Chloroethylnitrosoureas (CENUs) are important chemotherapies applied in the treatment of cancer. They exert anticancer activity by inducing DNA interstrand cross-links (ICLs) via the formation of two O6-alkylguanine intermediates, O6-chloroethylguanine (O6-ClEtG) and N1,O6-ethanoguanine (N1,O6-EtG). However, O6-alkylguanine-DNA alkyltransferase (AGT), a DNA-repair enzyme, can restore the O6-alkylguanine damages and thereby obstruct the formation of ICLs (dG-dC cross-link). In this study, the inhibitory mechanism of ICL formation was investigated to elucidate the drug resistance of CENUs mediated by AGT in detail. Based on the structures of the substrate-enzyme complexes obtained from docking and MD simulations, two ONIOM (QM/MM) models with different sizes of the QM region were constructed. The model with a larger QM region, which included the substrate (O6-ClEtG or N1,O6-EtG), a water molecule, and five residues (Tyr114, Cys145, His146, Lys165, and Glu172) in the active pocket of AGT, accurately described the repairing reaction and generated the results coinciding with the experimental outcomes. The repair process consists of two sequential steps: hydrogen transfer to form a thiolate anion on Cys145 and alkyl transfer from the O6 site of guanine (the rate-limiting step). The repair of N1,O6-EtG was more favorable than that of O6-ClEtG from both kinetics and thermodynamics aspects. Moreover, the comparison of the repairing process with the formation of dG-dC cross-link and the inhibition of AGT by O6-benzylguanine (O6-BG) showed that the presence of AGT could effectively interrupt the formation of ICLs leading to drug resistance, and the inhibition of AGT by O6-BG that was energetically more favorable than the repair of O6-ClEtG could not prevent the repair of N1,O6-EtG. Therefore, it is necessary to completely eliminate AGT activity before CENUs medication to enhance the chemotherapeutic effectiveness. This work provides reasonable explanations for the supposed mechanism of AGT-mediated drug resistance of CENUs and will assist in the development of novel CENU chemotherapies and their medication strategies.

The aim of this study was to analyze postsurgical outcomes for individuals with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) who underwent anterior temporal lobectomy, based on the presence of calcified neurocysticercosis (cNCC). A retrospective cross-sectional study was conducted on 89 patients with MTLE-HS who underwent anterior temporal lobectomy between January 2012 and December 2020 at a basic epilepsy surgery center located in Lima, Peru. We collected sociodemographic, clinical, and diagnostic information. The postsurgical results were analyzed using bivariate analysis according to the Engel classification. We included 89 individuals with a median age of 28 years (interquartile range [IQR]: 24-37), and more than half (55.1%) were male. Seventeen (19.1%) were diagnosed with cNCC. A greater number of patients with cNCC had lived in rural areas of Peru during their early life compared with those without cNCC (12 [70.6%] versus 26 [36.1%]; P = 0.010). Patients with cNCC exhibited a greater median frequency of focal to bilateral tonic-clonic seizures per month (1 [IQR: 0-2] versus 0 [0-0.5]; P = 0.009). Conversely, a lower proportion of patients with cNCC reported a history of an initial precipitating injury in comparison to the group without cNCC (4 [23.5%] versus 42 [58.3%]; P = 0.014). At the 1-year follow-up, most patients (82.4%) with cNCC were categorized as Engel IA. Similarly, at the 2-year follow-up, nine (75.0%) were classified as Engel IA. Our findings suggest that most patients diagnosed with cNCC exhibit favorable postsurgical outcomes, comparable to those without cNCC. Additionally, it can be postulated that cNCC may play a role as an initial precipitating injury.

UNASSIGNED: The presence of cancer stem cells (CSCs) significantly limits the therapeutic efficacy of radiotherapy (RT). Efficient elimination of potential CSCs is crucial for enhancing the effectiveness of RT.
UNASSIGNED: In this study, we developed a biomimetic hybrid nano-system (PMC) composed of MnCO3 as the inner core and platelet membrane (PM) as the outer shell. By exploiting the specific recognition properties of membrane surface proteins, PMC enables precise targeting of CSCs. Sonodynamic therapy (SDT) was employed using manganese carbonate nanoparticles (MnCO3 NPs), which generate abundant reactive oxygen species (ROS) upon ultrasound (US) irradiation, thereby impairing CSC self-renewal capacity and eradicating CSCs. Subsequent RT effectively eliminates common tumor cells.
UNASSIGNED: Both in vitro cell experiments and in vivo animal studies demonstrate that SDT mediated by PMC synergistically enhances RT to selectively combat CSCs while inhibiting tumor growth without noticeable side effects.
UNASSIGNED: Our findings offer novel insights for enhancing the efficacy and safety profiles of RT.

