Design and validation of a novel 3D-printed glenohumeral fusion prosthesis for the reconstruction of proximal humerus bone defects: a biomechanical study.

Background: All available methods for reconstruction after proximal humerus tumor resection have disadvantages, and the optimal reconstruction method remains uncertain. This study aimed to design a novel 3D-printed glenohumeral fusion prosthesis and verify its feasibility and safety using biomechanical methods. Methods: We verified the feasibility and safety of the 3D-printed glenohumeral fusion prosthesis by finite element analysis and biomechanical experimentation. In the finite element analysis, three reconstruction methods were used, and displacement and von Mises stress were observed; on this basis, in the biomechanical experiment, models constructed with sawbones were classified into two groups. The force‒displacement curve of the 3D-printed prosthesis was evaluated. Results: In terms of displacement, the finite element analysis showed greater overall stability for the novel prosthesis than traditional glenohumeral joint arthrodesis. There was no obvious stress concentration in the internal part of the 3D-printed glenohumeral fusion prosthesis; the stable structure bore most of the stress, and the force was well distributed. Adding lateral plate fixation improved the stability and mechanical properties of the prosthesis. Furthermore, the biomechanical results showed that without lateral plate fixation, the total displacement of the prosthesis doubled; adding lateral plate fixation could reduce and disperse strain on the glenoid. Conclusion: The design of the 3D-printed glenohumeral fusion prosthesis was rational, and its stability and mechanical properties were better than those of traditional glenohumeral joint arthrodesis. Biomechanical verification demonstrated the feasibility and safety of this prosthesis, indicating its potential for proximal humerus bone defect reconstruction after tumor resection.

Unveiling the functions of five recently characterized lncRNAs in cancer progression.

Numerous studies over the past few decades have shown that RNAs are multifaceted, multifunctional regulators of most cellular processes, contrary to the initial belief that they only act as mediators for translating DNA into proteins. LncRNAs, which refer to transcripts longer than 200nt and lack the ability to code for proteins, have recently been identified as central regulators of a variety of biochemical and cellular processes, particularly cancer. When they are abnormally expressed, they are closely associated with tumor occurrence, metastasis, and tumor staging. Therefore, through searches on Google Scholar, PubMed, and CNKI, we identified five five recently characterized lncRNAs-Lnc-SLC2A12-10:1, LncRNA BCRT1, lncRNA IGFBP4-1, LncRNA PCNAP1, and LncRNA CDC6-that have been linked to the promotion of cancer cell proliferation, invasion, and metastasis. Consequently, this review encapsulates the existing research and molecular underpinnings of these five newly identified lncRNAs across various types of cancer. It suggests that these novel lncRNAs hold potential as independent biomarkers for clinical diagnosis and prognosis, as well as candidates for therapeutic intervention. In parallel, we discuss the challenges inherent in the research on these five newly discovered lncRNAs and look forward to the avenues for future exploration in this field.

MOTAI: A Novel Method for the Study of O-GalNAcylation and Complex O-Glycosylation in Cancer.

The Tn antigen, an immature truncated O-glycosylation, is a promising biomarker for cancer detection and diagnosis. However, reliable methods for analyzing O-GalNAcylation and complex O-glycosylation are lacking. Here, we develop a novel method, MOTAI, for the sequential analysis of O-glycosylation using different O-glycoproteases. MOTAI conjugates glycopeptides on a solid support and releases different types of O-glycosylation through sequential enzymatic digestion by O-glycoproteases, including OpeRATOR and IMPa. Because OpeRATOR has less activity on O-GalNAcylation, MOTAI enriches O-GalNAcylation for subsequent analysis. We demonstrate the effectiveness of MOTAI by analyzing fetuin O-glycosylation and Jurkat cell lines. We then apply MOTAI to analyze colorectal cancer and benign colorectal polyps. We identify 32 Tn/sTn-glycoproteins and 43 T/sT-glycoproteins that are significantly increased in tumor tissues. Gene Ontology analysis reveals that most of these proteins are ECM proteins involved in the adhesion process of the intercellular matrix. Additionally, the protein disulfide isomerase CRELD2 has a significant difference in Tn expression, and the abnormally glycosylated T345 and S349 O-glycosylation sites in cancer group samples may promote the secretion of CRELD2 and ultimately tumorigenesis through ECM reshaping. In summary, MOTAI provides a powerful new tool for the in-depth analysis of O-GalNAcylation and complex O-glycosylation. It also reveals the upregulation of Tn/sTn-glycoproteins in colorectal cancer, which may provide new insights into cancer biology and biomarker discovery.

