The prognostic value of co-expression of stemness markers CD44 and CD133 in endometrial cancer.

Objective: The purpose of this study was to investigate the correlation between stemness markers (CD44 and CD133) and clinical pathological features, and to further explore the prognostic value of co-expression of CD44 & CD133 in endometrial cancer (EC). Methods: Clinical data of stage I-III EC patients who underwent initial surgical treatment at two large tertiary medical centers from 2015 to 2020 were retrospectively collected. Cohen's kappa coefficient was used to show the consistency of the expression between CD44 and CD133. The correlation between co-expression of CD44 & CD133 and prognosis of EC patients was explored using univariate and multivariate Cox regression analysis. Then, the prognosis models for early-stage (stage I-II) EC patients were constructed. Finally, stratified analysis was performed for EC patients in high-intermediate-risk and high-risk groups, Kaplan-Meier analysis was used to compare the survival differences between patients with and without adjuvant therapy in different co-expression states (low expression, mixed expression, high expression) of CD44 & CD133. Results: A total of 1168 EC patients were included in this study. The consistency of the expression between CD44 and CD133 was 70.5%, the kappa coefficient was 0.384. High expression of CD44 & CD133 was associated with early FIGO stage (P=0.017), superficial myometrial invasion (P=0.017), and negative lymphatic vessel space invasion (P=0.017). Cox regression analysis showed that the co-expression of CD44 & CD133 was significantly correlated with the prognosis of early-stage (stage I-II) patients (P=0.001 for recurrence and P=0.005 for death). Based on this, the nomogram models were successfully constructed to predict the prognosis of early-stage EC patients. Meanwhile, Kaplan-Meier analysis showed that patients with adjuvant therapy had a better overall prognosis than those without adjuvant therapy in high-intermediate-risk and high-risk groups. However, there was no statistically significant difference in survival between patients with and without adjuvant therapy in high expression of CD44 & CD133 group (P=0.681 for recurrence, P=0.621 for death). Conclusion: High expression of CD44 & CD133 was closely related to the adverse prognosis of early-stage EC patients. Meanwhile, patients with high expression of CD44 & CD133 may not be able to achieve significant survival benefits from adjuvant therapy.

Mendelian randomization identifies causal effects of major depressive disorder on accelerated aging.

BACKGROUND: Evidence links major depressive disorder (MDD) with aging, but it's unclear if MDD accelerates aging and what factors mediate this transition. METHODS: Two-sample Mendelian randomization (MR) analyses were applied to estimate the causal association between MDD and frailty index (FI), telomere length (TL), and appendicular lean mass (ALM) from available genome-wide association studies in populations of European ancestry. Furthermore, we conducted mediation MR analyses to assess the mediating effects of 31 lifestyle factors or diseases on the causal relationship between MDD and aging. RESULTS: MDD was significantly causally associated with increased FI (ßIVW = 0.23, 95 % CI = 0.18 to 0.28, p = 1.20 × 10-17), shorter TL (ßIVW = -0.04, 95 % CI = -0.07 to -0.01, p = 0.01), and decreased ALM (ßIVW = -0.07, 95 % CI = -0.11 to -0.03, p = 3.54 × 10-4). The mediation analysis through two-step MR revealed smoking initiation (9.09 %), hypertension (6.67 %) and heart failure (5.36 %) mediated the causal effect of MDD on FI. Additionally, alcohol use disorders and alcohol dependence on the causal relationship between MDD and TL were found to be 17.52 % and 17.13 % respectively. LIMITATIONS: Confounding, statistical power, and Euro-centric focus limit generalization. CONCLUSION: Overall, individuals with MDD may be at a higher risk of experiencing premature aging, and this risk is partially influenced by the pathways involving smoking, alcohol use, and cardiovascular health. It underscores the importance of early intervention and comprehensive health management in individuals with MDD to promote healthy aging and overall well-being.

Critical role of the gut microbiota in immune responses and cancer immunotherapy.

The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.

