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Abstract Carbon dots (CDs)‐based zero‐dimensional nanomaterials with dimensions ranging from 1 to 10 nm have shown tremendous potential in the application of regenerative medicine, because of their unique physicochemical properties and favorable attributes like good biocompatibility, unique biological functions, low cost and high stability. These newly synthesized CDs‐based nanomaterials could replace traditional semiconductor quantum dots, which have obvious toxicity drawbacks and higher costs. CDs not only show sustained fluorescent quality and biocompatibility, but also serve as superior carriers for drug delivery, as well as for bioimaging‐guided detection of cells, drugs, and growth factors. So, they have been shown to play a role in various fields such as chemical and biological sensing, bioimaging, drug delivery, and photocatalysis. Thus, they are considered potential candidates for regenerative medicine applications. In this review, we provide a comprehensive summary of the classification of CDs, focusing on their formation mechanisms, micro‐/nanostructures, and distinctive properties. We describe their properties and synthesis methods in detail. Furthermore, we systematically highlight recent remarkable advances in the applications of CDs in regenerative medicine, such as bone and cartilage repair, wound healing, nerve regeneration, and myocardial regeneration, are systematically highlighted. Finally, we discuss the key challenges that lie ahead, outline future research directions, and explore the prospects of CDs‐based materials in regenerative medicine.

Abstract Accumulating evidence indicates that metabolic reprogramming of cancer cells supports the energy and metabolic demands during tumor metastasis. However, the metabolic alterations underlying lymph node metastasis (LNM) of cervical cancer (CCa) have not been well recognized. In the present study, it is found that lymphatic metastatic CCa cells have reduced dependency on glucose and glycolysis but increased fatty acid oxidation (FAO). Inhibition of carnitine palmitoyl transferase 1A (CPT1A) significantly compromises palmitate‐induced cell stemness. Mechanistically, FAO‐derived acetyl‐CoA enhances H3K27 acetylation (H3K27Ac) modification level in the promoter of stemness genes, increasing stemness and nodal metastasis in the lipid‐rich nodal environment. Genetic and pharmacological loss of CPT1A function markedly suppresses the metastatic colonization of CCa cells in tumor‐draining lymph nodes. Together, these findings propose an effective method of cancer therapy by targeting FAO in patients with CCa and lymph node metastasis.

Abstract Background The gut is an important site for human immunodeficiency virus (HIV) infection and immune responses. The role of gut mucosal immune cells in immune restoration in patients infected with HIV undergoing antiretroviral therapy remains unclear. Methods Ileocytes, including 54 475 immune cells, were obtained from colonoscopic biopsies of five HIV‐negative controls, nine immunological responders (IRs), and three immunological non‐responders (INRs) and were analyzed using single‐cell RNA sequencing. Immunohistochemical assays were performed for validation. The 16S rRNA gene was amplified using PCR in faecal samples to analyze faecal microbiota. Flow cytometry was used to analyze CD4+ T‐cell counts and the activation of T cells. Results This study presents a global transcriptomic profile of the gut mucosal immune cells in patients infected with HIV. Compared with the IRs, the INRs exhibited a lower proportion of gut plasma cells, especially the IGKC+IgA+ plasma cell subpopulation. IGKC+IgA+ plasma cells were negatively associated with enriched f. Prevotellaceae the INRs and negatively correlated with the overactivation of T cells, but they were positively correlated with CD4+ T‐cell counts. The INRs exhibited a higher proportion of B cells than the IRs. Follicular and memory B cells were significantly higher in the INRs. Reduced potential was observed in the differentiation of follicular or memory B cells into gut plasma cells in INRs. In addition, the receptor‐ligand pairs CD74_MIF and CD74_COPA of memory B/ follicular helper T cells were significantly reduced in the INRs, which may hinder the differentiation of memory and follicular B cells into plasma cells. Conclusions Our study shows that plasma cells are dysregulated in INRs and provides an extensive resource for deciphering the immune pathogenesis of HIV in INRs. Key points An investigation was carried out at the single‐cell‐level to analyze gut mucosal immune cells alterations in PLWH after ART. B cells were significantly increased and plasma cells were significantly decreased in the INRs compared to the IRs and NCs. There are gaps in the transition from gut follicular or memory B cellsinto plasma cells in INRs.

