Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been approved for the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2−) breast cancers. The study aims were to evaluate the safety, tolerability, and antitumor activity of the novel selective small molecule CDK4/6 inhibitor bireociclib in advanced solid/breast cancer (ABC) patients. A multicenter, open-label, phase 1 trial which consisted of two parts. Part 1 evaluated bireociclib monotherapy at doses ranging from 20 mg once-daily (QD) to 480 mg twice-daily (BID), and part 2 evaluated bireociclib at the recommended dosage in combination with endocrine therapy for ABC patients, including bireociclib plus non-steroidal aromatase inhibitor (cohort A), bireociclib plus fulvestrant as first-line (cohort B), or second-line therapy (cohort C). The endpoints included observing dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD), as well as determining recommended phase 2 dosage for a single regimen (RP2D-S) and recommended phase 2 dosage for combination therapy (RP2D-C) and assessment of the general safety and efficacy of therapy. Thirty-five patients were included in the part 1 MTD analysis and no DLTs occurred. Bireociclib 480 mg BID had more stable blood concentration fluctuations as well as a superior tumor response rate (objective response rate [ORR], 17.5

Purpose:Previous studies have identified synovial T cells as key pathogenic drivers of rheumatoid arthritis (RA). To explore a novel therapeutic strategy targeting these cells, we aimed to develop mesenchymal stem cell-derived exosomes with enhanced PD-L1 expression (Exo-PD-L1) and evaluate their therapeutic potential in RA. Methods:Mouse bone marrow mesenchymal stem cells (MSCs) were stimulated with interferon γ (IFN-γ) to upregulate programmed death ligand 1 (PD-L1) expression. Exo-PD-L1 was isolated and administered to collagen-induced arthritis (CIA) model mice. Therapeutic effects were assessed through T cell activity assays, in vivo biodistribution tracking, clinical symptom scoring, and histopathological analysis of extremities and major organs. Results:Exo-PD-L1 significantly inhibited the activity of cultured T cells, was highly concentrated in the joints of RA mice, and significantly improved RA manifestations and histological abnormalities in the extremities of mice. No histological abnormalities were observed in the main organs of the mice. Conclusion:Exo-PD-L1 can be homed to inflammatory lesions and have the potential to treat RA.

PurposeColorectal cancer (CRC) remains a major global health concern, necessitating innovative therapeutic strategies to enhance treatment efficacy. In this study, we investigated the role of AKR1C4 in CRC and its impact on chemotherapy response.MethodsAKR1C4 stable knockout CRC cell lines were generated using CRISPR/Cas9 technology. The impact of AKR1C4 depletion on chemotherapy sensitivity was assessed using Sulforhodamine B assay. Long-term, low-dose drug induction with increasing concentrations of 5FU, irinotecan, and oxaliplatin were employed to establish acquired chemoresistant CRC cell lines. Ferroptosis induction and inhibition were examined through total iron content and lipid peroxidation measurements.ResultsWe found that AKR1C4 knockout enhances CRC cell sensitivity to chemotherapy, specifically by inducing ferroptosis. The enzymatic activity of AKR1C4 is crucial for regulating chemotherapy sensitivity in CRC cells, as evidenced by the inability of a Y55A mutant to reverse the sensitizing effect. Additionally, AKR1C4 inhibitors enhance chemotherapy sensitivity by inducing ferroptosis. Notably, AKR1C4 depletion resensitizes the acquired chemoresistant CRC cells to chemotherapy, suggesting its potential as a therapeutic target for overcoming acquired chemoresistance. Clinical analysis reveals that high AKR1C4 expression is associated with poor prognosis in CRC patients undergoing chemotherapy, highlighting its significance as a prognostic marker and a potential target for therapeutic intervention.ConclusionThis study illuminates the multifaceted role of AKR1C4 in CRC, demonstrating its significance in regulating chemotherapy sensitivity, overcoming acquired resistance, and impacting clinical outcomes. The insights provided may pave the way for novel therapeutic strategies in CRC management.

