The effects of dabrafenib and/or trametinib treatment in Braf V600-mutant glioma: a systematic review and meta-analysis.

This study aimed to evaluate the effects of dabrafenib and/or trametinib therapy in BRAF v600-mutant glioma treatment. PubMed, the Cochrane Library, EMBASE and Web of Science were searched from inception to Sep 2023. Inclusion criteria were designed based on the PICO principle to select relevant articles. Search keywords included 'dabrafenib', 'trametinib', 'glioma' and other related keywords. Outcomes included overall survival (OS), progression-free survival (PFS), adverse events (AEs), and death events. Methodological index for non-randomized studies (MINORS) was used to assess the methodological quality. Stata 14.0 was selected to perform the Cochrane Q and I2 statistics to test the heterogeneity among all studies. As for publication bias assessment and sensitivity analysis, the funnel plot, Egger regression test, Begg test, and trim and fill method were selected. Including 8 studies for meta-analysis. The pooled results of the single-arm trials showed that the median PFS and median OS after treatment were 6.10 months and 22.73 months, respectively. Notably, this study found a high incidence of AEs and death events of 50% and 43% after treatment. All the above findings were statistically significant. Also, this study statistically supported the advantage of disease response improvement after the combination therapy in BRAF v600-mutant glioma patients, which were shown as a pooled rate of PR (30%), a pooled rate of CR (18%), and a pooled rate of ORR (39%). And the AE rate was lower in the monotherapy group (AE: 25%) than in the combination treatment group (AE: 60%). Sensitivity analysis indicated that all the results were robust. Based on current literature outcomes, dabrafenib and/or trametinib may lead to the median PFS of 6.10 months and median OS as 22.73 months for BRAF v600-mutant glioma patients, and the safety of monotherapy is better than that of combination therapy. This conclusion needs to be treated with caution and further verified.

A novel flow diverter device (Tubridge) for the treatment of intracranial aneurysms: a systematic review and meta-analysis.

The flow diverter (FD) device has become a feasible and effective option for treating intracranial aneurysms. This study aimed to evaluate the efficacy and safety of Tubridge FD (TFD) in treating intracranial aneurysms and provide evidence for further research and clinical application. Electronic databases, including PubMed, Web of Science, Embase, and the Cochrane Library from inception to July 31, 2022, were searched. The eligible studies should include TFD investigations in treating intracranial aneurysms. Pooled technical success rate, complete occlusion rate, improvement rate, stable rate, symptom elimination rate, and adverse events rate were calculated with either the fixed-effects model or the random-effects model, depending on the results of tests for heterogeneity. Egger's tests were performed to assess the potential publication bias. A total of 7 studies (145 patients) were included in this study. The pooled technical success rate was 0.98, the complete occlusion rate was 0.79, the improvement rate was 0.21, and the stable rate was 0.05. One included study reported that the surgery-related mortality rate in the Tubridge group was higher than that in the control group (3.66% vs. 1.61%), while the surgery-related morbidity rate in the Tubridge group was 2.4% and that in the control group was 0. Findings of this meta-analysis indicate that TFD manifests promising and effective performance with acceptable adverse events in the treatment of intracranial aneurysms.

USP31 acetylation at Lys1264 is essential for its activity and cervical cancer cell growth.

Ubiquitin-specific protease 31 (USP31) is a member of deubiquitinase family that is involved in nuclear factor-κB activation and sarcomagenesis. However, little is known about posttranslational modification in the regulation of its activity and cervical cancer cell growth. In our study, we found that the Lys1264 residue of USP31 can be modified with an acetyl group by high-resolution mass spectrometry in HeLa cell line, and site-specific mutagenesis can significantly increase USP31 ubiquitin hydrolase activity and decrease the expression of p65. When being transfected with a plasmid expressing mutated USP31, the number of cancer cells was significantly decreased. We also observed that mutated USP31 could promote apoptosis but not cell cycle by flow cytometer analysis. Overexpression of mutated USP31 could reverse the effect in USP31 knockdown cell line. To further investigate its activity in tumorigenesis, deacetylase sirtuin 1 (Sirt1) was shown to interact with USP31 by co-immunoprecipitation and blocking the function of Sirt1 by knockdown or the inhibitor nicotinamide could increase the acetylation of USP31. When Lys1264 of USP31 mutated, Sirt1 could not remove its acetylation and alter the expression level of p65. Finally, inhibition or knockdown of Sirt1 suppressed USP31 activity in HeLa cell line, leading to cisplatin-induced apoptosis resistance. Therefore, acetylation at Lys1264 suppresses USP31 activity and plays a protective role in cancer cell growth. Our study contributes to understanding the mechanism of USP31 activity regulation and its role in tumorigenesis.

