LILRB4 on multiple myeloma cells promotes bone lesion by p-SHP2/NF-κB/RELT signal pathway.

BACKGROUND: Leukocyte Ig-like receptor B family 4 (LILRB4) as an immune checkpoint on myeloid cells is a potential target for tumor therapy. Extensive osteolytic bone lesion is the most characteristic feature of multiple myeloma. It is unclear whether ectopic LILRB4 on multiple myeloma regulates bone lesion. METHODS: The conditioned medium (CM) from LILRB4-WT and -KO cells was used to analyze the effects of LILRB4 on osteoclasts and osteoblasts. Xenograft, syngeneic and patient derived xenograft models were constructed, and micro-CT, H&E staining were used to observe the bone lesion. RNA-seq, cytokine array, qPCR, the activity of luciferase, Co-IP and western blotting were used to clarify the mechanism by which LILRB4 mediated bone damage in multiple myeloma. RESULTS: We comprehensively analyzed the expression of LILRB4 in various tumor tissue arrays, and found that LILRB4 was highly expressed in multiple myeloma samples. The patient's imaging data showed that the higher the expression level of LILRB4, the more serious the bone lesion in patients with multiple myeloma. The conditioned medium from LILRB4-WT not -KO cells could significantly promote the differentiation and maturation of osteoclasts. Xenograft, syngeneic and patient derived xenograft models furtherly confirmed that LILRB4 could mediate bone lesion of multiple myeloma. Next, cytokine array was performed to identify the differentially expressed cytokines, and RELT was identified and regulated by LILRB4. The overexpression or exogenous RELT could regenerate the bone damage in LILRB4-KO cells in vitro and in vivo. The deletion of LILRB4, anti-LILRB4 alone or in combination with bortezomib could significantly delay the progression of bone lesion of multiple myeloma. CONCLUSIONS: Our findings indicated that LILRB4 promoted the bone lesion by promoting the differentiation and mature of osteoclasts through secreting RELT, and blocking LILRB4 singling pathway could inhibit the bone lesion.

Application of network pharmacology and dock of molecules on the exploration of the mechanism of frankincense-myrrh for lumbar intervertebral disc degeneration: A review.

To investigate the efficacy of Frankincense-Myrrh in lumbar Intervertebral degenerative diseases (LIDD). The active components of frankincense-myrrh was retrieved with a unique system pharmacology platform for Traditional Chinese Medicine Systems Pharmacology (TCMSP). The LIDD-related target genes were screened with DisGeNET and Genecards databases. Then, STRING & Cytoscape were used for analyzing the Protein-Protein Interaction network. DAVID was used for analyzing Gene Ontology (GO) & Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, molecules of AutoDockVina and Pymol were used for docking the molecules for verifying active ingredients and key targets' binding force. The 105 LIDD-related targets identified in Ruxiang (RX)-Moyao (MY) involve 53 active ingredients. In addition, topological analysis was conducted for identifying the 12 key targets. According to the analysis results of GO & KEGG, RX-MY is significant for treating LIDD through participating in many pathways and biological processes, such as signaling pathways of inflammatory response reactive process, MAP kinase activity, TNF, and MAPK, etc. According to the dock results, the active components oxo-tirucalic, acid, isofouquierone, (7S, 8R, 9S, 10R, 13S, 14S,17Z)-17-ethylidene-7-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15-decahydrocyclopenta [a] phenanthrene-3,16-dion in RX-MY binds actively. The basic pharmacological action and RX-MY-related mechanism in the treatment of LIDD was revealed in this study for the first time. It is predicted that the results may provide a treatment plan for RX-MY with replacement of NSAIDs and warrant investigation of new therapeutic alternatives for LIDD. However, these predictions should be validated by relevant pharmacological trials.

[Analysis of correlation between high expression of nucleoporin 85 (NUP85) and immune cell infiltration in hepatocellular carcinoma].

