Poliovirus receptor-based chimeric antigen receptor T cells combined with NK-92 cells exert potent activity against glioblastoma.

BACKGROUND: Poliovirus receptor interacts with 3 receptors: T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif, CD96, and DNAX accessory molecule 1, which are predominantly expressed on T cells and natural killer (NK) cells. Many solid tumors, including IDH wild-type glioblastoma, have been reported to overexpress poliovirus receptor, and this overexpression is associated with poor prognosis. However, there are no preclinical or clinical trials investigating the use of cell-based immunotherapies targeting poliovirus receptor in IDH wild-type glioblastoma. METHODS: We analyzed poliovirus receptor expression in transcriptome sequencing databases and specimens from IDH wild-type glioblastoma patients. We developed poliovirus receptor targeting chimeric antigen receptor T cells using lentivirus. The antitumor activity of chimeric antigen receptor T cells was demonstrated in patient-derived glioma stem cells, intracranial and subcutaneous mouse xenograft models. RESULTS: We verified poliovirus receptor expression in primary glioma stem cells, surgical specimens from IDH wild-type glioblastoma patients, and organoids. Accordingly, we developed poliovirus receptor-based second-generation chimeric antigen receptor T cells. The antitumor activity of chimeric antigen receptor T cells was demonstrated in glioma stem cells and xenograft models. Tumor recurrence occurred in intracranial xenograft models because of antigen loss. The combinational therapy of tyrosine-based inhibitory motif extracellular domain-based chimeric antigen receptor T cells and NK-92 cells markedly suppressed tumor recurrence and prolonged survival. CONCLUSIONS: Poliovirus receptor-based chimeric antigen receptor T cells were capable of killing glioma stem cells and suppressing tumor recurrence when combined with NK-92 cells.

Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape.

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors. Although instances of rapid tumor remissions have been observed in animal models and clinical trials, tumor relapses occur with multiple therapeutic resistance mechanisms. Furthermore, while the mechanisms underlying the long-term therapeutic resistance are well-known, short-term adaptation remains less understood. However, more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term resistance. In this study, we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells, a reversal of previously documented processes. This mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction, also leading to short-term antigen loss and antigen masking. Such type of intercellular communication is independent of CAR downstream signaling, CAR-T cell condition, target antigen, and tumor cell type. However, it is mainly dependent on antigen density and CAR sensitivity, and is associated with tumor cell cholesterol metabolism. Partial mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR sensitivities. Together, our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.

Fabrication of Laser-Induced Graphene Based Flexible Sensors Using 355 nm Ultraviolet Laser and Their Application in Human-Computer Interaction System.

In recent years, flexible sensors based on laser-induced graphene (LIG) have played an important role in areas such as smart healthcare, smart skin, and wearable devices. This paper presents the fabrication of flexible sensors based on LIG technology and their applications in human-computer interaction (HCI) systems. Firstly, LIG with a sheet resistance as low as 4.5 Ω per square was generated through direct laser interaction with commercial polyimide (PI) film. The flexible sensors were then fabricated through a one-step method using the as-prepared LIG. The applications of the flexible sensors were demonstrated by an HCI system, which was fabricated through the integration of the flexible sensors and a flexible glove. The as-prepared HCI system could detect the bending motions of different fingers and translate them into the movements of the mouse on the computer screen. At the end of the paper, a demonstration of the HCI system is presented in which words were typed on a computer screen through the bending motion of the fingers. The newly designed LIG-based flexible HCI system can be used by persons with limited mobility to control a virtual keyboard or mouse pointer, thus enhancing their accessibility and independence in the digital realm.

Effect of Food on the Pharmacokinetics of Tenofovir Amibufenamide: A Phase I, Randomized, Open-Label, Two-Period Crossover Trial in Healthy Adult Subjects.