Abstract Background Active surveillance (AS) with delayed intervention has gained acceptance as a management strategy for small renal masses (SRMs). However, during AS, there is a risk of tumor growth. Thus, we aim to investigate whether tumor growth in patients with SRMs leads to tumor progress. Methods In this study, we enrolled 16,070 patients from the Surveillance, Epidemiology, and End Results database with T1a renal cell carcinoma (RCC) between 2004 and 2017. The 16,070 patients were divided into three groups: 10,526 in the partial nephrectomy (PN) group, 2768 in the local ablation (LA) group, and 2776 in the AS group. Associations of tumor size with all‐cause and cancer‐specific mortality were evaluated using Kaplan–Meier analyses and Cox regression models. Results Four tumor size categories were delineated (≤1, >1–2, >2–3, and > 3–4 cm in diameter), and 10‐year all‐cause and cancer‐specific mortality both significantly increased with increasing tumor size in the PN, LA, and AS groups (all p 2–4 cm). All‐cause and cancer‐specific mortality were significantly higher in T1aB tumors than T1aA tumors in each group (hazard ratio = 1.395 and 1.538, respectively; all p

Abstract High lymphocyte infiltration and immunosuppression characterize the tumor microenvironment (TME) in renal cell carcinoma (RCC). There is an urgent need to elucidate how tumor cells escape the immune attack and to develop novel therapeutic targets to enhance the efficacy of immune checkpoint blockade (ICB) in RCC. Overactivated IFN‐γ‐induced JAK/STAT signaling involves in such TME, but the underlying mechanisms remain elusive. Here, EH domain‐binding protein 1‐like protein 1 (EHBP1L1) is identified as a crucial mediator of IFN‐γ/JAK1/STAT1/PD‐L1 signaling in RCC. EHBP1L1 is highly expressed in RCC, and high EHBP1L1 expression levels are correlated with poor prognosis and resistance to ICB. EHBP1L1 depletion significantly inhibits tumor growth, which is attributed to enhanced CD8+ T cell‐mediated antitumor immunity. Mechanistically, EHBP1L1 interacts with and stabilizes JAK1. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, which leads to elevated JAK1 protein levels and JAK1/STAT1/PD‐L1 signaling activity, thereby forming an immunosuppressive TME. Furthermore, the combination of EHBP1L1 inhibition and ICB reprograms the immunosuppressive TME and prevents tumor immune evasion, thus significantly reinforcing the therapeutic efficacy of ICB in RCC patient‐derived xenograft (PDX) models. These findings reveal the vital role of EHBP1L1 in immune evasion in RCC, which may be a potential complement for ICB therapy.

Abstract Aims This study sought to investigate the association between blood pressure (BP) trajectories from early to middle adulthood and echocardiographic indices of structure and function in middle age. Methods and results This prospective cohort study included 4717 black and white adults aged 18–30 years at baseline (1985–86) who were followed over 30 years in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Trajectories of systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) from the Year 0 examination to Year 30 examination were identified using latent mixture modelling. Echocardiographic indices of myocardial structure, systolic function, and diastolic function were assessed at the Year 30 examination. Five distinct SBP trajectory groups were identified: low‐stable [1110 participants (23.5%)], moderate‐stable [2188 (46.4%)], high‐stable [850 (18.0%)], moderate‐increasing [416 (8.8%)], and high‐increasing [153 (3.2%)]. After adjustment for clinical variables, a significant decreasing trend was observed from the high‐increasing and moderate‐increasing groups through to the low‐stable group for left ventricular (LV) mass index [mean (SE): high‐increasing, 112.3 (3.4); moderate‐increasing, 99.3 (2.6); high‐stable, 88.9 (2.5); moderate‐stable, 86.1 (2.3); low‐stable, 82.1 (2.4), P trend

