Association between genetically proxied glucosamine and risk of cancer and non-neoplastic disease: A Mendelian randomization study.

Introduction: Observational investigations have examined the impact of glucosamine use on the risk of cancer and non-neoplastic diseases. However, the findings from these studies face limitations arising from confounding variables, reverse causation, and conflicting reports. Consequently, the establishment of a causal relationship between habitual glucosamine consumption and the risk of cancer and non-neoplastic diseases necessitates further investigation. Methods: For Mendelian randomization (MR) investigation, we opted to employ single-nucleotide polymorphisms (SNPs) as instruments that exhibit robust associations with habitual glucosamine consumption. We obtained the corresponding effect estimates of these SNPs on the risk of cancer and non-neoplastic diseases by extracting summary data for genetic instruments linked to 49 varied cancer types amounting to 378,284 cases and 533,969 controls, as well as 20 non-neoplastic diseases encompassing 292,270 cases and 842,829 controls. Apart from the primary analysis utilizing inverse-variance weighted MR, we conducted two supplementary approaches to account for potential pleiotropy (MR-Egger and weighted median) and assessed their respective MR estimates. Furthermore, the results of the leave-one-out analysis revealed that there were no outlying instruments. Results: Our results suggest divergence from accepted biological understanding, suggesting that genetically predicted glucosamine utilization may be linked to an increased vulnerability to specific illnesses, as evidenced by increased odds ratios and confidence intervals (95% CI) for diseases, such as malignant neoplasm of the eye and adnexa (2.47 [1.34-4.55]), benign neoplasm of the liver/bile ducts (2.12 [1.32-3.43]), benign neoplasm of the larynx (2.01 [1.36-2.96]), melanoma (1.74 [1.17-2.59]), follicular lymphoma (1.50 [1.06-2.11]), autoimmune thyroiditis (2.47 [1.49-4.08]), and autoimmune hyperthyroidism (1.93 [1.17-3.18]). In contrast to prior observational research, our genetic investigations demonstrate a positive correlation between habitual glucosamine consumption and an elevated risk of sigmoid colon cancer, lung adenocarcinoma, and benign neoplasm of the thyroid gland. Conclusion: Casting doubt on the purported purely beneficial association between glucosamine ingestion and prevention of neoplastic and non-neoplastic diseases, habitual glucosamine ingestion exhibits dichotomous effects on disease outcomes. Endorsing the habitual consumption of glucosamine as a preventative measure against neoplastic and non-neoplastic diseases cannot be supported.

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.

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.

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.

HPV E6/E7 promotes aerobic glycolysis in cervical cancer by regulating IGF2BP2 to stabilize m6A-MYC expression.

Enhanced aerobic glycolysis constitutes an additional source of energy for tumor proliferation and metastasis. Human papillomavirus (HPV) infection is the main cause of cervical cancer (CC); however, the associated molecular mechanisms remain poorly defined, as does the relationship between CC and aerobic glycolysis. To investigate whether HPV 16/18 E6/E7 can enhance aerobic glycolysis in CC, E6/E7 expression was knocked down in SiHa and HeLa cells using small interfering RNA (siRNA). Then, glucose uptake, lactate production, ATP levels, reactive oxygen species (ROS) content, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were evaluated. RNA-seq was used to probe the molecular mechanism involved in E6/E7-driven aerobic glycolysis, and identified IGF2BP2 as a target of E6/E7. The regulatory effect of IGF2BP2 was confirmed by qRT-PCR, western blot, and RIP assay. The biological roles and mechanisms underlying how HPV E6/E7 and IGF2BP2 promote CC progression were confirmed in vitro and in vivo. Human CC tissue microarrays were used to analyze IGF2BP2 expression in CC. The knockdown of E6/E7 and IGF2BP2 attenuated the aerobic glycolytic capacity and growth of CC cells, while IGF2BP2 overexpression rescued this effect in vitro and in vivo. IGF2BP2 expression was higher in CC tissues than in adjacent tissues and was positively correlated with tumor stage. Mechanistically, E6/E7 proteins promoted aerobic glycolysis, proliferation, and metastasis in CC cells by regulating MYC mRNA m6A modifications through IGF2BP2. We found that E6/E7 promote CC by regulating MYC methylation sites via activating IGF2BP2 and established a link between E6/E7 and the promotion of aerobic glycolysis and CC progression. Blocking the HPV E6/E7-related metabolic pathway represents a potential strategy for the treatment of CC.

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.

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.

Advances in prognostic biomarkers for esophageal cancer.

INTRODUCTION: Esophageal cancer (EC) is one of the deadliest neoplasms in Asian countries. The high mortality rate and low survival rate of this disease are the major challenges for patients. Therefore, exploring novel biomarkers for prognosis analysis is still an important task for cancer research. Areas covered: The aim of our review is to summarize the recent advances in prognostic markers for EC. We also discuss the pros and cons of different types of biomarkers for improving the judgment of prognosis. These biomarkers mainly include liquid biopsy, genomics biomarkers, and proteomic molecules. In this sense, we found that liquid biopsies, especially circulating tumor cells, should be fully considered in clinical practice, as they show high specificity and accuracy. Proteomic biomarkers also show potential value, but the costs of associated techniques may be expensive for routine use. Alternatively, epigenetic markers (such as miRNAs) appear to be very promising since they can be easily detected in both tissues and bodily fluids. Expert commentary: So far, the defined and available biomarkers for prognosis judgment of EC are insufficient. Future studies and clinical trials should be carried out to improve the clinical use of the biomarkers discussed here.