. Especially when infection occurs, it not only leads to impair healing of the wound but even leads to the occurrence of death. In this study, a self-healing supramolecular hydrogel with antibacterial abilities was developed for wound healing. The supramolecular hydrogels inherited excellent self-healing and mechanical properties are produced by the polymerization of N-acryloyl glycinamide monomers which carries a lot of amides. In addition, excellent antibacterial properties are obtained by integrating silver nanoparticles (Ag NPs) into the hydrogels. The resultant hydrogel has a demonstrated ability in superior mechanical properties, including stretchability and self-healing. Also, the good biocompatibility and antibacterial ability have been proven in hydrogels. Besides, the prepared hydrogels were employed as wound dressings to treat skin wounds of animals. It was found that the hydrogels could significantly promote wound repair, including relieving inflammation, promoting collagen deposition, and enhancing angiogenesis. Therefore, such self-healing supramolecular hydrogels with composite functional nanomaterials are expected to be used as new wound dressings in the field of healthcare.

Extracellular matrix bioink boosts stemness and facilitates transplantation of intestinal organoids as a biosafe Matrigel alternative.

Organoids hold inestimable therapeutic potential in regenerative medicine and are increasingly serving as an in vitro research platform. Still, their expanding applications are critically restricted by the canonical culture matrix and system. Synthesis of a suitable bioink of bioactivity, biosecurity, tunable stiffness, and printability to replace conventional matrices and fabricate customized culture systems remains challenging. Here, we envisaged a novel bioink formulation based on decellularized extracellular matrix (dECM) from porcine small intestinal submucosa for organoids bioprinting, which provides intestinal stem cells (ISCs) with niche-specific ECM content and biomimetic microstructure. Intestinal organoids cultured in the fabricated bioink exhibited robust generation as well as a distinct differentiation pattern and transcriptomic signature. This bioink established a new co-culture system able to study interaction between epithelial homeostasis and submucosal cells and promote organoids maturation after transplantation into the mesentery of immune-deficient NODSCID-gamma (NSG) mice. In summary, the development of such photo-responsive bioink has the potential to replace tumor-derived Matrigel and facilitate the application of organoids in translational medicine and disease modeling.

Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment.

Blocking the PD-1/PD-L1 interaction has become an important strategy for tumor therapy, which has shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse effects limit the use of anti-PD1/PD-L1 antibodies. Here, we report the discovery and identification of S4-1, an innovative small-molecule inhibitor of PD-L1. In vitro, S4-1 effectively altered the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, improved its localization to endoplasmic reticulum, and thus enhanced the cytotoxicity of peripheral blood mononuclear cells toward tumor cells. In vivo, S4-1 significantly inhibited tumor growth in both lung and colorectal cancer models, particularly in colorectal cancer, where it led to complete clearance of a portion of the tumor cells. Furthermore, S4-1 induced T-cell activation and inversed the inhibitory tumor microenvironment, consistent with the PD-L1/PD-1 pathway blockade. These data support the continued evaluation of S4-1 as an alternative ICB therapeutic strategy.

Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents.

Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50 = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50 > 5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

Multifunctional hydrogel based on dopamine-modified hyaluronic acid, gelatin and silver nanoparticles for promoting abdominal wall defect repair.

Abdominal wall defects are often accompanied by severe infections and complications, creating a significant challenge for clinicians. There is an urgent need to develop a novel wound dressing that can effectively prevent intra-abdominal infection and promote the healing of defective abdominal walls. Based on a hydrogel dressing containing hyaluronic acid (HA) and gelatin (GT), herein we integrated dopamine with a catechol structure to enhance its antioxidant and adherent properties. HA is oxidized to form an aldehyde group, and subsequently grafted with dopamine. The dopamine-modified HA undergoes amidation reaction with GT at different concentrations. In addition, silver nanoparticles (AgNPs) were introduced to the hydrogel to enhance the antibacterial properties. The in vitro studies on GT/DA-HA demonstrated excellent physical and chemical properties, biodegradability, and biocompatibility. In a rat full-thickness skin defect model and a full-thickness abdominal wall defect model, the GT/DA-HA hydrogel could accelerate the healing process by improving wet adhesion, reducing wound inflammation, and promoting angiogenesis and formation of granulation tissues. The multifunctional hydrogel developed in this study shows great potential for treating full-thickness abdominal wall defects.

Human circulating bacteria and dysbiosis in non-infectious diseases.

Blood microorganisms were once thought to indicate infection. Blood in healthy people appears to be devoid of growing bacteria; nonetheless, intracellular dormant forms of bacteria have been reported previously. With breakthroughs in sequencing and bioinformatics, the presence of bacterial DNA in healthy human blood initiated the controversy of human blood microbiota (HBM). Recently, bacteria-specific DNA and culturable bacteria were found in healthy human blood. Researchers wanted to study the phenomena of a "healthy blood microbiota" by providing a thorough description of bacterially produced nucleic acids using many complementing molecular and traditional microbiological approaches. Because blood is a relatively limited and particular environment, culturability and plate count issues can be overcome using enhanced cultured procedures. However, more evidence is required to confirm that healthy human blood contains normal microbiota. Cavities, mouth and intestinal microbiota, trauma, surgery, and animal/insect bites can introduce bacteria into human blood. All these factors strengthen the concept of transient blood bacteria too. The presence of blood bacteria may be caused by temporary immunological clearance and absorption by dendritic or M cells. This review provides an extensive and comprehensive analysis that suggests that healthy blood bacteria may not be typical microbiota but transient circulatory microorganisms. In this study, we look at how contaminants (Escherichia, Shigella, Pseudomonads, etc.) from the skin, laboratory environments, and reagents can affect the interpretation of blood-derived microbial information and the relationship between the circulating bacteria and non-communicable diseases. Circulating transient bacteria may play a role in the pathogenesis of non-infectious diseases such as diabetes and CVD. Contamination-free hematological studies can aid in understanding the disease mechanisms, therapy, and biomarkers.