Amplification of chromosome 7p11 (7p11) is the most common alteration in primary glioblastoma (GBM), resulting in gains of epidermal growth factor receptor (EGFR) copy number in 50 to 60% of GBM tumors. However, treatment strategies targeting EGFR have thus far failed in clinical trials, and the underlying mechanism remains largely unclear. We here demonstrate that EGFR amplification at the 7p11 locus frequently encompasses its neighboring genes and identifies SEC61G as a critical regulator facilitating GBM immune evasion and tumor growth. We found that SEC61G is always coamplified with EGFR and is highly expressed in GBM. As an essential subunit of the SEC61 translocon complex, SEC61G promotes translocation of newly translated immune checkpoint ligands (ICLs, including PD-L1, PVR, and PD-L2) into the endoplasmic reticulum and promotes their glycosylation, stabilization, and membrane presentation. Depletion of SEC61G promotes the infiltration and cytolytic activity of CD8+ T cells and thus inhibits GBM occurrence. Further, SEC61G inhibition augments the therapeutic efficiency of EGFR tyrosine kinase inhibitors in mice. Our study demonstrates a critical role of SEC61G in GBM immune evasion, which provides a compelling rationale for combination therapy of EGFR-amplified GBMs.

Abstract Overproduction of reactive oxygen species (ROS) and aberrant lipid metabolism are established hallmarks of cancers; however, the role of ROS in lipid synthesis during tumorigenesis is almost unknown. Herein, we show that ROS critically regulates lipid synthesis and thus controls colorectal tumorigenesis through a p53-dependent mechanism. In p53 wild-type colorectal cancers (CRCs), ROS-induced p53 expression represses the transcription of deubiquitinase USP22, which otherwise deubiquitinates and stabilizes Fatty Acid Synthase (FASN), and thus inhibits fatty acid synthesis and tumor growth. Whereas, in p53-deficient CRC cells, ROS-mediated inhibition of USP22 is relieved, leading to FASN stabilization, which thus promotes lipid synthesis and colorectal tumorigenesis. In human CRC specimens, the expression levels of USP22 and FASN are positively correlated and high USP22/FASN level predicts poor prognosis. Our study demonstrates that ROS critically controls lipid synthesis and tumorigenesis through the USP22-FASN axis in a p53-dependent manner, and that targeting the USP22-FASN axis may represent a potential strategy for the treatment of colorectal cancer.

Overproduction of reactive oxygen species (ROS) and aberrant lipid metabolism are established hallmarks of cancer; however, the role of ROS in lipid synthesis during tumorigenesis is almost unknown. Herein, we show that ROS regulates lipid synthesis and thus controls colorectal tumorigenesis through a p53-dependent mechanism. In p53 wild-type colorectal cancer (CRC) cells, hydrogen peroxide (H2O2)-induced p53 expression represses the transcription of deubiquitinase USP22, which otherwise deubiquitinates and stabilizes Fatty Acid Synthase (FASN), and thus inhibits fatty acid synthesis. Whereas, in p53-deficient CRC cells, ROS-mediated inhibition of USP22 is relieved, leading to FASN stabilization, which thus promotes lipid synthesis and tumor growth. In human CRC specimens, USP22 expression is positively correlated with FASN expression. Our study demonstrates that ROS critically regulates lipid synthesis and tumorigenesis through the USP22-FASN axis in a p53-dependent manner, and targeting the USP22-FASN axis may represent a potential strategy for the treatment of colorectal cancer.