Objective To investigate the significance of nucleoporin 85 (NUP85) ex-pression in hepatocellular carcinoma (HCC) and analyze its relevance to immune response. Methods A comprehensive analysis was conducted using various online databases to assess the mRNA and protein expression of NUP85 in HCC, as well as its mutation status and prognostic diagnostic value. The immune relevance of NUP85 was evaluated using single-cell sequencing data and resources from the Tumor Immune Estimation Resource (TIMER) and the Gene Expression Profiling Interactive Analysis 2021 (GEPIA2021) databases. The drug sensitivity of NUP85 was analyzed through the Genomic Landscape of Cancer (GSCA) and the Clinical Bioinformatics Home. Co-expressed genes of NUP85 in HCC were filtered using the Hepatocellular Carcinoma Comprehensive Molecular Database (HCCDB), and the correlation between NUP85 and its related genes was analyzed using the R language "limma" package. The gene ontology (GO) functions, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) of NUP85 and its related genes were performed using the R language "clusterProfiler" package. The Clinical Bioinformatics Home was utilized to construct heatmaps and prognostic risk scoring models for NUP85 and its related genes. Results NUP85 mRNA and protein expression were upregulated in HCC, showing high levels across dif-ferent stages and grades, which indicates a poor prognosis for patients. The mutation rate of NUP85 in HCC samples was 19%, significantly affecting the overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) of patients. NUP85 was highly expressed in various immune cells, including macrophages, B cells, and T cells, and was positively correlated with the infiltration levels of multiple immune cells. The expression of NUP85 was significantly correlated with multiple drugs, such as Milademetan (PD0325901), a structural analog of Vemurafenib (PLX4720), and Regorafenib (PD0325901). The GO functions of NUP85 and its co-expressed genes were mainly enriched in organelle fission, nuclear division, and chromosome segregation, while the KEGG pathways were primarily enriched in the cell cycle and kinesin proteins. These factors significantly and unfavorably affected the OS of HCC patients, and the areas under the ROC curve (AUC) for the 1-year, 3-year, and 5-year OS prognostic diagnosis of HCC patients were all greater than 0.7. Conclusion The high expression of NUP85 in HCC is correlated with a poor prognosis and is related to various immune cells and drugs, making it a potential biomarker for di-agnosis, treatment, and prognosis in HCC.

hPMSCs prevent erythrocytes dysfunction caused by graft versus host disease via promoting GSH synthesis.

BACKGROUND: Oxidative stress is increased in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients and leads to the development of graft versus host disease (GVHD). Mesenchymal stromal cells (MSCs) can ameliorate GVHD by regulating the function of T cells. However, whether MSCs can modulate erythrocyte antioxidant metabolism and thus reduce GVHD is not known. METHODS: Forty female BALB/c mice were randomly assigned to four groups: the control, GVHDhigh, hPMSC, and PBS groups. A hypoxanthine/xanthine oxidase system was used to steadily and gradually produce superoxide in an in vitro experiment. A scanning microscope was used to examine the ultrastructure of erythrocytes. Laser diffraction analyses were used to analyze erythrocyte deformability. Western blotting was used to measure the expression of the erythrocyte membrane skeleton proteins Band 3 and ß-Spectrin. Corresponding kits were used to assess the levels of oxidative damage and the activity of antioxidant enzymes. RESULTS: Morphological and deformability defects were significantly increased in erythrocytes from GVHD patients. Band 3 and ß-Spectrin expression was also reduced in GVHD patients and model mice. Furthermore, we observed significantly increased oxidative stress-induce injury and decreased antioxidant capability in erythrocytes from both GVHD patients and model mice. Subsequent research showed that human placenta-derived MSC (hPMSC) therapy decreased the GVHD-induced redox imbalance in erythrocytes. Furthermore, our findings suggested that upregulating glucose metabolism promoted both the de novo synthesis and recycling of GSH, which is the primary mechanism by which hPMSCs mediate the increase in antioxidant capacity in erythrocytes. CONCLUSION: Together, our findings suggest that hPMSCs can increase antioxidant capacity by increasing erythrocyte GSH production and thus ameliorate GVHD.

Circadian-driven tissue specificity is constrained under caloric restricted feeding conditions.

Tissue specificity is a fundamental property of an organ that affects numerous biological processes, including aging and longevity, and is regulated by the circadian clock. However, the distinction between circadian-affected tissue specificity and other tissue specificities remains poorly understood. Here, using multi-omics data on circadian rhythms in mice, we discovered that approximately 35% of tissue-specific genes are directly affected by circadian regulation. These circadian-affected tissue-specific genes have higher expression levels and are associated with metabolism in hepatocytes. They also exhibit specific features in long-reads sequencing data. Notably, these genes are associated with aging and longevity at both the gene level and at the network module level. The expression of these genes oscillates in response to caloric restricted feeding regimens, which have been demonstrated to promote longevity. In addition, aging and longevity genes are disrupted in various circadian disorders. Our study indicates that the modulation of circadian-affected tissue specificity is essential for understanding the circadian mechanisms that regulate aging and longevity at the genomic level.

