Characterization of 2-Oxindole Forming Heme Enzyme MarE, Expanding the Functional Diversity of the Tryptophan Dioxygenase Superfamily.

3-Substituted 2-oxindoles are important structural motifs found in many biologically active natural products and pharmaceutical lead compounds. Here, we report an enzymatic formation of the 3-substituted 2-oxindoles catalyzed by MarE in the maremycin biosynthetic pathway in Streptomyces sp. B9173. MarE is a homologue of FeII/heme-dependent tryptophan 2,3-dioxygenases (TDOs). Typical TDOs usually catalyze the insertion of two oxygen atoms from O2 into an indole ring to generate N-formylkynurenine (NFK)-like products. In contrast, MarE catalyzes the insertion of a single oxygen atom from O2 into an indole ring, to probably generate an epoxyindole intermediate that undergoes an unprecedented 2,3-hydride migration to form 2-oxindole structure. MarE shows substrate robustness to catalyze the conversion of a series of 3-substituted indoles into their corresponding 3-substituted 2-oxindoles. Although containing most key amino acid residues conserved in well-known TDO homologues, MarE falls into a separate new subgroup in the phylogenetic tree. The characterization of MarE and its homologue enriches the functional diversities of TDO superfamily and provides a new strategy for discovering novel natural products containing 3-substituted 2-oxindole pharmacophores by genome mining.

A Comprehensive Pan-Cancer Analysis of the Regulation and Prognostic Effect of Coat Complex Subunit Zeta 1.

The Coatomer protein complex Zeta 1 (COPZ1) has been reported to play an essential role in maintaining the survival of some types of tumors. In this study, we sought to explore the molecular characteristics of COPZ1 and its clinical prognostic value through a pan-cancers bioinformatic analysis. We found that COPZ1 was extremely prevalent in a variety of cancer types, and high expression of COPZ1 was linked to poor overall survival in many cancers, while low expression in LAML and PADC was correlated with tumorigenesis. Besides, the CRISPR Achilles' knockout analysis revealed that COPZ1 was vital for many tumor cells' survival. We further demonstrated that the high expression level of COPZ1 in tumors was regulated in multi-aspects, including abnormal CNV, DNA-methylation, transcription factor and microRNAs. As for the functional exploration of COPZ1, we found a positive relationship between COPZ1's expression and stemness and hypoxia signature, especially the contribution of COPZ1 on EMT ability in SARC. GSEA analysis revealed that COPZ1 was associated with many immune response pathways. Further investigation demonstrated that COPZ expression was negatively correlated with immune score and stromal score, and low expression of COPZ1 has been associated to more antitumor immune cell infiltration and pro-inflammatory cytokines. The further analysis of COPZ1 expression and anti-inflammatory M2 cells showed a consistent result. Finally, we verified the expression of COPZ1 in HCC cells, and proved its ability of sustaining tumor growth and invasion with biological experiments. Our study provides a multi-dimensional pan-cancer analysis of COPZ and demonstrates that COPZ1 can serve as both a prospective target for the treatment of cancer and a prognostic marker for a variety of cancer types.

Oral vinorelbine and continuous low doses of cyclophosphamide in pediatric rhabdomyosarcoma: a real-world study.

Introduction: Metronomic maintenance therapy (MMT) has significantly improved the survival of patients with high-risk rhabdomyosarcoma in clinical trials. However, there remains a lack of relevant data on its effectiveness in real-world situations. Methods: We retrospectively retrieved data of 459 patients < 18 years of age diagnosed with rhabdomyosarcoma at Sun Yat-sen University Cancer Center from January 2011 to July 2020 from our database. The MMT regimen was oral vinorelbine 25-40 mg/m2 for twelve 4-week cycles on days 1, 8, and 15, and oral cyclophosphamide 25-50 mg/m2 daily for 48 consecutive weeks. Results: A total of 57 patients who underwent MMT were included in the analysis. The median follow-up time was 27.8 (range: 2.9-117.5) months. From MMT to the end of follow-up, the 3-year PFS and OS rates were 40.6% ± 6.8% and 58.3% ± 7.2%, respectively. The 3-year PFS was 43.6% ± 11.3% in patients who were initially diagnosed as low- and intermediate-risk but relapsed after comprehensive treatment (20/57), compared with 27.8% ± 10.4% in high-risk patients (20/57) and 52.8% ± 13.3% in intermediate-risk patients who did not relapse (17/57). The corresponding 3-year OS for these three groups was 65.8% ± 11.4%, 50.1% ± 12.9%, and 55.6% ± 13.6%, respectively. Conclusion: We present a novel study of MMT with oral vinorelbine and continuous low doses of cyclophosphamide in real-world pediatric patients with RMS. Our findings showed that the MMT strategy significantly improved patient outcomes and may be an effective treatment for high-risk and relapsed patients.

Risk factors for totally implantable access ports-associated thrombosis in pediatric oncology patients.

The application of totally implantable access ports (TIAPs) reduces treatment-related discomfort; however, the existence of catheter may cause side effects, with the most common one being the occurrence of TIAPs-associated thrombosis. The risk factors for TIAPs-associated thrombosis in pediatric oncology patients have not been fully described. A total of 587 pediatric oncology patients undergoing TIAPs implantation at a single center over a 5-year period were retrospectively analyzed in the present study. We investigated the risk factors for thrombosis, emphasizing the internal jugular vein distance, by measuring the vertical distance from the highest point of the catheter to the upper border of the left and right extremitas sternalis claviculae on chest X-ray images. Among 587 patients, 143 (24.4%) had thrombosis. Platelet count, C-reactive protein, and the vertical distance from the highest point of the catheter to the upper border of the left and right extremitas sternalis claviculae were demonstrated to be the main risk factors for the development of TIAPs-associated thrombosis. TIAPs-associated thrombosis, especially asymptomatic events, is common in pediatric cancer patients. The vertical distance from the highest point of the catheter to the upper border of the left and right extremitas sternalis claviculae was a risk factor for TIAPs-associated thrombosis, which deserved additional attention.