PurposeThis study aimed to identify independent prognosis-associated factors of bone-metastatic prostate cancer. The nomograms were further developed to obtain indicators for the prognostic evaluation.MethodsA total of 7315 bone-metastatic prostate cancer (PCa) patients from 2010 to 2016 were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly divided into the training cohort (n=5,120) and test cohort (n=2,195) in a ratio of 7:3. Univariate and multivariate Cox regression models were applied to evaluate potential risk factors. A 1:1 propensity score matching (PSM) was further performed to decrease the confounding effect and re-evaluate the influence of radical prostatectomy and chemotherapy on prognosis. Combining these potential prognosis factors, the nomograms of cancer-specific survival (CSS) and overall survival (OS) at different times were established. C-indexes, calibration curves, and decision curves were developed to evaluate the discrimination, calibration, and clinical benefit of the nomograms.ResultsEleven independent prognosis factors for CSS and twelve for OS were utilized to conduct the nomograms respectively. The C-indexes of nomograms for CSS and OS were 0.712 and 0.702, respectively. A favorable consistency between the predicted and actual survival probabilities was demonstrated by adopting calibration curves. Decision curves also exhibited a positive clinical benefit of the nomograms.ConclusionsNomograms were formulated successfully to predict 3-year and 5-year CSS and OS for bone-metastatic PCa patients. Radical prostatectomy and chemotherapy were strongly associated with the bone-metastatic PCa prognosis.

BackgroundPyroptosis is a critical type of programmed cell death that is strongly associated with the regulation of tumor and immune cell functions. However, the role of pyroptosis in tumor progression and remodeling of the tumor microenvironment in gliomas has not been extensively studied. Thus, in this study, we aimed to establish a comprehensive pyroptosis-related signature and uncover its potential clinical application in gliomas. MethodsThe TCGA glioma cohort was obtained and divided into training and internal validation cohorts, while the CGGA glioma cohort was used as an external validation cohort. Unsupervised consensus clustering was performed to identify pyroptosis-related expression patterns. A Cox regression analysis was performed to establish a pyroptosis-related risk signature. Real-time quantitative PCR was performed to analyze the expression of signature genes in glioma tissues. Immune infiltration was analyzed and validated by immunohistochemical staining. The expression patterns of signature genes in different cell types were analyzed using single-cell RNA sequencing data. Finally, therapeutic responses to chemotherapy, immunotherapy, and potential small-molecule inhibitors were investigated. ResultsPatients with glioma were stratified into clusters 1 and 2 based on the expression patterns of pyroptosis-related genes. Cluster 2 showed a longer overall (P<0.001) and progression-free survival time (P<0.001) than Cluster 1. CD8+ T cell enrichment was observed in Cluster 1. A pyroptosis-related risk signature (PRRS) was then established. The high PRRS group showed a significantly poorer prognosis than the low PRRS group in the training cohort (P<0.001), with validation in the internal and external validation cohorts. Immunohistochemical staining demonstrated that CD8+ T cells were enriched in high PRRS glioma tissues. PRRS genes also showed cell-specific expression in tumor and immune cells. Moreover, the high PRRS risk group showed higher temozolomide sensitivity and increased response to anti-PD1 treatment in a glioblastoma immunotherapy cohort. Finally, Bcl-2 inhibitors were screened as candidates for adjunct immunotherapy of gliomas. ConclusionThe pyroptosis-related signature established in this study can be used to reliably predict clinical outcomes and immunotherapy responses in glioma patients. The correlation between the pyroptosis signature and the tumor immune microenvironment may be used to further guide the sensitization of glioma patients to immunotherapy.

Objective To prepare and identify rabbit anti-breakpoint cluster region-Abelson leukemia virus oncogene (BCR-ABL) b3a2 subtype polyclonal antibody. Methods A peptide containing the fusion sequence of the b3a2 subtype BCR-ABL fusion protein was designed and synthesized with the purity higher than 90%. The fusion polypeptide was coupled to Keyhole Limpet hemocyanin (KLH) and used to immune New Zealand rabbits. Antiserum was purified after multiple immunizations, in addition to using the b3a2 subtype fusion polypeptide for affinity purification. Peptides harboring only BCR or c-ABL amino acid sequences were also synthesized and used to purify the antibody in the secondary purification. The antibody that only bound to part of the epitope was absorbed and removed. ELISA and Western blotting were performed to determine the antibody titer and specificity. Results The rabbit serum background was low before immunization. The titer of the polyclonal antibody reached 1:32 000 after immunization, which met the experimental requirements. Western blotting showed that the antibody could specifically recognize the b3a2 subtype fusion protein of BCR-ABL. Conclusion The experiment has prepared the specific rabbit polyclonal antibody against BCR-ABL b3a2 subtype.