A multifunctional cascade enzyme system for enhanced starvation/chemodynamic combination therapy against hypoxic tumors.

Starvation therapy has shown promise as a cancer treatment, but its efficacy is often limited when used alone. In this work, a multifunctional nanoscale cascade enzyme system, named CaCO3@MnO2-NH2@GOx@PVP (CMGP), was fabricated for enhanced starvation/chemodynamic combination cancer therapy. CMGP is composed of CaCO3 nanoparticles wrapped in a MnO2 shell, with glucose oxidase (GOx) adsorbed and modified with polyvinylpyrrolidone (PVP). MnO2 decomposes H2O2 in cancer cells into O2, which enhances the efficiency of GOx-mediated starvation therapy. CaCO3 can be decomposed in the acidic cancer cell environment, causing Ca2+ overload in cancer cells and inhibiting mitochondrial metabolism. This synergizes with GOx to achieve more efficient starvation therapy. Additionally, the H2O2 and gluconic acid produced during glucose consumption by GOx are utilized by MnO2 with catalase-like activity to enhance O2 production and Mn2+ release. This process accelerates glucose consumption, reactive oxygen species (ROS) generation, and CaCO3 decomposition, promoting the Ca2+ release. CMGP can alleviate tumor hypoxia by cycling the enzymatic cascade reaction, which increases enzyme activity and combines with Ca2+ overload to achieve enhanced combined starvation/chemodynamic therapy. In vitro and in vivo studies demonstrate that CMGP has effective anticancer abilities and good biosafety. It represents a new strategy with great potential for combined cancer therapy.

The Future of Checkpoint Inhibitors in Uveal Melanoma: A Narrative Review.

INTRODUCTION: Immune checkpoint inhibitors have made tremendous progress over the last decade in the treatment of cutaneous melanoma, but their application in uveal melanoma treatment is less successful, owing in part to the immunological privilege of the eye and the liver, the most frequent site of metastasis. Nevertheless, the therapeutic outcomes reported currently are less pessimistic. METHODS: In this review, we provide an overview of recent studies of immune checkpoint inhibitors in uveal melanoma and its metastasis and classify studies in this field into three groups: monotherapy of immune checkpoint inhibitors, dual-agent immune checkpoint inhibitors, and immune checkpoint inhibitors combined with other systemic or regional therapies. RESULTS: Briefly, monotherapy with immune checkpoint inhibitors performed poorly. Dual-agent immune checkpoint inhibitors had slightly better outcomes than traditional treatments, especially in specific patient populations. As for the combination therapy, the combination with other systemic therapies did not show superiority over dual-agent immune checkpoint inhibitors, but combination with hepatic regional therapies was quite promising. Moreover, research on emerging checkpoints is currently limited to the stage of mechanistic studies. CONCLUSION: We propose that immune checkpoint inhibitors remain alternative treatments for patients with uveal melanoma, but factors such as cost-effectiveness should also be taken into account. The combination therapy with immune checkpoint inhibitors deserves to be further explored.

Intrahepatic homeobox protein MSX-1 is a novel host restriction factor of hepatitis B virus.