Detour of prenostodione synthesis towards pyrazolones for antibacterial activity.

Our attempts to prepare indolyl acid (3), enroute to prenostodione (2), from phenyl-hydrazine following a reported procedure of Fischer-Indole synthesis rather lead to ethyl 2-(5-oxo-1-phenyl-2,5-dihydro-1H-pyrazol-3-yl)acetate as a major product, which underwent facile condensation with aldehydes to provide the pyrazolones. Intrigued by the opportunity for the diversity oriented synthesis of substituted pyrazolones, we have developed a facile one pot approach for pyrazolones and screened for antibacterial activity and, herein, results are reported.

The significance of IDH1 mutations in tumor-associated seizure in 60 Chinese patients with low-grade gliomas.

BACKGROUND: Seizure is a common clinical presentation in patients suffering from primary brain tumors, especially from low-grade gliomas (LGGs). However, the genetic factors of tumor-associated seizure, at present, are still very poorly understood. The aim of this study was to investigate the potential correlation between tumor-associated epilepsy and IDH1 mutations in a Chinese population with LGGs. MATERIALS AND METHODS: This study reviewed 60 patients with histologically confirmed low-grade gliomas, and the status of IDH1 was detected after the operation at our institution. Univariate and multivariate logistic regression analysis were used to explore the potential risk factors for tumor-related seizures. Results. IDH1 mutation was detected in 46 (76.7%) patients, among which 14 patients had no epilepsies and 32 patients had epilepsies (P = 0.023, chi-square test). Multivariate logistic regression analysis demonstrated that the mutation of IDH1 seems to be the strongest predictor for preoperative seizure (OR, 6.130; 95% CI, 1.523-24.669; P = 0.011). CONCLUSIONS: IDH1 mutation was frequently detected in LGGs, and it may result in tumor-related seizures.

Effects of postoperative radiotherapy and docetaxel and PD-1 inhibitors on the survival and safety of glioblastoma patients: a systematic review and meta-analysis.

Background: The present standard treatment rarely allows the complete removal of glioblastoma (GBM). So postoperative treatments are provided to prevent or delay tumor recurrence. The overall survival (OS) rate and safety of postoperative chemotherapy alone, or combined with radiotherapy (RT), or programmed cell death-1 (PD-1) inhibitor in GBM is still unclear. The present goal was to explore postoperative treatment's effect on the survival and safety of patients with GBM. Methods: We searched the mainstream online databases for clinical studies of RT and chemotherapy and PD-1 inhibitors in the treatment of GBM published up to May 2020. The patients in the experimental group accepted an anti-PD-1 drug alone and RT + chemotherapy, whereas the controlled patients were treated with docetaxel alone. The literature qualities were assessed using Cochrane Risk of Bias 2.0, and studies were assigned. The meta-analysis was conducted by RevMan 5.4 software. Results: A total of 927 articles were identified through the online database search. The articles unable to meet the inclusion criteria were excluded leaving 6 studies for inclusion in the study. Compared with docetaxel-based chemotherapy for GBM, combined RT chemotherapy and PD-1 inhibitor therapy had better OS [mean difference (MD), -1.75; 95% confidence interval (CI): -2.99 to -0.51; P=0.006] and progression-free survival (PFS) and a lower incidence of adverse reactions (MD, -7.03; 95% CI: -7.64 to -6.42; P<0.00001) above grade III. Conclusions: Postoperative combination of RT and chemotherapy and PD-1 inhibitors had some advantages over docetaxel in terms of effectiveness. More clinical trials are needed to confirm effectiveness.

A Rare Case of Acute Infectious Purpura Fulminans Caused by Klebsiella Pneumoniae and Human Herpesvirus Type 5.