Background: Chemotherapy remains a major clinical option for the successful treatment of cancer by eliminating fast-growing populations of cancer cells. However, drug resistance causes the failure of antitumor treatment. Increasing evidence suggests that a small subpopulation of cancer cells will enter a "persister state" under drug pressure. The persister cell pool constitutes a reservoir from which drug resistance may emerge. Therefore, targeting persister cells presents a therapeutic opportunity to prevent drug resistance and impede tumor relapse. Materials and methods: RT-qPCR, Western blot, Seahorse, apoptosis assay, clonogenic assay, and xenografted mouse model were used for this study. Results: We showed that a similar therapy-resistant cell state underlies the behavior of persister cells derived from sorafenib treatments with reversible, nonmutational mechanisms. Then, we demonstrated that persister cells showed upregulated glycolysis, as evidenced by higher ECAR, as well as increased glucose consumption and lactate production. A database analysis showed that sorafenib-tolerant persister cells exhibited the increased expression of the glycolytic enzyme hexokinase 2, which is closely related to the poor prognosis in liver cancer. We found that the combined treatment with the glycolytic inhibitor 2-DG and sorafenib increased persister cell apoptosis and inhibited colony formation. Consequently, we demonstrated that when persister cells were exposed to a low concentration of sorafenib, they suffered mitochondrial dysfunction but showed compensatory increases in glycolysis, which contributes to cell growth and proliferation. Finally, we showed that the combination of 2-DG and sorafenib reduced persister tumor growth in mice. Conclusions: These findings suggest that such a combination can effectively hamper persister cell growth and may represent a promising therapeutic strategy to prevent persister cell resistance.

Objectives Our present study has shown a potential role for VEGF-A-mediated autocrine signalling to promote survival and proliferation of SU-DHL-6 cells, but the cells could not undergo apoptosis but rather decrease proliferation after bevacizumab treatment. Therefore, we would like to further study the antitumour efficacy of venetoclax (BCL2 inhibitor) in combination with bevacizumab in B-cell NHL. Methods The human cytokine antibody array, RT-qPCR, Western blot, ELISA, apoptosis assay and xenografted mouse model et al were used. Results We described a unique phenomenon that SU-DHL-6 cells showed cell density-dependent survival and growth. Then, we suggested the expression of VEGF-A was positively correlated with the cell density using a human cytokine antibody array and indicated an important role of VEGF-A in the survival and proliferation of SU-DHL-6 cells. Additionally, xenografted SU-DHL-6 cells formed tumours in mice that grew in response to VEGF stimulation. GEO data set also suggested that high VEGF-A expression reflected poor prognosis. The combination therapy with bevacizumab and navitoclax could significantly induce of cell death in vitro and reduce the tumour size and weight with well tolerated in vivo. Conclusions Our findings propose a novel combined strategy in which bevacizumab synergises with the BCL2 inhibitor venetoclax that is effective against B-cell NHL.

Cancer cells exhibit profound alterations in their metabolism.The process of increased aerobic glycolysis supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism.In recent years, extensive efforts have been devoted to revealing the mechanisms underlying for metabolic alterations in cancer, thus products of intermediary metabolism has been a topic of considerable research interest over the past decades.Metabolomics is defined as the quantitative measurement of the dynamic multiparametric metabolites.Identification and quantification of intermediary metabolism by metabolomics can better understand the metabolic changes in tumors.Hence metabolic profiling may be of broad utility for investigating the metabolic pathways and molecular mechanism of carcinogenesis, and as the powerful tool to screen the potential biomarkers for the early diagnosis of human cancer and drug responsiveness.This review article will summarize the overview of metabolomics and the target identification in metabolic pathway by metabolomics, as well as the application in cancer diagnosis and prognosis.In addition, we also critically evaluating the limitation of this approach, and present the potential applications of metabolite profiling in development of novel therapeutic strategy for cancer and precision medicine.