ASF1B is an essential prognostic indicator linked to the growth and resistance characteristics of bladder cancer.

BACKGROUND: Anti-silencing function 1 (ASF1) is a conserved histone H3-H4 chaperone protein. ASF1B (Anti-Silencing Function 1B Histone Chaperone), a paralog of ASF1, is involved in tumor metabolism and growth. The regulatory network of ASF1B in cancer is intricate and remains inadequately explored. The objective of this study was to examine the biological role of ASF1B in bladder cancer (BC). METHODS: The presence of ASF1B in BC was examined using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases. In addition, a correlation analysis was performed to evaluate the association between the BC pathway scores and ASF1B. ASF1B expression in BC cells was detected using western blott and RT-PCR. Several investigations were conducted, both within and outside of a living organism, to confirm the involvement of ASF1B in the regulation of biological processes in BC cells. RESULTS: Our examination of the database indicates that ASF1B exhibits significant expression levels in BC cells and is potentially strongly associated with the growth of BC cells and the repair of DNA. The expression of ASF1B in BC cells was found to be significantly elevated, as indicated by the results of western blot and RT-PCR. The findings of the cell plate cloning test, edu analysis, flow cytometry, and transwell experiments demonstrated that the inhibition of ASF1B greatly impeded the proliferation and migration of BC cells. After establishing drug-resistant BC cell lines in a lab, suppressing ASF1B gene expression led to a notable reduction in BC cells' resistance to cisplatin. Confirmation was achieved by flow cytometry and western blott assays. Our in vivo findings demonstrated that the suppression of ASF1B resulted in an amelioration of the pathological condition, a decrease in resistance to cisplatin, and an inhibition of the growth of BC in mice.

Polystyrene nanoplastics of different particle sizes regulate the polarization of pro-inflammatory macrophages.

Microplastics (MPs) are defined as plastic particles smaller than 5 mm in size, and nanoplastics (NPs) are those MPs with a particle size of less than 1000 nm or 100 nm. The prevalence of MPs in the environment and human tissues has raised concerns about their potential negative effects on human health. Macrophages are the major defence against foreign substances in the intestine, and can be polarized into two types: the M1 phenotype and the M2 phenotype. However, the effect of NPs on the polarization of macrophages remains unclear. Herein, we selected polystyrene, one of the most plastics in the environment and controlled the particle sizes at 50 nm and 500 nm respectively to study the effects on the polarization of macrophages. We used mouse RAW264.7 cell line models in this macrophage-associated study. Experiments on cell absorption showed that macrophages could quickly ingest polystyrene nanoplastics of both diameters with time-dependent uptake. Compared to the untreated group and 10 µg/mL treatment group, macrophages exposed to 50 µg/mL groups (50 nm and 500 nm) had considerably higher levels of CD86, iNOS, and TNF-α, but decreased levels of aCD206, IL-10, and Arg-1. According to these findings, macrophage M1 and M2 polarization can both be induced and inhibited by 50 µg/mL 50 nm and 500 nm polystyrene nanoplastics. This work provided the first evidence of a possible MPs mode of action with appropriate concentration and size through the production of polarized M1, providing dietary and environmental recommendations for people, particularly those with autoimmune and autoinflammatory illnesses.

Dural arteriovenous fistulas in the falx cerebri: case series and literature review.

Dural arteriovenous fistulas (DAVFs) within the falx cerebri are infrequently documented and may be linked with the falcine sinus/venous plexus. The falcine sinus/venous plexus, often regarded as a normal venous structure, can exhibit pathological characteristics, differing from the persistent fetal falcine sinus. A retrospective analysis was conducted at a single center to identify all cases of DAVFs within the falx cerebri spanning from 2002 to 2022. Demographic data, fistula features, treatment modalities, clinical outcomes, and fistula closure were collected and analyzed. Additionally, relevant literature on DAVFs in this location was reviewed. Ten cases were identified at our center, supplemented by 13 cases reported in the literature. In our cohort, patients had an average age of 49.4 ± 8.1 years, with a male predominance of 90%. Trans-arterial embolization (TAE) alone achieved immediate complete occlusion in eight cases, while conservative treatment was pursued in two cases. No treatment-related complications or fistula recurrences were observed. In the literature, seven patients underwent direct surgery, three underwent TAE, and one underwent both direct surgery and radiosurgery for complete fistula closure. No instances of fistula recurrence or treatment complications were reported. Dural arteriovenous fistulas within the falx cerebri are rare, with limited literature available. They typically present as aggressive lesions. Treatment options include direct surgery or TAE. However, due to a lack of long-term DSA follow-up, the cure and recurrence rates are unknown for endovasdcular therapy. Further investigation is warranted to elucidate the involvement of the falcine sinus/venous plexus in falx cerebri DAVFs.