Background: Purpura fulminans (PF), a rare, life-threatening disorder, is a hematological emergency in which there is skin necrosis, disseminated intravascular coagulation (DIC), and protein C deficiency. In PF, the skin necrosis and DIC are secondary to protein C deficiency. This may progress rapidly to multiorgan failure caused by the thrombotic occlusion of small- and medium-sized blood vessels. Case Report: This article presents the case of a 22-year-old male with fever as well as necrotic and purpuric skin lesions. The ultrasound and computed tomography scans revealed infections in the skin wounds as well as venous microthrombosis and thrombosis in multiple intracranial and pulmonary vessels. The laboratory tests showed signs of sepsis, thrombocytopenia, an abnormal decrease in protein C and antithrombin III, DIC, multiple organ and system failures, gastric varices, and gastrointestinal hemorrhage. The blood, sputum, and secretions under the skin lesions were cultured and were positive for Klebsiella pneumoniae. The results of the high-throughput genetic testing of the pathogenic microorganism DNA were consistent. In addition, human herpesvirus type 5 was detected. The histopathological examination of the skin lesions revealed pathological features consistent with PF. After successful treatment by the departments of Dermatology, Emergency Critical Care Medicine, and the Intensive Care Unit, the patient was discharged after 67 days of hospitalization. Conclusion: Adults with acquired protein C and/or S deficiency states, including certain bacterial and viral infections, who drink alcohol and take varieties of non-steroidal anti-inflammatory analgesics at the same time, may develop acute infectious PF. Clinicians should be aware of this for early diagnosis and treatment.

Flower-like hierarchical ZnS-Ga2S3 heterojunction for the adsorption-photo-reduction of Cr(VI).

Adsorption-photo-reduction is considered as a potential route to remove Cr(VI) from wastewater. To explore the novel photocatalysts with efficient adsorption-photocatalytic activity, flower-like hierarchical ZnS-Ga2S3 heterojunction was prepared for the solar-light-driven reduction of Cr(VI). Its adsorption-photocatalytic capacity is greatly affected by the ZnS/Ga2S3 molar ratio, Cr(VI) content, pH values, and inorganic ions. Among these obtained composites, ZnS-Ga2S3-3 with a ZnS/Ga2S3 molar ratio of 3:1 exhibits the best adsorption-photocatalytic capacity. The adsorption capacity of ZnS-Ga2S3-3 is 54.42 mg g-1, and its total removal efficiency is 99.10% for 100 mg L-1 Cr(VI) solution after 160 min. In addition, the adsorption-photo-reduction performance of ZnS-Ga2S3-3 is slightly deactivated after nine cycle times. The Langmuir, pseudo-second-order, and first-order models well describe the adsorption isotherm, adsorption kinetic, and photo-reduction kinetic of ZnS-Ga2S3-3, respectively. The synergy effect of ZnS and Ga2S3 are favorable for the efficient transfer and separation of charge carriers, and provide sufficient vacant sites at the junction interface for the adsorption of Cr(VI).

An Efficient Exogenous Gene Insertion Site in CHO Cells with High Transcription Level to Enhance AID-Induced Mutation.

Antibodies have been extensively used for the purpose of scientific research, clinical diagnosis, and therapy. Combination of in vitro somatic hypermutation and mammalian cell surface display has been an efficient technology for antibody or other proteins optimization, in which the efficiency of activation-induced cytidine deaminase (AID) mutations in genes is one of the most important key factors. Gene transcriptional level has been found to be positively proportional to AID-induced mutation frequency. Thus, construction of the cell clone bearing a gene of interest (GOI) with high transcription level can increase AID-induced mutations. In this study, a retargetable gene cassette is inserted onto predetermined chromosome site (ywhae gene site) which is among the genes with the highest as well as stable transcription, and is found that one subsite is suitable to be retargeted for efficient protein display in Chinese hamster ovary (CHO) cells. The resultant cell clone (T31) has higher and more stable transcription/expression than CHO-puro clone which was previously established through the strategy of random insertion followed by a high-throughput selection. It also possesses a significantly higher mutation frequency to GOI than CHO-puro cells; thus, it is a better clone for the in vitro improvement of antibody affinity, and probably other properties.

High efficiency CHO cell display-based antibody maturation.

Previously, we developed a CHO cell display-based antibody maturation procedure in which an antibody (or other protein) gene of interest was induced to mutate by activation-induced cytidine deaminase (AID) and then form a library by simply proliferating the CHO cells in culture. In this study, we further improved the efficiency of this maturation system by reengineering AID, and optimizing the nucleic acid sequence of the target antibody gene and AID gene as well as the protocol for AID gene transfection. These changes have increased both the mutation rate and the number of mutation type of antibody genes by more than 10 fold, and greatly improved the maturation efficiency of antibody/other proteins.

