Novel Nonthermal Atmospheric Plasma Irradiation of Titanium Implants Promotes Osteogenic Effect in Osteoporotic Conditions.

Osteoporosis is a metabolic disease characterized by bone density and trabecular bone loss. Bone loss may affect dental implant osseointegration in patients with osteoporosis. To promote implant osseointegration in osteoporotic patients, we further used a nonthermal atmospheric plasma (NTAP) treatment device previously developed by our research group. After the titanium implant (Ti) is placed into the device, the working gas flow and the electrode switches are turned on, and the treatment is completed in 30 s. Previous studies showed that this NTAP device can remove carbon contamination from the implant surface, increase the hydroxyl groups, and improve its wettability to promote osseointegration in normal conditions. In this study, we demonstrated the tremendous osteogenic enhancement effect of NTAP-Ti in osteoporotic conditions in rats for the first time. Compared to Ti, the proliferative potential of osteoporotic bone marrow mesenchymal stem cells on NTAP-Ti increased by 180% at 1 day (P = 0.004), while their osteogenic differentiation increased by 149% at 14 days (P < 0.001). In addition, the results indicated that NTAP-Ti significantly improved osseointegration in osteoporotic rats in vivo. Compared to the Ti, the bone volume fraction (BV/TV) and trabecular number (Tb.N) values of NTAP-Ti in osteoporotic rats, respectively, increased by 18% (P < 0.001) and 25% (P = 0.007) at 6 weeks and the trabecular separation (Tb.Sp) value decreased by 26% (P = 0.02) at 6 weeks. In conclusion, this study proved a novel NTAP irradiation titanium implant that can significantly promote osseointegration in osteoporotic conditions.

Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis.

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

Interleukin-6 signaling pathway in Mendelian randomization: A 10-year bibliometric analysis.

Interleukin 6 (IL-6), a pleiotropic cytokine, is crucial in a variety of inflammatory and immunological disorders. In recent years, mendelian randomization, which is a widely used and successful method of analyzing causality, has recently been investigated for the relationship between the IL-6 pathway and related diseases. However, no studies have been conducted to review the research hotspots and trends in the field of IL-6 signaling pathway in Mendelian randomization. In this study, the Web of Science Core Collection (WoSCC) served as our literature source database to gather articles about the IL-6 signaling pathway in Mendelian randomization from 2013 to 2023. VOSviewer (version 1.6.18), Microsoft Excel 2021, and Scimago Graphica were employed for bibliometric and visualization analysis. A total of 164 documents that were written by 981 authors coming from 407 institutions across 41 countries and published in 107 journals were located from January 2013 to August 2023. With 64 and 25, respectively, England and the University of Bristol had the highest number of publications. Frontiers in Immunology is the most prolific journal, and Golam M Khandaker has published the highest number of significant articles. The most co-cited article was an article entitled the interleukin-6 receptor as a target for prevention of coronary-heart-disease: a Mendelian randomization analysis, written by Daniel I Swerdlow. The most popular keywords were "mendelian randomization," "interleukin-6," "il-6," "c-reactive protein," "association," "coronary-heart-disease," "inflammation," "instruments," "risk," "rheumatoid arthritis," "depression." The full extent of the existing literature over the last 10 years is systematically revealed in this study, which can provide readers with a valuable reference for fully comprehending the research hotspots and trends in the field of IL-6 signaling pathway in Mendelian randomization.

Lymphatic endothelial cell-mediated accumulation of CD177+Treg cells suppresses antitumor immunity in human esophageal squamous cell carcinoma.

Regulatory T (Treg) cells are critical in shaping an immunosuppressive microenvironment to favor tumor progression and resistance to therapies. However, the heterogeneity and function of Treg cells in esophageal squamous cell carcinoma (ESCC) remain underexplored. We identified CD177 as a tumor-infiltrating Treg cell marker in ESCC. Interestingly, expression levels of CD177 and PD-1 were mutually exclusive in tumor Treg cells. CD177+ Treg cells expressed high levels of IL35, in association with CD8+ T cell exhaustion, whereas PD-1+ Treg cells expressed high levels of IL10. Pan-cancer analysis revealed that CD177+ Treg cells display increased clonal expansion compared to PD-1+ and double-negative (DN) Treg cells, and CD177+ and PD-1+ Treg cells develop from the same DN Treg cell origin. Importantly, we found CD177+ Treg cell infiltration to be associated with poor overall survival and poor response to anti-PD-1 immunotherapy plus chemotherapy in ESCC patients. Finally, we found that lymphatic endothelial cells are associated with CD177+ Treg cell accumulation in ESCC tumors, which are also decreased after anti-PD-1 immunotherapy plus chemotherapy. Our work identifies CD177+ Treg cell as a tumor-specific Treg cell subset and highlights their potential value as a prognostic marker of survival and response to immunotherapy and a therapeutic target in ESCC.