Doping proves to be an efficacious method of establishing intermetallic interactions for enhancing toluene oxidation performance of bimetallic oxides. However, conventional bimetallic oxide catalysts are yet to overcome their inadequacy in establishing intermetallic interactions. In this work, the dispersion of Mn-Co bimetallic sites was improved by hydrolytic co-precipitation, strengthening the intermetallic interactions which improved the structural and physicochemical properties of the catalysts, thus significantly enhancing its catalytic behavior. MnCo-H catalysts fabricated by the hydrolytic co-precipitation method showed promising catalytic performance (T50 = 223 °C, T90 = 229 °C), robust stability (at least 100 h) and impressive water resistance (under 10 vol.% of water) for toluene elimination. Hydrolytic co-precipitation has been found to improve dispersion of MnCo elements and to enhance interaction between Co and Mn ions (Mn4+ + Co2+ = Mn3+ + Co3+), resulting in a lower reduction temperature (215 °C) and a weaker Mn-O bond strength, creating more lattice defects and oxygen vacancies, which are responsible for superior catalytic properties of MnCo-H samples. Furthermore, in situ DRIFTs showed that gaseous toluene molecules adsorbed on the surface of MnCo-H were continuously oxidized to benzyl alcohol → benzaldehyde → benzoate, followed by a ring-opening reaction with surface-activated oxygen to convert to maleic anhydride as the final intermediate, which further generates water and carbon dioxide. It was also revealed that the ring-opening reaction for the conversion of benzoic acid to maleic anhydride is the rate-controlling step. This study reveals that optimizing active sites and improving reactive oxygen species by altering the dispersion of bimetals to enhance bimetallic interactions is an effective strategy for the improvement of catalytic behavior, while the hydrolytic co-precipitation method fits well with this corollary.

A novel manganese cobalt metal-organic framework based carbon nanofiber electrode (MnCo/CNF) was prepared and used as microbial fuel cell (MFC) anode. Pyrite was introduced into the anode chamber (MnCoPy_MFC). Synergistic function between pyrite and MnCo/CNF facilitated the pollutants removal and energy generation in MnCoPy_MFC. MnCoPy_MFC showed the highest chemical oxygen demand removal efficiency (82 ± 1%) and the highest coulombic efficiency (35 ± 1%). MnCoPy_MFC achieved both efficient electricity generation (maximum voltage: 658 mV; maximum power density: 3.2 W/m3) and total antimony (Sb) removal efficiency (99%). The application of MnCo/CNF significantly enhanced the biocatalytic efficiency of MnCoPy_MFC, attributed to its large surface area and abundant porous structure that provided ample attachment sites for electroactive microorganisms. This study revealed the synergistic interaction between pyrite and MnCo/CNF anode, which provided a new strategy for the application of composite anode MFC in heavy metal removal and energy recovery.

BACKGROUND: The primary analysis of the phase III NIBIT-M2 study showed a 41% 4-year overall survival (OS) of melanoma patients with asymptomatic brain metastases treated with ipilimumab plus nivolumab.
METHODS: Here, we report the 7-year efficacy outcomes and the Health-Related Quality of Life (HRQoL) analyses of the NIBIT-M2 study.
RESULTS: As of May 1, 2023, at a median follow-up of 67 months (mo), the median OS was 8.5 (95% CI: 6.6-10.3), 8.2 (95% CI: 2.1-14.3) and 29.2 (95% CI: 0-69.9) mo for the fotemustine (F) Arm A, ipilimumab plus fotemustine Arm B, and ipilimumab plus nivolumab Arm C, respectively. The 7-year OS rate was 10.0% (95% CI: 0-22.5) in Arm A, 10.3% (95% CI: 0-22.6) in Arm B, and 42.8% (95% CI: 23.4-62.2) in Arm C. HRQoL was preserved in all treatment arms. Most functional scales evaluated from baseline to W12 were preserved, with a lower mean score decrease for EORTC Quality of Life Questionnaire (QLQ)-C30 and an increase for EORTC QLQ-Brain neoplasm (BN20) in patients receiving ipilimumab plus nivolumab.
CONCLUSIONS: With the longest follow-up available to date in melanoma patients with asymptomatic brain metastases, the NIBIT-M2 study continues to show persistent therapeutic efficacy of I ipilimumab plus nivolumab while preserving HRQoL.