PPP1R14A is Associated with Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma Identified by Single-Cell and Bulk RNA-Sequencing.

Objective To identify nivolumab resistance-related genes in patients with head and neck squamous cell carcinoma (HNSCC) using single-cell and bulk RNA-sequencing data. Methods The single-cell and bulk RNA-sequencing data downloaded from the Gene Expression Omnibus database were analyzed to screen out differentially expressed genes (DEGs) between nivolumab resistant and nivolumab sensitive patients using R software. The Least Absolute Shrinkage Selection Operator (LASSO) regression and Recursive Feature Elimination (RFE) algorithm were performed to identify key genes associated with nivolumab resistance. Functional enrichment of DEGs was analyzed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The relationships of key genes with immune cell infiltration, differentation trajectory, dynamic gene expression profiles, and ligand-receptor interaction were explored. Results We found 83 DEGs. They were mainly enriched in T-cell differentiation, PD-1 and PD-L1 checkpoint, and T-cell receptor pathways. Among six key genes identified using machine learning algorithms, only PPP1R14A gene was differentially expressed between the nivolumab resistant and nivolumab sensitive groups both before and after immunotherapy (P < 0.05). The high PPP1R14A gene expression group had lower immune score (P < 0.01), higher expression of immunosuppressive factors (such as PDCD1, CTLA4, and PDCD1LG2) (r > 0, P < 0.05), lower differentiation of infiltrated immune cells (P < 0.05), and a higher degree of interaction between HLA and CD4 (P < 0.05). Conclusions PPP1R14A gene is closely associated with resistance to nivolumab in HNSCC patients. Therefore, PPP1R14A may be a target to ameliorate nivolumab resistance of HNSCC patients.

Human CD127 negative ILC2s show immunological memory.

ILC2s are key players in type 2 immunity and contribute to maintaining homeostasis. ILC2s are also implicated in the development of type 2 inflammation-mediated chronic disorders like asthma. While memory ILC2s have been identified in mouse, it is unknown whether human ILC2s can acquire immunological memory. Here, we demonstrate the persistence of CD45RO, a marker previously linked to inflammatory ILC2s, in resting ILC2s that have undergone prior activation. A high proportion of these cells concurrently reduce the expression of the canonical ILC marker CD127 in a tissue-specific manner. Upon isolation and in vitro stimulation of CD127-CD45RO+ ILC2s, we observed an augmented ability to proliferate and produce cytokines. CD127-CD45RO+ ILC2s are found in both healthy and inflamed tissues and display a gene signature of cell activation. Similarly, mouse memory ILC2s show reduced expression of CD127. Our findings suggest that human ILC2s can acquire innate immune memory and warrant a revision of the current strategies to identify human ILC2s.

Near-infrared visualisation of single microparticle electrochemistry for batteries.

While optical microscopy of single particle electrochemistry has proven insightful for future nanoparticle-based batteries, little is explored for micron-sized particles of more practical interest. This is largely hindered by the currently limited methodology. Accordingly, we report transmission optical microscopy using near-infrared light for accessing intra-particle electrochemistry in virtue of strong light penetration as compared to visible light. Using near-infrared (λ > 730 nm) bright-field microscopy, the redox electrochemistry of single LiCoO2 microparticles can be readily measured based on the measurements of optical contrast changes during electrochemical cycling. Further using the established methodology, we discover that the solid-state diffusion inside most single microparticles is distinctly directional, instead of in an isotropic manner from outer to inner as observed for the other particles. This phenomenon is also observed using dark field scattering microscopy with near-infrared light, suggesting non-uniform crystal inner structures responsible for the geometrically asymmetric heterogeneity of charge transfer kinetics within each single particle. These results indicate potential opportunities offered by the near-infrared optical methodology for operando studying practical battery materials.

Feasibility and safety of modified en-bloc resection in endoscopic thyroid surgery via bilateral areolar approach - long-term institutional analysis ten years after surgery.

