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Abstract Background Immunotherapies, notably immune checkpoints inhibitors that target programmed death 1/programmed death ligand 1(PD‐1/PD‐L1) and cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4), had profoundly changed the way advanced and metastatic cancers are treated and dramatically improved overall and progression‐free survival. Aims This review article aimed to explore the underlying molecular mechanisms by which the gut microbiota affects antitumor immunity and the efficacy of cancer immunotherapy. Methods We summarized the latest knowledge supporting the associations among the gut microbiota, antitumor immunity, and immunotherapy. Moreover, we disscussed the therapeutic strategy for improving immunotherapy efficacy by modulating gut microbiota in cancer treatment. Results The potential molecular mechanisms underlying these associations are explained in terms of four aspects: immunomodulation, molecular mimicry, mamps, and microbial metabolites. Conclusion The gut microbiota significantly impacts antitumor immunity and alters the effectiveness of cancer immunotherapy.

Abstract Flavonoids are the representative active substances of citrus with various biological activities and high nutritional value. In order to evaluate and utilize citrus flavonoids, isolation and purification are necessary steps. This manuscript reviewed the research advances in the extraction and purification of citrus flavonoids. The structure classification, the plant and nutritional functions, and the biosynthesis of citrus flavonoids were summarized. The characteristics of citrus flavonoids and the selection of separation strategies were explained. The technical system of extraction and purification of citrus flavonoids was systematically described. Finally, outlook and research directions were proposed.

Background Neuroarthropathy of the knee or Charcot knee, leading to chronic joint destruction, is a rare disease that is difficult to diagnose. The treatment of this condition is difficult and controversial. Case Presentation A 74‐year‐old Asian woman has had bilateral knee pain for 22 years and deformity for 10 years, which has been aggravating for 2 months. Physical examination showed bilateral knee varus deformity greater than 15°, and −20 to 90° range of motion. X‐ray revealed bilateral varus deformity with massive free body hyperplasia. Combined with medical history as syringomyelia, the patient was diagnosed with bilateral Charcot knees and bilateral joint replacements were performed using Legacy Constrained Condylar Knee prostheses (LCCK; Zimmer, USA). The patient reported satisfactory treatment outcomes, pain relief, and improved range of motion in both knees, without postoperative complications or prosthesis loosening at 2 year after operation. Conclusions Total knee arthroplasty (TKA) may be considered a viable option for treating the Charcot knee. The use of constrained condylar prostheses can produce satisfactory results. Attention should be given to survival risks, complications, and other potential determining factors associated with TKA when devising a treatment strategy for the Charcot knee.

Abstract Staphylococcus aureus (SA) is a major cause of sepsis, leading to acute lung injury (ALI) characterized by inflammation and oxidative stress. However, the role of the Nrf2/PHB2 pathway in SA‐induced ALI (SA‐ALI) remains unclear. In this study, serum samples were collected from SA‐sepsis patients, and a SA‐ALI mouse model was established by grouping WT and Nrf2−/− mice after 6 h of intraperitoneal injection. A cell model simulating SA‐ALI was developed using lipoteichoic acid (LTA) treatment. The results showed reduced serum Nrf2 levels in SA‐sepsis patients, negatively correlated with the severity of ALI. In SA‐ALI mice, downregulation of Nrf2 impaired mitochondrial function and exacerbated inflammation‐induced ALI. Moreover, PHB2 translocation from mitochondria to the cytoplasm was observed in SA‐ALI. The p‐Nrf2/total‐Nrf2 ratio increased in A549 cells with LTA concentration and treatment duration. Nrf2 overexpression in LTA‐treated A549 cells elevated PHB2 content on the inner mitochondrial membrane, preserving genomic integrity, reducing oxidative stress, and inhibiting excessive mitochondrial division. Bioinformatic analysis and dual‐luciferase reporter assay confirmed direct binding of Nrf2 to the PHB2 promoter, resulting in increased PHB2 expression. In conclusion, Nrf2 plays a role in alleviating SA‐ALI by directly regulating PHB2 transcription and maintaining mitochondrial function in lung cells.

