Targeting RBM39 through indisulam induced mis-splicing of mRNA to exert anti-cancer effects in T-cell acute lymphoblastic leukemia.

BACKGROUND: Despite the use of targeted therapeutic approaches, T-cell acute lymphoblastic leukemia (T-ALL) is still associated with a high incidence of complications and a poor prognosis. Indisulam (also known as E7070), a newly identified molecular glue compound, has demonstrated increased therapeutic efficacy in several types of cancer through the rapid degradation of RBM39. This study aimed to evaluate the therapeutic potential of indisulam in T-ALL, elucidate its underlying mechanisms and explore the role of the RBM39 gene. METHODS: We verified the anticancer effects of indisulam in both in vivo and in vitro models. Additionally, the construction of RBM39-knockdown cell lines using shRNA confirmed that the malignant phenotype of T-ALL cells was dependent on RBM39. Through RNA sequencing, we identified indisulam-induced splicing anomalies, and proteomic analysis helped pinpoint protein changes caused by the drug. Comprehensive cross-analysis of these findings facilitated the identification of downstream effectors and subsequent validation of their functional roles. RESULTS: Indisulam has significant antineoplastic effects on T-ALL. It attenuates cell proliferation, promotes apoptosis and interferes with cell cycle progression in vitro while facilitating tumor remission in T-ALL in vivo models. This investigation provides evidence that the downregulation of RBM39 results in the restricted proliferation of T-ALL cells both in vitro and in vivo, suggesting that RBM39 is a potential target for T-ALL treatment. Indisulam's efficacy is attributed to its ability to induce RBM39 degradation, causing widespread aberrant splicing and abnormal translation of the critical downstream effector protein, THOC1, ultimately leading to protein depletion. Moreover, the presence of DCAF15 is regarded as critical for the effectiveness of indisulam, and its absence negates the ability of indisulam to induce the desired functional alterations. CONCLUSION: Our study revealed that indisulam, which targets RBM39 to induce tumor cell apoptosis, is an effective drug for treating T-ALL. Targeting RBM39 through indisulam leads to mis-splicing of pre-mRNAs, resulting in the loss of key effectors such as THOC1.

Prognostic Role of Mitochondrial Transcription Termination Factor 3 in Thyroid Carcinoma.

Background: Studies have shown that the Mitochondrial Transcription Termination Factor 3 (MTERF3) negatively regulates mitochondrial gene expression and energy metabolism, and plays a significant role in many cancer types. Nevertheless, the expression and prognostic role of MTERF3 in patients with thyroid carcinoma (THCA) is still unclear. Thus, we investigated the expression, clinicopathological significance, and prognostic value of MTERF3 in THCA. Methods: The protein and mRNA expression levels of MTERF3 were, respectively, analyzed using immunohistochemistry (IHC) from THCA tissues and RNA-Seq data downloaded from The Cancer Genome Atlas. In addition, the relationships among the expression of MTERF3, the stemness feature, the extent of immune infiltration, drug sensitivity, the expression of ferroptosis, and N6-methyladenosine (m6A) methylation regulators, were evaluated as prognostic indicators for patients with THCA using the Kaplan-Meier plotter database. Results: The IHC and RNAseq results showed that the protein and mRNA expression levels of MTERF3 in adjacent nontumor tissues were significantly higher than in THCA tissues. The survival analysis indicated that decreased expression of MTERF3 was associated with a poorer prognosis. Furthermore, the expression of MTERF3 not only negatively correlated with the enhancement of the stemness of THCA and the reduction of drug sensitivity but also was implicated in ferroptosis and m6A methylation. Conclusion: The data from this study support the hypothesis that decreased expression of MTERF3 in THCA is associated with a poor prognosis.

Four new species of Diglyphomorphomyia Girault (Hymenoptera, Eulophidae) from China, with a key to Chinese species.

Four new species of Diglyphomorphomyia Girault, D.depressa sp. nov., D.fossa sp. nov., D.hainana sp. nov., and D.octoseta sp. nov., are described from China. A key to the eight species of the genus Diglyphomorphomyia occurring in China is provided.

Two new species of Deutereulophus Schulz (Hymenoptera, Eulophidae) from China, with a key to Chinese species.

Two new species of Deutereulophus Schulz, D.felix sp. nov. and D.daguisiensis sp. nov., are described from China. A key to species of Deutereulophus known from China is provided.

Two new species of Hemiptarsenus Westwood (Hymenoptera, Eulophidae) from China, with a key to Chinese species.

