The role of Keap1-Nrf2 signaling pathway in the treatment of respiratory diseases and the research progress on targeted drugs.

Lungs are exposed to external oxidants from the environment as in harmful particles and smog, causing oxidative stress in the lungs and consequently respiratory ailment. The NF-E2-related factor 2 (Nrf2) is the one with transcriptional regulatory function, while its related protein Kelch-like ECH-associated protein 1 (Keap1) inhibits Nrf2 activity. Together, they form the Keap1-Nrf2 pathway, which regulates the body's defense against oxidative stress. This pathway has been shown to maintain cellular homeostasis during oxidative stressing, inflammation, oncogenesis, and apoptosis by coordinating the expression of cytoprotective genes and making it a potential therapeutic target for respiratory diseases. This paper summarizes this point in detail in Chapter 2. In addition, this article summarizes the current drug development and clinical research progress related to the Keap1-Nrf2 signaling pathway, with a focus on the potential of Nrf2 agonists in treating respiratory diseases. Overall, the article reviews the regulatory mechanisms of the Keap1-Nrf2 signaling pathway in respiratory diseases and the progress of targeted drug research, aiming to provide new insights for treatment.

Thoracic epithelioid inflammatory myofibroblastic sarcoma: a rare and aggressive disease with case report and literature review.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare subtype of inflammatory myofibroblastic tumor, characterized to be an aggressive disease with high frequency of ALK rearrangement, rapid recurrence, and poor prognosis. Primary EIMS of thoracic origin is rarely observed. Herein, we described a case of 28-year-old female developed primary EIMS in the anterior mediastinum with hepatic metastasis. The EIMS displayed sheet-like growth of epithelioid and spindle cells with enlarged nuclei, abundant and eosinophilic cytoplasm, and infiltration of inflammatory cells. Immunohistochemical staining revealed positive expression of ALK in the nuclear membrane, and ALK rearrangement was identified by polymerase chain reaction assay. Alectinib showed partial response, and achieved a meaningful survival benefit for four months. Based on this case report and literature review, ALK inhibitor reveals promising activity on the rare but aggressive EIMS. Awareness of EIMS in thoracic disease and its clinicopathological features is essential to avoid erroneous diagnosis.

Roles of naïve CD4+ T cells and their differentiated subtypes in lung adenocarcinoma and underlying potential regulatory pathways.

BACKGROUND: Naïve CD4+ T cells and their differentiated counterparts play a significant regulatory role in the tumor immune microenvironment, yet their effects on lung adenocarcinoma (LUAD) are not fully understood. METHODS: We utilized Mendelian randomization to assess the causal association between naïve CD4+ T cells and LUAD. Employing a modified single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm with The Cancer Genome Atlas (TCGA) database, we determined the infiltration levels of naïve CD4+ T cells and their differentiation subtypes and investigated their correlation with clinical characteristics. Potential regulatory pathways of T helper cells were identified through Mantel tests and Kyoto Encyclopedia of Genes and Genomes (KEGG) database enrichment analysis. RESULTS: Mendelian randomization analysis revealed an inhibitory effect of naïve CD4+ T cells on LUAD (false discovery rate < 0.05), which was corroborated by observational experiments using TCGA database. Specifically, T helper cell type 2 demonstrated a promotive effect on LUAD in terms of overall, disease-free, and progression-free survival (p < 0.05). Moreover, regulatory T cells exhibited a protective effect on LUAD in terms of disease-specific survival (p < 0.01). Concurrently, we explored the overall impact of naïve CD4+ T cell differentiation subtypes on LUAD, revealing upregulation in pathways such as neutrophil degranulation, MAPK family signaling pathways, and platelet activation, signaling, and aggregation. CONCLUSION: Naïve CD4+ T cells and their differentiated counterparts play essential regulatory roles in the tumor immune microenvironment, demonstrating bidirectionality in their effects.Thus, elucidating the mechanisms and developing novel cell differentiation-inducing agents will benefit anti-cancer therapy.

Progress in culture technology and active substance research on Nostoc sphaeroides Kützing.

Nostoc sphaeroides Kützing is a freshwater edible cyanobacterium that is rich in active substances such as polysaccharides, proteins and lipids; it has a variety of pharmacological effects such as antioxidant, anti-inflammatory, antitumor and cholesterol-lowering effects; and is often used as a traditional Chinese medicine with many potential applications in food, cosmetics, medical diagnostics and disease treatment. However, to meet the needs of different fields, such as medicine, there is an urgent need for basic research and technological innovation in culture technology, extraction and preparation of active substances, and the pharmacological mechanism of N. sphaeroides. This paper reviews the pharmacological effects of N. sphaeroides active substances, discusses current culture techniques and methods for extracting active components, and outlines the challenges encountered in cultivating and industrializing N. sphaeroides while discussing future development trends. © 2024 Society of Chemical Industry.

Clinical and structural insights into the rare but oncogenic HER2-activating missense mutations in non-small cell lung cancer: a retrospective ATLAS cohort study.