Abstract Aim This study aims to explore the current level and associated factors of appetite and death anxiety amongst COVID‐19 patients and also to identify correlation between the two variables. Design A cross‐sectional study. Methods Demographic and characteristic questionnaires, templer death anxiety scale, council on nutrition of appetite questionnaire and medical coping modes questionnaire were utilized. Results The average scores of appetite and death anxiety were 19.46 (4.09) and 6.58, (3.21) respectively. 76 patients (100%) suffered from appetite loss, whilst 27 (35.50%) patients suffered from severe death anxiety. Marital status, COVID‐19 disease condition ranks, educational level and death anxiety were explained 55.20% of the total variance in the appetite regression model (F = 31.83, p

Abstract Aim To comprehensively assess the current level and identify associated factors of intention to response and emergency preparedness of clinical nurses during COVID‐19 outbreak. Design A cross‐sectional study was designed. Methods Demographic and characteristic questionnaire, intention to response scale, emergency preparedness scale and a self‐designed questionnaire related to effects of events and intention to leave were used in this study. Results The mean scores of intention to response and emergency preparedness were 82.00 (SD = 18.17) and 64.99 (SD = 12.94), respectively. Moral consideration, engaged in COVID‐19 protection training, had working experience in SARS, and the other eight factors were explained 34.6% of the total model variance in intention to response model (F = 80.05, p

Abstract Background HOXD9, a Hox family member, is involved in cancer growth and metastasis. But, its regulation mechanism at the molecular level particularly in colorectal cancer (CRC), is mostly unknown. Methods The HOXD9 protein expression levels were analyzed using immunofluorescence, immunohistochemistry (IHC) assays, and western blot. The in vivo and in vitro roles of HOXD9 in CRC were determined using colony formation and EdU incorporation, CCK‐8, wound scratch and transwell invasion assay, and animal models. Results Expression of HOXD9 was higher in CRC than in matched healthy tissues. High expression of HOXD9 has significantly associated with the American Joint Committee on Cancer (AJCC) stages, tumor differentiation, lymph node metastasis, and other serious invasions, and it had a poor prognosis. In vitro, HOXD9 encouraged proliferation, movement and EMT processes in cells of CRC. Also, TGF‐β1 promoted the expression of HOXD9 and this effect was dependent on the dose and downregulation of HOXD9 repressed TGF‐β1 ‐induced EMT. In vivo, HOXD9 promoted the invasive and metastasis of CRC cells via orthotopic implantation. Conclusions The ectopic expression of HOXD9 promoted the invasion metastasis in cells of the colorectal tumor by induction of EMT in vitro and vivo.

Abstract A high‐salt diet can induce hypertension, so salt reduction can prevent hypertension. γ‐Glutamyl peptides (GGPs) have obvious taste‐enhancing effects, while their contents in natural foods are relatively low. Yeast protein rich in Glu/Gln is a good precursor for the preparation of GGPs. In this study, yeast protein‐derived GGPs were prepared through hydrolysis and transpeptidation reactions, followed by sensory evaluation and E‐tongue analysis. Peptide sequences were identified by LC−MS/MS and screened for molecular docking. The optimal reaction conditions were hydrolysis for 4 h, enzyme concentration of 16 U/g, and transpeptidation for 4 h. GGPs could increase salt and umami intensity by 60.78% and 40.93% based on sensory evaluation, 22.52%, and 16.40% according to E‐tongue analysis. Fifteen γ‐glutamyl peptides with different peptide lengths were selected for molecular docking. Molecular docking confirmed their binding to calcium‐sensing receptors (CaSr) through hydrogen bonds and hydrophobic interaction, while interaction between CaSR receptor and γ‐glutamyl di‐, tri‐, and oligo‐peptides varied in binding energy. The stimulation received by CaSR lasted a longer time and varied in intensity. It was further proved that the flavor of mixed peptides has a layered sense and can give people a rich taste experience. Overall, yeast protein‐derived GGPs can enhance salt and umami taste, which can reduce salt usage without compromising taste.