Two new species of Hemiptarsenus Westwood, H.tianshuiensis sp. nov. and H.longjiangensis sp. nov., are described from China. New distributional data for H.jilinus Tao, 2021 are provided, and a key to Chinese species of the genus is given based on females.

Three new species of Stenomesius Westwood (Hymenoptera, Eulophidae) from China, with a key to Chinese species.

Three new species of Stenomesius Westwood, S.guanshanensis sp. nov., S.hani sp. nov., and S.harbinensis sp. nov., are described from China. A key to all species of the genus Stenomesius in China is provided.

Anionic Chiral Co(III) Complexes Mediated Asymmetric Halocyclization─Synthesis of 5-Halomethyl Pyrazolines and Isoxazolines.

An asymmetric synthesis of 5-halomethyl pyrazolines and isoxazolines which bear a tertiary stereocenter by catalytic halocyclization of ß,γ-unsaturated hydrazones and ketoximes is described. By using Brønsted acids of anionic chiral Co(III) complexes as catalysts, a variety of chiral 5-halomethyl pyrazolines and isoxazolines were obtained in good yields with high enantioselectivities (up to 99% yield, 97:3 er). Preliminary bioassay results indicated that several isoxazoline derivatives exhibited significant antifungal activities.

Porous SiO2 -coated ultrasmall selenium particles nanospheres attenuate cerulein-induce acute pancreatitis in mice by downregulating oxidative stress.

OBJECTIVE: To investigate the potential therapeutic role of porous SiO2 -coated ultrasmall selenium particles nanospheres (Se@SiO2 nanospheres) pretreatment in acute pancreatitis (AP) and to investigate the related mechanism. METHODS: C57BL/6 mice were randomized to the normal control (CON) group, the AP (induced by cerulein injection) (CAE) group, and AP pretreated with Se@SiO2 nanocomposites at 1 and 2 mg/kg (CAE + 1 or 2 mg/kg Se@SiO2 ) groups, respectively. Serum levels of amylase and lipase, inflammatory cytokines (interleukin [IL]-6, IL-1ß and tumor necrosis factor [TNF]-α), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) were measured, and histopathology was performed to examine the tissue samples of the pancreas, lungs, kidneys and liver. Immunofluorescence assay of reactive oxygen species (ROS), myeloperoxidase (MPO) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling were conducted, and levels of MPO, malondialdehyde, superoxide dismutase and glutathione were evaluated. Finally, Western blot analysis was used to evaluate protein expressions of Nrf2, HO-1, NQO1, TLR4, MyD88 and p-p65 in pancreatic tissue. RESULTS: Se@SiO2 nanospheres alleviated pathological damage to the pancreas, and reduced pancreatic enzymes and inflammatory cytokines. Injury to other organs such as the liver, lungs and kidneys was also alleviated, as indicated by decreased ALT, AST, BUN, and Cr levels as well as improved histopathology. Moreover, Se@SiO2 nanospheres reduced oxidative stress, and ultimately inhibited TLR4/ MyD88/p-p65 pathway and increased the protein expressions of NQO1, Nrf2, and HO-1. CONCLUSION: Se@SiO2 nanospheres may alleviate AP by relieving oxidative stress and targeting the TLR4/Myd88/p-p65 and NQO1/Nrf2/HO-1 pathways.

Pretreatment with chitosan oligosaccharides attenuate experimental severe acute pancreatitis via inhibiting oxidative stress and modulating intestinal homeostasis.

Severe acute pancreatitis (SAP) is a severe acute abdominal disease. Recent evidence shows that intestinal homeostasis is essential for the management of acute pancreatitis. Chitosan oligosaccharides (COS) possess antioxidant activity that are effective in treating various inflammatory diseases. In this study we explored the potential therapeutic effects of COS on SAP and underlying mechanisms. Mice were treated with COS (200 mg·kg-1·d-1, po) for 4 weeks, then SAP was induced in the mice by intraperitoneal injection of caerulein. We found that COS administration significantly alleviated the severity of SAP: the serum amylase and lipase levels as well as pancreatic myeloperoxidase activity were significantly reduced. COS administration suppressed the production of proinflammatory cytokines (TNF-α, IL-1ß, CXCL2 and MCP1) in the pancreas and ileums. Moreover, COS administration decreased pancreatic inflammatory infiltration and oxidative stress in SAP mice, accompanied by activated Nrf2/HO-1 and inhibited TLR4/NF-κB and MAPK pathways. We further demonstrated that COS administration restored SAP-associated ileal damage and barrier dysfunction. In addition, gut microbiome analyses revealed that the beneficial effect of COS administration was associated with its ability to improve the pancreatitis-associated gut microbiota dysbiosis; in particular, probiotics Akkermansia were markedly increased, while pathogenic bacteria Escherichia-Shigella and Enterococcus were almost eliminated. The study demonstrates that COS administration remarkably attenuates SAP by reducing oxidative stress and restoring intestinal homeostasis, suggesting that COS might be a promising prebiotic agent for the treatment of SAP.