Purpose: This study aimed to introduce a new modified en-bloc resection method and evaluate its feasibility and safety in endoscopic thyroid surgery via bilateral areolar approach (BAA). Methods: Papillary thyroid carcinoma (PTC) patients who underwent lobectomy and ipsilateral central node dissection (CND) via the BAA approach were retrospectively reviewed. Their clinical characteristics and outcomes were evaluated, including operative duration, lymph node yield (LNY), surgical complications, recurrence rate, and metastasis rate, over a ten-year follow-up period. Simultaneous lobectomy and CND were performed in the modified en-bloc group, whereas lobectomy was performed first, followed by CND in the conventional group. Results: The study included 108 patients in the modified en-bloc group and 213 in the conventional group. There were no significant differences in gender, age, tumor locations, tumor dominant nodule size, or the incidence of concomitant Hashimoto thyroiditis when comparing clinicopathologic characteristics. The comparison of operative duration (P = 0.14), blood loss (P = 0.13), postoperative hospital stay (P = 0.58), incidence of transient vocal cord paralysis (P = 0.90) and hypocalcemia (P = 0.60) did not show any differences. The mean LNY achieved in the central compartment of the modified en-bloc group (7.5 ± 4.5) was significantly higher than that in the conventional group (5.6 ± 3.6). Two patients in the modified en-bloc group and two in the conventional group experienced metastasis after surgery during the ten-year follow-up (1.8% vs. 0.9%, P = 0.60). The learning curve analysis showed a significant decrease in operative duration after the 25-35th cases for modified en-bloc resection. Conclusions: The modified en-bloc resection method in endoscopic thyroid surgery via BAA is a technically feasible and safe procedure with excellent cosmetic outcomes for selective PTC patients.

Design, synthesis and biological evaluation of 5H-[1,2,4]triazino[5,6-b]indole derivatives bearing a pyridinocycloalkyl moiety as iron chelators.

The avidity of cancer cells for iron highlights the potential for iron chelators to be used in cancer therapy. Herein, we designed and synthesized a novel series of 5H-[1,2,4]triazino[5,6-b]indole derivatives bearing a pyridinocycloalkyl moiety using a ring-fusion strategy based on the structure of an iron chelator, VLX600. The antiproliferative activity evaluation against cancer cells and normal cells led to the identification of compound 3k, which displayed the strongest antiproliferative activity in vitro against A549, MCF-7, Hela and HepG-2 with IC50 values of 0.59, 0.86, 1.31 and 0.92 µM, respectively, and had lower cytotoxicity against HEK293 than VLX600. Further investigations revealed that unlike VLX600, compound 3k selectively bound to ferrous ions, but not to ferric ions, and addition of Fe2+ abolished the cytotoxicity of 3k. Flow cytometry assays demonstrated that 3k arrested the cell cycle at the G1 phase and induced significant apoptosis in A549 cells in dose and time-dependent manners, corresponding to JC-1 staining assay results. Western blot analysis of Bcl-2, Bax and cleaved caspase-3 proteins further provided evidences that induction of apoptosis by 3k in A549 cells might be at least via the mitochondria pathway. These above results highlight that 3k is a valuable lead compound that deserves further investigation as an iron chelator for the treatment of cancer.

Prediction of the pathological subtypes by intraoperative frozen section for patients with cT1N0M0 invasive lung adenocarcinoma (ECTOP-1015): a prospective multi-center study.

BACKGROUND: The aim of this study is to assess the diagnostic accuracy of intraoperative frozen section (FS) in determining the pathological subtypes among patients diagnosed with cT1N0M0 invasive lung adenocarcinoma. MATERIALS AND METHODS: This was a prospective, multi-center (7 centers in China) clinical trial of Eastern Cooperative Thoracic Oncology Projects (ECTOP-1015). Patients with cT1N0M0 invasive lung adenocarcinoma were enrolled in the study. Pathological images obtained from FS and final pathology (FP) were reviewed by at least two pathologists. The primary endpoint was the concordance between FS and FP diagnoses. The inter-observer agreement for identifying pathological subtypes on FS was evaluated among three pathologists. RESULTS: A total of 935 patients were enrolled. The best sensitivity of diagnosing the predominant subtype was 78.2% in the evaluation of acinar pattern. Presence of acinar pattern diagnosed by FS was an independent factor for the concordance between FS and FP (P=0.007, 95% CI: 2.332-4.736). Patients with tumor size ＞2 cm measured by pathology showed a better concordance rate for the predominant subtype (81.6% vs 74.6%, P=0.023). The presence of radiological ground glass opacity (GGO) component did not affect the diagnosis accuracy of FS for predominant subtype (concordance rate: 76.4% vs 75.2%, P=0.687). Patients with GGO component showed better accuracy of the identification in the presence of LPA (82.1% vs 71.0%, P= 0.026). Substantial agreement between the FS diagnosis from 3 pathologists for the predominant pathological pattern was revealed with κ = 0.846. CONCLUSIONS: This is the largest prospective trial evaluating FS diagnosing pathological subtype in cT1N0M0 invasive lung adenocarcinoma. A favorable concordance in the assessment of the pathological subtypes between FS and FP was observed, indicating the feasibility of utilizing accurate intraoperative pathological diagnoses from FS in guiding surgical strategies. And combination of radiology could improve the precision of FS.

