Alternative splicing variants involved in pyroptosis and cuproptosis contribute to phenotypic remodeling of the tumor microenvironment in cervical cancer.

Cervical cancer (CC) remains a prevalent gynecological malignancy, posing a significant health burden among women worldwide. With the remarkable discoveries of cellular pyroptosis and cuproptosis, there has been a growing focus on exploring the intricate relationship between these two forms of cell death and their impact on tumor progression. In recent years, alternative splicing has emerged as a significant field in cancer research. Thus, the integration of alternative splicing, pyroptosis, and cuproptosis holds immense value in studying their collective impact on the occurrence and progression of cervical cancer. In this study, alternative splicing data of pyroptosis- and cuproptosis-associated genes were integrated with public databases, including TCGA, to establish a prognostic model for cervical cancer based on COX regression modeling. Subsequently, the tumor microenvironment (TME) phenotypes in the high-risk and low-risk patient groups were characterized through a comprehensive bioinformatics analysis. The findings of this study revealed that the low-risk group exhibited a predominant immune-active TME phenotype, while the high-risk group displayed a tumor-favoring metabolic phenotype. These results indicate that the alternative splicing of pyroptosis- and cuproptosis-associated genes plays a pivotal role in remodeling the phenotypic landscape of the cervical cancer TME by modulating immune responses and metabolic pathways. This study provides valuable insights into the interplay between alternative splicing variants involved in pyroptosis and cuproptosis and the TME, contributing to a deeper understanding of cervical cancer pathogenesis and potential therapeutic avenues.

Dalpiciclib partially abrogates ER signaling activation induced by pyrotinib in HER2+HR+ breast cancer.

Recent evidences from clinical trials (NCT04486911) revealed that the combination of pyrotinib, letrozole, and dalpiciclib exerted optimistic therapeutic effect in treating HER2+HR+ breast cancer; however, the underlying molecular mechanism remained elusive. Through the drug sensitivity test, the drug combination efficacy of pyrotinib, tamoxifen, and dalpiciclib to BT474 cells was tested. The underlying molecular mechanisms were investigated using immunofluorescence, Western blot analysis, immunohistochemical staining, and cell cycle analysis. Potential risk factor that may indicate the responsiveness to drug treatment in HER2+/HR+ breast cancer was identified using RNA-sequence and evaluated using immunohistochemical staining and in vivo drug susceptibility test. We found that pyrotinib combined with dalpiciclib exerted better cytotoxic efficacy than pyrotinib combined with tamoxifen in BT474 cells. Degradation of HER2 could enhance ER nuclear transportation, activating ER signaling pathway in BT474 cells, whereas dalpiciclib could partially abrogate this process. This may be the underlying mechanism by which combination of pyrotinib, tamoxifen, and dalpiciclib exerted best cytotoxic effect. Furthermore, CALML5 was revealed to be a risk factor in the treatment of HER2+/HR+ breast cancer and the usage of dalpiciclib might overcome the drug resistance to pyrotinib + tamoxifen due to CALML5 expression. Our study provided evidence that the usage of dalpiciclib in the treatment of HER2+/HR+ breast cancer could partially abrogate the estrogen signaling pathway activation caused by anti-HER2 therapy and revealed that CALML5 could serve as a risk factor in the treatment of HER2+/HR+ breast cancer.

Phenotypic Plasticity Conferred by the Metastatic Microenvironment of the Brain Strengthens the Intracranial Tumorigenicity of Lung Tumor Cells.

Lung cancer is the leading cause of cancer-related deaths and is the primary source of brain metastases. Despite great advances in the study of the genetics and etiology of lung cancer in previous decades, the identification of the factors and mechanisms underlying the brain metastasis of lung tumors is still an open question. In this study, the results of bioinformatic conjoint analysis revealed that the metastatic microenvironment in the brain conferred lung tumor cell phenotypic plasticity, characterized by neural cell-like and embryonic-stem cell-like features. Meanwhile, the metabolic phenotype of the educated tumor cells underwent transition characterized by oxygen-related metabolism. The results of the experiments demonstrated that the downregulation of HOXB9 weakened the tumorigenicity of lung tumor cells. Bioinformatic prediction analysis also determined that many cell cycle-associated factors were potentially transcribed by HOXB9. Collectively, the results of this study suggested that under the influence of the metastatic environment of the brain, lung tumor cells seemed to acquire phenotypic plasticity characterized by neural cell-like features, and this transition may be associated with the aberrant upregulation of HOXB9.

BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining.

Tumor microenvironment (TME) plays a crucial role in the initiation and progression of lung adenocarcinoma (LUAD); however, there is still a challenge in understanding the dynamic modulation of the immune and stromal components in TME. In the presented study, we applied CIBERSORT and ESTIMATE computational methods to calculate the proportion of tumor-infiltrating immune cell (TIC) and the amount of immune and stromal components in 551 LUAD cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were analyzed by COX regression analysis and protein-protein interaction (PPI) network construction. Then, Bruton tyrosine kinase (BTK) was determined as a predictive factor by the intersection analysis of univariate COX and PPI. Further analysis revealed that BTK expression was negatively correlated with the clinical pathologic characteristics (clinical stage, distant metastasis) and positively correlated with the survival of LUAD patients. Gene Set Enrichment Analysis (GSEA) showed that the genes in the high-expression BTK group were mainly enriched in immune-related activities. In the low-expression BTK group, the genes were enriched in metabolic pathways. CIBERSORT analysis for the proportion of TICs revealed that B-cell memory and CD8+ T cells were positively correlated with BTK expression, suggesting that BTK might be responsible for the preservation of immune-dominant status for TME. Thus, the levels of BTK might be useful for outlining the prognosis of LUAD patients and especially be a clue that the status of TME transition from immune-dominant to metabolic activity, which offered an extra insight for therapeutics of LUAD.

Cross-talk of Signaling Pathways in the Pathogenesis of Allergic Asthma and Cataract.

Allergic asthma is a chronic inflammatory disease, which involves many cellular and cellular components. Cataract is a condition that affects the transparency of the lens, which the opacity of the lens caused by any innate or acquired factor degrades its transparency or changes in color. Both of them belong to diseases induced by immune disorders or inflammation. We want to confirm the signaling pathways involved in the regulation of asthma and cataract simultaneously, and provide reference for the later related experiments. So we conducted a scoping review of many databases and searched for studies (Academic research published in Wiley, Springer and Bentham from 2000 to 2019) about the possible relationship between asthma and cataract. It was found that during the onset of asthma and cataract, Rho/Rock signaling pathway, Notch signaling pathway, Wnt/ß-catenin signaling pathway, PI3K/AKT signaling pathway, JAK/STAT signaling pathway, MAPK signaling pathway, TGF-ß1/Smad signaling pathway and NF-κB signaling pathway are all active, so they may have a certain correlation in pathogenesis. Asthma may be associated with cataract through the eight signaling pathways, causing inflammation or immune imbalance based on allergy that can lead to cataract. According to these studies, we speculated that the three most likely signaling pathways are PI3K/AKT, MAPK and NF-κB signaling pathway.

Structural optimization and anti-allergic activity of nucleotide aptamers target to Cε3-Cε4.

Nucleic acid aptamers have shown a broad application prospect in basic research, clinical diagnosis and treatment, new drug development and various other fields. We have screened the DNA aptamer A1 and A2 target at Cε3-Cε4 with high affinity and specificity, another aptamer A8, no affinity with Cε3-Cε4 protein, was as a negative control in this study. The structures of aptamer A1 and A2 were optimized using the deletion method, complementary sequence method, and point mutation method, to make them perform biological functions better, improve the pertinence of the subsequent modification and study the mechanism of action of aptamers coupled Cε3-Cε4. Additionally, the affinity was detected using competitive ELISA, then the most optimal and minimalist aptamer G39-A1-29C was obtained. The results indicated that the G39-A1-29C can significantly inhibit the IgE-dependent cell degranulation, but no effect in IgE-independent manner, and have a notable therapeutic effect with dose-dependent on PCA experiments in vivo. Moreover, it is found that the aptamer maintains the secondary structure through the fixed sequence, consecutive four GC pairings can significantly increase the binding affinity, and the G base on the loop region of A1 may be the key sites for binding to the domain of the target protein Cε3-Cε4. Therefore, the stem-loop structure of A1 is the structural basis of its binding, too short sequence cannot maintain the secondary structure, so that its affinity is significantly reduced. The results facilitated the modification and chemical synthesis of aptamers in next work, which provided the foundation for the development of new drugs for the treatment of allergy diseases.