Probing Dual Covalent Irreversible Inhibition of EGFR/FGFR4 by Electrophilic-Based Natural Compounds to Overcome Resistance and Enhance Combination Therapeutic Potentials and Management of Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) is one of the most prevalent cancer types in the world and accounts for the majority of cases of primary liver cancer. A crucial part of the carcinogenesis of HCC involves aberrant stimulation of the FGF19-FGFR4 signaling pathway. Therefore, FGFR4 inhibition has become a strategic therapeutic approach for the treatment of HCC. However, the clinical treatment procedure is significantly hampered by the prevalence of kinase inhibitors resistance. It was recently established that the activation of EGFR signaling was found to be one of the primary mechanisms mediating the acquired resistance to FGFR4 inhibitors, moreover, sensitivity to FGFR4 inhibitors was effectively restored by inhibiting EGFR. These results provide compelling evidence that dual inhibition of EGFR and FGFR4 could represent a viable therapeutic approach to overcome resistance, hence enhanced management of HCC. To this end, we proposed a dual irreversible inhibition strategy through covalent binding by naturally occurring electrophilic warhead-bearing compounds (curcumin, deoxyelephantopin, eupalmerin acetate, syringolin A and andrographolide) to covalently target both EGFR and FGFR4 through cysteine residues, Cys797 and Cys552, respectively. Covalent docking and covalent molecular dynamics (MM/MDcov) simulations combined with thermodynamic binding free energy calculations were performed, and the results were compared against known potent and selective covalent EGFR and FGFR4 inhibitors with available X-ray crystal structures, Afatinib and BLU9931, respectively. Curcumin, deoxyelephantopin, eupalmerin acetate, syringolin A, and andrographolide showed relative binding free energies of -22.85, -17.14, -12.98, -21.81, and - 19.00 kcal/mol against EGFR and - 41.06, -29.45, -24.76, -40.11, and - 37.55 kcal/mol against FGFR4, respectively. The mechanisms of binding were emphasized by hydrogen bonding and binding forces analysis as well as active site physicochemical profiling. The findings of this study identified that curcumin, syringolin A and andrographolide-but not eupalmerin acetate or deoxyelephantopin -could be viable dual EGFR and FGFR4 covalent irreversible inhibitors and could be implemented in HCC combination therapy protocols alone or in conjunction with other chemotherapeutic agents. Investigations of this study conclusively indicate dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for enhanced management of HCC.

Sagittal en bloc resection of thoracolumbar tumours: a report of thirty one cases.

PURPOSE: To develop a novel classification of sagittal en bloc resection (SEBR) based on anatomical locations for thoracolumbar spine tumors and assess the clinical outcomes of this surgical procedure. METHODS: 31 patients with thoracolumbar tumours treated with SEBR were enrolled in this study. The individualized surgical strategy was adopted based on our surgical classification. Demographics, perioperative outcomes, complications and postoperative outcomes were assessed. RESULTS: Based on our surgical classifications, patients were divided into four types. All bony resection margins were negative, wide resection was achieved in 25 patients, marginal resection in four, and intralesional resection in two. 18 patients underwent anterior reconstruction. Complications were encountered in five patients, and instrumentation failure occurred in one patient. The median follow-up was 24 (range, 6-72) months and recurrence was found in only one patient. CONCLUSION: SEBR is a safe and effective surgical procedure for patients with thoracolumbar spinal tumours in specific anatomical locations. The proposed surgical classification covers all SEBR types and is easy to apply, it may assist surgical decision-making in patients with spinal tumours.

Targeting JUNB to modulate M2 macrophage polarization in preeclampsia.