Accumulation of astaxanthin in Microcystis aeruginosa under NaCl and KCl stresses.

Astaxanthin is a high-value natural antioxidant, and can be accumulated in Microcystis aeruginosa. To enhance astaxanthin accumulation in the microalgae by using salt stress, the cell growth, photosynthetic abilities, reactive oxygen species (ROS) levels, astaxanthin and its precursor content, and gene expression were investigated under NaCl and KCl stresses. The two salt stresses inhibited the cell growth by lowering photosynthetic abilities and raising ROS levels. During the 6-day treatment, the two salt stresses improved the levels of astaxanthin, precursors (ß-carotene and zeaxanthin) and carotenoids, which might be caused by the raised ROS up-regulating expression of 7 related genes. At the same concentration, KCl stress showed stronger inducing effect on astaxanthin and its precursor production than NaCl stress, due to higher expression of related genes. Therefore, NaCl and KCl stresses have obvious ion differences on astaxanthin accumulation, of which KCl stress is more suitable for the high-value antioxidant production from microalgae.

A Tumor Environment-Activated Photosensitized Biomimetic Nanoplatform for Precise Photodynamic Immunotherapy of Colon Cancer.

Aggressive nature of colon cancer and current imprecise therapeutic scenarios simulate the development of precise and effective treatment strategies. To achieve this, a tumor environment-activated photosensitized biomimetic nanoplatform (PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM) is fabricated by encapsulating metal-organic framework loaded with developed photosensitizer PEG2000-SiNcTI-Ph and immunoadjuvant CpG oligodeoxynucleotide within fusion cell membrane expressing programmed death protein 1 (PD-1) and cluster of differentiation 47 (CD47). By stumbling across, systematic evaluation, and deciphering with quantum chemical calculations, a unique attribute of tumor environment (low pH plus high concentrations of adenosine 5'-triphosphate (ATP))-activated photodynamic effect sensitized by long-wavelength photons is validated for PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM, advancing the precision of cancer therapy. Moreover, PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM evades immune surveillance to target CT26 colon tumors in mice mediated by CD47/signal regulatory proteins α (SIRPα) interaction and PD-1/programmed death ligand 1 (PD-L1) interaction, respectively. Tumor environment-activated photodynamic therapy realized by PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM induces immunogenic cell death (ICD) to elicit anti-tumor immune response, which is empowered by enhanced dendritic cells (DC) uptake of CpG and PD-L1 blockade contributed by the nanoplatform. The photodynamic immunotherapy efficiently combats primary and distant CT26 tumors, and additionally generates immune memory to inhibit tumor recurrence and metastasis. The nanoplatform developed here provides insights for the development of precise cancer therapeutic strategies.

Transpiration-Inspired Fabric Dressing for Acceleration Healing of Wound Infected with Biofilm.

In chronic wound management, efficacious handling of exudate and bacterial infections stands as a paramount challenge. Here a novel biomimetic fabric, inspired by the natural transpiration mechanisms in plants, is introduced. Uniquely, the fabric combines a commercial polyethylene terephthalate (PET) fabric with asymmetrically grown 1D rutile titanium dioxide (TiO2) micro/nanostructures, emulating critical plant features: hierarchically porous networks and hydrophilic water conduction channels. This structure endows the fabric with exceptional antigravity wicking-evaporation performance, evidenced by a 780% one-way transport capability and a 0.75 g h-1 water evaporation rate, which significantly surpasses that of conventional moisture-wicking textiles. Moreover, the incorporated 1D rutile TiO2 micro/nanostructures present solar-light induced antibacterial activity, crucial for disrupting and eradicating wound biofilms. The biomimetic transpiration fabric is employed to drain exudate and eradicate biofilms in Staphylococcus aureus (S. aureus)-infected wounds, demonstrating a much faster infection eradication capability compared to clinically common ciprofloxacin irrigation. These findings illuminate the path for developing high-performance, textile-based wound dressings, offering efficient clinical platforms to combat biofilms associated with chronic wounds.