Abstract Osteoporotic tendon‐to‐bone healing (TBH) after rotator cuff repair (RCR) is a significant orthopedic challenge. Considering the aligned architecture of the tendon, inflammatory microenvironment at the injury site, and the need for endogenous cell/tissue infiltration, there is an imminent need for an ideal scaffold to promote TBH that has aligned architecture, ability to modulate inflammation, and macroporous structure. Herein, a novel macroporous hydrogel comprising sodium alginate/hyaluronic acid/small extracellular vesicles from adipose‐derived stem cells (sEVs) (MHA‐sEVs) with aligned architecture and immunomodulatory ability is fabricated. When implanted subcutaneously, MHA‐sEVs significantly improve cell infiltration and tissue integration through its macroporous structure. When applied to the osteoporotic RCR model, MHA‐sEVs promote TBH by improving tendon repair through macroporous aligned architecture while enhancing bone regeneration by modulating inflammation. Notably, the biomechanical strength of MHA‐sEVs is approximately two times higher than the control group, indicating great potential in reducing postoperative retear rates. Further cell‐hydrogel interaction studies reveal that the alignment of microfiber gels in MHA‐sEVs induces tenogenic differentiation of tendon‐derived stem cells, while sEVs improve mitochondrial dysfunction in M1 macrophages (Mφ) and inhibit Mφ polarization toward M1 via nuclear factor‐kappaB (NF‐κb) signaling pathway. Taken together, MHA‐sEVs provide a promising strategy for future clinical application in promoting osteoporotic TBH.

Objective Prosthetic joint infection (PJI) is the main reason of failure of total joint arthroplasty (TJA). This study aimed to investigate the global trends and network visualization in research of PJI. Methods Publications in PJI search during 1980–2022 were extracted from the Science Citation Index‐Expanded of Web of Science Core Collection database (WoSCC). The source data was investigated and analyzed by bibliometric methodology. For network visualization, VOS viewer and R software was used to perform bibliographic coupling, co‐citation, co‐authorship and co‐occurrence analysis and to predict the publication trends in PJI research. Results There were 7288 articles included. The number of publications and relative research interests increased gradually per year globally. The USA made the highest contributions in the world and with the highest H‐index and the most citations. Journal of Arthroplasty published the highest number of articles in this area. The Mayo Clinic, Thomas Jefferson University (Rothman Institute), Hospital Special Surgery and the Rush University were the most contributive institutions by network visualization. Included studies were divided into four clusters: bacterial pathogenic mechanism and antibacterial drugs study, TJA complications, risk factors and epidemiology of PJI, diagnosis of PJI, and revision surgical management. More articles in PJI could be published over the next few years. Conclusion The number of publications about PJI will be increasing dramatically based on the global trends and network visualization. The USA made the highest contributions in PJI. Diagnosis and revision management may be the next hot spots in this field.

Objective Musculoskeletal pain is the most prominent clinical manifestation of more than 150 musculoskeletal disease conditions, and its effective long‐term management poses a great challenge to healthcare systems globally. For this, it is important to understand current research progress on musculoskeletal pain management. The purpose of the present study is to provide a comprehensive insight into the current state of research and global trends in musculoskeletal pain management. Methods Publications on musculoskeletal pain management from 1972 to 2021 were retrieved from the Science Citation Index‐Expanded (SCIE) database. Included articles were any article type related to aspects of musculoskeletal pain management, including etiology, mechanisms, epidemiology, treatment, outcomes, side effects, and patient compliance. Publication data were analyzed using bibliometric methods. The software VOSviewer was employed to perform bibliographic coupling, co‐authorship, co‐citation, and co‐occurrence analysis, and to visualize publication tendencies in musculoskeletal pain management. Results A total of 5475 articles were included in this study. The number of global publications on musculoskeletal pain management has escalated annually. Based on the number of publications and citations from the published literature, as well as the H‐index, the United States led global contributions in this area. The institutions making the highest contributions were the League of European Research Universities (LERU), the University of Sydney, and Harvard University. The journal BMC Musculoskeletal Disorders published the highest number of articles in this area. The published studies fall under six groups: “Prevention and rehabilitation,” “Etiology and diagnosis,” “Clinical study,” “Epidemiology,” “Mental health,” and “Education.” High‐quality primary studies and epidemiology are predicted to be the next prevailing topics in this field of research. Conclusions Based on current global trends, the number of publications on musculoskeletal pain management will continue to increase. Future studies will likely place more emphasis on high‐quality randomized controlled trials (RCTs) and epidemiological studies.