The rapid proximity labeling system PhastID identifies ATP6AP1 as an unconventional GEF for Rheb.

Rheb is a small G protein that functions as the direct activator of the mechanistic target of rapamycin complex 1 (mTORC1) to coordinate signaling cascades in response to nutrients and growth factors. Despite extensive studies, the guanine nucleotide exchange factor (GEF) that directly activates Rheb remains unclear, at least in part due to the dynamic and transient nature of protein-protein interactions (PPIs) that are the hallmarks of signal transduction. Here, we report the development of a rapid and robust proximity labeling system named Pyrococcus horikoshii biotin protein ligase (PhBPL)-assisted biotin identification (PhastID) and detail the insulin-stimulated changes in Rheb-proximity protein networks that were identified using PhastID. In particular, we found that the lysosomal V-ATPase subunit ATP6AP1 could dynamically interact with Rheb. ATP6AP1 could directly bind to Rheb through its last 12 amino acids and utilizes a tri-aspartate motif in its highly conserved C-tail to enhance Rheb GTP loading. In fact, targeting the ATP6AP1 C-tail could block Rheb activation and inhibit cancer cell proliferation and migration. Our findings highlight the versatility of PhastID in mapping transient PPIs in live cells, reveal ATP6AP1's role as an unconventional GEF for Rheb, and underscore the importance of ATP6AP1 in integrating mTORC1 activation signals through Rheb, filling in the missing link in Rheb/mTORC1 activation.

Efficacy and safety of traditional Chinese medicine in the treatment of menopause-like syndrome for breast cancer survivors: a systematic review and meta-analysis.

BACKGROUND: In recent years, breast cancer (BC) incidence and mortality have been the highest in females. Menopause-like syndrome (MLS), arising from hypoestrogenism caused by endocrine therapy, significantly affects the quality of life for females. Traditional Chinese Medicine (TCM) has advantages in ameliorating MLS, but the efficacy of TCM in patients with BC has not been systematically evaluated. METHODS: A comprehensive search was performed on PubMed, Web of Science, Embase, Ovid, Cochrane Library, China National Knowledge Infrastructure, Wanfang database, Chinese Scientific Journals Database, and Clinical Trial Registry from inception to September 4, 2023. The Cochrane Risk of Bias assessment tool was used for the quality evaluation of the randomized controlled trials (RCTs). Review Manager 5.4 software was used for statistical analysis, and the Grading of Recommendations Assessment, Development, and Evaluation was used for quality evaluation of the synthesized evidence. RESULTS: This review included 42 studies involving 3112 female patients with BC. The results showed that the TCM group was better at decreasing the Kupperman Menopausal Index (KMI) scores (standardized MD, SMD = - 1.84, 95% confidence interval, CI [- 2.21--1.46], Z = 9.63, P < 0.00001). Regarding the main symptoms of MLS, the TCM groups could significantly decrease the scores of hot flashes and night sweats (SMD = - 0.68, 95% CI [- 1.1--0.27], Z = 3.24, P = 0.001), paraesthesia (SMD = - 0.48, 95% CI [- 0.74--0.21], Z = 3.53, P = 0.0004), osteoarthralgia (SMD = - 0.41, 95% CI [- 0.6-0.21], Z = 4.09, P < 0.0001), anxiety (MD = - 0.85, 95% CI [- 1.13, - 0.58], Z = 6.08, P < 0.00001) and insomnia (MD = - 0.61, 95% CI [- 0.8, - 0.43], Z = 6.51, P < 0.00001). TCM can effectively improve the symptoms of MLS in patients with BC. Moreover, TCM could improve the objective response rate (ORR) by 50% (RR = 1.5, 95% CI [1.37-1.64], Z = 9.01, P < 0.00001). Follicle-stimulating hormone (FSH) and oestradiol (E2) had no significant difference compared with the control group (p = 0.81 and p = 0.87), and luteinizing hormone (LH) in the TCM group decreased significantly (MD = - 0.99, 95% CI [- 1.38, - 0.5], Z = 5.01, P < 0.00001). This means that the use of TCM does not negatively affect endocrine therapy and may even have a synergistic effect. The incidence of adverse events (AEs) was lower in the TCM groups than in the control groups. CONCLUSIONS: The meta-analysis stated that TCM could better improve the MLS of patients, alleviate related symptoms, and did not increase adverse drug reactions in BC survivors. This review brings more attention to MLS, and the present findings shed light on the potential applications of TCM in the treatment of MLS in BC survivors.

