Elevated ubiquitination contributes to protective immunity against severe SARS-CoV-2 infection.

BACKGROUND: The crosstalk between the ubiquitin-proteasome and the immune system plays an important role in the health and pathogenesis of viral infection. However, there have been few studies of ubiquitin activation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We investigated the effect of ubiquitination on SARS-CoV-2 infection and patient prognosis by integrating published coronavirus disease 2019 (COVID-19) multi-transcriptome data and bioinformatics methods. RESULTS: The differential expression of COVID-19 samples revealed changed ubiquitination in most solid and hollow organs, and it was activated in lymphatic and other immune tissues. In addition, in the respiratory system of COVID-19 patients, the immune response was mainly focused on the alveoli, and the expression of ubiquitination reflected increasing immune infiltration. Ubiquitination stratification could significantly differentiate patients' prognosis and inflammation levels through the general transcriptional analysis of the peripheral blood of patients with COVID-19. Moreover, high ubiquitination levels were associated with a favourable prognosis, low inflammatory response, and reduced mechanical ventilation and intensive care unit. Moreover, high ubiquitination promoted a beneficial immune response while inhibiting immune damage. Finally, prognostic stratification and biomarker screening based on ubiquitination traits played an important role in clinical management and drug development. CONCLUSION: Ubiquitination characteristics provides new ideas for clinical intervention and prognostic guidance for COVID-19 patients.

Recent Insight on Regulations of FBXW7 and Its Role in Immunotherapy.

SCFFBXW7 E3 ubiquitin ligase complex is a crucial enzyme of the ubiquitin proteasome system that participates in variant activities of cell process, and its component FBXW7 (F-box and WD repeat domain-containing 7) is responsible for recognizing and binding to substrates. The expression of FBXW7 is controlled by multiple pathways at different levels. FBXW7 facilitates the maturity and function maintenance of immune cells via functioning as a mediator of ubiquitination-dependent degradation of substrate proteins. FBXW7 deficiency or mutation results in the growth disturbance and dysfunction of immune cell, leads to the resistance against immunotherapy, and participates in multiple illnesses. It is likely that FBXW7 coordinating with its regulators and substrates could offer potential targets to improve the sensitivity and effects of immunotherapy. Here, we review the mechanisms of the regulation on FBXW7 and its tumor suppression role in immune filed among various diseases (mostly cancers) to explore novel immune targets and treatments.

Development of Diagnosis Model for Early Lung Nodules Based on a Seven Autoantibodies Panel and Imaging Features.

Background: There is increasing incidence of pulmonary nodules due to the promotion and popularization of low-dose computed tomography (LDCT) screening for potential populations with suspected lung cancer. However, a high rate of false-positive and concern of radiation-related cancer risk of repeated CT scanning remains a major obstacle to its wide application. Here, we aimed to investigate the clinical value of a non-invasive and simple test, named the seven autoantibodies (7-AABs) assay (P53, PGP9.5, SOX2, GAGE7, GUB4-5, MAGEA1, and CAGE), in distinguishing malignant pulmonary diseases from benign ones in routine clinical practice, and construct a neural network diagnostic model with the development of machine learning methods. Method: A total of 933 patients with lung diseases and 744 with lung nodules were identified. The serum levels of the 7-AABs were tested by an enzyme-linked Immunosorbent assay (ELISA). The primary goal was to assess the sensitivity and specificity of the 7-AABs panel in the detection of lung cancer. ROC curves were used to estimate the diagnosis potential of the 7-AABs in different groups. Next, we constructed a machine learning model based on the 7-AABs and imaging features to evaluate the diagnostic efficacy in lung nodules. Results: The serum levels of all 7-AABs in the malignant lung diseases group were significantly higher than that in the benign group. The sensitivity and specificity of the 7-AABs panel test were 60.7% and 81.5% in the whole group, and 59.7% and 81.1% in cases with early lung nodules. Comparing to the 7-AABs panel test alone, the neural network model improved the AUC from 0.748 to 0.96 in patients with pulmonary nodules. Conclusion: The 7-AABs panel may be a promising method for early detection of lung cancer, and we constructed a new diagnostic model with better efficiency to distinguish malignant lung nodules from benign nodules which could be used in clinical practice.

The Clinical Prediction Value of the Ubiquitination Model Reflecting the Immune Traits in LUAD.