Chronic hepatitis B virus (HBV) infection (CHB) is a risk factor for the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Covalently closed circular DNA serves as the sole transcription template for all viral RNAs and viral transcription is driven and enhanced by viral promoter and enhancer elements, respectively. Interactions between transcription factors and these cis-elements regulate their activities and change the production levels of viral RNAs. Here, we report the identification of homeobox protein MSX-1 (MSX1) as a novel host restriction factor of HBV in liver. In both HBV-transfected and HBV-infected cells, MSX1 suppresses viral gene expression and genome replication. Mechanistically, MSX1 downregulates enhancer II/core promoter (EnII/Cp) activity via direct binding to an MSX1 responsive element within EnII/Cp, and such binding competes with hepatocyte nuclear factor 4α binding to EnII/Cp due to partial overlap between their respective binding sites. Furthermore, CHB patients in immune active phase express higher levels of intrahepatic MSX1 but relatively lower levels of serum and intrahepatic HBV markers compared to those in immune tolerant phase. Finally, MSX1 was demonstrated to induce viral clearance in two mouse models of HBV persistence, suggesting possible therapeutic potential for CHB.IMPORTANCECovalently closed circular DNA plays a key role for the persistence of hepatitis B virus (HBV) since it serves as the template for viral transcription. Identification of transcription factors that regulate HBV transcription not only provides insights into molecular mechanisms of viral life cycle regulation but may also provide potential antiviral targets. In this work, we identified host MSX1 as a novel restriction factor of HBV transcription. Meanwhile, we observed higher intrahepatic MSX1 expression in chronic hepatitis B virus (CHB) patients in immune active phase compared to those in immune tolerant phase, suggesting possible involvement of MSX1 in the regulation of HBV activity by the host. Lastly, intrahepatic overexpression of MSX1 delivered by recombinant adenoviruses into two mouse models of HBV persistence demonstrated MSX1-mediated repression of HBV in vivo, and MSX1-induced clearance of intrahepatic HBV DNA in treated mice suggested its potential as a therapeutic target for the treatment of CHB.

Application of clinical indicators in evaluating vestibular compensation efficacy in benign recurrent vestibular vertigo patients with short-term personalized vestibular rehabilitation.

BACKGROUND: Short-term personalized vestibular rehabilitation (ST-PVR) can establish stable vestibular compensation. However, there is a lack of a clear definition for clinical indicators that can dynamically reflect the progress of vestibular rehabilitation (VR). OBJECTIVE: To explore the clinical indicators suitable for evaluating the effectiveness of ST-PVR in treating benign recurrent vertigo (BRV). METHODS: In total, 50 patients diagnosed with BRV were enrolled. All patients received the ST-PVR treatment program. At 2 and 4 weeks after rehabilitation, subjective scales, including the visual analogue scale (VAS), dizziness handicap inventory scale (DHI), activities-specific balance confidence scale (ABC) and generalized anxiety disorder (GAD-7) were assessed. Objective vestibular function tests were performed. VR grading was determined. RESULTS: At 2 weeks after rehabilitation, significant enhancements were observed in VAS, DHI, ABC, GAD-7, UW, vHIT results, and VR grading scores (p < 0.05). The sensory organization test (SOT) results demonstrated statistically significant improvements at 2 weeks and 4 weeks after rehabilitation (p < 0.05). CONCLUSION AND SIGNIFICANCE: Both subjective scales and partial examination results in objective assessment can serve as indicators to dynamically monitor the compensatory process of vestibular function in patients with BRV. The VR efficacy grading score, which incorporates the above indicators, allows for quantification of the changes that occur during the vestibular rehabilitation process.

Incidence, risk factors, and a prognostic nomogram for distant metastasis in endometrial cancer: A SEER-based study.

OBJECTIVE: To evaluate the metastatic pattern, identify the risk factors, and establish a nomogram for predicting prognosis of endometrial cancer (EC) with distant metastasis. METHODS: A retrospective cohort study of women diagnosed with EC was conducted according to the Surveillance, Epidemiology, and End Results (SEER) database during 2010-2017. Multivariate logistic analysis and Cox analysis were performed to identify the risk factors in promoting distant metastasis and predictors associated with overall survival (OS) in this particular subpopulation. A nomogram was then constructed and validated by the concordance index (C-index), the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis. RESULTS: A total of 2799 cases of distant metastasis in EC patients were identified, with an overall incidence rate of 3.74% from 2010 to 2017. Black race, unmarried status, non-endometrioid histologic types, and grade IV were significant risk factors for distant metastasis in EC patients. Meanwhile, race, histology, grade, metastasis status, surgery, lymphadenectomy, and chemotherapy were identified as independent prognostic factors for OS. A nomogram to predict 1-, 3-, and 5-year OS was established, and presented favorable accuracy and clinical applicability. Patients were further divided into high- and low-risk groups according to the model. CONCLUSION: The nomogram was developed as a highly accurate, individualized tool to better predict the prognosis of EC patients with distant metastasis, which would help clinicians to identify high-risk patients, and adjust and tailor their treatment strategies.