The NEDD8-activating enzyme E1 UBA3 orchestrates the immunosuppressive microenvironment in lung adenocarcinoma via the NF-кB pathway.

Immunosuppressive cells play important roles in generating an immunosuppressive tumor microenvironment and facilitating tumor immune escape. However, the molecular mechanisms underlying their immunosuppressive effects remain unclear. UBA3, the sole catalytic subunit of the neural precursor cell expressed developmentally down-regulated protein 8 (NEDD8)-activating enzyme E1, is highly expressed in various human malignancies, along with an activated neddylation pathway. In this study, we investigated the relationships between the UBA3-dependent neddylation pathway and the infiltration of several immunosuppressive cell populations in lung adenocarcinoma (LUAD). We explored the regulatory mechanisms of UBA3 in LUAD cells by using mRNA sequencing and functional enrichment analyses. Correlations between neddylation and immune infiltrates were assessed by Western blotting, real-time PCR, and analyses of public databases. We found elevated levels of UBA3 expression in LUAD tissues compared to adjacent normal tissues. Blocking UBA3 and the neddylation pathway promoted the accumulation of the phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (p-IκBα), inhibiting the gene expression of tumor cell-derived cytokines such as C-C motif chemokine ligand (CCL) 2, C-X-C motif ligand (CXCL)1, CXCL2, colony-stimulating factor (CSF) 1, CSF2 interleukin (IL)-6, and IL-1B. Moreover, the overexpression of UBA3 in LUAD cells was associated with the secretion of these cytokines, and the recruitment and infiltration of immunosuppressive cells including tumor-associated macrophages (TAMs), plasmacytoid dendritic cells (pDCs), Th2 cells and T-regulatory cells (Tregs). This could facilitate the tumor immune escape and malignant progression of LUAD. Our findings provide new insights into the role of UBA3 in establishing an immunosuppressive tumor microenvironment by modulating nuclear factor kappa B (NF-кB) signaling and the neddylation pathway.

Effect of traditional Chinese medicine on postoperative depression of breast cancer: a systematic review and meta-analysis.

Background: Depression is one of the common complications in patients with postoperative breast cancer (BC). Conventional therapies for postoperative depression of BC always have modest treatment outcomes and undesirable side effects. Clinical practice and many studies have shown that traditional Chinese medicine (TCM) has a good effect on postoperative depression of BC. This meta-analysis aimed to assess the clinical effect of TCM as an add-on treatment for postoperative depression of BC. Methods: A systematic and thorough search was conducted on eight online electronic databases up to 20 July 2022. The control group received conventional therapies, and intervention groups received what control groups received plus TCM treatment. Review Manager 5.4.1 was used for statistical analysis. Results: Nine RCTs involved 789 participants who met the inclusion standards. The results showed the intervention group was better at decreasing the score of the Hamilton rating scale for depression (HAMD) (mean difference, MD = -4.21, 95% CI -5.54 to -2.88) and the self-rating depression scale (SDS) (MD = -12.03, 95% CI -15.94 to -8.13), improving clinical efficacy (RR = 1.25, 95% CI 1.14-1.37), increasing the levels of 5-hydroxytryptamine (5-HT) (MD = 0.27, 95% CI 0.20-0.34), dopamine (DA) (MD = 26.28, 95% CI 24.18-28.77), and norepinephrine (NE) (MD = 11.05, 95% CI 8.07-14.04), and influencing the immune index, including the levels of CD3+ (MD = 15.18, 95% CI 13.61-16.75), CD4+ (MD = 8.37, 95% CI 6.00-10.74), and CD4+/CD8+ (MD = 0.33, 95% CI 0.27-0.39). The level of CD8+ (MD = -4.04, 95% CI -11.98 to 3.99) had no obvious difference between the two groups. Conclusion: The meta-analysis stated that a therapeutic regimen involving TCM could better improve the depression status in postoperative BC.