Efficacy and safety of programmed cell death receptor 1 inhibition-based regimens in patients with pediatric malignancies: the real-world study in China.

Background: Programmed death receptor 1 (PD-1) inhibition has shown durable response and mild adverse events (AEs) in adult malignancies. However, data on the clinical activity of PD-1 inhibition in pediatric patients are lacking. We comprehensively assessed the efficacy and safety of PD-1 inhibitor-based regimens for pediatric malignancies. Methods: We conducted a real-world, multi-institutional, retrospective analysis of pediatric malignancies treated with PD-1 inhibitor-based regimens. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints included disease control rate (DCR), duration of response (DOR), and AEs. The Kaplan-Meier method was used to calculate PFS and DOR. The National Cancer Institute Common Toxicity Criteria for AEs (version 5.0) were used to grade toxicity. Results: A total of 93 and 109 patients were evaluated for efficacy and safety, respectively. For all efficacy-evaluable patients, PD-1 inhibitor monotherapy, combined chemotherapy, combined histone deacetylase inhibitor, and combined vascular endothelial growth factor receptor tyrosine kinase inhibitor cohorts, the ORR and DCR were 53.76%/81.72%, 56.67%/83.33%, 54.00%/80.00%, 100.00%/100.00%, and 12.50%/75.00%, respectively; the median PFS and DOR were 17.6/31.2 months, not achieved/not achieved, 14.9/31.2 months, 17.6/14.9 months, and 3.7/1.8 months, respectively; the incidence rate of AEs were 83.49%, 55.26%, 100.00%, 80.00%, and 100.00%, respectively. One patient in the PD-1 inhibitor-combined chemotherapy cohort discontinued treatment due to diabetic ketoacidosis. Conclusions: This largest retrospective analysis demonstrate that PD-1 inhibitor-based regimens are potentially effective and tolerable in pediatric malignancies. Our findings provide references for future clinical trials and practice of PD-1 inhibitors in pediatric cancer patients.

IDO1 plays a tumor-promoting role via MDM2-mediated suppression of the p53 pathway in diffuse large B-cell lymphoma.

With the intensive therapeutic strategies, diffuse large B-cell lymphoma (DLBCL) is still a fatal disease due to its progressive characteristics. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator that catalyzes the commitment step of the kynurenine pathway in the immune system, its aberrant activation may contribute to malignant cell escape eradication. However, the role of IDO1 in DLBCL progression remains elusive. Our study showed IDO1 expression was upregulated in DLBCL and was associated with a poor prognosis and low overall survival. Inhibition of IDO1 suppressed DLBCL cell proliferation in vitro and impeded xenograft tumorigenesis in vivo. RNA-seq analyses revealed MDM2 was downregulated while TP53 was upregulated in IDO1 inhibition OCI-Ly10 cells. Mechanistically, IDO1 inhibition decreased the expression of MDM2, a major negative regulator of p53, and restored p53 expression in OCI-Ly3 and OCI-Ly10 cells, resulting in cell cycle arrest and apoptosis. IDO1 inhibition induced cell apoptosis coupled with PUMA and BAX upregulation, as well as BCL2 and BCL-XL downregulation. In addition, p21, a p53 transcriptional target, was upregulated in cell cycle arrest. Taken together, this study revealed IDO1 is essential for the proliferation of DLBCL cells and may be a potential therapeutic target for the treatment of DLBCL.

Venous thromboembolic events in T-cell lymphoma patients: Incidence, risk factors and clinical features.

INTRODUCTION: Patients with hematologic malignancies are prone to developing thromboembolism. The incidence, risk factors and clinical features for developing venous thromboembolism (VTE) are not well-elucidated in patients with T-cell lymphoma. MATERIALS AND METHODS: The present study retrospectively analyzed 668 patients with VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), who were admitted to Tianjin Medical University Cancer Institute and Hospital and Sun Yat-sen University Cancer Center from January 2006 to December 2018. All patients were diagnosed with T-cell lymphoma, and all episodes of symptomatic VTE were confirmed by imaging and ultrasound. The follow-up results were obtained through telephone communication and outpatient visits. RESULTS: A total of 668 patients were analyzed. Thirty-three (4.94%) patients had at least one episode of VTE, and all of which were deep vein thrombosis alone. All VTEs occurred in patients who received chemotherapy, while no VTE occurred in patients who did not receive chemotherapy. By univariate analysis, central venous catheter (CVC) (odds ratio [OR] 6.63, confidence interval [CI] 2.24-19.57, P = 0.001), Eastern Cooperative Oncology Group (ECOG) performance status 2, 3, or 4 (OR: 62.15, CI: 15.42-250.48, P = 0.000), and stage III or IV (OR: 4.06, CI: 1.00-16.40, P = 0.049) were identified as risk factors for developing VTE. By multivariate analysis, CVC (OR: 3.23, CI: 1.49-7.23, P = 0.003) and stage III or IV (OR: 2.30, CI: 1.06-4.97, P = 0.035) were still significant risk factors for developing VTE. CONCLUSION: The incidence of VTE in the present study population was comparable to that of lymphoma patients, other than T-cell lymphoma, and VTE was associated with CVC and advanced stage.