A multicenter noninferior randomized controlled study of sentinel lymph node biopsy alone versus sentinel lymph node biopsy plus lymphadenectomy for patients with stage I endometrial cancer, INSEC trial concept.

BACKGROUND: Up to the present time, there has remained a lack of strong evidence as to whether sentinel lymph node biopsy can replace lymphadenectomy for early endometrial cancer. The traditional surgery for endometrial cancer includes pelvic lymphadenectomy and paraaortic lymph node resection, but complications often seriously affect patients' quality of life. Two randomized controlled trials with large samples have proved that lymphadenectomy does not improve the overall recurrence rate and survival rate of patients. On the contrary, it increases the incidence of complications and even mortality. The current trial is designed to clarify whether sentinel lymph node biopsy can replace lymphadenectomy for early endometrial cancer patients with negative lymph nodes. METHODS: This study is a randomized, open-label, multicenter and non-inferiority controlled clinical trial in China. Potential participants will be patients with pathologically confirmed endometrial cancer at the Zhejiang Cancer Hospital, Jiaxing Maternity and Child Health Care Hospital, and the First Hospital of Jiaxing in China. The total sample size for this study is 722. Patients will be randomly assigned in a 1:1 ratio to two groups. Patients in one group will undergo sentinel lymph node biopsy + total hysterectomy + bilateral salpingo-oophorectomy ± paraaortic lymph node resection. Patients in the other group will undergo sentinel lymph node biopsy + total hysterectomy + bilateral salpingo-oophorectomy + pelvic lymphadenectomy ± paraaortic lymph node resection. The 3-year disease-free survival rate, overall survival rate, quality of life (use EORTC QLQ-C30 + QLQ-CX24), and perioperative related indexes of the two groups will be compared. RESULTS: We expect to find that for patients with early endometrial cancer, the 3-year disease-free survival rate following sentinel lymph node biopsy with indocyanine green combined with near-infrared fluorescence imaging is similar to that following lymphadenectomy. The operation time, as well as incidence of pelvic lymphocyst, lymphedema of lower limb, and edema of vulva in patients who only undergo sentinel lymph node biopsy are expected to be significantly lower than in patients who undergo lymphadenectomy. The quality of life of patients who undergo sentinel lymph node biopsy alone will be significantly better than that of patients who undergo lymph node dissection. CONCLUSION: This will prove that the prognosis of sentinel lymph node biopsy alone with indocyanine green combined with near-infrared fluorescence imaging is not inferior to that of sentinel lymph node biopsy plus lymphadenectomy for early stage endometrial cancer with negative nodal assessment intraoperatively. In addition, sentinel lymph node biopsy alone with indocyanine green combined with near-infrared fluorescence imaging results in fewer surgical complications and gives patients better quality of life. TRIAL REGISTRATION: chictr.org.cn, ChiCTR1900023161. Registered 14 May 2019, http://www.chictr.org.cn/edit.aspx?pid=38659&htm=4 .

[Establishment of a quantitative method for GC analysis of polyoxyethylene (35) castor oil in microemulsion extracts].