A nickel-based metal-organic framework as a new cathode for chloride ion batteries with superior cycling stability.

Chloride ion batteries (CIBs) have drawn growing attention as attractive candidates for large-scale energy storage technology because of their high theoretical energy densities (2500 W h L-1), dendrite-free characteristics and abundance of chloride-containing materials available worldwide. However, the further development of CIBs is greatly limited by sluggish Cl- diffusion and distinct structural variation of cathode materials, resulting in severe decayed capacity and inferior rate performance. Metal-organic framework (MOF) materials possess regular pores/channels and flexible structural designability to accommodate charge carrier ions, but the application of MOFs in anion-type batteries has not been reported. Here, we demonstrate the first example of Ni(dpip) with two different opening sizes of tubular channels serving as the cathode for high performance CIBs. The Ni-based MOF exhibited a stable reversible capacity of 155 mA h g-1 with an admirable low capacity decay of 0.026% per cycle over 500 cycles and superior kinetics with a 10-10 cm2 s-1 average diffusion coefficient for chloride ions as well. The high performance of the Ni(dpip) cathode results from the synergetic redox couples of Ni metal nodes and N-ligands, the unique double-channel structure for reversible Cl-storage, and the low chloride diffusion energy barrier. This work switches on the new application of MOF-based materials as cathodes for CIBs.

A retrospect study based on real-world data to observe metabolic function in cancer patients using albumin-bound paclitaxel.

There is substantial evidence that albumin-bound paclitaxel (nab-paclitaxel) is effective and safe for the treatment of breast, lung and pancreatic cancers. However, it can still cause adverse effects by affecting cardiac enzymes, hepatic enzyme metabolism and blood routine related indicators, which affects the use of chemotherapy for a full course of treatment. However, there are no relevant clinical studies to systematically observe the effects and dynamics of albumin-bound paclitaxel on cardiac enzymes, liver enzyme metabolism, and routine blood-related indices. The purpose of our study was to determine the levels of serum creatinine (Cre), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), white blood cells (WBC) and hemoglobin (HGB) in cancer patients treated with albumin-conjugated paclitaxel. This study retrospectively analyzed 113 patients with cancer. Patients who had received two cycles of nab-paclitaxel 260 mg/m2 (administered intravenously on days 1, 8, and 15 of each 28-day cycle) were selected. Serum Cre, AST, ALT, LDH, CK, and CK-MB activities, WBC counts, and HGB levels were measured before and after treatment with two cycles. Fourteen cancer types were analyzed. The distribution of cancer types in patients was mainly concentrated in lung, ovarian, and breast cancer. Nab-paclitaxel treatment markedly decreased Cre, AST, LDH, and CK activities in the serum and WBC counts and HGB levels, respectively. Serum Cre and CK activities and HGB levels were remarkably downregulated at baseline compared to healthy controls. Patients receiving nab-paclitaxel treatment cause metabolic disorders in tumor patients by reducing the decrease of Cre, AST, LDH, CK, CK-MB, WBC and HGB indexes, thus inducing the occurrence of cardiovascular events, hepatotoxic events and fatigue and other symptoms. Therefore, for tumor patients, although receiving nab-paclitaxel improves the anti-tumor effect, it is still necessary to closely monitor the changes of related enzymatic and routine blood indicators, so as to detect and intervene at an early stage.

A High-Nickel Layered Double Hydroxides Cathode Boosting the Rate Capability for Chloride Ion Batteries with Ultralong Cycling Life.

Chloride-ion batteries (CIBs) have drawn growing attention in large-scale energy storage applications owing to their comprehensive merits of high theoretical energy density, dendrite-free characteristic, and abundance of chloride-containing materials. Nonetheless, cathodes for CIBs are plagued by distinct volume effect and sluggish Cl- diffusion kinetics, leading to inferior rate capability and short cycling life. Herein, an unconventional Ni5 Ti-Cl LDH is reported with a high nickel ratio as a cathode material for CIB. The reversible capacity of Ni5 Ti-Cl LDH retains 127.9 mAh g-1 over 1000 cycles at a large current density of 1000 mA g-1 , which exceeds that of ever reported CIBs, with extraordinary low volume change of 1.006% during a whole charge/discharge process. Such superior Cl-storage performance is attributed to synergetic contributions consisting of high redox activity from Ni2+ /Ni3+ and pinning Ti that restrains local structural distortion of LDH host layers and enhances adsorption intensity of chloride atoms during the reversible Cl- intercalation/de-intercalation in LDH gallery, which are revealed by a comprehensive study including X-ray photoelectron spectroscopy, kinetic investigations, and DFT calculations. This work provides an effective strategy to design low-cost LDHs materials for high-performance CIBs, which are also applicable to other types of halide-ion batteries (e.g., fluoride-ion and bromide-ion batteries).

