Oxidative cell death in cancer: mechanisms and therapeutic opportunities.

Reactive oxygen species (ROS) are highly reactive oxygen-containing molecules generated as natural byproducts during cellular processes, including metabolism. Under normal conditions, ROS play crucial roles in diverse cellular functions, including cell signaling and immune responses. However, a disturbance in the balance between ROS production and cellular antioxidant defenses can lead to an excessive ROS buildup, causing oxidative stress. This stress damages essential cellular components, including lipids, proteins, and DNA, potentially culminating in oxidative cell death. This form of cell death can take various forms, such as ferroptosis, apoptosis, necroptosis, pyroptosis, paraptosis, parthanatos, and oxeiptosis, each displaying distinct genetic, biochemical, and signaling characteristics. The investigation of oxidative cell death holds promise for the development of pharmacological agents that are used to prevent tumorigenesis or treat established cancer. Specifically, targeting key antioxidant proteins, such as SLC7A11, GCLC, GPX4, TXN, and TXNRD, represents an emerging approach for inducing oxidative cell death in cancer cells. This review provides a comprehensive summary of recent progress, opportunities, and challenges in targeting oxidative cell death for cancer therapy.

Combined influence of physical activity and C-reactive protein to albumin ratio on mortality among older cancer survivors in the United States: a prospective cohort study.

BACKGROUND: Although a high C-reactive protein-to-albumin ratio (CAR) is believed to increase mortality risk, the association between the physical activity (PA), CAR, and mortality among cancer survivors has not been investigated. This study aimed to examine this association among cancer survivors in the United States. METHODS: This cohort study used data from the National Health and Nutrition Examination Survey from 1999 to 2010. PA was self-reported using the Global Physical Activity Questionnaire, and C-reactive protein and albumin levels were obtained from laboratory data files. Mortality data were obtained by linkage of the cohort database to the National Death Index as of December 31, 2019. The analysis was conducted from November 1 to December 31, 2023. We used Cox proportional hazards multivariable regression to assess hazard ratios (HRs) and 95% confidence interval (CIs) for total and cancer-specific mortality risks attributable to PA and CAR. RESULTS: Among 2,232 cancer survivors, 325 (14.6%) reported no PA with a high CAR. During a follow-up of up to 20.75 years (median, 12.3 years; 27,453 person-years), 1,174 deaths occurred (cancer, 335; other, 839). A high CAR was observed to be consistently associated with the highest risks of total (HR, 1.59; 95% CI, 1.37-1.85) and cancer-specific (HR, 2.06; 95% CI, 1.55-2.73) mortality compared with a low CAR in a series of adjusted models. Multivariable models showed that PA was associated with a lower risk of all-cause (HR, 0.60; 95% CI, 0.52-0.69) and cancer-specific (HR, 0.64; 95% CI, 0.49-0.84) mortality compared with no PA. In the joint analyses, survivors with PA ≥ 600 metabolic equivalent min/wk and a low CAR were more likely to reduce the risk of total (HR, 0.41; 95% CI, 0.32-0.51) and cancer-specific (HR, 0.32; 95% CI, 0.20-0.50) mortality by 59% and 68% compared with those with no PA and a high CAR. CONCLUSION: The pairing of adequate PA and a low CAR was significantly associated with reduced all-cause and cancer-related mortality risks.

Molecular characterization and antimicrobial activity of cecropin family in Hermetia illucens.

Antimicrobial peptides are potential alternatives to traditional antibiotics in the face of increasing bacterial resistance. Insects possess many antimicrobial peptides and have become a valuable source of novel and highly effective antimicrobial peptides. Hermetia illucens as a resource insect, for example, has the highest number of antimicrobial peptides of any dipteran. However, most antimicrobial peptides, especially cecropin, have not been comprehensively identified and have not been evaluated for their antimicrobial ability. In this study, we analyzed the localization and gene structure of 33 cecropin molecules in the H. illucens genome and evaluated their activity against common human pathogens. The results showed that 32 cecropin molecules were concentrated on 1 chromosome, most with 2 exons. More importantly, most of the cecropins had a good antibacterial effect against Gram-negative bacteria, and were not hemolytic. The minimum inhibitory concentration (MIC) of the cecropin designated H3 against E. coli was 4 µg/mL. The toxicity, killing time kinetics, and anti-biofilm activity of H3 were further investigated and confirmed its antimicrobial ability. Overall, H3 is a potential candidate for the development of new antimicrobials to treat severe infections caused by Gram-negative pathogens such as E. coli.