Background: Increasing evidence shows that the ubiquitin-proteasome system has a crucial impact on lung adenocarcinoma. However, reliable prognostic signatures based on ubiquitination and immune traits have not yet been established. Methods: Bioinformatics was performed to analyze the characteristic of ubiquitination in lung adenocarcinoma. Principal component analysis was employed to identify the difference between lung adenocarcinoma and adjacent tissue. The ubiquitin prognostic risk model was constructed by multivariate Cox regression and least absolute shrinkage and selection operator regression based on the public database The Cancer Genome Atlas, with evaluation of the time-dependent receiver operating characteristic curve. A variety of algorithms was used to analyze the immune traits of model stratification. Meanwhile, the drug response sensitivity for subgroups was predicted by the "pRRophetic" package based on the database of the Cancer Genome Project. Results: The expression of ubiquitin genes was different in the tumor and in the adjacent tissue. The ubiquitin model was superior to the clinical indexes, and four validation datasets verified the prognostic effect. Additionally, the stratification of the model reflected distinct immune landscapes and mutation traits. The low-risk group was infiltrating plenty of immune cells and highly expressed major histocompatibility complex and immune genes, which illustrated that these patients could benefit from immune treatment. The high-risk group showed higher mutation and tumor mutation burden. Integrating the tumor mutation burden and the immune score revealed the patient's discrepancy between survival and drug response. Finally, we discovered that the drug targeting ubiquitin and proteasome would be a beneficial prospective treatment for lung adenocarcinoma. Conclusion: The ubiquitin trait could reflect the prognosis of lung adenocarcinoma, and it might shed light on the development of novel ubiquitin biomarkers and targeted therapy for lung adenocarcinoma.

METTL3-mediated m6A mRNA modification of FBXW7 suppresses lung adenocarcinoma.

BACKGROUND: FBXW7 m6A modification plays an important role in lung adenocarcinoma (LUAD) progression; however, the underlying mechanisms remain unclear. METHODS: The correlation between FBXW7 and various genes related to m6A modification was analyzed using The Cancer Genome Atlas database. The regulatory effects of METTL3 on FBXW7 mRNA m6A modification were examined in a cell model, and the underlying mechanism was determined by methylated RNA immunoprecipitation, RNA immunoprecipitation, luciferase reporter, and mutagenesis assays. In vitro experiments were performed to further explore the biological effects of METTL3-mediated FBXW7 m6A modification on LUAD development. RESULTS: Decreased FBXW7 expression was accompanied by downregulated METTL3 expression in human LUAD tissues and was associated with a worse prognosis for LUAD in The Cancer Genome Atlas database. m6A was highly enriched in METTL3-mediated FBXW7 transcripts, and increased m6A modification in the coding sequence region increased its translation. Functionally, METTL3 overexpression or knockdown affected the apoptosis and proliferation phenotype of LUAD cells by regulating FBXW7 m6A modification and expression. Furthermore, FBXW7 overexpression in METTL3-depleted cells partially restored LUAD cell suppression in vitro and in vivo. CONCLUSIONS: Our findings reveal that METTL3 positively regulates FBXW7 expression and confirm the tumor-suppressive role of m6A-modified FBXW7, thus providing insight into its epigenetic regulatory mechanisms in LUAD initiation and development.

Assessment of Financial Toxicity Among Patients With Advanced Lung Cancer in Western China.

Background: Lung cancer is the leading source of cancer-caused disability-adjusted life years. Medical cost burden impacts the well-being of patients through reducing income, cutting daily expenses, curtailing leisure activities, and depleting exhausting savings. The COmprehensive Score for Financial Toxicity (COST) was created and validated by De Souza and colleagues. Our study intends to measure the financial burdens of cancer therapy and investigate the link between financial toxicity and health-related quality of life (HRQoL) in an advanced lung cancer population. Methods: Patients aged ≥ 18 years with confirmed stage III to IV lung cancer were eligible. The COST questionnaire verified by de Souza et al. was used to identify financial toxicity. Multivariable linear regression analysis with log transformation univariate analysis and Pearson correlations were used to perform the analysis. Results: The majority of the patients (90.8%, n = 138/152) had an annual income of $50,000 ($7,775). The cohort's insurance situation was as follows: 64.5% of the cohort had social insurance, 20.4% had commercial insurance, and 22.0% had both. Patients who were younger age (50-59, P < 0.001), employed but on sick leave, and had lower income reported increased levels of financial toxicity (P < 0.05). The risk factors for high financial toxicity: (i) younger age (50-59), (ii) <1 month of savings, and (iii) being employed but on sick leave. Increased financial toxicity is moderately correlated with a decrease in QoL. Conclusion: Poorer psychological status and specific demographics are linked to increased financial toxicity (lower COST). Financial toxicity has a modest relationship with HRQoL and may have a clear link with HRQoL measurements.