Correlation between IL3 signaling pathway-related genes and immune checkpoint inhibitor efficacy in patients with renal cell carcinoma.

BACKGROUND: There is a lack of effective biomarkers that predict immunotherapy efficacy in clear cell renal cell carcinoma(KIRC). OBJECTIVE: We aimed to identify biomarkers that would predict the efficacy of KIRC treatment with immune checkpoint inhibitors (ICIs). METHODS: Cohort data of KIRC patients with somatic mutations, mRNA expression and survival data from The Cancer Genome Atlas (TCGA) database and immunotherapy cohort and Genomics of Drug Sensitivity in Cancer (GDSC) database were analyzed and divided into interleukin 3 (IL3) pathway-related genes high expression (IL3-High) and IL3 pathway-related genes low expression (IL3-Low) groups according to pathway expression status to assess the relationship between the IL3 pathway-related genes activation status and the prognosis of KIRC patients treated with ICIs. The data were validated by immunohistochemistry experiments, and possible mechanisms of action were explored at the level of gene mutation landscape, immune microenvironment characteristics, transcriptome and copy number variation(CNV) characteristicsRESULTS: The IL3 pathway-related genes was an independent predictor of the efficacy of ICIs in KIRC patients, and the IL3-High group had a longer overall survival (OS); KIRC patients in the IL3-High group had increased levels of chemokines, cytolysis, immune checkpoint gene expression and abundant immunity. The IL3-Low group had poor immune cell infiltration and significant downregulation of complement activation, cytophagy, B-cell activation, and humoral immune response pathways. The high group was more sensitive to targeted drugs of some signaling pathways, and its efficacy in combining these drugs with immunity has been predicted in the published literature. CONCLUSION: The IL3 pathway-related genes can be used as a predictor of the efficacy of ICIs in KIRC. The IL3 pathway-related genes may affect the therapeutic efficacy of ICIs by affecting the expression of immune-related molecules, immune cell infiltration, and the level of immune response pathways.

CACNA1C mutation as a prognosis predictor of immune checkpoint inhibitor in skin cutaneous melanoma.

Aims: There is an urgent need for appropriate biomarkers that can precisely and reliably predict immunotherapy efficacy, as immunotherapy responses can differ in skin cutaneous melanoma (SKCM) patients. Methods: In this study, univariate regression models and survival analysis were used to examine the link between calcium voltage-gated channel subunit alpha 1C (CACNA1C) mutation status and immunotherapy outcome in SKCM patients receiving immunotherapy. Mutational landscape, immunogenicity, tumor microenvironment and pathway-enrichment analyses were also performed. Results: The CACNA1C mutation group had a better prognosis, higher immunogenicity, lower endothelial cell infiltration, significant enrichment of antitumor immune response pathways and significant downregulation of protumor pathways. Conclusion: CACNA1C mutation status is anticipated to be a biomarker for predicting melanoma immunotherapy effectiveness.

Aims: The treatment to make the immune system work better is also used to treat a skin cancer called skin cutaneous melanoma (SKCM). We need new ways to predict if the treatment will work. Methods: We looked at two groups of people getting the treatment to make the immune system work better. One group had a special change in their bodies, and the other group did not. We looked at how this change affected the patients. We also looked at how to make their immune system stronger. Results: We found that people with mutations tend to have better chances of getting better from their sickness. Conclusion: We think that this might be a good way to tell if immunotherapy will work well for this type of SKCM.

Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database.