With the continuous exploration of microemulsions as solvents for traditional Chinese medicine extraction, polyoxyethy-lene(35) castor oil(CrEL), a commonly used surfactant, is being utilized by researchers. However, the problem of detecting residues of this surfactant in microemulsion extracts has greatly hampered the further development of microemulsion solvents. Based on the chemical structures of the components in CrEL and the content determination method of castor oil in the 2020 edition of the Chinese Pharmacopoeia(Vol. Ⅳ), this study employed gas chromatography(GC) and single-factor experiments to optimize the preparation method of methyl ricinoleate from CrEL. The conversion coefficient between the two was validated, and the optimal sample preparation method was used to process microemulsion extracts of Zexie Decoction from three batches. The content of methyl ricinoleate generated was determined, and the content of CrEL in the microemulsion extracts of Zexie Decoction was calculated using the above conversion coefficient. The results showed that the optimal preparation method for CrEL was determined. Specifically, 10 mL of 1 mol·L~(-1) KOH-methanol solution was heated at 60 ℃ for 15 min in a water bath. Subsequently, 10 mL of boron trifluoride etherate-methanol(1∶3) solution was heated at 60 ℃ for 15 min in a water bath, followed by extraction with n-hexane twice. CrEL could stably produce 20.84% methyl ricinoleate. According to this conversion coefficient, the average mass concentration of CrEL in the three batches of Zexie Decoction microemulsion extracts was 11.94 mg·mL~(-1), which was not significantly different from the CrEL mass concentration of 11.57 mg·mL~(-1) during microemulsion formulation, indicating that the established content determination method of this study was highly accurate, sensitive, and repeatable. It can be used for subsequent research on microemulsion extracts of Zexie Decoction and provide a reference for quality control of other drug formulations containing CrEL.

Adsorption Process Optimization and Adsorbent Evaluation Based on Langmuir Isotherm Model.

Adsorption separation is considered one of the most commonly used gas purification methods. At present, the most widely used adsorption methods are mainly pressure swing adsorption (PSA) and temperature swing adsorption (TSA). In both adsorption methods, a comprehensive understanding of the equilibrium data and the adsorption capacity of the adsorbent is essential for process design and optimization, and the adsorption isotherm can provide a powerful aid in this regard. In this study, through mathematical analysis of the Langmuir isotherm model, the optimal cyclic adsorption conditions and the optimal thermodynamic parameters (entropy change and enthalpy change) under PSA and TSA were obtained. In addition, the isotherm model can be used to predict the isobaric adsorption capacity, and the objective function was established according to the cyclic adsorption capacity and the regeneration sensible heat consumption per unit adsorption capacity to calculate the optimal adsorption/desorption temperatures and optimal cyclic adsorption capacity of various adsorbents.

YAP1 affects the prognosis through the regulation of stemness in endometrial cancer.

Background: Endometrial cancer stem-like cells (ECSCs) have been proven to be responsible for recurrence, metastasis, and drug-resistance in patients with endometrial cancer. The HIPPO pathway has been shown to play an important role in the development and maintenance of stemness in a variety of tumors. While there was less research about its function in ECSCs. The aim of this study was to explore the role of YAP1, a core molecular of HIPPO pathway, in the stemness of endometrial cancer and to reveal its influence on prognosis. Methods: We collected specimens and clinical data from 774 patients with endometrial cancer to analyze the correlation between YAP1 expression and prognosis. We then examined the expression of YAP1 in ECSCs and EC cell lines (Ishikawa; HEC1-A) in vitro experiments. Changes in the stemness of cell lines were detected after YAP1 silencing by siRNA. Finally, high-throughput sequencing was used to predict the potential molecular interactions and mechanisms of YAP1's effect on stemness. Result: Down-regulation of YAP1 significantly suppresses the stemness of EC cell lines. High expression of YAP1 leads to poor prognosis in EC by regulation of stemness. Conclusion: YAP1 plays an important role in the prognosis of patients with EC by regulation of stemness.

Synthesis of Polymer-Grafted Carbon Dots Serving as Multifunctional Lubricant Additives with Excellent Tribological Performance and Additional Rust Resistance Function for Steel/Steel Contact.