Duplex sequencing (DS) is an error-corrected next-generation sequencing method in which molecular barcodes informatically link PCR-copies back to their source DNA strands, enabling computational removal of errors in consensus sequences. The resulting background of less than one artifactual mutation per 107 nucleotides allows for direct detection of somatic mutations. TwinStrand Biosciences, Inc. has developed a DS-based mutagenesis assay to sample the rat genome, which can be applied to genetic toxicity testing. To evaluate this assay for early detection of mutagenesis, a time-course study was conducted using male Hsd:Sprague Dawley SD rats (3 per group) administered a single dose of 40 mg/kg N-ethyl-N-nitrosourea (ENU) via gavage, with mutation frequency (MF) and spectrum analyzed in stomach, bone marrow, blood, and liver tissues at 3 h, 24 h, 7 d, and 28 d post-exposure. Significant increases in MF were observed in ENU-exposed rats as early as 24 h for stomach (site of contact) and bone marrow (a highly proliferative tissue) and at 7 d for liver and blood. The canonical, mutational signature of ENU was established by 7 d post-exposure in all four tissues. Interlaboratory analysis of a subset of samples from different tissues and time points demonstrated remarkable reproducibility for both MF and spectrum. These results demonstrate that MF and spectrum can be evaluated successfully by directly sequencing targeted regions of DNA obtained from various tissues⁠, a considerable advancement compared to currently used in vivo gene mutation assays.

This study aimed to explore the potential of Host-Guest coupling with Nanocarrier graphyne (GPH) to enhance the bioavailability of the drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (LUM) for brain tumor therapy. The electronic, geometric, and excited-state properties of GPH, LUM, and the graphyne@1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea-complex (GPH@LUM-complex) were studied using DFT B3LYP/6-31G** level of theory. The results showed that the GPH@LUM-complex was stable with negative adsorption energy (-0.20 eV), and there was good interaction between GPH and LUM in the solvent phase. The weak interaction forces between the two indicated an easy release of the drug at the target site. The Frontier Molecular Orbitals (FMO), Charge Density Analysis (CDA), and Natural Bond Orbital (NBO) analysis supported LUM to GPH charge transfer during complex formation, and the Reduced Density Gradient (RDG) isosurfaces identified steric effects and non-bonded interactions. UV-visible examination showed the potential of the GPH@LUM-complex as a drug carrier with a blue shift of 23 nm wavelength in the electronic spectra. The PET process analysis revealed a fluorescence-quenching process, facilitating systematic drug delivery. The study concluded that GPH had potential as a carrier for delivering LUM, and different 2D nanomaterials could be explored for drug delivery applications. The theoretical study\'s findings may motivate researchers to investigate the practical applications of GPH@LUM-complex in oncology.

Treatment of brain tumors, particularly malignant gliomas, is challenging using only surgical resection and radiation therapy, and medical treatment plays an important role in the management of these malignancies. Temozolomide has been mainly used for the treatment of malignant gliomas over a decade. However, novel therapeutic options, such as molecular-targeted drugs and oncolytic virus therapeutic agents have been introduced in recent years. Classical anticancer medications, such as nitrosoureas and platinum-based drugs, continue to be administered for treatment of some types of malignant brain tumors.

BACKGROUND: Retinitis pigmentosa (RP) refers to a group of progressive photoreceptor degenerative diseases. The activation of microglia has been reported to play an important role in the photoreceptor degeneration in RP retinal. Bujing Yishi tablets (BJYS), a Chinese herbal medicine, has been used to treat retinal diseases in China with desirable effect in improving visual function. However, the mechanisms underlying the efficacy of BJYS treatment in RP are not yet fully understood.
OBJECTIVE: Based on the preliminary experiments, this study aimed to investigate the therapeutic mechanism involved in treating N-Methyl-N-Nitrosourea (MNU)-induced retinal degeneration of RP with BJYS.
METHODS: To explore the efficacy of BJYS, a rat experimental RP model was established through intraperitoneal injection of MNU (50 mg/kg). Two experiment was carried out. After the treatment, we conducted H&E, TUNEL, retinal cytokine levels and IBA-1 expression in microglia to confirm the impact on RP model. The specific mechanism of action of BJYS tablet was assessed by western blot, real-time polymerase chain reaction (RT-PCR), and immunofluorescence to determine the mRNA and protein expression levels involved in clarifying the effectiveness of BJYS exerted through P2X7R/CX3CL1/CX3CR1 pathway.
RESULTS: Significant alleviation of retinal morphological structure and photoreceptor degeneration by BJYS treatment was observed in the retinal of MNU-induced RP rats, BJYS prevented the reduction of ONL thickness and decreased the level of apoptotic cells in ONL. It also inhibited microglia overactivation and reduced retinal levels of IL-1β, IL-6, TNF-α. In addition, BJYS decreased the protein expression and mRNA expression of P2X7, CX3CL1 and CX3CR1 and reduced the phosphorylation of p38 MAPK.
CONCLUSIONS: In summary, this study suggested that BJYS treatment could alleviate photoreceptors degeneration of RP by inhibiting microglia overactivation and inflammation through the P2X7R/CX3CL1/CX3CR1 pathway. These effects suggest that BJYS tablets may serve as a promising oral therapeutic agent for RP.