Preeclampsia (PE) is a complex disorder affecting pregnant women, leading to significant maternal and fetal morbidity and mortality. Understanding the cellular dynamics and molecular mechanisms underlying PE is crucial for developing effective therapeutic strategies. This study utilized single-cell RNA sequencing (scRNA-seq) to delineate the cellular landscape of the placenta in PE, identifying 11 distinct cell subpopulations, with macrophages playing a pivotal role in mediating cell-cell communication. Specifically, the transcription factor JUNB was found to be a key gene in macrophages from PE samples, influencing the interaction between macrophages and both epithelial and endothelial cells. Functional experiments indicated that interference with JUNB expression promoted macrophage polarization towards an M2 phenotype, which facilitated trophoblast invasion, migration, and angiogenesis. Mechanistically, JUNB regulated the MIIP/PI3K/AKT pathway, as evidenced by gene expression analysis following JUNB knockdown. The study further demonstrated that targeting JUNB could activate the PI3K/AKT pathway by transcriptionally activating MIIP, thus promoting M2 polarization and potentially delaying the onset of PE. These findings present new insights into the pathogenesis of PE and suggest a novel therapeutic approach by modulating macrophage polarization.

Immune Regulation Patterns in Response to Environmental Pollutant Chromate Exposure-Related Genetic Damage: A Cross-Sectional Study Applying Machine Learning Methods.

Exposure to hexavalent chromium damages genetic materials like DNA and chromosomes, further elevating cancer risk, yet research rarely focuses on related immunological mechanisms, which play an important role in the occurrence and development of cancer. We investigated the association between blood chromium (Cr) levels and genetic damage biomarkers as well as the immune regulatory mechanism involved, such as costimulatory molecules, in 120 workers exposed to chromates. Higher blood Cr levels were linearly correlated with higher genetic damage, reflected by urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and blood micronucleus frequency (MNF). Exploratory factor analysis revealed that both positive and negative immune regulation patterns were positively associated with blood Cr. Specifically, higher levels of programmed cell death protein 1 (PD-1; mediated proportion: 4.12%), programmed cell death ligand 1 (PD-L1; 5.22%), lymphocyte activation gene 3 (LAG-3; 2.11%), and their constitutive positive immune regulation pattern (5.86%) indirectly positively influenced the relationship between blood Cr and urinary 8-OHdG. NOD-like receptor family pyrin domain containing 3 (NLRP3) positively affected the association between blood Cr levels and inflammatory immunity. This study, using machine learning, investigated immune regulation and its potential role in chromate-induced genetic damage, providing insights into complex relationships and emphasizing the need for further research.

3D-printed modular prostheses for reconstruction of intercalary bone defects after joint-sparing limb salvage surgery for femoral diaphyseal tumours.

Aims: The aim of this study was to investigate the safety and efficacy of 3D-printed modular prostheses in patients who underwent joint-sparing limb salvage surgery (JSLSS) for malignant femoral diaphyseal bone tumours. Methods: We retrospectively reviewed 17 patients (13 males and four females) with femoral diaphyseal tumours who underwent JSLSS in our hospital. Results: In all, 17 patients with locally aggressive bone tumours (Enneking stage IIB) located in the femoral shaft underwent JSLSS and reconstruction with 3D-printed modular prostheses between January 2020 and June 2022. The median surgical time was 153 minutes (interquartile range (IQR) 117 to 248), and the median estimated blood loss was 200ml (IQR 125 to 400). Osteosarcoma was the most common pathological type (n = 12; 70.6%). The mean osteotomy length was 197.53 mm (SD 12.34), and the median follow-up was 25 months (IQR 19 to 38). Two patients experienced local recurrence and three developed distant metastases. Postoperative complications included wound infection in one patient and screw loosening in another, both of which were treated successfully with revision surgery. The median Musculoskeletal Tumor Society score at the final follow-up was 28 (IQR 27 to 28). Conclusion: The 3D-printed modular prosthesis is a reliable and feasible reconstruction option for patients with malignant femoral diaphyseal tumours. It helps to improve the limb salvage rate, restore limb function, and achieve better short-term effectiveness.

Relationships between blood chromium exposure and liver injury: Exploring the mediating role of systemic inflammation in a chromate-exposed population.