Symptom burden survey and symptom clusters in patients with cervical cancer: a cross-sectional survey.

PURPOSE: The purpose of this study is to determine the incidence and severity of symptoms of patients with cervical cancer within 6 months after radiotherapy and chemotherapy, form a symptom burden report, evaluate the distribution characteristics of symptoms, identify symptom clusters, and provide a basis for clinical doctors and nurses to improve the symptom management of patients with cervical cancer after radiotherapy and chemotherapy. METHODS: The patients with cervical cancer within 6 months after radiotherapy and chemotherapy were recruited to investigate their symptom burden. Exploratory factor analysis was used to identify symptom clusters. RESULTS: A total of 250 patients participated in the study. The study found that the most common symptom among the 40 symptoms was fatigue, and the most serious symptom was nocturia. Based on the occurrence rate and severity of symptoms, nine symptom clusters were identified, including psycho-emotion-related symptom cluster, pain-disturbed sleep-related symptom cluster, menopausal symptom cluster, tinnitus-dizziness-related symptom cluster, urinary-related symptom cluster, dry mouth-bitter taste-related symptom cluster, intestinal-related symptom cluster, memory loss-numbness-related symptom cluster, and emaciation-related symptom cluster. The three most serious symptom clusters are pain-disturbed sleep-related symptom cluster, urinary-related symptom cluster, and memory loss-numbness-related symptom cluster. CONCLUSION: The symptoms of patients with cervical cancer within 6 months after radiotherapy and chemotherapy are complex, and nine symptom clusters can be identified according to the incidence and severity of symptoms. We can find the potential biological mechanism of each symptom cluster through the discussion of previous mechanism research and clinical research. The number of symptom clusters and the number of symptoms within the symptom cluster are closely related to the symptom evaluation scale selected for the study. Therefore, the symptom cluster study urgently needs a targeted symptom evaluation scale that can comprehensively reflect the patient's condition.

PTC-MAS: A Deep Learning-Based Preoperative Automatic Assessment of Lymph Node Metastasis in Primary Thyroid Cancer.

BACKGROUND: Identifying cervical lymph node metastasis (LNM) in primary thyroid cancer preoperatively using ultrasound is challenging. Therefore, a non-invasive method is needed to assess LNM accurately. PURPOSE: To address this need, we developed the Primary Thyroid Cancer Lymph Node Metastasis Assessment System (PTC-MAS), a transfer learning-based and B-mode ultrasound images-based automatic assessment system for assessing LNM in primary thyroid cancer. METHODS: The system has two parts: YOLO Thyroid Nodule Recognition System (YOLOS) for obtaining regions of interest (ROIs) of nodules, and LMM assessment system for building the LNM assessment system using transfer learning and majority voting with extracted ROIs as input. We retained the relative size features of nodules to improve the system's performance. RESULTS: We evaluated three transfer learning-based neural networks (DenseNet, ResNet, and GoogLeNet) and majority voting, which had the area under the curves (AUCs) of 0.802, 0.837, 0.823, and 0.858, respectively. Method III preserved relative size features and achieved higher AUCs than Method II, which fixed nodule size. YOLOS achieved high precision and sensitivity on a test set, indicating its potential for ROIs extraction. CONCLUSIONS: Our proposed PTC-MAS system effectively assesses primary thyroid cancer LNM based on preserving nodule relative size features. It has potential for guiding treatment modalities and avoiding inaccurate ultrasound results due to tracheal interference.

Genome-Wide Identification and Characterization of the PPO Gene Family in Cotton (Gossypium) and Their Expression Variations Responding to Verticillium Wilt Infection.