Purpose: Tenofovir amibufenamide (TMF) is a novel nucleotide reverse transcriptase inhibitor. The aim of this study was to investigate the effect of food on the single-dose pharmacokinetic properties of TMF. Patients and Methods: In this open-label, randomized, crossover study, after an overnight fast, eligible subjects received a single 25 mg dose of TMF tablet, either under fasted conditions or following consumption of a high-fat, high-calorie meal, followed by a two-week washout period. Blood samples were collected until 144 h after administration. TMF and its metabolite, tenofovir (TFV), were analyzed using validated liquid chromatography-tandem mass spectrometry methods. The geometric mean ratio (GMR) and the corresponding 90% confidence interval (CI) values of AUC0-t, AUC0-∞, and Cmax were acquired for analysis. The absence of an effect of food was indicated if the 90% CI values were within the predefined equivalence limits of 80%-125%. Safety and tolerability were also assessed. Results: For TMF, adjusted GMR (90% CI) values for the fed versus fasted states were 150.28% (125.36%-180.16%), 158.24% (130.42%-192.00%), and 57.65% (45.68%-72.76%) for AUC0-t, AUC0-∞, and Cmax, respectively. For TFV, the GMR (90% CI) of Cmax was 82.00% (74.30%-90.49%) after administration under fed conditions, slightly outside the bioequivalence boundary of 80%-125%, while the corresponding values for AUC0-t and AUC0-∞ were within range. The absorption of TMF was delayed by food, with median Tmax values of 0.33 and 1.00 h in fasted and fed conditions, respectively. The adverse events observed in subjects were all mild. Conclusion: Our results demonstrated that TMF tablets were well-tolerated in healthy volunteers. When TMF tablets were taken with food, Tmax was delayed and exposures of TMF and TFV were higher than under fasted conditions. The modest changes observed are not considered clinically relevant, so TMF can be taken with or without food.

RUNX-3-expressing CAR T cells targeting glypican-3 in patients with heavily pretreated advanced hepatocellular carcinoma: a phase I trial.

Background: Glypican-3 (GPC3) is a well-characterized hepatocellular carcinoma (HCC)-associated antigen and a promising target for HCC treatment. CT017 CAR T cells were engineered to co-express CAR-GPC3 and runt-related transcription factor 3 (RUNX3), which triggers CD8+ T-cell infiltration into the cancer microenvironment. Methods: This single-center, single-arm, open-label, phase I clinical study enrolled heavily pretreated patients with GPC3-positive HCC between August 2019 and December 2020 (NCT03980288). Patients were treated with CT017 CAR T cells at a dose of 250 × 106 cells. The primary objective was to assess the safety and tolerability of this first-in-human product. Findings: Six patients received 7 infusions (one patient received 2 infusions) at the 250 × 106 cells dose. Three patients received CT017 monotherapy, and three patients received CT017-tyrosine kinase inhibitor (TKI) combination therapy at the first infusion. One patient received CT017-TKI combination therapy at the second infusion after CT017 monotherapy. All patients experienced cytokine release syndrome (CRS), with 50% (3/6) at Grade 2, 50% (3/6) at Grade 3, and all events resolved after treatment. No immune effector cell-associated neurotoxicity syndrome was observed. Dose escalation was not performed due to the investigator's decision regarding safety. Of six evaluable patients, one achieved partial response and two had stable disease for a 16.7% objective response rate, 50% disease control rate, 3.5-month median progression-free survival, 3.2-month median duration of disease control, and 7.9-month median overall survival (OS) with 7.87-month median follow-up. The longest OS was 18.2 months after CT017 infusion. Interpretation: Current preliminary phase I data showed a manageable safety profile and promising antitumor activities of CT017 for patients with advanced HCC. These results need to be confirmed in a robust clinical trial. Funding: This study was funded by CARsgen Therapeutics Co., Ltd.

Development of an integrated and comprehensive clinical trial process management system.