Background: With the increasing use of immune checkpoint inhibitors (ICIs) for tumour immunotherapy, the immune-related adverse events (irAEs) caused by their collateral effect on the immune system pose a key challenge for the clinical application of ICIs. Psychiatric adverse events are a class of adverse events associated with ICIs that are realistically observed in the real world. We aim to provide a comprehensive study and summary of psychiatric adverse events associated with ICIs. Methods: We obtained ICI adverse reaction reports during January 2012-December 2021 from the FDA Adverse Event Reporting System (FAERS) database. ICI reports underwent screening to minimize the influence of other adverse reactions, concomitant medications, and indications for medication use that may also contribute to psychiatric disorders. Disproportionality analysis was performed to find psychiatric adverse events associated with ICIs by comparing ICIs with the full FAERS database using the reporting odds ratio (ROR). Influencing factors were explored based on univariate logistic regression analysis. Finally, the Cancer Genome Atlas (TCGA) pan-cancer transcriptome data were combined to explore the potential biological mechanisms associated with ICI-related pAEs. Findings: Reports of psychiatric adverse events accounted for 2.71% of the overall ICI adverse event reports in the FAERS database. Five categories of psychiatric adverse events were defined as ICI-related psychiatric adverse events (pAEs). The median age of reports with ICI-related pAEs was 70 (interquartile range [IQR] 24-95), with 21.54% of reports having a fatal outcome. Cases with indications for lung cancer, skin cancer and kidney site cancer accounted for the majority. The odds of ICI-related pAEs increased in older patients (65-74: OR = 1.44 [1.22-1.70], P < 0.0001: ≥75: OR = 1.84 [1.54-2.20], P < 0.0001). The occurrence of ICI-related pAEs may be related to NOTCH signalling and dysregulation of synapse-associated pathways. Interpretation: This study investigated psychiatric adverse events highly associated with ICI treatment, their influencing factors and potential biological mechanisms, which provides a reliable basis for further in-depth study of ICI-related pAEs. However, as an exploratory study, our findings need to be further confirmed in a large-scale prospective study. Funding: This work was supported by the Natural Science Foundation of Guangdong Province (2018A030313846 and 2021A1515012593), the Science and Technology Planning Project of Guangdong Province (2019A030317020) and the National Natural Science Foundation of China (81802257, 81871859, 81772457, 82172750 and 82172811). Guangdong Basic and Applied Basic Research Foundation (Guangdong - Guangzhou Joint Fouds) (2022A1515111212). This work was supported by Key Research and Development Projects of Sichuan Science and Technology (2022YFS0221, 2022YFS0074, 2022YFS0156 and 2022YFS0378). Sichuan Provincial People's Hospital Hospital Young Talent Fund (2021QN08).

Adverse reactions associated with immune checkpoint inhibitors and bevacizumab: A pharmacovigilance analysis.

Immune checkpoint inhibitors (ICIs) combined with the anti-angiogenesis drug bevacizumab is one of the future directions of immunotherapy. However, the potential adverse drug reactions (ADRs) caused by combination therapy remain unclear. Current research on ADRs of combination therapy in cancer patients is extremely limited. Our study aims to help determine the safety of combination therapy. We downloaded the ADR reports on combination therapy, from the first quarter of 2012 to the fourth quarter of 2021, from the FDA adverse event reporting system (FAERS) database and conducted a large-scale retrospective study. The ADR signals were monitored by reporting odds ratio (ROR) and analyzing the risk of different ADRs in patients with Pan-cancer. A total of 2094 cases were selected, after excluding duplicate data and the use of chemotherapy drugs. We evaluated the risk of ADR in Pan-cancer patients. Combination therapy was an independent risk factor for adverse drug reactions associated with interstitial lung disease (OR: 8.62; 95% CI: 6.14-12.10, P < .0001), hypertension (OR: 1.35; 95% CI: 1.11-1.65, P < .01) and gastrointestinal bleeding (OR: 3.16; 95% CI: 2.21-4.51, P < .0001). A subgroup analysis revealed that the risk of endocrine system-related ADRs was elevated in patients receiving different combination therapies or with certain tumor types. We retrospectively studied the ADR of combination therapy in Pan-cancer patients and analyzed the distribution characteristics of ADR from the perspectives of treatment strategy and cancer types to provide recommendations for the individualized management of patients receiving combination therapy.

Profile analysis with reconstruction robustness for measurement data subject to outliers.