A Trilayer Dressing with Self-Pumping and pH Monitoring Properties for Promoting Abdominal Wall Defect Repair.

Due to abdominal infection, excessive wound exudation, and intestinal fistula formation, the treatment of full-thickness abdominal wall defects has become a difficult challenge for clinic doctors. This clinical problem cannot be resolved with existing biomaterials. To facilitate the repair of the abdominal wall, we developed a novel wound dressing with directional biofluid transport. We used electrospinning to spin a trilayer dressing consisting of hydrolyzed poly-acrylonitrile (HPAN)/Curcumin (CUR), polyurethane (PU), and polycaprolactone (PCL). In vitro results show that the three-layer wound dressing is biocompatible, capable of directional transport of excessive wound exudation, preventing reverse penetration, and monitoring the pH of the wound. Furthermore, in vivo results show the trilayer wound dressing improves the wound microenvironment, reduces inflammatory factors, promotes angiogenesis, and accelerates abdominal wall repair. Thus, we believe that the novel trilayer electrospinning dressing could facilitate abdominal wall defect repair.

Solid-state molecular oxygen activation using ball milling and a piezoelectric material for aerobic oxidation of thiols.

The agitation of BaTiO3 via ball milling converts mechanical energy into electrical energy, leading to the reduction of molecular oxygen via a single electron transfer pathway analogous to the photocatalytic reaction. This mechanoredox strategy for the oxidative coupling of thiols could eliminate waste and develop a recyclable methodology to accomplish organic transformations in a greener fashion, exhibiting promising potential for large-scale chemical manufacturing.

Multifunctional Electrospun Textiles for Wound Healing.

The novel multifunctional electrospun textiles were fabricated by incorporating sheet-like kaolinite and silver nanoparticles (AgNps) into a polyurethane (PU) textile by using electrostatic spinning to promote wound-healing process. Threedimensional network of PU electrospun textiles offered an appropriate framework for loading kaolinite nanosheets and AgNps. Moreover, the kaolinite nanosheets healed bleeding wounds by accelerating plasma absorption, increasing blood cell concentrations, and stimulating coagulation factors. Furthermore, the AgNps killed microbes by destroying the cell membrane, while the deleterious effects were controlled by incorporation into the electrospun textile. The therapeutic effects of multifunctional electrospun textile in treating full-thickness abdominal wall defect were explored. The wound healing process could be accelerated via the textile by restoring the abdominal physiological environment, reducing the inflammatory response, and promoting collagen deposition, angiogenesis, and epithelization.

Micro-Gel Ensembles for Accelerated Healing of Chronic Wound via pH Regulation.

The pH value in the wound milieu plays a key role in cellular processes and cell cycle processes involved in the process of wound healing. Here, a microfluidic assembly technique is employed to fabricate micro-gel ensembles that can precisely tune the pH value of wound surface and accelerate wound healing. The micro-gel ensembles consist of poly (hydroxypropyl acrylate-co-acrylic acid)-magnesium ions (poly-(HPA-co-AA)-Mg2+ ) gel and carboxymethyl chitosan (CMCS) gel, which can release and absorb hydrogen ion (H+ ) separately at different stages of healing in response to the evolution of wound microenvironment. By regulating the wound pH to affect the proliferation and migration of cell on the wound and the activity of various biological factors in the wound, the physiological processes are greatly facilitated which results in much accelerated healing of chronic wound. This work presents an effective strategy in designing wound healing materials with vast potentials for chronic wound management.

Trocar Puncture With a Sump Drain for Crohn's Disease With Intra-Abdominal Abscess: A 10-Year Retrospective Cohort Study.

Background: Traditional percutaneous catheter drainage (PCD) and surgical intervention could not always achieve satisfactory results for patients with Crohn's disease (CD) who have complications with intra-abdominal abscess. We proposed a trocar puncture with sump drainage for the treatment of CD with intra-abdominal abscess and compared it with the conventional PCD and surgical intervention. Methods: Crohn's disease patients with intra-abdominal abscess and admitted to our hospital from 2011 to 2020 were identified by reviewing the electronic medical records. We divided them into Trocar, PCD, and fecal diverting (FD) groups, according to the ways of treating an abscess. Outcomes, risk factors for abscess recurrence, and postoperative complications were compared among the three groups. Results: A total of 69 patients were included and they were divided into Trocar (n = 18), PCD (n = 29), and FD (n = 22) groups. Four patients in the PCD group were transferred to receive the FD surgery due to the failure of initial treatment. The incidence of abscess recurrence was significantly higher in the PCD (48%) and FD (50%) groups compared to the patients using the trocar puncture with the sump drain (Trocar group) (16.7%). There were 8 patients in Trocar, 22 in PCD, and 20 s in the FD group who received enterectomy. None of the patients in the Trocar had an ultimate stoma and the incidence of postoperative complications was statistically lower [0% (Trocar) vs. 31.8% (PCD) vs. 45% (FD), P < 0.05]. The way of initial treating of the abscess was significantly correlated with the abscess recurrence and postoperative complications. Conclusions: Trocar puncture with a sump drain had a lower incidence of abscess recurrence, abdominal adhesions, postdrainage, and postoperative complications compared to the conventional PCD or surgical intervention.