Abstract Synthetic biomaterials are emerging candidate solutions for treating large bone defects. However, the clinical performances of most synthetic materials are not satisfactory, with the need for improvement in design and synthesis. Although bone is highly innervated, the central role during healing of the peripheral nervous system, and in particular sensory nerves (SNs), has only recently been acknowledged. SNs can improve osteogenic differentiation of bone marrow stem/stromal cells through neurotransmitters and peptides; the interplay between SNs and the vascular system also facilitates vascular network reconstruction, indirectly facilitating bone healing. These factors suggest the importance of SNs in bone healing, a vital point that has been overlooked in bone biomaterial design until very recently. SN regeneration represents a novel direction in the development of biomaterials for bone regeneration. The current perspective paper summarizes the cellular and molecular mechanisms under the regulatory influence of SNs in the bone healing process and outlines the recent advances in biomaterials for innervated bone tissue regeneration. This establishes potential future directions for bone engineering biomaterial design.

Abstract The escalating spread of drug‐resistant bacteria and viruses is a grave concern for global health. Nucleic acids dominate the drug‐resistance and transmission of pathogenic microbes. Here, imidazolium‐type poly(ionic liquid)/porphyrin (PIL‐P) based electrospun nanofibrous membrane and its cerium (IV) ion complex (PIL‐P‐Ce) are developed. The obtained PIL‐P‐Ce membrane exhibits high and stable efficiency in eradicating various microorganisms (bacteria, fungi, and viruses) and decomposing microbial antibiotic resistance genes and viral nucleic acids under light. The nuclease‐mimetic and photocatalytic mechanisms of the PIL‐P‐Ce are elucidated. Co‐infection wound models in mice with methicillin‐resistant S. aureus and hepatitis B virus demonstrate that PIL‐P‐Ce integrate the triple effects of cationic polymer, photocatalysis, and nuclease‐mimetic activities. As revealed by proteomic analysis, PIL‐P‐Ce shows minimal phototoxicity to normal tissues. Hence, PIL‐P‐Ce has potential as a “green” wound dressing to curb the spread of drug‐resistant bacteria and viruses in clinical settings.

Abstract Background The relationship between molecular characteristics and the prognosis of colorectal cancer (CRC) patients has not been fully understood. This study explored the impact of targeted therapy on the prognosis of CRC patients with different TP53 mutations, in the context of comprehensive treatment. Methods This study included patients with stage III/IV primary CRC from the electronic medical record system. TP53 mutations were detected via next‐generation sequencing (NGS) using formalin‐fixed paraffin‐embedded (FFPE) tissues. Applying two methods, we classified TP53 mutations as gain of function (GOF)/non‐GOF mutations or known/likely loss of function (LOF) mutations. Kaplan–Meier plot and parametric survival analysis were performed to evaluate the prognosis of CRC patients and identify potential predictors. Results There were 286 patients included, of which 166 (58.04%) patients received targeted therapy and 120 (41.96%) did not. There were 286 patients in the TP53 GOF classification set and 247 in the TP53 LOF classification set. Parametric survival analysis, adjusted for sex, onset, KRAS mutation, sidedness, stage, and surgery, showed that receiving targeted therapy predicted better overall survival (OS) among patients who harbored TP53 GOF mutations (HR 0.40, 95% confidence interval (CI) [0.21, 0.76], p = 0.005) or known LOF mutations (HR 0.21, 95% CI [0.07, 0.60], p = 0.002). However, there was no significant impact of receiving targeted therapy on OS among patients harboring TP53 non‐GOF mutations (HR 1.68, 95% CI [0.50, 5.63], p = 0.403) or likely LOF mutations (HR 0.90, 95% CI [0.34, 2.39], p = 0.837). Conclusions Receiving targeted therapy had a heterogeneous impact on the prognosis of CRC patients harboring different TP53 mutations. These results provide promising value for future personalized treatment and precision medicine.