Poly(bis(2-ethylhexyl) phosphoric) methacrylic anhydride-grafted carbon dots (CD-g-PEPMA) have been controllably synthesized and used as multifunctional lubricant additives of poly(ethylene glycol) (PEG200). The polymers on the surfaces of CD-g-PEPMA not only endow them with particularly excellent dispersion stability but also enhance their adsorbability on the steel surface and embedded stability between the rubbing surfaces. Hence, CD-g-PEPMA as an additive showed outstanding rust resistance and tribological performance. Among CD-g-PEPMA-X (X represents the polymerization time), CD-g-PEPMA-2 (X = 2 h) exhibited the best tribological performance. At the optimum c of 2.0 wt %, CD-g-PEPMA-2 reduced the coefficient of friction and wear volume of PEG200 by 60.1 and 74.0%, respectively. The striking friction-reducing and antiwear functions of CD-g-PEPMA as additives can be attributed to the synergistic lubrication effect of carbon cores and polymers. The rolling, polishing, and mending effects of carbon cores combined with the favorable adsorbability and reactivity of polymers on steel surfaces synergistically induced the formation of boundary lubrication films on wear track surfaces. The films are composed of tribochemical reaction products such as Fe2(CO3)3, Fe3C, and FePO4 embedded with carbon cores, tremendously reducing the friction and wear of the friction pair. The research results can provide substantial theoretical guidance and data support for designing and developing high-efficiency polymer-CD integrative multifunctional nanoadditives toward PEG.

A network pharmacology approach to investigate dehydrocostus lactone inhibits the proliferation and epithelial-mesenchymal transition of human gastric cancer cells via regulating the PI3K/Akt and extracellular signal-regulated kinases/mitogen-activated protein kinase signalling pathways.

OBJECTIVES: Dehydrocostus lactone (DHE), a sesquiterpene lactone, has been proven the significant inhibition of multiple cancer cells. However, there are limited reports on the activity of DHE in gastric cancer (GC). In this research, Network pharmacology predicted the anti-GC mechanism of DHE, and the prediction was verified by in-vitro experiments. METHODS: Network pharmacology confirmed the major effect signalling pathway of DHE in treating GC. Cell viability assay, colony formation assay, wound healing assay, cell migration and invasion assay, apoptosis assay, western blot and real-time quantitative polymerase chain reaction verified the mechanism of DHE in GC cell lines. KEY FINDINGS: The results showed that DHE inhibited the growth and metastasis of MGC803 and AGS GC cells. Mechanistically, the analysis results indicated that DHE significantly induced the apoptosis process by suppressing the PI3K/protein kinase B (Akt) signalling pathway, and inhibited epithelial-mesenchymal transition by suppressing the extracellular signal-regulated kinases (ERK)/MAPK signalling pathway. The Akt activator (SC79) inhibited DHE induced apoptosis, and DHE had similar effects with the ERK inhibitor (FR180204). CONCLUSIONS: All results suggested that DHE was a potential natural chemotherapeutic drug in GC treatment.

Application of 3D-Printed Personalized Guide for Lateral Femoral Positioning in Anterior Cruciate Ligament Reconstruction of the Knee.

Objective: This research aims to investigate the effectiveness of 3D computer-assisted customized guided positioning of the lateral femoral tunnel compared to conventional methods for Anterior Cruciate Ligament (ACL) reconstruction surgery. Methods: A total of 80 patients with a complete ACL tear who underwent arthroscopic reconstruction with autologous tendon transplantation (semitendinosus-gracilis tendon) were included in this study. The patients were admitted to our hospital between March 2020 and January 2022 and were randomly divided into two groups: the conventional group (n = 40) and the personalized guide group (n = 40), based on the positioning method. The conventional group underwent ACL restoration using standard surgical techniques, while the personalized guide group opted for the more precise computer-assisted personalized guide method. The lateral femoral tunnel times were compared between both groups. Additionally, the International Knee Documentation Committee (IKDC) and Lysholm scores were assessed, and the lateral femoral location was evaluated using X-ray imaging at 2 weeks postoperatively. Results: After surgery, both groups showed a statistically significant increase (P < .05) in Lysholm and IKDC scores compared to their pre-surgery scores. However, the two groups had no evident difference (P > .05). X-ray evaluation at 2 weeks post-surgery revealed no significant difference between the two groups in NL/ML, AL/BL, α, and ß angles (P > .05). The preparation time for the femoral tunnel was significantly shorter in the personalized guide group (6.18 ± 0.92 min) compared to the traditional group (15.94 ± 3.12 min) (P < .05). Conclusions: The computer-assisted 3D personalized guide positioning method is more effective in locating the lateral femoral tunnel for ACL reconstruction of the knee and can substantially reduce the positioning time. This study provides valuable insights for clinicians when selecting surgical methods.