A Lipid-Sensitive Spider Peptide Toxin Exhibits Selective Anti-Leukemia Efficacy through Multimodal Mechanisms.

Anti-cancer peptides (ACPs) represent a promising potential for cancer treatment, although their mechanisms need to be further elucidated to improve their application in cancer therapy. Lycosin-I, a linear amphipathic peptide isolated from the venom of Lycosa singorensis, shows significant anticancer potential. Herein, it is found that Lycosin-I, which can self-assemble into a nanosphere structure, has a multimodal mechanism of action involving lipid binding for the selective and effective treatment of leukemia. Mechanistically, Lycosin-I selectively binds to the K562 cell membrane, likely due to its preferential interaction with negatively charged phosphatidylserine, and rapidly triggers membrane lysis, particularly at high concentrations. In addition, Lycosin-I induces apoptosis, cell cycle arrest in the G1 phase and ferroptosis in K562 cells by suppressing the PI3K-AKT-mTOR signaling pathway and activating cell autophagy at low concentrations. Furthermore, intraperitoneal injection of Lycosin-I inhibits tumor growth of K562 cells in a nude mouse xenograft model without causing side effects. Collectively, the multimodal effect of Lycosin-I can provide new insights into the mechanism of ACPs, and Lycosin-I, which is characterized by high potency and specificity, can be a promising lead for the development of anti-leukemia drugs.

Cost-effectiveness of sotorasib as a second-line treatment for non-small cell lung cancer with KRASG12C mutation in China and the United States.

Purpose: To evaluate the cost-effectiveness of sotorasib versus docetaxel in non-small cell lung cancer (NSCLC) patients with KRASG12C mutation from the China and United States'social perspective. Materials and Methods: A Markov model that included three states (progression-free survival, post-progression survival, and death) was developed. Incremental cost-effectiveness ratio (ICER), quality-adjusted life-year (QALY), and incremental QALY were calculated for the two treatment strategies. One-way sensitivity analysis was used to investigate the factors that had a greater impact on the model results, and tornado diagrams were used to present the results. Probabilistic sensitivity analysis was performed with 1,000 Monte Carlo simulations. Assume distributions based on parameter types and randomly sample all parameter distributions each time., The results were presented as cost-effectiveness acceptable curves. Results: This economic evaluation of data from the CodeBreak 200 randomized clinical trial. In China, sotorasib generated 0.44 QAYL with a total cost of $84372.59. Compared with docetaxel, the ICER value of sotorasib was $102701.84/QALY, which was higher than willingness to pay (WTP), so sotorasib had no economic advantage. In the US, sotorasib obtained 0.35 QALY more than docetaxel, ICER was $15,976.50/QALY, which was more than 1 WTP but less than 3 WTP, indicating that the increased cost of sotorasib was acceptable. One-way sensitivity analysis showed that the probability of sotorasib having economic benefits gradually increased when the cost of follow-up examination was reduced in China. And there was no influence on the conclusions within the range of changes in China. When the willingness to pay (WTP) exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%. Conclusion: Sotorasib had a cost effect from the perspective in the United States. However, sotorasib had no cost effect from the perspective in China, and only when the WTP exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%.

Development of an artificial intelligent model for pre-endoscopic screening of precancerous lesions in gastric cancer.