The Trends in Global Gene Expression in Mouse Embryonic Stem Cells During Spaceflight.

The environment in space differs greatly from the environment on the ground. Spaceflight causes a number of physiological changes in astronauts, such as bone loss and immune system dysregulation. These effects threaten astronauts' space missions, and understanding the underlying cellular and molecular mechanisms is important to manage the risks of space missions. The biological effects of spaceflight on mammalian cells, especially with regards to DNA damage, have attracted much attention. Rad9 -/- mouse embryonic stem cells (mESCs) are known to be extremely sensitive to DNA damage agents. In this study, a project of the SJ-10 satellite programme, we investigated the gene expression profiles of both Rad9 -/- mESCs and Rad9 +/+ (wild-type) mESCs in space with a focus on genes critical for inducing, preventing, or repairing genomic DNA lesions. We found that spaceflight downregulated more genes than it upregulated in both wild-type and Rad9 -/- mESCs, indicating a suppressive effect of spaceflight on global gene expression. In contrast, Rad9 deletion upregulated more genes than it downregulated. Of note, spaceflight mainly affected organ development and influenced a wide range of cellular functions in mESCs, while Rad9 deletion mainly affected the development and function of the hematological system, especially the development, differentiation and function of immune cells. The patterns of gene expression in mouse embryonic stem cells in space is distinct from those in other types of cells. In addition, both spaceflight and Rad9 deletion downregulated DNA repair genes, suggesting a possibility that spaceflight has negative effects on genome for embryonic stem cells and the effects are likely worsen when the genome maintenance mechanism is defective.

Simulated microgravity potentiates generation of reactive oxygen species in cells.

Microgravity (MG) and space radiation are two major environmental factors of space environment. Ionizing radiation generates reactive oxygen species (ROS) which plays a key role in radiation-induced DNA damage. Interestingly, simulated microgravity (SMG) also increases ROS production in various cell types. Thus, it is important to detect whether SMG could potentiate ROS production induced by genotoxins including radiation, especially at a minimal level not sufficient to induce detectable ROS. In this study, we treated mouse embryonic stem (MES) cells with H2O2 and SMG for 24 h. The concentration of H2O2 used was within 30 µmol/L at which intracellular ROS was the same as that in untreated cells. Exposure of cells to SMG for 24 h did not induce significantly higher levels of intracellular ROS than that of control cells either. Simultaneous exposure of cells to both SMG- and H2O2-induced ROS and apoptosis in MES cells. Although incubation in medium containing 5 or 30 µmol/L H2O2 induced a small enhancement of DNA double-strand breaks (DSBs), the addition of SMG treatment dramatically increased DSB levels. Taken together, SMG can significantly potentiate the effects of H2O2 at a low concentration that induce a small or negligible change in cells on ROS, apoptosis, and DNA damage. The results were discussed in relation to the combined effects of space radiation and MG on human body in this study.

Identification of Tmem10 as a novel late-stage oligodendrocytes marker for detecting hypomyelination.

Oligodendrocytes ensheath axons to form compact insulating multilamellar structures known as myelin. Tmem10 is a novel type I transmembrane glycoprotein that is highly expressed in oligodendrocytes and whose biological function remains largely unknown. Furthermore, the expression pattern of Tmem10 remains a matter of some controversy. Given the inconsistency of its expression pattern and the lack of validated specific antibodies, Tmem10 is not widely accepted as a marker for mature oligodendrocytes. As a means to solve these problems and to aid future studies of oligodendrocyte-associated diseases, we have generated a highly specific Tmem10 antibody. Using this Tmem10 antibody, we clarify that Tmem10 protein is firstly expressed at 2 weeks in the postnatal mouse brain with age-related increase, only in the central nervous system (CNS). We also reveal that Tmem10 is expressed specifically in late stage oligodendrocytes and later than MAG, a late-stage myelin marker. Finally, we show that Tmem10 co-expresses with MOG- and MBP-positive myelin fibers and is dramatically reduced in a hypomyelination mouse model. In conclusion, our study demonstrates that Tmem10 can be used as a specific marker for myelinating oligodendrocytes and perhaps for the evaluation of myelination diseases, such as multiple sclerosis.