[The prevalence and risk factors of occupational asthma in workers exposed to isocyanate].

OBJECTIVE: To investigate the prevalence of occupational asthma, airway inflammation and analyze the risk factors for workers exposed to isocyanates. METHODS: A cross-sectional study was applied. Totally 429 isocyanates exposed workers were surveyed and the prevalence of occupational asthma and airway inflammation situation were examined by questionnaire, physical examination and laboratory tests. Multivariate logistic regression was applied to analyze the possible risk factors of isocyanate-induced occupational asthma. RESULTS: (1) A total of 366 patients with complete data were included in the study, and finally 11 cases were diagnosed as isocyanate-induced occupational asthma with a prevalence of 3.0%. (2) Neutrophil percentage in the induced sputum of occupational asthma increased significantly [42.00% (34.00%-55.00%) before work and 59.00% (51.00%-70.00%) after work (Z = -2.940. P < 0.05)]. (3) Length of service (OR = 3.096, P = 0.025) and rhinitis (OR = 1.901, P = 0.008) were independent dangerous factors, and protective measures (OR = 0.074, P = 0.015) was protective factors to isocyanate-induced occupational asthma. CONCLUSIONS: Neutrophilic inflammation can be triggered by isocyanate exposure. Regular health examinations, effective protective measures can reduce the prevalence of isocyanate-induced occupational asthma.

Interference of internal waves due to two point vortices: linear analytical solution and nonlinear interaction.

In this work, we consider steady two-dimensional interfacial waves in a two-layer stratified fluid, which is induced by a vortex pair located in the lower layer of the fluids. A mathematical model based on the boundary integral equation method and the potential-flow theory is established. The linear analytical solution for the linearized model is given in the form of Cauchy integral and then asymptotic behaviour for large x is presented. The fully nonlinear model is solved by the Jacobian-free Newton-Krylov (JFNK) method numerically. Nonlinear characteristics of wave profiles are identified compared with the linear results under different vortex strengths and the distance between the vortex pair. The amplitude of steady downstream waves is found to vary periodically with respect to the distance of the vortex pair, which can be regarded as the interference between waves produced by each vortex. For equal-strength counter- and co-rotating pairs, the downstream wave heights of linear solutions can be eliminated for some special values of the distance between point vortices, namely, the destructive interference occurs. Meanwhile, the wave only exists between the vortex pair like trapped waves. So does the nonlinear counterpart for counter-rotating pairs, but it could not be diminished with any distance.

Efficacy of EGFR-TKI sequential therapy in patients with EGFR exon 19 insertion-positive non-small-cell lung cancer: A case report.

BACKGROUND: Insertions in exon 19 in the epidermal growth factor receptor gene (EGFR) is a rarely seen mutation in non-small cell lung cancer. These patients have been effectively treated with sequential EGFR tyrosine kinase inhibitors (TKIs). CASE SUMMARY: Here, we presented a case of non-small cell lung cancer, stage IIIB, with EGFR exon 19 insertion mutation as detected in the right lower lobe by next-generation sequencing. The patient was sequentially treated with first, second, and third-generation EGFR TKIs after the surgical operation. The overall survival of the patient was 21.3 mo. There was no dynamic analysis of drug resistance mechanisms in targeted therapy. CONCLUSION: This case emphasized the importance of following the guidelines. In patients with EGFR mutations, repeated and dynamic next-generation sequencing monitoring is necessary to prescribe a personalized treatment plan.

Histone Deacetylase Sirtuin 2 Enhances Viability of Trophoblasts Through p65-Mediated MicroRNA-146a/ACKR2 Axis.