[Safety and Efficacy of VDMP Re-induction Regimen in Chinese Children with Relapsed Acute Lymphoblastic Leukemia-A Report from Jiangsu Childhood Hematology Group].

OBJECTIVE: To evaluate the therapeutic safety and efficacy of VDMP re-induction regimen in Chinese children with relapsed acute lymphoblastic leukemia (ALL). METHODS: Forty-one patients with relapsed ALL were prospectively enrolled in this study. All the patients were distributed in 3 children's hospitals and treated with VDMP regimen as the first re-induction chemotherapy. Therapeutic efficacy and side-effects were analyzed. RESULTS: The ratio of male to female was 27:14. The median age was 7.9 (2.2-15.4) years old. Patients relapsed at very early, early, and late stage were 7 cases, 11 cases, and 23 cases, respectively.The immunophenotype analysis showed that 38 cases were B-ALL, and 3 cases were T-ALL. All patients suffered from grade 4 of neutropenia and forty(97.6%) cases got infection, of them one case died. Thirty-nine(95.1%) cases had nonhematologic adverse event at least one organ involved grade 3 in 38 out of 41 cases, the VDMP therapy was completed, 34(89.5%) cases achieved a complete remission (CR), 1 case achieved partial remission(PR), and 3 cases didn't get remission. Follow-up data of 38 cases with completing VDMP chemotherapy were obtained, only one case was lost. Among 37 cases available for evaluation, 16 cases received allo-hematopoietic stem cell transplantation(allo-HSCT) after chemotherapy, and 13 patients survived, while 21 cases did not receive allo-HSCT(treated with chemotherapy only), and 8 patients survived.The overall survival rate of allo-HSCT group was significantly higher than that of those treated with chemotherapy only(P<0.05). CONCLUSION: VDMP re-induction regimen is effective and well tolerable for pafients in the treated children with relapsed ALL. After remission, allo-HSCT is recommended with the aim of long survival.

[Clinical significance of glucocorticoid induction test in Chinese childhood acute lymphoblastic leukemia].

OBJECTIVE: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, while glucocorticoid (GC) is a critical component in multi-agent chemotherapy protocols currently used for the treatment of ALL. The purpose of this study was to investigate the relationship between the glucocorticoid induction test and the clinical features and the prognosis of Chinese childhood ALL. METHOD: The study recruited 309 hospitalized patients (187 male and 122 female) with childhood ALL, the sex, age, initial WBC count, immunophenotype, chromosome and gene expression were recorded. After diagnosis, all patients received GC induction test for 7 days. Then they were divided into prednisone good response (PGR) group and prednisone poor response (PPR) group according to the peripheral lymphoblast count on D8. Early responses to chemotherapy and treatment outcomes of the patients in the two groups were also analyzed. RESULT: Of the 309 patients, 263 belonged to PGR group and 46 belonged to PPR group. Initial WBC count was higher in PPR group than in PGR group (86.30×10(9)/L vs. 30.97×10(9)/L, P < 0.01) . B lineage ALL showed more sensitive to GC than T-ALL (86.6% vs. 60%, P < 0.05). Different initial-risk-group's sensitivity to GC differed from one another (high-risk:51.4%, medium-risk: 82.7%, standard risk: 93.7%, P < 0.0125). There was no significant difference between two groups in chromosomal karyotypes (P > 0.05). BCR-ABL positive ALL showed lower sensitivity to GC (P < 0.05) , while MLL, TEL-AML1, E2A-PBX1 positive rates in two groups were of no statistical significance (P > 0.05). Bone marrow was reviewed on D15 and D33, and the CR rates in PGR group were significantly higher than that in PPR group (D15: 60.5% vs. 32.6%, D33: 94.6% vs. 73.3%, P < 0.01) ; Minimal residual disease (MRD) levels were examined on D33, W12, and both were much lower in PGR group (D33: P < 0.01, W12: P < 0.05). Of the PGR group 215 patients (81.7%) remained continuously in complete remission (CCR) while only 28 cases (60.9%) in PPR group did so. The CCR rate was much higher in PGR group than that in PPR group (P < 0.01). CONCLUSION: Closely related to clinical features and the outcomes of treatment, GC induction test is also an important prognostic factor in Chinese childhood ALL.