Abstract Extracellular vesicle (EV) surface proteins, expressed by primary tumours, are important biomarkers for early cancer diagnosis. However, the detection of these EV proteins is complicated by their low abundance and interference from non‐EV components in clinical samples. Herein, we present a MEmbrane‐Specific Separation and two‐step Cascade AmpLificatioN (MESS2CAN) strategy for direct detection of EV surface proteins within 4 h. MESS2CAN utilises novel lipid probes (long chains linked by PEG2K with biotin at one end, and DSPE at the other end) and streptavidin‐coated magnetic beads, permitting a 49.6% EV recovery rate within 1 h. A dual amplification strategy with a primer exchange reaction (PER) cascaded by the Cas12a system then allows sensitive detection of the target protein at 10 EV particles per microliter. Using 4 cell lines and 90 clinical test samples, we demonstrate MESS2CAN for analysing HER2, EpCAM and EGFR expression on EVs derived from cells and patient plasma. MESS2CAN reports the desired specificity and sensitivity of EGFR (AUC = 0.98) and of HER2 (AUC = 1) for discriminating between HER2‐positive breast cancer, triple‐negative breast cancer and healthy donors. MESS2CAN is a pioneering method for highly sensitive in vitro EV diagnostics, applicable to clinical samples with trace amounts of EVs.

Abstract Conn et al. have recently reported circRNA: DNA hybrids (circR loops) to promote oncogenic gene translocations and impair genome stability which drive leukemia. Herein, we will summarize potential molecular mechanisms and discuss clinical significance of uncovering circR loops as endogenous RNA carcinogens.

Background Periprosthetic osteolysis is a serious complication following total hip arthroplasty (THA). However, most orthopedic surgeons only focus on bone loss and hip reconstruction. Thus, it was required to understand the treatment algorithm for periprosthetic osteolysis integrally. Case Presentation A 52‐year‐old Asian male presented with chronic hip pain. A mass appeared on the medial side of the proximal left thigh at more than 20 years after bilateral THA. Radiographs revealed catastrophic periprosthetic osteolysis, especially on the acetabular side. Large amounts of necrotic tissue and bloody fluids were thoroughly debrided during revision THA. A modular hemipelvic prosthesis was used for revision of the left hip. Four years later, the patient presented with right hip pain, where a mass appeared on the medial side of the proximal right thigh. A primary acetabular implant with augment was used for revision of the right hip. Laboratory evaluation of bloody fluid retrieved from surgery revealed elevated levels of inflammatory markers. Conclusion Inflammatory responses to polyethylene wear debris can lead to severe bone resorption and aseptic loosening in the long‐term following THA. Therefore, in spite of revision THA, interrupting the cascade inflammatory might be the treatment principle for periprosthetic osteolysis.

Abstract Ferroptosis is a newly discovered form of cell death that is characterized by the accumulation of iron‐dependent lipid peroxidation. Research on ferroptosis has seen exponential growth over the past few years. Tumor cells are strongly dependent on iron for their growth, which makes them develop mechanisms to increase iron uptake and inhibit iron output, thereby completing iron accumulation. Ferroptosis can be induced or inhibited by various stresses through multiple mechanisms, making it stands at the crossroads of stresses related cancer cell fate determination. In this review, we give a brief summary of ferroptosis hallmarks and provide a systematic analysis of the current molecular mechanisms and regulatory networks of diverse stress conditions on ferroptosis. We also discuss the relationships between ferroptosis and cancer therapy responses to further understand potential targets and therapeutic strategies for cancer treatment.