BACKGROUND: Given the high cost of endoscopy in gastric cancer (GC) screening, there is an urgent need to explore cost-effective methods for the large-scale prediction of precancerous lesions of gastric cancer (PLGC). We aim to construct a hierarchical artificial intelligence-based multimodal non-invasive method for pre-endoscopic risk screening, to provide tailored recommendations for endoscopy. METHODS: From December 2022 to December 2023, a large-scale screening study was conducted in Fujian, China. Based on traditional Chinese medicine theory, we simultaneously collected tongue images and inquiry information from 1034 participants, considering the potential of these data for PLGC screening. Then, we introduced inquiry information for the first time, forming a multimodality artificial intelligence model to integrate tongue images and inquiry information for pre-endoscopic screening. Moreover, we validated this approach in another independent external validation cohort, comprising 143 participants from the China-Japan Friendship Hospital. RESULTS: A multimodality artificial intelligence-assisted pre-endoscopic screening model based on tongue images and inquiry information (AITonguequiry) was constructed, adopting a hierarchical prediction strategy, achieving tailored endoscopic recommendations. Validation analysis revealed that the area under the curve (AUC) values of AITonguequiry were 0.74 for overall PLGC (95% confidence interval (CI) 0.71-0.76, p < 0.05) and 0.82 for high-risk PLGC (95% CI 0.82-0.83, p < 0.05), which were significantly and robustly better than those of the independent use of either tongue images or inquiry information alone. In addition, AITonguequiry has superior performance compared to existing PLGC screening methodologies, with the AUC value enhancing 45% in terms of PLGC screening (0.74 vs. 0.51, p < 0.05) and 52% in terms of high-risk PLGC screening (0.82 vs. 0.54, p < 0.05). In the independent external verification, the AUC values were 0.69 for PLGC and 0.76 for high-risk PLGC. CONCLUSION: Our AITonguequiry artificial intelligence model, for the first time, incorporates inquiry information and tongue images, leading to a higher precision and finer-grained pre-endoscopic screening of PLGC. This enhances patient screening efficiency and alleviates patient burden.

Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial.

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .

Application of S-transform-based nonlinear processing for accurate LIBS quantitative analysis of iron ore slurry.

Real-time Fe content monitoring in iron ore slurry is crucial for evaluating concentrate quality and enhancing mineral processing efficiency. Laser-induced breakdown spectroscopy (LIBS) is a promising technique for the online monitoring of elemental content at industrial sites. However, LIBS measurements are hampered by the matrix effect and the self-absorption effect, limiting the precision of linear analytical processes. To overcome this, we propose to introduce a nonlinear processing unit based on the S-transform to incorporate nonlinearity into the data analysis process. This approach integrates a feature selection unit based on the spectral distance variable selection method (SDVS), a nonlinear processing unit based on the S-transform (ST), and a partial least squares regression model (PLS). To demonstrate the improvement in accuracy achieved through nonlinear processing, a comparative analysis involving five models, Raw-PLS, SDVS-PLS, ST-PLS, SDVS-ANN, and SDVS-ST-PLS, is conducted. The results reveal a significant improvement in the performance of the SDVS-ST-PLS model, effectively facilitating the successful application of the LIBSlurry analyzer to the mineral flotation process.

Analysis of clinicopathological characteristics and prognosis on primary gastric adenosquamous carcinoma.

Primary gastric adenosquamous carcinoma (PGASC) is a rare type of gastric cancer with limited research and poorly understood clinicopathological features. This study investigated the clinicopathological features and outcomes of PGASC. Patients with PGASC from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology and from the published literature were enrolled in this study. Survival curves were generated using the Kaplan-Meier method, and prognostic factors were identified through Cox proportional hazards regression models. This study identified 76 eligible cases of PGASC, with 45 cases from published literature and 31 from our center. The most prevalent symptoms were abdominal pain and dysphagia, with a median age of 62 years (range: 29-84 years). The primary lesions were predominantly in the proximal stomach, with a median tumor size of 6.5 cm (range: 1.5-16.0 cm). Tumor stages II, III, and IV were detected in 12 (16.7%), 43 (59.7%), and 17 (23.6%) patients, respectively. Most tumors were poorly differentiated in both the squamous cell carcinoma (SCC) component and adenocarcinoma (AC) component. The median survival time was 17 months (range: 2-122 months). The 1, 3, and 5-year overall survival (OS) was 60.7%, 31.1%, and 24.1%, respectively. Multivariate analysis revealed that OS was independently predicted by the proportion of SCC component, differentiation of AC component, and tumor stage. PGASC is a rare disease with a poor prognosis. A high proportion of SCC components, low differentiated AC components, and advanced tumor were associated with worse survival in patients with PGASC. Adjuvant therapy did not improve survival time.