Polyphenol oxidases (PPOs) are copper-binding metalloproteinases encoded by nuclear genes, ubiquitously existing in the plastids of microorganisms, plants, and animals. As one of the important defense enzymes, PPOs have been reported to participate in the resistant processes that respond to diseases and insect pests in multiple plant species. However, PPO gene identification and characterization in cotton and their expression patterns under Verticillium wilt (VW) treatment have not been clearly studied. In this study, 7, 8, 14, and 16 PPO genes were separately identified from Gossypium arboreum, G. raimondii, G. hirsutum, and G. barbadense, respectively, which were distributed within 23 chromosomes, though mainly gathered in chromosome 6. The phylogenetic tree manifested that all the PPOs from four cotton species and 14 other plants were divided into seven groups, and the analyses of the conserved motifs and nucleotide sequences showed highly similar characteristics of the gene structure and domains in the cotton PPO genes. The dramatically expressed differences were observed among the different organs at various stages of growth and development or under the diverse stresses referred to in the published RNA-seq data. Quantitative real-time PCR (qRT-PCR) experiments were also performed on the GhPPO genes in the roots, stems, and leaves of VW-resistant MBI8255 and VW-susceptible CCRI36 infected with Verticillium dahliae V991, proving the strong correlation between PPO activity and VW resistance. A comprehensive analysis conducted on cotton PPO genes contributes to the screening of the candidate genes for subsequent biological function studies, which is also of great significance for the in-depth understanding of the molecular genetic basis of cotton resistance to VW.

A ratiometric fluorescent probe for fast detection and bioimaging of formaldehyde.

A novel ratiometric probe (SWJT-10) based on isophorone derivatives has been designed and synthesized for the detection of formaldehyde (FA). This probe displayed an obvious ratiometric fluorescence response to FA with a blue shift from the NIR (680 nm) to the yellow light region (600 nm) in aqueous solution. And it showed good selectivity, high sensitivity and a fast response to FA (less than 5 s) due to a new recognition mechanism. Moreover, SWJT-10 has been applied to monitor FA in living cells and zebrafish.

Oleic acid-bound FABP7 drives glioma cell proliferation through regulation of nuclear lipid droplet formation.

Fatty acid-binding protein 7 (FABP7), one of the fatty acid (FA) chaperones involved in the modulation of intracellular FA metabolism, is highly expressed in glioblastoma, and its expression is associated with decreased patients' prognosis. Previously, we demonstrated that FABP7 requires its binding partner to exert its function and that a mutation in the FA-binding site of FABP7 affects tumour biology. Here, we explored the role of FA ligand binding for FABP7 function in tumour proliferation and examined the mechanism of FABP7 and ligand interaction in tumour biology. We discovered that among several FA treatment, oleic acid (OA) boosted cell proliferation of FABP7-expressing cells. In turn, OA increased FABP7 nuclear localization, and the accumulation of FABP7-OA complex in the nucleus induced the formation of nuclear lipid droplet (nLD), as well as an increase in colocalization of nLD with promyelocytic leukaemia (PML) nuclear bodies. Furthermore, OA increased mRNA levels of proliferation-related genes in FABP7-expressing cells through histone acetylation. Interestingly, these OA-boosted functions were abrogated in FABP7-knockout cells and mutant FABP7-overexpressing cells. Thus, our findings suggest that FABP7-OA intracellular interaction may modulate nLD formation and the epigenetic status thereby enhancing transcription of proliferation-regulating genes, ultimately driving tumour cell proliferation.

Conversion Surgery Following Immunochemotherapy in Initially Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma-A Real-World Multicenter Study (RICE-Retro).

Purpose: The present study sets out to evaluate the feasibility, safety, and effectiveness of conversion surgery following induction immunochemotherapy for patients with initially unresectable locally advanced esophageal squamous cell carcinoma (ESCC) in a real-world scenario. Materials and Methods: In this multi-center, real-world study (NCT04822103), patients who had unresectable ESCC disease were enrolled across eight medical centers in China. All patients received programmed death receptor-1 (PD-1) inhibitor plus chemotherapy every 3 weeks for at least two cycles. Patients with significant relief of cancer-related clinical symptoms and radiological responsive disease were deemed surgical candidates. Feasibility and safety profile of immunochemotherapy plus conversion surgery, radiological and pathological tumor responses, as well as short-term survival outcomes were evaluated. Moreover, data of an independent ESCC cohort receiving induction chemotherapy (iC) were compared. Results: One hundred and fifty-five patients were enrolled in the final analysis. Esophagectomy was offered to 116 patients, yielding a conversion rate of 74.8%. R0 resection rate was 94%. Among the 155 patients, 107 (69.0%) patients experienced at least one treatment-related adverse event (TRAE) and 45 (29.0%) patients reported grade 3 and above TRAEs. Significant differences in responsive disease rate were observed between iC cohort and induction immunochemotherapy (iIC) cohort [objective response rate: iIC: 63.2% vs. iC: 47.7%, p = 0.004; pathological complete response: iIC: 22.4% vs. iC: 6.7%, p = 0.001). Higher anastomosis fistula rate was observed in the iC group (19.2%) compared with the iIC group (4%). Furthermore, Significantly higher event-free survival was observed in those who underwent conversion surgery. Conclusion: Our results supported that conversion surgery following immunochemotherapy is feasible and safe for patients with initially unresectable locally advanced ESCC. Both radiological and pathological response rates were significantly higher in the iIC cohort compared with those in the traditional iC cohort.