BACKGROUND: The process of initiating and completing clinical drug trials in hospital settings is highly complex, with numerous institutional, technical, and record-keeping barriers. In this study, we independently developed an integrated clinical trial management system (CTMS) designed to comprehensively optimize the process management of clinical trials. The CTMS includes system development methods, efficient integration with external business systems, terminology, and standardization protocols, as well as data security and privacy protection. METHODS: The development process proceeded through four stages, including demand analysis and problem collection, system design, system development and testing, system trial operation, and training the whole hospital to operate the system. The integrated CTMS comprises three modules: project approval and review management, clinical trial operations management, and background management modules. These are divided into seven subsystems and 59 internal processes, realizing all the functions necessary to comprehensively perform the process management of clinical trials. Efficient data integration is realized through extract-transform-load, message queue, and remote procedure call services with external systems such as the hospital information system (HIS), laboratory information system (LIS), electronic medical record (EMR), and clinical data repository (CDR). Data security is ensured by adopting corresponding policies for data storage and data access. Privacy protection complies with laws and regulations and de-identifies sensitive patient information. RESULTS: The integrated CTMS was successfully developed in September 2015 and updated to version 4.2.5 in March 2021. During this period, 1388 study projects were accepted, 43,051 electronic data stored, and 12,144 subjects recruited in the First Affiliated Hospital, Zhejiang University School of Medicine. CONCLUSION: The developed integrated CTMS realizes the data management of the entire clinical trials process, providing basic conditions for the efficient, high-quality, and standardized operation of clinical trials.

Diffuse Isocitrate Dehydrogenase-Mutant Gliomas With Histone H3 Alterations Are Distinguished by Unique Clinical Characteristics, Molecular Expression Profile, and Survival Prognosis.

BACKGROUND AND OBJECTIVES: Histopathological features and molecular biomarkers have been studied as potential prognostic factors. This study aimed to investigate the clinical features, molecular phenotypes, and survival prognosis of isocitrate dehydrogenase (IDH)-mutant (IDHmt) gliomas with histone H3 alterations (H3-alterations). METHODS: A total of 236 and 657 patients with whole-exome sequencing data were separately collected from the Chinese Glioma Genome Atlas and The Cancer Genome Atlas databases. Survival analysis of patients with glioma was performed using Kaplan-Meier survival curves stratified by histone H3 status. Univariate and multivariate analyses were used to identify the associations between histone H3 status and other clinicopathological factors with survival in patients with IDH-mutant gliomas. RESULTS: Diffuse gliomas with H3 alterations are more likely to be high grade in 2 cohorts ( P = .025 and P = .021, respectively). IDHmt glioma patients with H3-alteration had significantly less life expectancy than histone H3 wild-type ( P = .041 and P = .008, respectively). In the Chinese Glioma Genome Atlas cohort, Karnofsky performance scores ≤ 80 (HR 2.394, 95% CI 1.257-4.559, P = .008), extent of resection (HR 0.971, 95% CI 0.957-0.986, P < .001), high WHO grade (HR 6.938, 95% CI 2.787-17.269, P < .001), H3-alteration (HR 2.482, 95% CI 1.183-4.981, P = .016), and 1p/19q codeletion (HR 0.169, 95% CI 0.073-0.390, P < .001) were independently associated with IDHmt gliomas. In the The Cancer Genome Atlas cohort, age (HR 1.034, 95% CI 1.008-1.061, P = .010), high WHO grade (HR 2.365, 95% CI 1.263-4.427, P = .007), and H3-alteration (HR 2.501, 95% CI 1.312-4.766, P = .005) were independently associated with IDHmt gliomas. CONCLUSION: Identification and assessment of histone H3 status in clinical practice might help improve prognostic prediction and develop therapeutic strategies for these patient subgroups.

Bioequivalence study of domperidone dry suspension in healthy Chinese subjects under fasted and fed conditions: An open-label, randomized, single-dose, crossover trial.