Network pharmacology and molecular-docking-based strategy to explore the potential mechanism of salidroside-inhibited oxidative stress in retinal ganglion cell.

BACKGROUND: Salidroside (SAL), the main component of Rhodiola rosea extract, is a flavonoid with biological activities, such as antioxidative stress, anti-inflammatory, and hypolipidemic. In this study, the potential therapeutic targets and mechanisms of SAL against oxidative stress in retinal ganglion cells (RGCs) were investigated on the basis of in-vitro experiments, network pharmacology, and molecular docking techniques. METHODS: RGC oxidative stress models were constructed, and cell activity, reactive oxygen species (ROS), and apoptosis levels were examined for differences. The genes corresponding to rhodopsin, RGCs, and oxidative stress were screened from GeneCards, TCMSP database, and an analysis platform. The intersection of the three was taken, and a Venn diagram was drawn. Protein interactions, GO functional enrichment, and KEGG pathway enrichment data were analyzed by STRING database, Cytohubba plugin, and Metascape database. The key factors in the screening pathway were validated using qRT-PCR. Finally, molecular docking prediction was performed using MOE 2019 software, molecular dynamic simulations was performed using Gromacs 2018 software. RESULTS: In the RGC oxidative stress model in vitro, the cell activity was enhanced, ROS was reduced, and apoptosis was decreased after SAL treatment. A total of 16 potential targets of oxidative stress in SAL RGCs were obtained, and the top 10 core targets were screened by network topology analysis. GO analysis showed that SAL retinal oxidative stress treatment mainly involved cellular response to stress, transcriptional regulatory complexes, and DNA-binding transcription factor binding. KEGG analysis showed that most genes were mainly enriched in multiple cancer pathways and signaling pathways in diabetic complications, nonalcoholic fatty liver, and lipid and atherosclerosis. Validation by PCR, molecular docking and molecular dynamic simulations revealed that SAL may attenuate oxidative stress and reduce apoptosis in RGCs by regulating SIRT1, NRF2, and NOS3. CONCLUSION: This study initially revealed the antioxidant therapeutic effects and molecular mechanisms of SAL on RGCs, providing a theoretical basis for subsequent studies.

Renal function after ureteral reconstruction surgery in patients with solitary kidney.

Background: Ureteral strictures (US) could lead to impaired kidney function, which was alleviated by ureteral reconstruction surgery. However, solitary kidney (SK) patients with US were more complicated to treat. This study aimed to evaluate the impact of reconstruction surgery on renal function based on estimated glomerular filtration rate (eGFR) in patients with SK. Methods: We retrospectively enrolled patients who underwent reconstruction surgery between April 2014 to March 2022. eGFR was measured pre- and postoperatively. The 'static renal function' was defined as a change in eGFR of 20% or less at the last follow-up, and the 'worsening renal function group' was defined as a decrease of greater than 20%. Results: A total of 61 SK patients were involved. The success rate of ureteral reconstruction surgery was 90.16% (55/61). The median follow-up time was 20.8 months (range, 3.7-109.2 months). The median eGFR was 65.5 (range, 15.1-99.9) and 65.3 (range, 3.8-123.4) mL/min/1.73 m2 at the baseline and the last follow-up. No statistically significant difference in eGFR was observed between the preoperative baseline and last follow-up visits (P=0.58). However, in patients with baseline renal dysfunction [chronic kidney disease (CKD) stage 3-5], the eGFR significantly improved at the last follow-up compared to the baseline (P=0.02). Three patients developed a 'worsening renal function' (4.92%). Besides, the systolic blood pressures (SBP) at follow-up significantly reduced compared to the preoperative baseline (P=0.002). Conclusions: Ureteral reconstruction surgery is an effective treatment to preserve renal function, which also achieves a high success rate and is associated with the reduction of SBP for SK patients with US.

Epidermal growth factor receptor­targeted antibody nimotuzumab combined with chemoradiotherapy improves survival in patients with locally advanced head and neck squamous cell carcinoma: a propensity score matching real-world study.

Patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) have poor survival outcomes. The real-world efficacy of nimotuzumab plus intensity modulated radiotherapy (IMRT)-based chemoradiotherapy in patients with LA-HNSCC remains unclear. A total of 25,442 HNSCC patients were screened, and 612 patients were matched by propensity score matching (PSM) (1:1). PSM was utilized to balance known confounding factors. Patients who completed at least five doses of nimotuzumab were identified as study group. The primary end point was 3-year overall survival (OS) rate. Log-rank test examined the difference between two survival curves and Cloglog transformation test was performed to compare survival at a fixed time point. The median follow-up time was 54.2 (95% confidence interval [CI]: 52.7-55.9) months. The study group was associated with improved OS (hazard ratio [HR] = 0.75, 95% CI: 0.57-0.99, p = 0.038) and progression-free survival (PFS) (HR = 0.74, 95% CI: 0.58-0.96, p = 0.021). Subgroup analysis revealed that aged 50-60 year, IV, N2, radiotherapy dose ≥ 60 Gy, without previous surgery, and neoadjuvant therapy have a trend of survival benefit with nimotuzumab. Nimotuzumab showed favorable safety, only 0.2% had nimotuzumab-related severe adverse events. Our study indicated the nimotuzumab plus chemoradiotherapy provides survival benefits and safety for LA-HNSCC patients in an IMRT era.

Retinitis pigmentosa and stem cell therapy.

Retinitis pigmentosa (RP) is a group of genetic disorders characterized by progressive degeneration of photoreceptors and retinal pigment epithelium (RPE) cells. Its main clinical manifestations include night blindness and progressive loss of peripheral vision, making it a prevalent debilitating eye disease that significantly impacts patients' quality of life. RP exhibits significant phenotypic and genetic heterogeneity. For instance, numerous abnormal genes are implicated in RP, resulting in varying clinical presentations, disease progression rates, and pathological characteristics among different patients. Consequently, gene therapy for RP poses challenges due to these complexities. However, stem cells have garnered considerable attention in the field of RPE therapy since both RPE cells and photoreceptors can be derived from stem cells. In recent years, a large number of animal experiments and clinical trials based on stem cell transplantation attempts, especially cord blood mesenchymal stem cell (MSC) transplantation and bone marrow-derived MSC transplantation, have confirmed that stem cell therapy can effectively and safely improve the outer retinal function of the RP-affected eye. However, stem cell therapy also has certain limitations, such as the fact that RP patients may involve multiple types of retinal cytopathia, which brings great challenges to stem cell transplantation therapy, and further research is needed to solve various problems faced by this approach in the clinic. Through comprehensive analysis of the etiology and histopathological changes associated with RP, this study substantiates the efficacy and safety of stem cell therapy based on rigorous animal experimentation and clinical trials, while also highlighting the existing limitations that warrant further investigation.

Association between indoor environmental risk factors and pneumonia among preschool children in Urumqi：A case-control study.

Background: Pediatric pneumonia presents a significant global health challenge, particularly in low- and middle-income countries. This study aimed to investigate the incidence of pneumonia in preschool children in Urumqi and its association with indoor environmental factors. Methods: This case-control study collected data from December 2018 to December 2019 on 1522 preschool children in Urumqi (779 boys and 743 girls) who were diagnosed with pneumonia by a physician. A control group of children who had never had pneumonia was matched in a 1:1 ratio based on gender, age, and ethnicity. Using questionnaires, data were collected on children's general characteristics, passive smoking, types of housing, flooring materials, and indoor dampness, analyzing potential factors associated with the incidence of pediatric pneumonia. Results: Multivariate analysis revealed that cesarean birth (odds ratio [OR] = 1.27; 95 % confidence interval [95%CI] = 1.08-1.48), being an only child (OR = 1.32; 95%CI = 1.13-1.55), antibiotic treatment during the first year of life (OR = 2.51; 95%CI = 1.98-3.19), passive smoking during the mother's pregnancy (OR = 1.62; 95%CI = 1.24-2.13), living in multi-family apartment housing (OR = 1.64; 95%CI = 1.28-2.10) and other types of housing (OR = 1.47; 95%CI = 1.09-1.99), laminate flooring (OR = 1.31; 95%CI = 1.01-1.72), and tile/stone/cement flooring flooring (OR = 1.31; 95%CI = 1.06-1.61), and dampness in dwelling (during first year of mother's pregnancy) (OR = 1.30; 95%CI = 1.04-1.63) were risk factors for pediatric pneumonia. The use of fresh air filtration systems in children's residences (OR = 0.66; 95%CI = 0.50-0.86) was identified as a protective factor. Conclusion: This study underscores the importance of indoor environmental factors in the prevention of pediatric pneumonia. Public health strategies should consider these factors to reduce the incidence of pneumonia in children. Future research needs to be conducted over a broader geographical range and consider a more comprehensive range of factors influencing pediatric pneumonia.