Design, Synthesis, and Evaluation of 8-(o-Tolyl)quinazoline Derivatives as Small-Molecule PD-1/PD-L1 Antagonists.

Small-molecule inhibitors targeting programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions can compensate for the shortcomings of antibody-based inhibitors and have attracted considerable attention, some of which have already entered clinical trials. Herein, based on our previous study on small-molecule PD-L1 inhibitors, we reported a series of 8-(o-tolyl)quinazoline derivatives by the skeleton merging strategy. Homogenous time-resolved fluorescence (HTRF) assay against PD-1/PD-L1 interaction identified compound A5, which showed the most potent inhibition with an IC50 value of 23.78 nM. Meanwhile, based on the results of HTRF assay, the structure-activity relationships (SARs) of the tail were focused on. Cell-based PD-1/PD-L1 blockade assay further revealed that A5 significantly blocked the PD-1/PD-L1 interaction at 1.1 µM in the co-culture system of Jurkat-NFAT-PD-1 cells and Hep3B-OS8-hPD-L1 cells with no significant cytotoxicity on Jurkat cells. Moreover, the proposed binding mode of A5 was investigated by a docking analysis. These results indicate that compound A5 is a promising lead compound that deserves further investigation.

Raman Study of 532-Nanometer Laser-Induced Degradation of Red Lead.

Red lead is commonly employed as a red pigment in numerous valuable cultural artifacts. Raman spectrometry has been widely employed as the primary tool in many nondestructive studies on red lead. Therefore, it is necessary to evaluate and study the impact of lasers on the pigment. The degradation of red lead induced by a 532 nm laser is investigated using micro-Raman spectroscopy. At room temperature, red lead begins to degrade into ß-PbO when the power density of the 532 nm laser reaches approximately 5.1 × 104 W/cm2 (laser: 532 nm, objective: 50×). At this point, the temperature at the focus of the sample is estimated to be at least 500 °C, aided by the Raman peak shift of ß-PbO. Furthermore, the power density of the laser-induced degradation decreases as the temperature of the red lead increases. Hence, the degradation of red lead can be attributed to the photothermal effect. The temperature rise can be explained by two factors. First, red lead exhibits a high absorbance of approximately 0.5942 at 532 nm. Second, red lead has significantly low thermal diffusivity and conductivity, measuring 0.039 mm2·s-1 and 0.078 W·m-1·K-1, respectively, which leads to heat accumulation at the focal point of the laser beam. To better preserve cultural heritage, the appropriate laser power should be prioritized when the degradation process is caused by the thermal effect of laser irradiation.

Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin for thromboprophylaxis after cancer surgery: a systematic review and meta-analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) used as an alternative to low-molecular-weight heparin (LMWH) for thromboprophylaxis after cancer surgery for venous thromboembolic events (VTE) remains unclear. This study aimed to investigate the efficacy and safety of DOACs versus LMWH in these patients. MATERIALS AND METHODS: A search of EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science was carried out and included all randomized controlled trials (RCTs) and observational studies that directly compared DOACs with LMWH for thromboprophylaxis in patients after cancer surgery through July 25, 2023. The primary efficacy and safety outcomes were VTE, major bleeding, and clinically relevant non-major bleeding (CRNMB) within 30 days of surgery. The risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB2) tool for RCTs and ROBINS-I tool for non-randomized studies. This study was registered in PROSPERO (CRD42023445386). RESULTS: We retrieved 5149articles, selected 27 for eligibility, and included 10 studies (three RCTs and seven observational studies) encompassing 3054 patients who underwent postoperative thromboprophylaxis with DOACs (41%) or LMWH (59%). Compared to LMWH thromboprophylaxis, DOACs had a comparable risk of VTE (RR:0.69[95% CI:0.46-1.02], I2 = 0%), major bleeding (RR:1.55 [95% CI:0.82-2.93], I2 = 2%), and CRNMB (RR, 0.89 [95% CI, 0.4-1.98], I2 = 31%) during the 30-day postoperative period. Subgroup analysis of VTE and major bleeding suggested no differences according to study type, extended thromboprophylaxis, tumor types, or different types of DOAC. CONCLUSION: DOACs are potentially effective alternatives to LMWH for thromboprophylaxis in patients undergoing cancer surgery, without increasing the risk of major bleeding events.