BACKGROUND: Domperidone has long been used as a prokinetic agent in the treatment of epigastric distress symptoms. This study aimed to provide adequate evidence for registration approval of a new generic dry suspension formulation of domperidone by comparing the safety and pharmacokinetic profiles between the test and branded reference formulation in the context of fasted and fed condition. MATERIALS AND METHODS: This was designed as a randomized, open-label, single-dose, two-period, two-treatment crossover study. 32 and 28 eligible healthy subjects were enrolled in the fasted and fed study, respectively. Each subject was randomly assigned to receive either the test or reference formulation in the first period, followed by a 1-week washout period and dosing of the alternate formulation in the second period. A series of blood samples were collected at scheduled timepoints within 48 hours after administration during each treatment period. Plasma concentrations of domperidone were determined by validated HPLC-MS/MS. Pharmacokinetic parameters, including Cmax, tmax, AUC0-t, AUC0-∞, and T1/2, were acquired based on the concentration vs. time profiles by non-compartmental analysis using WinNonlin software. Then the geometric mean ratios (GMR) of Cmax, AUC0-t, and AUC0-∞ between the two formulations and corresponding 90% confidence intervals (CIs) were calculated for bioequivalence determination. Safety was assessed as routine. RESULTS: The two formulations showed similar pharmacokinetic profiles. Under fasted condition, the GMR and corresponding 90% CIs of AUC0-t, AUC0-∞, and Cmax were 101.48% (96.79 - 106.38%), 101.17% (96.66 - 105.90%), and 104.61% (96.73 - 113.14%), respectively. Under fed condition, the GMR and corresponding 90% CIs were 105.46% (99.19 - 112.12%), 104.21% (98.19 - 110.61%), and 112.78% (103.64 - 122.73%), respectively, for AUC0-t, AUC0-∞, and Cmax. All values fell within the accepted bioequivalence range of 80 - 125%. Both the test and the reference products were well tolerated without any serious or unexpected adverse reactions. CONCLUSION: Pharmacokinetic bioequivalence was established between the two dry suspension formulations of domperidone in healthy Chinese subjects. Both products were safe and well tolerated.

EGFRvIII Promotes the Proneural-Mesenchymal Transition of Glioblastoma Multiforme and Reduces Its Sensitivity to Temozolomide by Regulating the NF-κB/ALDH1A3 Axis.

(1) Background: Glioblastoma multiforme (GBM) is the most common and malignant intracranial tumor in adults. At present, temozolomide (TMZ) is recognized as the preferred chemotherapeutic drug for GBM, but some patients have low sensitivity to TMZ or chemotherapy resistance to TMZ. Our previous study found that GBM patients with EGFRvIII (+) have low sensitivity to TMZ. However, the reasons and possible mechanisms of the chemoradiotherapy resistance in GBM patients with EGFRvIII (+) are not clear. (2) Methods: In this study, tissue samples of patients with GBM, GBM cell lines, glioma stem cell lines, and NSG mice were used to explore the causes and possible mechanisms of low sensitivity to TMZ in patients with EGFRvIII (+)-GBM. (3) Results: The study found that EGFRvIII promoted the proneural-mesenchymal transition of GBM and reduced its sensitivity to TMZ, and EGFRvIII regulated of the expression of ALDH1A3. (4) Conclusions: EGFRvIII activated the NF-κB pathway and further regulated the expression of ALDH1A3 to promote the proneural-mesenchymal transition of GBM and reduce its sensitivity to TMZ, which will provide an experimental basis for the selection of clinical drugs for GBM patients with EGFRvIII (+).

Immunological profiles of human oligodendrogliomas define two distinct molecular subtypes.

BACKGROUND: Human oligodendroglioma presents as a heterogeneous disease, primarily characterized by the isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion. Therapy development for this tumor is hindered by incomplete knowledge of somatic driving alterations and suboptimal disease classification. We herein aim to identify intrinsic molecular subtypes through integrated analysis of transcriptome, genome and methylome. METHODS: 137 oligodendroglioma patients from the Cancer Genome Atlas (TCGA) dataset were collected for unsupervised clustering analysis of immune gene expression profiles and comparative analysis of genome and methylome. Two independent datasets containing 218 patients were used for validation. FINDINGS: We identified and independently validated two reproducible subtypes associated with distinct molecular characteristics and clinical outcomes. The proliferative subtype, named Oligo1, was characterized by more tumors of CNS WHO grade 3, as well as worse prognosis compared to the Oligo2 subtype. Besides the clinicopathologic features, Oligo1 exhibited enrichment of cell proliferation, regulation of cell cycle and Wnt signaling pathways, and significantly altered genes, such as EGFR, NOTCH1 and MET. In contrast, Oligo2, with favorable outcome, presented increased activation of immune response and metabolic process. Higher T cell/APC co-inhibition and inhibitory checkpoint levels were observed in Oligo2 tumors. Finally, multivariable analysis revealed our classification was an independent prognostic factor in oligodendrogliomas, and the robustness of these molecular subgroups was verified in the validation cohorts. INTERPRETATION: This study provides further insights into patient stratification as well as presents opportunities for therapeutic development in human oligodendrogliomas. FUNDING: The funders are listed in the Acknowledgement.