Hyper-methylation and DNMT3A mediated LTC4S downregulation promoted lung adenocarcinoma tumorigenesis via mTORC1 signaling pathway.

Background: Lung adenocarcinoma is a malignancy characterized by high mortality rates and unfavorable prognosis. However, the role of Leukotriene C4 Synthase (LTC4S) in lung cancer remains uninvestigated. Methods: The expression and prognostic value of LTC4S in LUAD were analyzed using the GEPIA online database. Subsequently, the function of LTC4S in lung cancer cells was examined through gain-of function experiments, using assays to evaluate tumor malignant behavior. Subcutaneous xenograft experiments in vivo was used for investigating the functions of LTC4S. Then, tumor hallmark pathways were analyzed by GSEA. Western blot assay was used to validate the impact of LTC4S on mTORC1 pathway. Finally, the correlation of mRNA and methylation of LTC4S were analyzed by cBioPortal. qRT-PCR, ChIP-qPCR and ChIP-Atlas were used to verify the regulation factors of LTC4S low expression in LUAD cells. Results: LTC4S presented significant decreased expression and favorable prognostic significance in LUAD. LTC4S was correlated with clinical stages in LUAD, which showed decreased expression gradually and significantly along with TNM stages. LTC4S-co-expressed genes were closely related to Ras signaling pathway, and MAPK signaling pathway. Overexpression of LTC4S inhibited cancer malignant phenotype and tumor growth in vitro and vivo. GSEA analysis and Western blot assay suggested low expression of LTC4S activated mTORC1 signaling pathway in LUAD. Moreover, the DNA methylation level of LTC4S in LUAD tissue was markedly elevated compared to normal tissue. The hypermethylation of the LTC4S promoter by DNMT3A leads to the decreased expression of LTC4S in LUAD. Conclusions: In conclusion, low expression of LTC4S serves as an unfavorable prognostic marker and the critical function of LTC4S in controlling the progression of LUAD. This highlights the promise for exploring the clinical benefits of manipulating LTC4S in LUAD targeted therapies.

Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated BBB opening: A novel combinatorial immunotherapy regimen for gliomas.

BACKGROUND: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers. METHOD: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor associated macrophages/microglia (TAMs). RESULTS: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4 mediated selective depletion of intra-tumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge. CONCLUSION: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534).

Analysis of glutathione Stransferase mu class 5 gene methylation as a prognostic indicator in low-grade gliomas.

BACKGROUND: Low-grade gliomas (LGG) are a variety of brain tumors that show different clinical outcomes. The methylation of the GSTM5 gene has been noted in the development of LGG, however, its prognostic importance remains uncertain. OBJECTIVE: The objective of this study was to examine the correlation between GSTM5 DNA methylation and clinical outcomes in individuals diagnosed with LGG. METHODS: Analysis of GSTM5 methylation levels in LGG samples was conducted using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. The overall survival based on GSTM5 methylation status was evaluated using Kaplan-Meier curves. The DNA methylation heatmap for particular CpG sites in the GSTM5 gene was visualized using the "pheatmap" R package. RESULTS: The study analyzed that LGG tumors had higher levels of GSTM5 methylation than normal tissues. There was an inverse relationship discovered between GSTM5 expression and methylation. LGG patients with hypermethylation of GSTM5 promoter experienced a positive outcome. Age, grade, and GSTM5 methylation were determined as independent prognostic factors in LGG through both univariate and multivariate Cox regression analyses. CONCLUSION: Methylation of GSTM5 DNA, specifically at certain CpG sites, is linked to a positive outlook in patients with LGG. Utilizing the "pheatmap" R package to visualize GSTM5 methylation patterns offers important information for identifying prognostic markers and therapeutic targets in low-grade gliomas.