The Unique Inhibitory IgG Receptor--FcγRIIb.

BACKGROUND: FcγRIIb is the only inhibitory IgG receptor, which is divided into three subtypes of FcγRIIb1, FcγRIIb2 and FcγRIIb3. It is mainly responsible for the immune balance in vivo by cross-linking with the activated receptor to intracellular transduction inhibitory signals, and it plays an important biological role in the negative regulation of innate immunity and adaptive immunity. An abnormal expression of FcγRIIb on cells would result in autoimmune diseases, infectious diseases, and so forth. CONCLUSION: FcγRIIb modulates immune responses and further treats related diseases by inhibiting the activation of B lymphocytes, monocytes, mast cells, and basophils induced by activating receptors. It can be used in biotherapeutic methods such as monoclonal antibodies, chimeric recombinant proteins, bispecific antibodies, etc. Our increased understanding of FcγRIIb function also has a foundation for further research and development of FcγRIIb, which also provides potentially farreaching therapeutic implications.

Enhanced productivity of protease-sensitive heterologous proteins by disruption of multiple protease genes in the fission yeast Schizosaccharomyces pombe.

The creation of protease-deficient mutants to avoid product degradation is one of the current strategies employed to improve productivity and secretion efficiency of heterologous protein expression. We previously constructed a set of single protease-deficient mutants of the fission yeast Schizosaccharomyces pombe by respective disruption of 52 protease genes, and we succeeded in confirming useful disruptants (Idiris et al., Yeast 23:83-99, 2006). In the present study, we attempted multiple deletions of 13 protease genes, single deletions of which were previously confirmed as being beneficial for reducing extracellular product degradation. Using PCR-based gene replacement, a series of multiple deletion strains was constructed by multiple disruption of a maximum of seven protease genes. Effects of the resultant multiple deletion strains on heterologous expression were then measured by practical expression of a proteolytically sensitive model protein, the human growth hormone (hGH). Time profiles of hGH secretion from each resultant mutant demonstrated significantly enhanced hGH productivity with processing of the multiple protease deletions. The data clearly indicated that disruption of multiple protease genes in the fission yeast is an effective method for controlling proteolytic degradation of heterologous proteins particularly susceptible to proteases.

Construction of a protease-deficient strain set for the fission yeast Schizosaccharomyces pombe, useful for effective production of protease-sensitive heterologous proteins.

One of the major problems hindering effective production and purification of heterologous proteins from the fission yeast Schizosaccharomyces pombe is proteolytic degradation of the recombinant gene products by host-specific proteases. As an initial solution to this problem, we constructed a protease-deficient disruptant set by respective disruption of 52 Sz. pombe protease genes. Functional screening of the resultant set was performed by observing secretory production of a proteolytically sensitive model protein, human growth hormone (hGH). The results indicated that some of the resultant disruptants were effective in reducing hGH degradation, as observed during the hGH expression procedure and mainly as a result of unknown serine- and/or cysteine-type proteases in the culture medium. These findings also demonstrated that construction of a protease-deficient strain set is not only useful for practical application in protein production, but also for functional screening, specification and modification of proteases in Sz. pombe, where further investigations of proteolytic processes and improvement through multiple gene manipulations are required.

Distribution of virulence-associated genes in Vibrio mimicus isolates from clinical and environmental origins.

Distribution of virulence-associated genes in Vibrio mimicus was studied including the toxin genes ctxA, tdh, st and vmh and the genes necessary for regulation of toxin production, toxR, toxS, toxT, tcpA and tcpP. Approximately half of clinical V. mimicus isolates possessed one or more genes encoding V. cholerae enterotoxic factors such as ctxA, tdh and st. All of the clinical and environmental isolates possessed vmh encoding V. mimicus hemolysin (VMH). The ctxA encoding cholera toxin was detected in only 2 strains, 5% of the clinical isolates. Furthermore, there were very few strains possessing tcpP and toxT needed for the expression of ctxA. These results may suggest that VMH is a more important pathogenic factor than well recognized toxins such as cholera toxin (CT) in V. mimicus infection.