[Effects of imidazolium chloride ionic liquids on the acute toxicity and weight of earthworm].

Standard contact filter paper test of OECD and artificial soil test were used to study the acute lethal effect of three imidazolium chloride ionic liquids, 1-butyl- 3-methylimidazolium chloride ([Bmim] Cl), 1-hexyl- 3-methylimidazolium chloride ([Hmim] Cl), and 1-octyl- 3-methylimidazolium chloride ([Omim] Cl) on earthworm (Eisenia fetida), and the weight of the earthworms was measured after subtle exposure. The 24 h-LC50 values of [Bmim] Cl, [Hmim] Cl and [Omim] Cl using the contact filter paper method were 109.60, 50.38 and 7.94 microg x cm(-2), respectively. The 48 h-LC50 values were 98.52, 39.14 and 3.61 microg x cm(-2), respectively. Using the artificial soil method, the 7 d-LC50 values of [Bmim] Cl, [Hmim] Cl and [Omim] Cl were 447.78, 245.56 and 180.51 mg x kg(-1), respectively, and the 14 d-LC50 values were 288.42, 179.75, 150.35 mg x kg(-1), respectively. There were differences in poisoning symptoms of the three ionic liquids on earthworms. The growth of Eisenia fetida was inhibited and declined with increasing ionic liquid concentration. The toxicity of ionic liquids on Eisenia fetida increased with the length of carbon chain.

Separation and determination of cefotaxime enantiomers in injections by capillary zone electrophoresis.

Cefotaxime enantiomers have specific effects on Gram-negative bacteria. For quality control of cefotaxime it was necessary to establish a method for enantioseparation by capillary zone electrophoresis (CZE) using cyclodextrin (CD) as a chiral selector. The effects of various parameters on enantioseparation were studied. A fused silica capillary (40 cm effective length x 75 microm ID) was used. The cefotaxime enantiomers were separated on the baseline under conditions of 0.5 mmol/L CM-beta-CD, 75 mmol/L NaH2PO4 buffer at pH 7.0 using UV detection at 280 nm. Applied voltage and capillary temperature were 20 kV and 25 degrees C, respectively. Under these conditions for enantioseparation, linear calibration curves were obtained in the range 2 approximately 160 microg/mL. The limit of detection for both isomers was less than 0.5 microg/mL. The method was used for analysis of pharmaceutical preparations (dosage forms) of cefotaxime from various factories. A simple and specific CZE method was successfully demonstrated for the separation of cefotaxime enantiomers. The enantioseparation method should be established and this method should be used to control the quality of cefotaxime.

Separation of cefoperazone enantiomers using beta-cyclodextrin as chiral additive by capillary zone electrophoresis.

A capillary electrophoresis method was developed to separate the enantiomers of cefoperazone. Different cyclodextrins, including alpha-cyclodextrin (alpha-CD), beta-cyclodextrin (beta-CD), gamma-cyclodextrin (gamma-CD), 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and methyl-beta-cyclodextrin (Me-beta-CD), were tested as chiral additives in the running buffer. The effect of various parameters on enantioseparation such as concentration of NaH(2)PO(4), buffer pH, and CD concentration was also studied. The cefoperazone enantiomers were baseline separated under conditions of 0.04 mmol/L beta-CD, 75 mmol/L NaH(2)PO(4) buffer at pH 4.0. A fused silica capillary (40 cm effective length x 75 microm ID) was used. The applied voltage and capillary temperature were 20 kV and 25 degrees C, respectively. Under these conditions, linear calibration curves were obtained in the 5-500 microg/ml range using UV detection at 280 nm. The limit of detection for both isomers was 0.1 microg/ml. The method was used for the analysis of different pharmaceutical preparations (dose) and biological samples containing cefoperazone.

Liquid chromatography determination of 10-hydroxycamptothecin in human serum by a column-switching system containing a pre-column with restricted access media and its application to a clinical pharmacokinetic study.

A simple, rapid, sensitive column-switching HPLC method is described for the analysis of the 10-hydroxycamptothecin (HCPT) in human serum. A pre-column containing restricted access media (RAM) is used for the sample clean-up and trace enrichment and is combined with a C18 column for the final separation. The analytical time is 8 min. The HCPT is monitored with fluorescence detector, excitation and emission wavelengths being 385 and 539 nm, respectively. There is a linear response range of 1-1000 ng/ml with correlation coefficient of 0.998 while the limit of quantification is 0.1 ng/ml. The intra-day and inter-day variations are less than 5%. This analytic procedure has been applied to a pharmacokinetic study of HCPT in clinical patients and the pharmacokinetic parameters of one-compartment model are calculated.