Disintegrin Accutin inhibits A549 cell migration though suppression of EMT and FAK/AKT signaling pathway.

Integrins are heterodimers composed of two subunits, α(120-185kD) and ß (90-110kD), which mediate the connection between cells and their external environment, such as extracellular matrix (ECM), and play an important role in the regulation of cell shape, proliferation and migration. Herein, we identified a potent anti-tumor migration peptide Accutin from crude venom of Agkistrodon acutus using an A549 3D tumor sphere model, and simulation tools and RNA sequencing were performed to reveal the mechanism of Accutin. Accutin is a disintegrin and docking, molecular dynamics simulations and ITC assay indicate that the RGD motif in the Accutin sequence can stably bind to integrins α5ß1. 9.22 nM Accutin can significantly inhibit the migration and invasion of lung cancer cell lines. Transcriptome analysis indicated that many genes are involved in tumor cell adhesion-related biological processes. Several pathways, like the "mTOR signaling pathway", "TGF-ß signaling pathway", and "Focal adhesion" were enriched. Interestingly, pathways involved in "N-Glycan biosynthesis" etc. were significantly inhibited. These transcriptomics data suggested that the molecular basis of Accutin-mediated inhibition of cancer cell migration may be by inhibiting N-glycosylation of integrin, then inhibiting signaling pathways such as PI3K/AKT/mTOR and TGFß/smad. Western blotting analysis further confirmed that Accutin could suppress migration via down-regulating the phosphorylation of FAK and AKT and inhibiting EMT (epithelial-mesenchymal transition). Taken together, as a disintegrin with high efficiency, Accutin may be a potential precursor of a therapeutic agent for the treatment of lung cancer migration.

Nomogram of magnetic resonance imaging (MRI) histogram analysis to predict telomerase reverse transcriptase promoter mutation status in glioblastoma.

Background: Telomerase reverse transcriptase promoter (pTERT) status is a strong biomarker to diagnose and predict the prognosis of glioblastoma (GBM). In this study, we explored the predictive value of preoperative magnetic resonance imaging (MRI) histogram analysis in the form of nomogram for evaluating pTERT mutation status in GBM. Methods: The clinical and imaging data of 181 patients with GBM at our hospital between November 2018 and April 2023 were retrospectively assessed. We used the molecular sequencing results to classify the datasets into pTERT mutations (C228T and C250T) and pTERT-wildtype groups. FireVoxel software was used to extract preoperative T1-weighted contrast-enhanced (T1C) histogram parameters of GBM patients. The T1C histogram parameters were compared between groups. Univariate and multivariate logistic regression analyses were used to construct the nomogram, and the predictive efficacy of model was evaluated using calibration and decision curves. Receiver operating characteristic curve was used to assess model performance. Results: Patient age and percentage of unenhanced tumor area showed statistically significant differences between the pTERT mutation and pTERT-wildtype groups (P<0.001). Among the T1C histogram features, the maximum, standard deviation (SD), variance, coefficient of variation (CV), skewness, 5th, 10th, 25th, 95th and 99th percentiles were statistically significantly different between groups (P=0.000-0.040). Multivariate logistic regression analysis showed that age, percentage of unenhanced tumor area, SD and CV were independent risk factors for predicting pTERT mutation status in GBM patients. The logistic regression model based on these four features showed a better sample predictive performance, and the area under the curve (AUC) [95% confidence interval (CI)], accuracy, sensitivity, specificity were 0.842 (0.767-0.917), 0.796, 0.820, and 0.729, respectively. There were no significant differences in the T1C histogram parameters between the C228T and C250T groups (P=0.055-0.854). Conclusions: T1C histogram parameters can be used to evaluate pTERT mutations status in GBM. A nomogram based on conventional MRI features and T1C histogram parameters is a reliable tool for the pTERT mutation status, allowing for non-invasive radiological prediction before surgery.