Hexavalent chromium and its compounds are prevalent pollutants, especially in the work environment, pose a significant risk for multisystem toxicity and cancers. While it is known that chromium accumulation in the liver can cause damage, the dose-response relationship between blood chromium (Cr) and liver injury, as well as the possible potential toxic mechanisms involved, remains poorly understood. To address this, we conducted a follow-up study of 590 visits from 305 participants to investigate the associations of blood Cr with biomarkers for liver injury, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL), and to evaluate the mediating effects of systemic inflammation. Platelet (PLT) and the platelet-to-lymphocyte ratio (PLR) were utilized as biomarkers of systemic inflammation. In the linear mixed-effects analyses, each 1-unit increase in blood Cr level was associated with estimated effect percentage increases of 0.82% (0.11%, 1.53%) in TBIL, 1.67% (0.06%, 3.28%) in DBIL, 0.73% (0.04%, 1.43%) in ALT and 2.08% (0.29%, 3.87%) in AST, respectively. Furthermore, PLT mediated 10.04%, 11.35%, and 10.77% increases in TBIL, DBIL, and ALT levels induced by chromate, respectively. In addition, PLR mediated 8.26% and 15.58% of the association between blood Cr and TBIL or ALT. These findings shed light on the mechanisms underlying blood Cr-induced liver injury, which is partly due to worsening systemic inflammation.

Extracellular-vesicle-packaged S100A11 from osteosarcoma cells mediates lung premetastatic niche formation by recruiting gMDSCs.

The premetastatic niche (PMN) contributes to lung-specific metastatic tropism in osteosarcoma. However, the crosstalk between primary tumor cells and lung stromal cells is not clearly defined. Here, we dissect the composition of immune cells in the lung PMN and identify granulocytic myeloid-derived suppressor cell (gMDSC) infiltration as positively associated with immunosuppressive PMN formation and tumor cell colonization. Osteosarcoma-cell-derived extracellular vesicles (EVs) activate lung interstitial macrophages to initiate the influx of gMDSCs via secretion of the chemokine CXCL2. Proteomic profiling of EVs reveals that EV-packaged S100A11 stimulates the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway in macrophages by interacting with USP9X. High level of S100A11 expression or circulating gMDSCs correlates with the presentation of lung metastasis and poor prognosis in osteosarcoma patients. In summary, we identify a key role of tumor-derived EVs in lung PMN formation, providing potential strategies for monitoring or preventing lung metastasis in osteosarcoma.

Single-incision laparoscopic transabdominal preperitoneal repair in the treatment of adult female patients with inguinal hernia.

BACKGROUND: Women have a 3% lifetime chance of developing an inguinal hernia, which is not as common in men. Due to its cosmetic benefits, single-incision laparoscopic transabdominal preperitoneal (SIL-TAPP) inguinal hernia repair is becoming increasingly popular in the management of inguinal hernia in women. However, there are no studies comparing the safety and applicability of SIL-TAPP repair with conventional laparoscopic transabdominal preperitoneal (CL-TAPP) inguinal hernia repair for the treatment of inguinal hernia in women. AIM: To compare the outcomes of SIL-TAPP and CL-TAPP repair in adult female patients with inguinal hernia and to estimate the safety and applicability of SIL-TAPP repair in adult female inguinal hernia patients. METHODS: We retrospectively compared the clinical information and follow-up data of female inguinal hernia patients who underwent SIL-TAPP inguinal hernia repair and those who underwent CL-TAPP inguinal hernia repair at the Affiliated Hospital of Nantong University from February 2018 to December 2020 and assessed the long-term and short-term outcomes of both cohorts. RESULTS: This study included 123 patients, with 71 undergoing SIL-TAPP repair and 52 undergoing CL-TAPP repair. The two cohorts of patients and inguinal hernia characteristics were similar, with no statistically meaningful difference. The rate of intraoperative inferior epigastric vessel injury was lower in patients in the SIL-TAPP cohort (0, 0%) than in patients in the CL-TAPP cohort (4, 7.7%) and was significantly different (P < 0.05). In addition, the median [interquartile range (IQR)] total hospitalization costs were significantly lower in patients in the SIL-TAPP cohort [$3287 (3218-3325)] than in patients in the CL-TAPP cohort [$3511 (3491-3599)]. Postoperatively, the occurrence rate of trocar site hernia was lower in the SIL-TAPP cohort (0, 0%) than in the CL-TAPP cohort (4, 7.7%), and the median (IQR) cosmetic score was significantly higher in the SIL-TAPP cohort [10 (10-10)] than in the CL-TAPP cohort [9 (9-10)]. CONCLUSION: SIL-TAPP repair did not increase the incidence of intraoperative and postoperative complications in female inguinal hernia patients. Moreover, female inguinal hernia patients who underwent SIL-TAPP repair had a lower probability of trocar site hernia and inferior epigastric vessel injury than female inguinal hernia patients who underwent CL-TAPP repair. In addition, female inguinal hernia patients who underwent SIL-TAPP repair reported a more aesthetically pleasing postoperative abdominal incision. Therefore, SIL-TAPP repair is a better option for the treatment of inguinal hernias in women.