Abstract Background Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD‐L1 translocation in various tumor cells. Methods C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD‐L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD‐L1‐related pathways after being treated with PPIs. The related gene expression is performed by qRT‐PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD‐L1 in the tissue samples by immunohistochemistry. Results We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD‐L1 on cell membrane at clinically relevant concentrations. Furthermore, pre‐treatment with PPIs appeared to synergize the efficiency of anti‐PD‐L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD‐L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3β, then leading to PD‐L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD‐L1 was negated following GSK3β knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD‐L1 expression in esophageal cancer patients. Conclusion We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD‐L1 by inducing GSK3β phosphorylation and facilitate primary tumor progression and metastasis.

Abstract Background Identifying therapeutic targets and prognostic biomarkers significantly contributes to individualized treatment of acute myeloid leukemia (AML). Dihydropyrimidinase‐like 2 (DPYSL2) expression was decreased in homoharringtonine (HHT)‐resistant AML cells, which were established by our group. DPYSL2 plays an important role in axon growth and has oncogene effect in glioblastoma. However, little research has been conducted to investigate the function of DPYSL2 in AML pathogenesis. Methods Auto‐docking was used to reveal the targeting relationship between HHT and DPYSL2. Overall survival (OS), event‐free survival (EFS), and relapse‐free survival (RFS) were used to evaluate the prognostic impact of DPYSL2 for AML. ShRNA was used to knockdown the expression of SPATS2L. Apoptosis was assessed by flow cytometry. In vivo growth and survival were assessed using a xenotransplantation mice model. RNA sequencing was performed to elucidate the molecular mechanisms underlying the role of SPATS2L in AML and were confirmed by Western blot. Results We found DPYSL2 was the target of HHT. Next, we found AML cell lines and patients had higher DPYSL2 expression levels than the normal samples. Further multivariate analysis demonstrated that high DPYSL2 expression was an independent poor prognostic factor for OS, EFS, and RFS in AML. Inhibition of DPYSL2 expression suppressed cell growth, induced apoptosis in AML cell lines, and prolonged the survival of AML xenograft NCG mice. Through RNA‐seq analysis from TCGA and our data, the JAK2/STAT3/STAT5‐PI3K P85/AKT/GSK3b axis was thought to be the critical pathway in regulating DPYSL2 in AML development. Conclusions We first time confirmed that DPYSL2 was a target of HHT and played an oncogene role in AML by regulating JAK/STAT signaling pathway. Therefore, DPYSL2 could serve as a novel prognostic marker and therapeutic target for AML treatment.

Abstract Stimulating and harnessing circularly polarized luminescence (CPL) is not only a sine qua non for fundamentally unveiling chirogenesis in physical chemistry, but also a pivotal prerequisite for implementation of such phenomenon in research fields including chiral optoelectronics and theranostics. Herein, red‐emissive carbonized polymer dots (CPDs)‐based helical structures were synthesized in this work via biomolecule‐tailored organic–inorganic co‐assembly strategy. The surface states‐related chirality exhibits enhanced circular dichroism (CD) and CPL activities with anisotropic factors as high as gCD,max = 5.4 × 10−3 and glum,max = 1.5 × 10−2, respectively. The obtained CPL signals can be further manipulated in an excitation‐dependent manner, indicating that a synergistic‐competition phenomenon exists between configurational chirality and intermolecular energy‐transfer dynamics, which is further supported by simulations based on density function theory (DFT). Such tunable CPL behavior triggers revolutionary designs and applications of these chiral CPDs into the realm of chirality‐related biological issues and next‐generation chiral optoelectronics.