Targeting the Siglec-sialic acid axis promotes antitumor immune responses in preclinical models of glioblastoma.

Glioblastoma (GBM) is the most aggressive form of primary brain tumor, for which effective therapies are urgently needed. Cancer cells are capable of evading clearance by phagocytes such as microglia- and monocyte-derived cells through engaging tolerogenic programs. Here, we found that high expression of sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) correlates with reduced survival in patients with GBM. Using microglia- and monocyte-derived cell-specific knockouts of Siglec-E, the murine functional homolog of Siglec-9, together with single-cell RNA sequencing, we demonstrated that Siglec-E inhibits phagocytosis by these cells, thereby promoting immune evasion. Loss of Siglec-E on monocyte-derived cells further enhanced antigen cross-presentation and production of pro-inflammatory cytokines, which resulted in more efficient T cell priming. This bridging of innate and adaptive responses delayed tumor growth and resulted in prolonged survival in murine models of GBM. Furthermore, we showed the combinatorial activity of Siglec-E blockade and other immunotherapies demonstrating the potential for targeting Siglec-9 as a treatment for patients with GBM.

Neodb: a comprehensive neoantigen database and discovery platform for cancer immunotherapy.

Neoantigens derived from somatic deoxyribonucleic acid alterations are ideal cancer-specific targets. However, integrated platform for neoantigen discovery is urgently needed. Recently, many scattered experimental evidences suggest that some neoantigens are immunogenic, and comprehensive collection of these experimentally validated neoantigens is still lacking. Here, we have integrated the commonly used tools in the current neoantigen discovery process to form a comprehensive web-based analysis platform. To identify experimental evidences supporting the immunogenicity of neoantigens, we performed comprehensive literature search and constructed the database. The collection of public neoantigens was obtained by using comprehensive features to filter the potential neoantigens from recurrent driver mutations. Importantly, we constructed a graph neural network (GNN) model (Immuno-GNN) using an attention mechanism to consider the spatial interactions between human leukocyte antigen and antigenic peptides for neoantigen immunogenicity prediction. The new easy-to-use R/Shiny web-based neoantigen database and discovery platform, Neodb, contains currently the largest number of experimentally validated neoantigens. In addition to validated neoantigen, Neodb also includes three additional modules for facilitating neoantigen prediction and analysis, including 'Tools' module (comprehensive neoantigen prediction tools); 'Driver-Neo' module (collection of public neoantigens derived from recurrent mutations) and 'Immuno-GNN' module (a novel immunogenicity prediction tool based on a GNN). Immuno-GNN shows improved performance compared with known methods and also represents the first application of GNN model in neoantigen immunogenicity prediction. The construction of Neodb will facilitate the study of neoantigen immunogenicity and the clinical application of neoantigen-based cancer immunotherapy. Database URL https://liuxslab.com/Neodb/.

Biomarkers based on multiplatform comprehensive analysis: A systematic analysis of Geng-Nian-Shu in perimenopausal syndrome.