Reduced activity of trophoblast cells is well-recognized to lead to preeclampsia (PE) progression. This study aims to evaluate the roles of histone deacetylase sirtuin 2 (SIRT2) in activity of trophoblast cells and the molecules involved. Differentially expressed genes in placental tissues between PE patients and healthy individuals were screened using microarray analyses. SIRT2 and atypical chemokine receptor 2 (ACKR2) were downregulated while miR-146a was upregulated in PE patients. SIRT2 was localized in placental syncytiotrophoblasts. Upregulation of SIRT2 enhanced viability, migration and invasion, while reduced apoptosis of HTR-8/SVneo cells. SIRT2 was found to trigger p65 deacetylation level and suppress miR-146a expression according to the luciferase and ChIP assays, whereas miR-146a was found to target ACKR2. Downregulation of p65 promoted migration and invasion of cells. Overexpression of miR-146a inhibited cell viability and blocked the function of SIRT2. ACKR2 was downregulated in tissues from PE women and its upregulation blocked the role of miR-146a. To conclude, SIRT2 promotes p65 deacetylation to suppress miR-146a expression and upregulates ACKR2 expression, therefore enhancing proliferation, migration, and invasion of HTR-8/SVneo cells. This study may offer novel thoughts into the management of PE.

Identifying Genomic Alterations in Small Cell Lung Cancer Using the Liquid Biopsy of Bronchial Washing Fluid.

Objective: With the rapid development of cancer genomics and immunomics, some new treatments of small cell lung cancer (SCLC) are emerging. However, there are limitations to the clinical use of tumor tissue. Our study aimed to evaluate the potential use of bronchial washing fluid (BWF) in the liquid biopsy of SCLC. Methods: Twenty-one extensive SCLC (ES-SCLC) patients were enrolled in this study. For all patients, four sample types, BWF supernatant (BWFs), BWF precipitate (BWFp), plasma and tumor tissue, were collected before receiving chemotherapy, and one type, plasma, was collected after chemotherapy. All samples were conducted to NGS using the 1021-gene panel. The concordance rates of genomic profiling using NGS in the four types of samples were evaluated. Multiple clinical information was analyzed for correlation. Results: We successfully tested 20 BWFs samples, 21 BWFp samples, 21 tumor tissue samples, 20 pre-treatment plasma, and 13 post-treatment plasma of these 21 patients. The detectability of somatic mutations was 100% for BWFs, BWFp, tumor tissues, and post-treatment plasma, and only one pre-treatment plasma was absent with any mutation. Matched tumor tissue, BWFs, BWFp, and pre-treatment plasma samples were subsistent for 19 patients. For these patients, 204 genomic alterations were identified in tissue samples, while 189 (92.6%), 175 (85.5%), and 163 (79.9%) alterations were detected in the matched BWFs, BWFp, and pre-treatment plasma, respectively. Moreover, we found that the three tumor markers associated with SCLC have a lower sensitivity than genomic alterations. The endocrine resistance pathway was found enriched in hyponatremia patients which may be related to the hyponatremia. The TMBs of BWF, BWFp, and pre-treatment plasma samples all had a strong correlation with that of tissue samples. Both the VAF and the MVAF of mutations in post-treatment plasma were less than those in pre-treatment plasma, which was in accordance with the evaluation of curative effect. Conclusions: For ES-SCLC patients, the liquid biopsy of BWF showed a highly potential advantage to identify DNA alterations, which suggested that genomic analysis of BWF liquid biopsy may have clinical value as a supplement for tissue and blood detection. Through the restricted validation, it can be widely used in routine clinical practice.

Transcriptional and splicing dysregulation in the prefrontal cortex in valproic acid rat model of autism.

Gene-environmental interaction could be the major cause of autism. The aim of the current study is to detect the effects of valproic acid on gene expression profiles and alternatively spliced genes in the prefrontal cortex in rat models of autism. Female rats received a single intraperitoneal injection of 600 mg/kg valproic acid at day 12.5 post-conception, and controls were injected with saline. Only male offspring were employed in the current study. RNA sequencing was used to investigate transcriptome in the prefrontal cortex of VPA-exposed rats. There were 3228 differently expressed genes and 637 alternative spliced genes, in VPA rats compared to controls. Pathways enrichment among the differently expressed genes and alternatively spliced genes were associated with neurological diseases and neural system development. The results implied VPA affected transcriptional and splicing events genome-wide and the transcriptional and splicing events may be associated with the autistic behaviors of VPA rats.