Abstract Carbon dots (CDs) with excellent cytocompatibility, tunable optical properties, and simple synthesis routes are highly desirable for use in optical bioimaging. However, the majority of existing CDs are triggered by ultraviolet/blue light, presenting emissions in the visible/first near‐infrared (NIR‐I) regions, which do not allow deep tissue penetration. Emerging research into CDs with NIR‐II emission in the red region has generated limited designs with poor quantum yield, restricting their in vivo imaging applications due to low penetration depth. Developing novel CDs with NIR‐II emissions and high quantum yield has significant and far‐reaching applications in bioimaging and photodynamic therapy. Here, it is developed for the first time Fe‐doped CDs (Fe‐CDs) exhibiting the excellent linear relationship between 900–1200 nm fluorescence‐emission and pH values, and high quantum yield (QY‐1.27%), which can be used as effective probes for in vivo NIR‐II bioimaging. These findings demonstrate reliable imaging accuracy in tissue as deep as 4 mm, reflecting real‐time pH changes comparable to a standard pH electrode. As an important example application, the Fe‐CDs probe can non‐invasively monitor in vivo gastric pH changes during the digestion process in mice, illustrating its potential applications in aiding imaging‐guided diagnosis of gastric diseases or therapeutic delivery.

Abstract Background This study aimed to explore the prognostic value of tumor mutational burden (TMB) combined with smoking status in advanced non‐small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitor therapy (anti PD‐1/PD‐L1 therapy) combined with chemotherapy or anti‐angiogenesis therapy. Methods We conducted a retrospective analysis of NSCLC patients who underwent next‐generation sequencing test (either 295‐gene panel NGS or 1021‐gene panel NGS) from September 2017 to November 2020. The relationship between TMB and smoking status was investigated. Kaplan–Meier survival analysis was used to compare progression‐free survival (PFS) of the NSCLC patients who received combination immunotherapy grouped by TMB value and smoking status. Results We enrolled 323 cases and 388 cases of NSCLC patients in the 295‐gene panel cohort and 1021‐gene panel cohort, respectively. Positive correlation between TMB and smoking status was found in lung adenocarcinoma, but not in lung squamous cell carcinoma. Participants with both high TMB and smoking status who received immune checkpoint therapy combined with chemotherapy or anti‐angiogenesis therapy had longer PFS than other participants (p

Abstract Pseudomonas aeruginosa biofilm formation is a primary cause of chronic infections. This has been a highly active area of research over the past two decades due to causing high mortality risks in immunocompromised patients. This study evaluates global trends in the dynamic and rapidly evolving field of P. aeruginosa biofilm research through bibliometric and visualized analyses. Publications from 1994 to 2018 on P. aeruginosa biofilm research were retrieved from Web of Science, Scopus, and PubMed, and their bibliometric data were systematically studied. The VOSviewer software was used to conduct global analyses of bibliographic coupling, coauthorship, cocitation, and co‐occurrence. A total of 9,527 publications were included in this study. The overall number of publications and research interest in the field displayed a strongly rising trend. The USA made the greatest contributions to the field, with the highest h‐index and number of citations compared with other countries, while Denmark had the highest average citation per publication. The Journal of Bacteriology had the highest number of publications in the field, while the University of Copenhagen was the institution with the highest contribution influence. Co‐occurrence network maps revealed that the most prominent topics in P. aeruginosa biofilm research were mechanistic studies, in vitro/in vivo studies, and biofilm formation studies. Pseudomonas aeruginosa biofilms constitute a dynamic research area in microbiology with increasing global research interest. Future studies will likely focus on investigating the mechanisms of biofilm formation to solve infection‐associated clinical problems.

Abstract Epidermal growth factor receptor (EGFR) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and correlates with poor prognosis. EGFR has been demonstrated to be associated with cancer stem cell traits in HNSCC. However, the underlying molecular mechanism is far from elucidated. Here, SOX2, one of the most important stem cell markers, was identified as a binding partner and substrate of EGFR. EGFR signaling inhibition decreases SOX2 expression by promoting its autophagic degradation. Mechanistically, EGFR activation induces SOX2 phosphorylation at the Y277 site and reduces its ubiquitination, which inhibits its association with p62 and subsequent autophagic degradation. Gefitinib, an EGFR tyrosine kinase inhibitor, shows in vitro and in vivo protective effects against oral cancer cells that can be reversed through autophagy inhibition. Our study suggests that EGFR plays an important role in the development of cancer stem cells by stabilizing SOX2. Targeting EGFR in combination with conventional chemotherapy might be a promising strategy for the treatment of HNSCC through elimination of cancer stem cells.