In the surface profile analysis, there are often a few observations that contain outliers. Due to the existence of outliers, the application of non-robust reconstruction algorithms for measurement data will become a huge problem because these methods are often sensitive to outliers and the approximation effectiveness will be greatly aggravated. In view of this, this paper presents a novel angle-based moving total least squares reconstruction method, to the best of our knowledge, that applies two-step pre-treatment to handle outliers. The first step is an abnormal point detection process that characterizes the geometric features of discrete points in the support domain through a new angle-based parameter constructed by total least square. Then, the point with the largest anomaly degree is removed, and a relevant weight function is defined to adjust the weights of the remaining points. After pre-treatment, the final estimates are calculated by weighted total least squares (WTLS) based on the compact weight function. The detection and removal of outliers are automatic, and there is no need to set a threshold value artificially, which effectively avoids the adverse impacts of human operation. Numerical simulations and experiments verify the applicability of the proposed algorithm as well as its accuracy and robustness.

Comprehensive Analysis Identifies PI3K/Akt Pathway Alternations as an Immune-Related Prognostic Biomarker in Colon Adenocarcinoma Patients Receiving Immune Checkpoint Inhibitor Treatment.

Introduction: In recent years, immune checkpoint inhibitors (ICIs) have attracted widespread attention and made breakthroughs in progress towards the treatment of various cancers. However, ICI therapy is selective, and its effects on many patients are not ideal. It is therefore critical to identify prognostic biomarkers of response to ICI therapy. The PI3K/Akt pathway plays important roles in tumor formation and metastasis. However, there are no published reports clarifying the relationship between PI3K/Akt pathway mutations and prognosis for colon adenocarcinoma (COAD) patients receiving immunotherapy. Methods: We collected data from a COAD cohort from The Cancer Genome Atlas (TCGA) database, including whole-exome sequencing (WES) data, RNA-seq data, and clinical data. We also collected data, including clinical prognosis and targeted sequencing data, from a cohort of COAD patients receiving immunotherapy. We collected 50 COAD patients (Local-COAD) from the Zhujiang Hospital of Southern Medical University and performed targeted sequencing. We analyzed the effects of PI3K/Akt pathway mutations on the patients' clinical prognosis, immunogenicity, and immune microenvironments. Gene set enrichment analysis (GSEA) was used to analyze the significantly upregulated and downregulated signaling pathways. We used these results to hypothesize potential mechanisms by which PI3K/Akt mutations could affect the prognosis of COAD patients. Results: Univariate and multivariate Cox analyses and Kaplan-Meier (KM) survival curves showed that patients with PI3K-Akt mutations had better overall survival (OS) than those without PI3K-Akt mutations. Genes with significant mutation rates in the two cohorts were screened by panoramic view. CIBERSORT was used to analyze changes in 22 types of immune cells to identify immune activated cells. Similarly, patients in the PI3K/Akt-mutated type (PI3K/Akt-MT) group had significantly increased immunogenicity, including increases in tumor mutation burden (TMB), neoantigen load (NAL), and MANTIS score. Using GSEA, we identified upregulated pathways related to immune response. Conclusion: PI3K/Akt pathway mutation status can be used as an independent predictor of response to ICI treatment in COAD patients. PI3K/Akt mutations are correlated with improved OS, higher immunogenicity, greater immune response scores, and increases in activated immune cells.

Micro-dimensional oscillation-based optimization for a dielectric metalens in the mid-infrared.

In the past few decades, there has been significant progress made in metasurfaces and integrated and miniaturized optical devices. As one of the most prominent applications of metasurfaces, the metalens is the subject of significant research. In this paper, for achieving better focusing performance of the initial metalens designed by the Pancharatnam-Berry (PB) phase, a concept of micro-dimensional oscillation is proposed to optimize the geometric parameters of nanopillars. A strategy of grouping iteration is proposed to reduce the loss rate and computational effort in a holistic way. Its essence is to divide an extremely large-scale optimization space into many overlapping groups. Meanwhile, an improved genetic-simulated annealing (IGSA) algorithm is presented for the optimal solution of each group. By introducing the adaptive crossover and mutation probabilities in traditional genetic algorithms, the IGSA algorithm has both strong global searching capability and excellent local searching capability. After optimization, the maximum field intensity of the central hot spot can be increased by about 8% compared to the initial metalens. Moreover, the field intensity of the side lobes around the hot spot is almost constant, and the central hot spot increases, which provides a potential for the realization of high imaging contrast.