Bufalin suppresses hepatocellular carcinogenesis by targeting M2 macrophage-governed Wnt1/ß-catenin signaling.

BACKGROUND: The interplay of tumor-associated macrophages (TAMs) and tumor cells plays a key role in the development of hepatocellular carcinoma (HCC) and provides an important target for HCC therapy. The communication between them is still on the investigation. Bufalin, the active component derived from the traditional Chinese medicine (TCM) Chansu, has been evidenced to possess anti-HCC activity by directly suppressing tumor cells, while its immunomodulatory effect on the tumor microenvironment (TME) is unclear. PURPOSE: To explore the mechanism of M2 TAM-governed tumor cell proliferation and the inhibitory effect of bufalin on HCC growth by targeting M2 macrophages. METHODS: Morphology and marker proteins were detected to evaluate macrophage polarization via microscopy and flow cytometry. Cellular proliferation and malignant transformation of HCC cells cultured with macrophage conditioned medium (CM) or bufalin-primed M2-CM, were assessed by cell viability, colony formation and soft agar assays. Regulations of gene transcription and protein expression and release were determined by RT-qPCR, immunoblotting, immunoprecipitation, ELISA and immunofluorescence. Tumorigenicity upon bufalin treatment was verified in orthotopic and diethylnitrosamine-induced HCC mouse model. RESULTS: In this study, we first verified that M2 macrophages secreted Wnt1, which acted as a mediator to trigger ß-catenin activation in HCC cells, leading to cellular proliferation. Bufalin suppressed HCC cell proliferation and malignant transformation by inhibiting Wnt1 release in M2 macrophages, and dose-dependently inhibited HCC progression in mice. Mechanistically, bufalin specially targeted to block Wnt1 transcription, thus inactivating ß-catenin signaling cascade in HCC cells and leading to tumor regression in HCC mouse model. CONCLUSION: These results clearly reveal a novel potential of bufalin to suppress HCC through immunomodulation, and shed light on a new M2 macrophage-based modality of HCC immunotherapy, which additively enhances direct tumor-inhibitory efficacy of bufalin.

Mass Spectrometry-Based Proteomics Identifies Serpin B9 as a Key Protein in Promoting Bone Metastases in Lung Cancer.

Bone metastasis (BM) is one of the most common complications of advanced cancer. Immunotherapy for bone metastasis of lung cancer (LCBM) is not so promising and the immune mechanisms are still unknown. Here, we utilized a model of BM by injecting cancer cells through caudal artery (CA) to screen out a highly bone metastatic derivative (LLC1-BM3) from a murine lung cancer cell line LLC1. Mass spectrometry-based proteomics was performed in LLC1-parental and LLC1-BM3 cells. Combining with prognostic survival information from patients with lung cancer, we identified serpin B9 (SB9) as a key factor in BM. Molecular characterization showed that SB9 overexpression was associated with poor prognosis and high bone metastatic burden in lung cancer. Moreover, SB9 could increase the ability of lung cancer cells to metastasize to the bone. The mechanistic studies revealed that tumor-derived SB9 promoted BM through an immune cell-dependent way by inactivating granzyme B, manifesting with the decreased infiltration of cytotoxic T cells and increased expression level of exhausted markers. A specific SB9-targeting inhibitor [1,3-benzoxazole-6-carboxylic acid (BTCA)] significantly suppressed LCBM in the CA mouse model. This study reveals that SB9 may serve as a therapeutic target and potential prognostic marker for patients with LCBM. IMPLICATIONS: SB9 as a therapeutic target for LCBM.