Clinical characteristics and survival of glioblastoma complicated with non-central nervous system tumors.

BACKGROUND: Diagnosis and treatment of patients with glioblastoma (GBM) who are also diagnosed with primary non-central nervous system (CNS) tumors remain a challenge, yet little is known about the clinical characteristics and prognosis of these patients. The data presented here compared the clinical and pathological features between glioblastoma patients with or without primary non-CNS tumors, trying to further explore this complex situation. METHODS: Statistical analysis was based on the clinical and pathological data of 45 patients who were diagnosed with isocitrate dehydrogenase (IDH) wild-type glioblastoma accompanied by non-CNS tumors between January 2019 and February 2022 in Beijing Tiantan Hospital. Univariate COX proportional hazard regression model was used to determine risk factors for overall survival. RESULTS: It turned out to be no significant difference in the overall survival (OS) of the 45 patients with IDH-wild-type GBM plus non-CNS tumors, compared with the 112 patients who were only diagnosed with IDH-wild-type GBM. However, there was a significant difference in OS of GBM patients with benign tumors compared to those with malignant tumors. CONCLUSIONS: Implications for the non-central nervous system tumors on survival of glioblastomas were not found in this research. However, glioblastomas complicated with other malignant tumors still showed worse clinical outcomes.

Targeting mTOR Complex 2 in Castration-Resistant Prostate Cancer with Acquired Docetaxel Resistance.

Purpose: Mammalian Target of rapamycin (mTOR) plays a central role in regulating cell growth, proliferation, and cell cycle. The key component of mTORC2 is highly expressed in docetaxel-resistant prostate cells. However, the underlying molecular effects on prostate cells remain unclear. Methods: A docetaxel-resistant human prostate cell line (PC-3/DTX) was constructed to investigate the role of mTORC2 in docetaxel resistance. The lentivirus was transfected into cells to knock down the expression of Rictor, and cell viability was measured by Cell Counting Kit 8 (CCK-8). Flow cytometry was used to analyze the cell cycle, and the changes in related signal cascades were assessed by immunohistochemistry (IHC) staining and Western blot. Results: Docetaxel showed the lowest IC50 (50% inhibitory concentration) in PC-3/DTX cells with sh-RNA. Decreased Rictor expression resulted in a larger proportion of arrested cells in the G0/G1 phase in PC-3/DTX cells. The IC50 values of the AZD8055 group were lower than in the Rapamycin group when treated with docetaxel again. Furthermore, a larger proportion of PC-3/DTX cells were arrested in the G0/G1 phase in the AZD8055 group compared to the Rapamycin group. The IHC results of the prostate cancer tissues from a CRPC patient revealed the over expression of Rictor only, while Raptor expression was unaffected. Conclusion: We investigated the role of mTORC2 signaling on the acquired docetaxel -resistant PC-3 cells to identify potential methods for clinical treatment. MTORC2 expression is essential for docetaxel drug resistance of PC-3 cells. The mTORC1/2 inhibitor AZD8055 caused more significant disruption of mTORC2 kinase activity than the mTORC1 inhibitor Rapamycin, which lead to decreased docetaxel-mediated resistance. Therefore, reversing docetaxel resistance, may become a therapeutic option in the treatment of mCRPC patients.

A single-dose, randomized, open-labeled, parallel-group study comparing the pharmacokinetics, pharmacodynamics and safety of leuprolide acetate microspheres 3.75 mg and Enantone® 3.75 mg in healthy male subjects.