TNF-Alpha Pathway Alternation Predicts Survival of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer.

Translational research on immune checkpoint inhibitors (ICIs) has been underway. However, in the unselected population, only a few patients benefit from ICIs. Therefore, screening predictive markers of ICI efficacy has become the current focus of attention. We collected mutation and clinical data from an ICI-treated non-small cell lung cancer (NSCLC) cohort. Then, a univariate Cox regression model was used to analyze the relationship between tumor necrosis factor α signaling mutated (TNFα-MT) and the prognosis of immunotherapy for NSCLC. We retrospectively collected 36 NSCLC patients (local-cohort) from the Zhujiang Hospital of Southern Medical University and performed whole-exome sequencing (WES). The expression and mutation data of The Cancer Genome Atlas (TCGA)-NSCLC cohort were used to explore the association between TNFα-MT and the immune microenvironment. A local cohort was used to validate the association between TNFα-MT and immunogenicity. TNFα-MT was associated with significantly prolonged overall survival (OS) in NSCLC patients after receiving immunotherapy. Additionally, TNFα-MT is related to high immunogenicity (tumor mutational burden, neoantigen load, and DNA damage response signaling mutations) and enrichment of infiltrating immune cells. These results suggest that TNFα-MT may serve as a potential clinical biomarker for NSCLC patients receiving ICIs.

A Novel Reconstruction Method for Measurement Data Based on MTLS Algorithm.

Reconstruction methods for discrete data, such as the Moving Least Squares (MLS) and Moving Total Least Squares (MTLS), have made a great many achievements with the progress of modern industrial technology. Although the MLS and MTLS have good approximation accuracy, neither of these two approaches are robust model reconstruction methods and the outliers in the data cannot be processed effectively as the construction principle results in distorted local approximation. This paper proposes an improved method that is called the Moving Total Least Trimmed Squares (MTLTS) to achieve more accurate and robust estimations. By applying the Total Least Trimmed Squares (TLTS) method to the orthogonal construction way in the proposed MTLTS, the outliers as well as the random errors of all variables that exist in the measurement data can be effectively suppressed. The results of the numerical simulation and measurement experiment show that the proposed algorithm is superior to the MTLS and MLS method from the perspective of robustness and accuracy.

The mechanobiology of actin cytoskeletal proteins during cell-cell fusion.

Myosin II and spectrin ß display mechanosensitive accumulations in invasive protrusions during cell-cell fusion of Drosophila myoblasts. The biochemical inhibition and deactivation of these proteins results in significant fusion defects. Yet, a quantitative understanding of how the protrusion geometry and fusion process are linked to these proteins is still lacking. Here we present a quantitative model to interpret the dependence of the protrusion size and the protrusive force on the mechanical properties and microstructures of the actin cytoskeleton and plasma membrane based on a mean-field theory. We build a quantitative linkage between mechanosensitive accumulation of myosin II and fusion pore formation at the tip of the invasive protrusion through local area dilation. The mechanical feedback loop between myosin II and local deformation suggests that myosin II accumulation possibly reduces the energy barrier and the critical radius of fusion pores. We also analyse the effect of spectrin ß on maintaining the proper geometry of the protrusions required for the success of cell-cell fusion.

[Study on oil-soluble components obtained from the fruit of Evoldia rutaecarpa].

OBJECTIVE: To extract and isolate the biologic-active components of the oil-soluble components obtained from the fruit of Evodia rutaecarpa. METHODS: Various chromatographic techniques were used to isolate and purifie the biologic-active components, the IR and NMR spectra were used to identify the structure of this compound from Evodia rutaecarpa, and the content and the chemical structure was calibrated with a standard mixture was by TLC. RESULTS: A crystal compound was isolated from the Evodia rutaecarpa of Rutaceae, and was elucidated as oleanolic acid. CONCLUSION: The main chemical constituents of oil-soluble components obtained from the fruit of Evodia rutaecarpa are terpenoid compounds, the content of oleanolic acid is 1.8%.