Osteosarcoma Cells Secrete CXCL14 That Activates Integrin α11ß1 on Fibroblasts to Form a Lung Metastatic Niche.

Cooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naïve osteosarcoma using single-cell RNA sequencing and identified a stem cell-like cluster with tumor cell-initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell-like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin α11ß1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFß and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11ß1 axis inhibited fibroblast TGFß production, enhanced CD8+ T cell-mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin α11ß1 axis is a potential strategy to inhibit osteosarcoma lung metastasis. SIGNIFICANCE: Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11ß1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.

Surgical outcomes and risk factors for surgical complications after en bloc resection following reconstruction with 3D-printed artificial vertebral body for thoracolumbar tumors.

BACKGROUND: The outcomes of patients with tumors of the thoracolumbar spine treated with en bloc resection (EBR) using three-dimensional (3D)-printed endoprostheses are underreported. METHODS: We retrospectively evaluated patients with thoracolumbar tumors who underwent surgery at our institution. Logistic regression analysis was performed to identify the potential risk factors for surgical complications. Nomograms to predict complications were constructed and validated. RESULTS: A total of 53 patients with spinal tumors underwent EBR at our hospital; of these, 2 were lost to follow-up, 45 underwent total en bloc spondylectomy, and 6 were treated with sagittal en bloc spondylectomy. The anterior reconstruction materials included a customized 3D-printed artificial vertebral body (AVB) in 10 cases and an off-the-shelf 3D-printed AVB in 41 cases, and prosthesis mismatch occurred in 2 patients reconstructed with the off-the-shelf 3D-printed AVB. The median follow-up period was 21 months (range, 7-57 months). Three patients experienced local recurrence, and 5 patients died at the final follow-up. A total of 50 perioperative complications were encountered in 29 patients, including 25 major and 25 minor complications. Instrumentation failure occurred in 1 patient, and no prosthesis subsidence was observed. Using a combined surgical approach was a dependent predictor of overall complications, while Karnofsky performance status score, lumbar spine lesion, and intraoperative blood loss ≥ 2000 mL were predictors of major complications. Nomograms for the overall and major complications were constructed using these factors, with C-indices of 0.850 and 0.891, respectively. CONCLUSIONS: EBR is essential for the management of thoracolumbar tumors; however, EBR has a steep learning curve and a high complication rate. A 3D-printed AVB is an effective and feasible reconstruction option for patients treated with EBR.

Comprehensive analysis reveals potential therapeutic targets and an integrated risk stratification model for solitary fibrous tumors.

Solitary fibrous tumors (SFTs) are rare mesenchymal tumors with unpredictable evolution and with a recurrence or metastasis rate of 10-40%. Current medical treatments for relapsed SFTs remain ineffective. Here, we identify potential therapeutic targets and risk factors, including IDH1 p.R132S, high PD-L1 expression, and predominant macrophage infiltration, suggesting the potential benefits of combinational immune therapy and targeted therapy for SFTs. An integrated risk model incorporating mitotic count, density of Ki-67+ cells and CD163+ cells, MTOR mutation is developed, applying a discovery cohort of 101 primary non-CNS patients with negative tumor margins (NTM) and validated in three independent cohorts of 210 SFTs with the same criteria, and in 36 primary CNS SFTs with NTM. Compared with the existing models, our model shows significantly improved efficacy in identifying high-risk primary non-CNS and CNS SFTs with NTM for tumor progression.Our findings hold promise for advancing therapeutic strategies and refining risk prediction in SFTs.

AZGP1P2/UBA1/RBM15 Cascade Mediates the Fate Determinations of Prostate Cancer Stem Cells and Promotes Therapeutic Effect of Docetaxel in Castration-Resistant Prostate Cancer via TPM1 m6A Modification.

