Machine learning for the identification of neoantigen-reactive CD8 + T cells in gastrointestinal cancer using single-cell sequencing.

BACKGROUND: It appears that tumour-infiltrating neoantigen-reactive CD8 + T (Neo T) cells are the primary driver of immune responses to gastrointestinal cancer in patients. However, the conventional method is very time-consuming and complex for identifying Neo T cells and their corresponding T cell receptors (TCRs). METHODS: By mapping neoantigen-reactive T cells from the single-cell transcriptomes of thousands of tumour-infiltrating lymphocytes, we developed a 26-gene machine learning model for the identification of neoantigen-reactive T cells. RESULTS: In both training and validation sets, the model performed admirably. We discovered that the majority of Neo T cells exhibited notable differences in the biological processes of amide-related signal pathways. The analysis of potential cell-to-cell interactions, in conjunction with spatial transcriptomic and multiplex immunohistochemistry data, has revealed that Neo T cells possess potent signalling molecules, including LTA, which can potentially engage with tumour cells within the tumour microenvironment, thereby exerting anti-tumour effects. By sequencing CD8 + T cells in tumour samples of patients undergoing neoadjuvant immunotherapy, we determined that the fraction of Neo T cells was significantly and positively linked with the clinical benefit and overall survival rate of patients. CONCLUSION: This method expedites the identification of neoantigen-reactive TCRs and the engineering of neoantigen-reactive T cells for therapy.

Celastrol inhibits lung cancer growth by triggering histone acetylation and acting synergically with HDAC inhibitors.

Alterations in histone modification have been linked to cancer development and progression. Celastrol, a Chinese herbal compound, shows potent anti-tumor effects through multiple signaling pathways. However, the involvement of histone modifications in this process has not yet been illustrated. In this study, barcode sequencing of a eukaryotic genome-wide deletion library revealed that histone modifications, especially histone acetylation associated with the NuA4 histone acetyltransferase complex, were involved in the anti-proliferation actions of celastrol. The essential roles of histone modification were verified by celastrol sensitivity tests in cells lacking specific genes, such as genes encoding the subunits of the NuA4 and Swr1 complex. The combination of celastrol and histone deacetylase inhibitors (HDACi), rather than the combination of celastrol and histone acetyltransferase inhibitors, synergistically suppressed cancer cell proliferation. In addition to upregulating H4K16 acetylation (H4K16ac), celastrol regulates H3K4 tri-methylation and H3S10 phosphorylation. Celastrol treatment significantly enhanced the suppressive effects of HDACi on lung cancer cell allografts in mice, with significant H4K16ac upregulation, indicating that a combination of celastrol and HDACi is a potential novel therapeutic approach for patients with lung cancer.

The Medicinal Species of the Lycium Genus (Goji Berries) in East Asia: A Review of Its Effect on Cell Signal Transduction Pathways.

Natural plants contain numerous chemical compounds that are beneficial to human health. The berries from the Lycium genus are widely consumed and are highly nutritious. Moreover, their chemical constituents have attracted attention for their health-promoting properties. In East Asia, there are three varieties of the Lycium genus (Lycium barbarum L., Lycium chinense Miller, and L. ruthenicum Murray) that possess medicinal value and are commonly used for treating chronic diseases and improving metabolic disorders. These varieties are locally referred to as "red Goji berries" or "black Goji berries" due to their distinct colors, and they differ in their chemical compositions, primarily in terms of carotenoid and anthocyanin content. The pharmacological functions of these berries include anti-aging, antioxidant, anti-inflammatory, and anti-exercise fatigue effects. This review aims to analyze previous and recent studies on the active ingredients and pharmacological activities of these Lycium varieties, elucidating their signaling pathways and assessing their impact on the gut microbiota. Furthermore, the potential prospects for using these active ingredients in the treatment of COVID-19 are evaluated. This review explores the potential targets of these Lycium varieties in the treatment of relevant diseases, highlighting their potential value in drug development.

Berberine synergises with ferroptosis inducer sensitizing NSCLC to ferroptosis in p53-dependent SLC7A11-GPX4 pathway.

Berberine (BBR) is a compound derived from Chinese herbal medicine, known for its anticancer properties through multiple signaling pathways. However, whether BBR can inhibit tumor growth by participating in ferroptosis remains unconfirmed. In this study, we demonstrated that berberine synergistically inhibited NSCLC in combination with multiple ferroptosis inducers, and this combination synergistically down-regulated the mRNA and protein expression of SLC7A11, GPX4, and NRF2, resulting in ferroptosis accompanied by significant depletion of GSH, and aberrant accumulation of reactive oxygen species and malondialdehyde. In a lung cancer allograft model, the combination treatment exhibited enhanced anticancer effects compared to using either drug alone. Notably, p53 is critical in determining the ferroptosis sensitivity. We found that the combination treatment did not elicit a synergistic anticancer effect in cells with a p53 mutation or with exogenous expression of mutant p53. These findings provide insight into the mechanism by which combination induces ferroptosis and the regulatory role of p53 in this process. It may guide the development of new strategies for treating NSCLC, offering great medical potential for personal diagnosis and treatment.