Bioorthogonal Equipping CAR-T Cells with Hyaluronidase and Checkpoint Blocking Antibody for Enhanced Solid Tumor Immunotherapy.

Adoptive cellular therapy utilizing chimeric antigen receptor redirected T (CAR-T) cells has shown impressive therapeutic effects on hematological malignancies. In contrast, the efficacy of CAR-T therapies in treating solid tumors is still poor, which is largely due to inefficient penetration into solid tumors and the immunosuppressive tumor microenvironment. Herein, we engineered hyaluronidase (HAase) and the checkpoint blocking antibody α-PDL1 on the CAR-T cell surface via highly efficient and biocompatible bioorthogonal click chemistry to improve their therapeutic effects on solid tumors. The modified HAase degrades hyaluronic acid and destroys the tumor extracellular matrix, allowing CAR-T cells to penetrate deeply into solid tumors, as evidenced by in vitro infiltration experiments and in vivo biodistribution studies. In addition, in vitro cytotoxicity studies showed stronger antitumor activity of α-PDL1-decorated cells than traditional CAR-T cells. Importantly, HAase- and α-PDL1-engineered CAR-T cells showed better therapeutic efficacy on two solid tumor models and did not cause significant systemic side effects. In this work, we provide a simple, efficient, and biologically safe chemical strategy to engineer traditional CAR-T cells for enhanced therapeutic efficacy on solid tumors, which can be extended to other adoptive cellular immunotherapies and holds great potential for clinical application.

Nuclear FABP7 regulates cell proliferation of wild-type IDH1 glioma through caveolae formation.

Isocitrate dehydrogenase 1 (IDH1) is a key enzyme in cellular metabolism. IDH1 mutation (IDH1mut) is the most important genetic alteration in lower grade glioma, whereas glioblastoma (GB), the most common malignant brain tumor, often has wild-type IDH1 (IDH1wt). Although there is no effective treatment yet for neither IDH1wt nor IDHmut GB, it is important to note that the survival span of IDH1wt GB patients is significantly shorter than those with IDH1mut GB. Thus, understanding IDH1wt GB biology and developing effective molecular-targeted therapies is of paramount importance. Fatty acid-binding protein 7 (FABP7) is highly expressed in GB, and its expression level is negatively correlated with survival in malignant glioma patients; however, the underlying mechanisms of FABP7 involvement in tumor proliferation are still unknown. In this study, we demonstrate that FABP7 is highly expressed and localized in nuclei in IDH1wt glioma. Wild-type FABP7 (FABP7wt) overexpression in IDH1wt U87 cells increased cell proliferation rate, caveolin-1 expression, and caveolae/caveosome formation. In addition, FABP7wt overexpression increased the levels of H3K27ac on the caveolin-1 promoter through controlling the nuclear acetyl-CoA level via the interaction with ACLY. Consistent results were obtained using a xenograft model transplanted with U87 cells overexpressing FABP7. Interestingly, in U87 cells with mutant FABP7 overexpression, both in vitro and in vivo phenotypes shown by FABP7wt overexpression were disrupted. Furthermore, IDH1wt patient GB showed upregulated caveolin-1 expression, increased levels of histone acetylation, and increased levels of acetyl-CoA compared with IDH1mut patient GB. Taken together, these data suggest that nuclear FABP7 is involved in cell proliferation of GB through caveolae function/formation regulated via epigenetic regulation of caveolin-1, and this mechanism is critically important for IDH1wt tumor biology.