Leuprolide acetate microspheres developed by Shanghai Livzon Pharmaceutical Co., Ltd. (T) have been marketed in China for more than 10 years, benefiting a large number of patients, and will continue to play an important role in China. However, as a generic drug, it is unclear whether there is a difference in efficacy between T and the original product Enantone® (R). This study compared the differences in efficacy and safety of two 1-month depot formulations in 48 healthy Chinese male subjects by comparing multiple pharmacokinetic (PK) and pharmacodynamic (PD) parameters. The main research indicators were the PK parameters of leuprolide (Cmax, AUC0-t, AUC0-D7, and AUCD7-t) and the PD parameters of testosterone (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) after 42 days of administration. The Cmax, AUC0-t, AUC0-D7 and AUCD7-t of leuprolide were slightly higher in the T group than in the R group with 90% confidence intervals (CIs) of 94.43-118.53%, 109.13-141.88%, 109.53-139.54%, and 105.17-145.74%, respectively. No significant differences in the PD parameters (Emax, AUEC0-t, AUEC0-D7, and AUECD7-t) existed between the T and R groups, and 90% CIs were 62.80-93.57%, 88.17-110.55, 95.72%-118.50%, and 79.77-105.63, respectively. At 672 h (D28), the castration rate of T was 91.30% (21/23) and that of R was 60.87% (14/23). The PK characteristics were consistent and the inhibitory effects on testosterone levels were similar in both T and R groups; further, clinical safety was observed for both T and R formulations, suggesting that these two products can replace each other in clinical practice. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier CTR20200641.

Association between Depression and Clinical Outcomes following Percutaneous Coronary Intervention: A Meta-Analysis.

BACKGROUND: Several studies suggested that depression was associated with poor prognosis following percutaneous coronary intervention (PCI) in coronary heart disease (CHD), whereas other studies showed that there were no associations between depression and poor outcomes. OBJECTIVES: Considering these problems, this meta-analysis was conducted to evaluate the relationship between depression and clinical outcomes after PCI. METHODS: Articles published before July 2021 were analyzed from the databases: PubMed, Web of Science, EMBASE, Medline, and Google Scholar. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed to generate a pooled effect size and 95% CI with a random or fixed effects model. Q test and I2 were used to assess heterogeneities between studies. RESULTS: The meta-analysis indicated that depression was associated with a higher risk of major adverse cardiac events (MACE) after PCI with a random effects model (HR = 1.89, 95% CI: 1.33-2.68, I2 = 57.0%, p = 0.023). The study indicated that depression was associated with a higher risk of all-cause mortality after PCI with a fixed effects model (HR = 1.71, 95% CI: 1.43-2.05, I2 = 0.0%, p = 0.756). The study indicated no significant association between depression and risk of repeat revascularization after PCI with a random effects model (HR = 2.10, 95% CI: 0.96-4.58, I2 = 68.9%, p = 0.022). CONCLUSION: Results indicated that depression is associated with adverse clinical outcomes in CHD patients' post-PCI. Appropriate mental health check and psychological treatment may be necessary for the prognosis of CHD patients who receive PCI.

An MRI radiomics approach to predict survival and tumour-infiltrating macrophages in gliomas.

Preoperative MRI is one of the most important clinical results for the diagnosis and treatment of glioma patients. The objective of this study was to construct a stable and validatable preoperative T2-weighted MRI-based radiomics model for predicting the survival of gliomas. A total of 652 glioma patients across three independent cohorts were covered in this study including their preoperative T2-weighted MRI images, RNA-seq and clinical data. Radiomic features (1731) were extracted from preoperative T2-weighted MRI images of 167 gliomas (discovery cohort) collected from Beijing Tiantan Hospital and then used to develop a radiomics prediction model through a machine learning-based method. The performance of the radiomics prediction model was validated in two independent cohorts including 261 gliomas from the The Cancer Genomae Atlas database (external validation cohort) and 224 gliomas collected in the prospective study from Beijing Tiantan Hospital (prospective validation cohort). RNA-seq data of gliomas from discovery and external validation cohorts were applied to establish the relationship between biological function and the key radiomics features, which were further validated by single-cell sequencing and immunohistochemical staining. The 14 radiomic features-based prediction model was constructed from preoperative T2-weighted MRI images in the discovery cohort, and showed highly robust predictive power for overall survival of gliomas in external and prospective validation cohorts. The radiomic features in the prediction model were associated with immune response, especially tumour macrophage infiltration. The preoperative T2-weighted MRI radiomics prediction model can stably predict the survival of glioma patients and assist in preoperatively assessing the extent of macrophage infiltration in glioma tumours.