Formosanin C inhibits non-small-cell lung cancer progression by blocking MCT4/CD147-mediated lactate export.

BACKGROUND: Tumor cells reprogram their metabolic network to maintain their uncontrolled proliferation, metastasis, and resistance to cancer therapy. Treatments targeting abnormal cellular metabolism may have promising therapeutic effects. Formosanin C (FC), a diosgenin derived from the rhizoma of Paris polyphylla var. yunnanensis, has shown potent anti-cancer activities against various cancer types. However, the effect of FC on cancer metabolism remains to be elucidated. PURPOSE: In this research, we aimed to elucidate FC's effect and potential mechanisms on metabolism in lung cancer. METHODS: Colony formation, transwell cell migration, and apoptosis were detected in multiple NSCLC cell lines to assess the cytotoxicity of FC. 1H NMR metabolomics approach was applied to screen the differential metabolites in H1299 cells and the culture medium. Western blotting, flow cytometry, and other molecular biological techniques were performed to verify the latent mechanism involved in metabolites. An allograft tumor model was employed to investigate the anti-tumor effects of FC in vivo. RESULTS: FC significantly inhibited monoclonal formation and migration and induced cell cycle arrest and apoptosis in NSCLC cells. FC altered the abundances of 12 metabolites in lung cancer cells and 3 metabolites in the medium. These differential metabolites are primarily involved in glycolysis, citric acid cycle, and glutathione pathways. Notably, there was a remarkable increase in intracellular lactate and a reduction in extracellular lactate after FC treatment. Mechanically, FC downregulated the expression of MCT4 and CD147, blocking the export of lactate. Furthermore, FC also evoked mitochondrial dysfunction coupled with excessive oxidative stress, decreased mitochondrial membrane potential, ATP production reduction, glutathione depletion, and Ca2+ overload. Moreover, FC suppressed tumor progression in vivo with reduced protein levels of the MCT4 and CD147 in tumor tissues. CONCLUSION: FC inhibits lung cancer growth by the novel mechanism in which MCT4/CD147-mediated inhibition of lactate transport and disruption of mitochondrial functions are involved.

Community health workers' job satisfaction in Ebola-stricken areas of Sierra Leone and its implication for COVID-19 containment: a cross-sectional mixed-methods study.

OBJECTIVES: Community health workers (CHWs) played important roles in supplementing scarce healthcare workforce in Sierra Leone during the Ebola outbreak, causing the government to launch the National Community Health Worker Policy 2016-2020. This study evaluated this ambitious policy and examined CHWs' sustainability through their job satisfaction and the underlying factors to inform new policy recommendations, especially the implication for COVID-19 containment. DESIGN: A mixed-methods approach applying structured questionnaires and semistructured interviews. SETTING AND PARTICIPANTS: 188 CHWs in Bombali District (key Ebola-stricken areas) of Sierra Leone, 184 of them participated in follow-up interviews. PRIMARY AND SECONDARY OUTCOME MEASURES: Quantitative and qualitative elements were triangulated to improve robustness of investigation: job satisfaction was measured by the Minnesota Satisfaction Questionnaire (MSQ), and factors associated with job satisfaction were identified through thematic analysis and multivariable logistic regression. RESULTS: The MSQ score of CHWs in Sierra Leone was 65.09, extremely low even among low-income and middle-income countries. Five themes (grouped from 16 subthemes) emerged through the semistructured interviews and were tested quantitatively. Payment was CHWs' top concern. Low stipend and payment tardiness were significantly associated with dissatisfaction. Those with Ebola experience were 5.20 times (95% CI 1.51 to 17.95, p=0.009) more likely to be dissatisfied. This study also found that working conditions, medical material supplies and career development were far from what the CHW policy promised. CHWs' commitment was the only 'positive' theme, and their intrinsic job satisfaction (mean=3.61) was much higher than the extrinsic job satisfaction (mean=2.72). CONCLUSIONS: Some critical components of the 2016 National Community Health Worker Policy, aiming to promote CHWs and strengthen primary healthcare, have severe shortfalls in practice. The Sierra Leone government should address the underlying factors that have impaired CHWs' job satisfaction to ensure sustainability of its CHW network, especially during the combat against COVID-19.