Abstract In addition to maintaining immune tolerance, Foxp3+ regulatory T cells (Tregs) perform specialized functions in tissue homeostasis and remodeling. However, whether Tregs in aortic aneurysms have a tissue‐specific phenotype and function is unclear. Here, a special group of Tregs that potentially inhibit abdominal aortic aneurysm (AAA) progression are identified and functionally characterized. Aortic Tregs gradually increase during the process of AAA and are mainly recruited from peripheral circulation. Single‐cell TCR sequencing and bulk RNA sequencing demonstrate their unique phenotype and highly expressed trefoil factor 1 (Tff1). Foxp3cre/creTff1flox/flox mice are used to clarify the role of Tff1 in AAA, suggesting that aortic Tregs secrete Tff1 to regulate smooth muscle cell (SMC) survival. In vitro experiments confirm that Tff1 inhibits SMC apoptosis through the extracellular signal‐regulated kinase (ERK) 1/2 pathway. The findings reveal a tissue‐specific phenotype and function of aortic Tregs and may provide a promising and novel approach for the prevention of AAA.

Abstract Metal‐coordinated supramolecular nanoassemblies have recently attracted extensive attention as materials for cancer theranostics. Owing to their unique physicochemical properties, metal‐coordinated supramolecular self‐assemblies can bridge the boundary between traditional inorganic and organic materials. By tailoring the structural components of the metal ions and binding ligands, numerous multifunctional theranostic nanomedicines can be constructed. Metal‐coordinated supramolecular nanoassemblies can modulate the tumor microenvironment (TME), thus facilitating the development of TME‐responsive nanomedicines. More importantly, TME‐responsive organic–inorganic hybrid nanomaterials can be constructed in vivo by exploiting the metal‐coordinated self‐assembly of a variety of functional ligands, which is a promising strategy for enhancing the tumor accumulation of theranostic molecules. In this review, recent advancements in the design and fabrication of metal‐coordinated supramolecular nanomedicines for cancer theranostics are highlighted. These supramolecular compounds are classified according to the order in which the coordinated metal ions appear in the periodic table. Furthermore, the prospects and challenges of metal‐coordinated supramolecular self‐assemblies for both technical advances and clinical translation are discussed. In particular, the superiority of TME‐responsive nanomedicines for in vivo coordinated self‐assembly is elaborated, with an emphasis on strategies that enhance the accumulation of functional components in tumors for an ideal theranostic outcome.

Abstract Background and aims 4‐phenylbutyric acid (4‐PBA) is a low molecular weight fatty acid that is used in clinical practice to treat inherited urea cycle disorders. In previous reports, it acted as a chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown. Methods 4‐PBA was administered alone or in combination with diethylnitrosamine to investigate its long‐term effect on liver tumorigenesis. The role of 4‐PBA in oncogene‐induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co‐expressed with hMet and β‐catenin point mutation (S45Y) was also observed. RNA‐seq and PCR array were used to screen the pathways and genes involved. In vitro and in vivo studies were conducted to explore the effect of 4‐PBA on liver and validate the underlying mechanism. Results 4‐PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b‐Fzd5 mediating β‐catenin signaling. Peroxisome proliferator‐activated receptors (PPAR)‐α induced by 4‐PBA was responsible for the activation of β‐catenin signaling. Thus, intervention of PPAR‐α reversed 4‐PBA‐induced initiation of LCSCs and HCC development in vivo. Further study revealed that 4‐PBA could not only upregulate the expression of PPAR‐α transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR‐α expression predicted poor prognosis in HCC patients. Conclusions 4‐PBA could upregulate PPAR‐α to initiate LCSCs by activating β‐catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor‐promoting effect of 4‐PBA under HCC‐inducing environment.