The impact of rifampicin on the pharmacokinetics of fuzuloparib in healthy Chinese male volunteers.

AIMS: This clinical study was conducted to evaluate the impact of rifampicin on the pharmacokinetics of fuzuloparib. METHODS: In this single-centre, single-arm, open-label, fixed-sequence study, healthy male subjects took a single 50 mg dose of fuzuloparib on two separate occasions: the first was on Day 1 as monotherapy, and the second was on Day 12 after oral administration of rifampicin 600 mg once daily for 8 days. Series of blood samples were obtained before and after fuzuloparib administration at different time points: pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours post-dose. All samples were examined using liquid chromatography with tandem mass spectrometry. PK parameters were estimated by using a non-compartmental method with Phoenix WinNonlin software. Safety was assessed by monitoring for changes in vital signs and laboratory tests, physical examinations, and incidences of adverse events (AEs). RESULTS: A total of 16 Chinese male subjects were enrolled. Of these, 16 and 15 cases were evaluable for PK analysis following administration with fuzuloparib alone and pretreatment with rifampicin, respectively. Pretreatment with rifampicin resulted in a statistically significant reduction in the systemic exposure to fuzuloparib. The treatment ratio and 90% confidence intervals (CIs) for AUC0-∞ and Cmax were 0.10 (0.095-0.115) and 0.32 (0.281-0.365), respectively. A single administration of fuzuloparib after multiple oral dosing of rifampicin was well-tolerated, without severe AEs. CONCLUSION: The exposure of fuzuloparib was dramatically decreased when pretreated with rifampicin. Strong CYP3A4 inducers should be avoided during fuzuloparib treatment.

Clinical characterization and immunosuppressive regulation of CD161 (KLRB1) in glioma through 916 samples.

BACKGROUND: Glioblastoma is a paradigm of cancer-associated immunosuppression, limiting the effects of immunotherapeutic strategies. Thus, identifying the molecular mechanisms underlying immune surveillance evasion is critical. Recently, the preferential expression of inhibitory natural killer (NK) cell receptor CD161 on glioma-infiltrating cytotoxic T cells was identified. Focusing on the molecularly annotated, large-scale clinical samples from different ethnic origins, the data presented here provide evidence of this immune modulator's essential roles in brain tumor biology. METHODS: Retrospective RNA-seq data analysis was conducted in a cohort of 313 patients with glioma in the Chinese Glioma Genome Atlas (CGGA) database and 603 patients in The Cancer Genome Atlas (TCGA) database. In addition, single-cell sequencing data from seven surgical specimens of glioblastoma patients and a model in which patient-derived glioma stem cells were cocultured with peripheral lymphocytes, were used to analyze the molecular evolution process during gliomagenesis. RESULTS: CD161 was enriched in high-grade gliomas and isocitrate dehydrogenase (IDH)-wildtype glioma. CD161 acted as a potential biomarker for the mesenchymal subtype of glioma and an independent prognostic factor for the overall survival (OS) of patients with glioma. In addition, CD161 played an essential role in inhibiting the cytotoxicity of T cells in glioma patients. During the process of gliomagenesis, the expression of CD161 on different lymphocytes dynamically evolved. CONCLUSION: The expression of CD161 was closely related to the pathology and molecular pathology of glioma. Meanwhile, CD161 promoted the progression and evolution of gliomas through its unique effect on T cell dysfunction. Thus, CD161 is a promising novel target for immunotherapeutic strategies in glioma treatment.

TREM2 is associated with tumor immunity and implies poor prognosis in glioma.

Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in myeloid cells of the central nervous system (CNS), which mediate the immunological response in a variety of diseases. Uncertain is the function of TREM2 in glioma and tumor immune responses. In this research, the expression patterns of TREM2 in glioma were analyzed, along with its prognostic value and functional roles. TREM2 expression is increased in glioblastomas, gliomas with a mesenchymal subtype, gliomas with wild-type isocitrate dehydrogenase, and gliomas without 1p/19q deletion, all of which suggest the aggressiveness and poor prognosis of gliomas. Gene ontology, KEGG, and Gene set variation analyses indicated that TREM2 may serve as an immune response mediator. However, the function of T cells against tumor cells was negatively correlated with TREM2, suggesting that TREM2 may suppress tumor immunity. Further investigation demonstrated a correlation between TREM2 expression and immune checkpoint expression. CIBERSORT research revealed a link between a higher TREM2 expression level and the enrichment of tumor-associated macrophages, especially M2 subtype. Single-cell analysis and multiple immunohistochemical staining results showed that microglia and macrophage cells expressed TREM2. Immunofluorescent staining indicated that knocking down the expression of TREM2 would result in a decrease in M2 polarization. TREM2 was discovered to be an independent prognostic factor in glioma. In conclusion, our findings revealed that TREM2 was significantly expressed in microglia and macrophage cells and was intimately associated with the tumor immune microenvironment. Thus, it is expected that small-molecule medications targeting TREM2 or monoclonal antibodies would enhance the efficacy of glioma immunotherapy.

Molecular Characterization and Clinical Relevance of ANXA1 in Gliomas via 1,018 Chinese Cohort Patients.

Annexin A1 (ANXA1) is a calcium-dependent phospholipid-binding protein and has been implicated in multiple functions essential in cancer, including cell proliferation, apoptosis, chemosensitivity, metastasis, and invasion. However, the biological role and clinical behavior of ANXA1 in glioma remain unclear. In this study, RNA-seq (n = 1018 cases) and whole-exome sequencing (WES) (n = 286 cases) data on a Chinese cohort, RNA-seq data with different histological regions of glioblastoma blocks (n = 270 cases), and scRNA-seq data (n = 7630 cells) were used. We used the R software to perform statistical calculations and graph rendering. We found that ANXA1 is closely related to the malignant progression in gliomas. Meanwhile, ANXA1 is significantly associated with clinical behavior. Furthermore, the mutational profile revealed that glioma subtypes classified by ANXA1 expression showed distinct genetic features. Functional analyses suggest that ANXA1 correlates with the immune-related function and cancer hallmark. At a single-cell level, we found that ANXA1 is highly expressed in M2 macrophages and tumor cells of the mesenchymal subtype. Importantly, our result suggested that ANXA1 expression is significant with the patient's survival outcome. Our study revealed that ANXA1 was closely related to immune response. ANXA1 plays a key factor in M2 macrophages and MES tumor cells. Patients with lower ANXA1 expression levels tended to experience improved survival. ANXA1 may become a valuable factor for the diagnosis and treatment of gliomas in clinical practice.

Galectin-9/TIM-3 as a Key Regulator of Immune Response in Gliomas With Chromosome 1p/19q Codeletion.

Gliomas with chromosome 1p/19q codeletion were considered a specific tumor entity. This study was designed to reveal the biological function alterations tightly associated with 1p/19q codeletion in gliomas. Clinicopathological and RNA sequencing data from glioma patients were obtained from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. Gene set variation analysis was performed to explore the differences in biological functions between glioma subgroups stratified by 1p/19q codeletion status. The abundance of immune cells in each sample was detected using the CIBERSORT analytical tool. Single-cell sequencing data from public databases were analyzed using the t-distributed stochastic neighbor embedding (t-SNE) algorithm, and the findings were verified by in vitro and in vivo experiments and patient samples.We found that the activation of immune and inflammatory responses was tightly associated with 1p/19q codeletion in gliomas. As the most important transcriptional regulator of Galectin-9 in gliomas, the expression level of CCAAT enhancer-binding protein alpha in samples with 1p/19q codeletion was significantly decreased, which led to the downregulation of the immune checkpoints Galectin-9 and TIM-3. These results were validated in three independent datasets. The t-SNE analysis showed that the loss of chromosome 19q was the main reason for the promotion of the antitumor immune response. IHC protein staining, in vitro and in vivo experiments verified the results of bioinformatics analysis. In gliomas, 1p/19q codeletion can promote the antitumor immune response by downregulating the expression levels of the immune checkpoint TIM-3 and its ligand Galectin-9.