Although Geng-Nian-Shu has been shown to be clinically effective in perimenopausal syndrome, its active components and mechanism have not yet been elucidated. To demonstrate the mechanism-based biomarkers of Geng-Nian-Shu in treating perimenopausal syndrome, a total of 135 chemical constituents including 52 prototype blood constituents were identified via high-performance liquid chromatography-quadrupole-time of flight/mass spectrometry. Then, network pharmacology showed significant enrichment for the PhosphoInositide-3 Kinase/Akt pathway, suggesting that it may be the main regulatory pathway for the Geng-Nian-Shu treatment of the perimenopausal syndrome. Subsequently, multivariate analysis was performed between the Geng-Nian-Shu sham-treated and Geng-Nian-Shu ovariectomy-treated groups and further screened out 18 prototype blood constituents by correlation analysis with plasma estrogen levels to identify potential biomarkers associated with Geng-Nian-Shu treat the ovariectomy-induced perimenopausal syndrome. Finally, the results of pharmacological experimental verification and Pearson correlation analysis indicated that catalpol, ligustilide, paeoniflorin, and gallic acid were selected as biomarkers of Geng-Nian-Shu which were strongly and positively correlated with PhosphoInositide-3 Kinase/Akt signaling pathway. In this study, based on high-performance liquid chromatography-quadrupole-time of flight/mass spectrometry combined with pharmacodynamics, network pharmacology, pharmacology, and other disciplines, we explored the effects and mechanisms of Geng-Nian-Shu in the treatment of perimenopausal syndrome at multiple levels. Using multiplatform technology to investigate the role of Geng-Nian-Shu represents a new strategy for the selection and verification of biomarkers of Geng-Nian-Shu and provides a basis for further development and utilization of Geng-Nian-Shu.

Copy number alteration features in pan-cancer homologous recombination deficiency prediction and biology.

Homologous recombination deficiency (HRD) renders cancer cells vulnerable to unrepaired double-strand breaks and is an important therapeutic target as exemplified by the clinical efficacy of poly ADP-ribose polymerase (PARP) inhibitors as well as the platinum chemotherapy drugs applied to HRD patients. However, it remains a challenge to predict HRD status precisely and economically. Copy number alteration (CNA), as a pervasive trait of human cancers, can be extracted from a variety of data sources, including whole genome sequencing (WGS), SNP array, and panel sequencing, and thus can be easily applied clinically. Here we systematically evaluate the predictive performance of various CNA features and signatures in HRD prediction and build a gradient boosting machine model (HRDCNA) for pan-cancer HRD prediction based on these CNA features. CNA features BP10MB[1] (The number of breakpoints per 10MB of DNA is 1) and SS[ > 7 & <=8] (The log10-based size of segments is greater than 7 and less than or equal to 8) are identified as the most important features in HRD prediction. HRDCNA suggests the biallelic inactivation of BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BARD1 as the major genetic basis for human HRD, and may also be applied to effectively validate the pathogenicity of BRCA1/2 variants of uncertain significance (VUS). Together, this study provides a robust tool for cost-effective HRD prediction and also demonstrates the applicability of CNA features and signatures in cancer precision medicine.

Interpreting the Therapeutic Efficiency of Multifunctional Hybrid Nanostructure against Glioblastoma.

Glioblastoma is considered the most fatal malignant brain tumor that starts from the central nervous system (CNS), where the blood-brain barrier (BBB) remains the biggest challenge for active targeting of drugs in malignant brain tumor. Thereby, we have designed a paclitaxel PTX@ANG/FA-NPs hybrid novel nanodrug delivery system that can overcome the clinical BBB. The structural and morphological characterization of PTX@ANG/FA-NPs confirmed successful synthesis of nanomicelles with the size range of about 160 to 170 nm. The overall repressive effect of PTX@ANG/FA-NPs on human glioblastoma U251 cells was 1.2-times that of PTX alone. In vitro cellular uptake assay also demonstrated that the dual-targeted nanoparticles (NPs) were more easily taken up by glioblastoma U251 cells. Although the antiglioblastoma activity was confirmed by cell migration assay, apoptosis assay, and cellular uptake assay, the absorption was studied by in vivo fluorescence imaging and brain distribution. The synthesized PTX@ANG/FA-NPs probe significantly inhibited the migration of U251 within the cells and promoted the apoptosis process. Moreover, the RhB@ANG/FA-NPs and PTX@ANG/FA-NPs showed higher accumulating potential at sites of tumor BBB disruption. The novel nanodrug delivery system mediated enhanced distribution of drugs at the targeted site for therapeutics efficacies against glioblastomas across the BBB.