Integrated machine learning and deep learning for predicting diabetic nephropathy model construction, validation, and interpretability.

OBJECTIVE: To construct a risk prediction model for assisted diagnosis of Diabetic Nephropathy (DN) using machine learning algorithms, and to validate it internally and externally. METHODS: Firstly, the data was cleaned and enhanced, and was divided into training and test sets according to the 7:3 ratio. Then, the metrics related to DN were filtered by difference analysis, Least Absolute Shrinkage and Selection Operator (LASSO), Recursive Feature Elimination (RFE), and Max-relevance and Min-redundancy (MRMR) algorithms. Ten machine learning models were constructed based on the key variables. The best model was filtered by Receiver Operating Characteristic (ROC), Precision-Recall (PR), Accuracy, Matthews Correlation Coefficient (MCC), and Kappa, and was internally and externally validated. Based on the best model, an online platform had been constructed. RESULTS: 15 key variables were selected, and among the 10 machine learning models, the Random Forest model achieved the best predictive performance. In the test set, the area under the ROC curve was 0.912, and in two external validation cohorts, the area under the ROC curve was 0.828 and 0.863, indicating excellent predictive and generalization abilities. CONCLUSION: The model has a good predictive value and is expected to help in the early diagnosis and screening of clinical DN.

Use of the improved tug-of-war acupuncture for promoting cartilage repair by inducing macrophage polarization in knee osteoarthritis.

Introduction: Knee osteoarthritis (KOA) is a type of joint disease causing degenerative changes that are challenging to treat. The improved tug-of-war acupuncture (BHZF) can improve joint pain in KOA. However, the associated mechanism has not been validated. Methods: The KOA rabbit model was established. After the surgery, the improved BHZF was provided as an intervention, and the animals were euthanized after 2 weeks. Histopathological changes in the synovium and cartilage were observed on hematoxylin & eosin staining and Safranin O-Fast Green staining. Synovial fluid and serum samples were collected to assess the presence of cytokines using the enzyme-linked immunosorbent assay. The expression of M1 macrophage (CD86) and M2 macrophage (ARG1) markers in the cartilage and synovium was detected via immunohistochemistry and immunofluorescence assays. Results: The improved BHZF could reduce KOA-related pain and inhibit joint swelling. Further, it significantly maintained the morphology of articular chondrocytes in KOA and reduced the decomposition of the cartilage matrix. Then, it significantly reduced the expression of CD86-positive cells (P < 0.05), and increased the expression of ARG1-positive cells in the cartilage and synovium (P < 0.05). Moreover, it significantly decreased the expression of inflammatory factors interleukin (IL)-1 beta and tumor necrosis factor-alpha in the serum and synovial fluid (P < 0.05), and significantly increased the expression levels of anti-inflammatory cytokines IL-4 and IL-10 (P < 0.05). Conclusions: The improved BHZF can relieve pain and improve cartilage damage by regulating macrophage polarization in KOA.

Advances in the research and application of neurokinin-1 receptor antagonists. / 神经激肽1å—ä½“æ‹®æŠ—å‰‚çš„ç ”ç©¶ä¸Žåº”ç”¨è¿›å±•.

Recently, the substance P (SP)/neurokinin-1 receptor (NK-1R) system has been found to be involved in various human pathophysiological disorders including the symptoms of coronavirus disease 2019 (COVID-19). Besides, studies in the oncological field have demonstrated an intricate correlation between the upregulation of NK-1R and the activation of SP/NK-1R system with the progression of multiple carcinoma types and poor clinical prognosis. These findings indicate that the modulation of SP/NK-1R system with NK-1R antagonists can be a potential broad-spectrum antitumor strategy. This review updates the latest potential and applications of NK-1R antagonists in the treatment of human diseases and cancers, as well as the underlying mechanisms. Furthermore, the strategies to improve the bioavailability and efficacy of NK-1R antagonist drugs are summarized, such as solid dispersion systems, nanonization, and nanoencapsulation. As a radiopharmaceutical therapeutic, the NK-1R antagonist aprepitant was originally developed as radioligand receptor to target NK-1R-overexpressing tumors. However, combining NK-1R antagonists with other drugs can produce a synergistic effect, thereby enhancing the therapeutic effect, alleviating the symptoms, and improving patients quality of life in several diseases and cancers.