Prostate cancer (PCa) is a common malignant tumor with high morbidity and mortality worldwide. The prostate cancer stem cell (PCSC) model provides novel insights into the pathogenesis of PCa and its therapeutic response. However, the roles and molecular mechanisms of specific genes in mediating fate decisions of PCSCs and carcinogenesis of PCa remain to be elusive. In this study, we have explored the expression, function, and mechanism of AZGP1P2, a pseudogene of AZGP1, in regulating the stemness and apoptosis of PCSCs and treatment resistance of docetaxel in castration-resistant prostate cancer (CRPC). We revealed that AZGP1P2 was downregulated in CRPC cell lines and PCSCs, while it was positively associated with progression-free interval. Upregulation of the AZGP1P2 enhanced the sensitivity of docetaxel treatment in CRPCs via inhibiting their stemness. RNA pull-down associated with mass spectrometry analysis, co-immunoprecipitation assay, and RNA immunoprecipitation assay demonstrated that AZGP1P2 could bind to UBA1 and RBM15 as a "writer" of methyltransferase to form a compound. UBA1, an E1 ubiquitin-activating enzyme, contributed to RBM15 protein degradation via ubiquitination modification. Methylated RNA immunoprecipitation assay displayed that RBM15 controlled the mRNA decay of TPM1 in m6A methylation. Furthermore, a xenograft mouse model and patient-derived organoids showed that the therapeutic effect of docetaxel in CRPC was increased by AZGP1P2 in vivo. Collectively, these results imply that AZGP1P2 mediates the stemness and apoptosis of PCSCs and promotes docetaxel therapeutic effect by suppressing tumor growth and metastasis via UBA1/RBM15-mediated TPM1 mRNA decay in CRPC.

An investigation of the flexural behaviour of large-span prestressed and steel-reinforced concrete slabs.

The prestressed and steel-reinforced concrete slab (PSRCS) is an innovative composite structural member offering high load capacity and stiffness and exceptional anti-crack performance, making it a leading trend in composite structures. This paper presents the derived calculation formulas for bearing capacity, section stiffness, mid-span deflection of PSRCS. Additionally, a numerical analysis of PSRCS is conducted using ABAQUS software, with several models created to systematically investigate bearing capacity, section stiffness, anti-crack performance, and failure mode. Concurrently, PSRCS member parameters are analyzed for optimal design, and the results of finite element (FE) calculations are compared with theoretical formula calculations. The results demonstrate that PSRCS exhibits superior load capacity, section stiffness, and anti-crack performance comparing to conventional slabs. The parametric analysis offers optimal design for each parameter and presents the corresponding recommended span-to-depth ratios for various spans in PSRCS applications.

The efficacy and safety of short-course neoadjuvant denosumab for en bloc spondylectomy in spinal giant cell tumor of bone: a preliminary report.

PURPOSE: This study aimed to investigate whether short course of neoadjuvant denosumab treatment for spinal GCTB could (1) Induce radiological and histological response? (2) Facilitate en bloc resection? (3) Achieve satisfactory oncological and functional outcomes? METHODS: The clinical information of ten consecutive patients between 2018 and 2022 with spinal GCTB treated with short course of neoadjuvant denosumab (≤ 5 doses) and en bloc spondylectomy was retrospectively reviewed. The radiological and histological response, operative data, oncological and functional outcomes were analyzed. RESULTS: The mean doses of neoadjuvant denosumab were 4.2 (range 3-5 doses). After neoadjuvant denosumab, there were 9 cases showing new ossification and 5 cases with reappearance of cortical integrity. The values of Hounsfield units (HU) of the soft tissue component were increased by > 50% in 7 cases. The signal intensity (SI) ratios of tumor/muscle in T2WI of plain MRI were decreased by > 10% in 60% of the cases. Shrinkage of soft tissue mass by > 10% was observed in 4 cases. The mean duration of operation was 575 ± 174 min, and the mean estimated blood loss (EBL) was 2790 ± 1934 ml. No obvious adhesion to dura mater or major vessels was encounter intraoperatively. There is no tumor collapse or breakage during surgery. Multinucleated giant cells were decreased in 6 cases (60%) with the remaining 4 cases showing absence of multinucleated giant cells. Mononuclear stromal cells existed in most of the cases (8 cases, 80%). New bone formation was noticed in 8 cases (80%). No patient had a worsening of neurologic function after surgery. No tumor recurrence was noticed within the mean follow-up of 24 ± 20 months. CONCLUSION: Short-term neoadjuvant denosumab could yield radiological and histological responses and might facilitate en bloc spondylectomy by hardening the tumor and causing less adhesion to segmental vessels, major vessels and nerve roots, which was beneficial to achieve the optimal oncological and functional outcomes.