BACKGROUND: Unlike human epidermal growth factor receptor 2 (HER2) amplification or exon 20 insertions, missense mutations in the extracellular domain (ECD), transmembrane domain (TMD), and intracellular domain (ICD) of the HER2 protein have been implicated as oncogenic in non-small cell lung cancer (NSCLC). However, their molecular subtypes, structural disparities, and clinical responses to current medical treatments, particularly HER2-targeted tyrosine kinase inhibitors (TKIs), remain unclear in NSCLC and warrant investigation. METHODS: A real-world observational ATLAS study was conducted to gather and analyze therapeutic outcomes of chemotherapy or TKIs for heterogeneous HER2 missense mutations in NSCLC. Computational models of typical ECD, TMD, and ICD mutations were utilized to explore their structural variances. RESULTS: We screened 37 eligible patients with HER2-activating missense mutations, of which 35 patients who had received chemotherapy or HER2-targeted TKIs as first-line therapy were available for response assessment. The median progression-free survival (PFS) for chemotherapy was 4.43 months (95% confidence interval [CI], 3.77-5.10), with an objective response rate (ORR) of 26.1% (6/23) and a disease control rate (DCR) of 17/23 (73.9%). The administration of afatinib, dacomitinib, and pyrotinib, HER2-targeted TKIs, achieved a median PFS of 4.65 months, with an ORR of 33.3% (4/12) and a DCR of 83.3% (10/12). Molecular modeling and computational simulations of ECD, TMD, and ICD mutations revealed their distinct structural characteristics. CONCLUSION: In comparison to chemotherapy, HER2-targeted TKIs demonstrated similar activity and PFS benefits for HER2-activating missense mutations in NSCLC.

Rule-based omics mining reveals antimicrobial macrocyclic peptides against drug-resistant clinical isolates.

Antimicrobial resistance remains a significant global threat, driving up mortality rates worldwide. Ribosomally synthesized and post-translationally modified peptides have emerged as a promising source of novel peptide antibiotics due to their diverse chemical structures. Here, we report the discovery of new aminovinyl-(methyl)cysteine (Avi(Me)Cys)-containing peptide antibiotics through a synergistic approach combining biosynthetic rule-based omics mining and heterologous expression. We first bioinformatically identify 1172 RiPP biosynthetic gene clusters (BGCs) responsible for Avi(Me)Cys-containing peptides formation from a vast pool of over 50,000 bacterial genomes. Subsequently, we successfully establish the connection between three identified BGCs and the biosynthesis of five peptide antibiotics via biosynthetic rule-guided metabolic analysis. Notably, we discover a class V lanthipeptide, massatide A, which displays excellent activity against gram-positive pathogens, including drug-resistant clinical isolates like linezolid-resistant S. aureus and methicillin-resistant S. aureus, with a minimum inhibitory concentration of 0.25 µg/mL. The remarkable performance of massatide A in an animal infection model, coupled with a relatively low risk of resistance and favorable safety profile, positions it as a promising candidate for antibiotic development. Our study highlights the potential of Avi(Me)Cys-containing peptides in expanding the arsenal of antibiotics against multi-drug-resistant bacteria, offering promising drug leads in the ongoing battle against infectious diseases.

Dacomitinib exhibits promising activity against the rare HER2 exon 20 insertion M774delinsWLV in lung cancer: A case report and literature review.

A775_G776insYVMA, the typical and predominant HER2 exon 20 insertion variant in non-small cell lung cancer, exhibits relative insensitivity to covalent HER2-targeted tyrosine kinase inhibitors. However, other less common insertions have shown better responses to HER2-targeted inhibitors. M774delinsWLV is a rare HER2 exon 20 insertion subtype and its clinical sensitivity to HER2-targeted inhibitors remains unclear. Furthermore, there is a lack of current studies to elucidate its structure and predict its sensitivity to HER2-targeted tyrosine kinase inhibitors. Herein, we presented a case of non-small cell lung cancer harboring M774delinsWLV who derived favorable response and significant survival benefit from HER2-targeted tyrosine kinase inhibitors. A 60-year-old male with metastatic lung adenocarcinoma carrying M774delinsWLV received pyrotinib monotherapy as first-line treatment. After rapid disease progression at three months, sequential combination therapy with pyrotinib and bevacizumab yielded promising antitumor activity and sustained progression-free survival benefits for nearly a year. Subsequent dacomitinib monotherapy displayed significant activity against this uncommon insertion, resulting in a rapid decrease in tumor markers and partial response, along with progression-free survival of one year. The molecular simulation revealed no significant differences in the overall protein structure and binding pocket region between M774delinsWLV and the HER2 wild type. Drug binding dynamics simulation indicated that dacomitinib exhibited the most potent binding activity compared to afatinib, pyrotinib and poziotinib. Conclusively, dacomitinib exhibited promising efficacy against the rare HER2 exon 20 insertion M774delinsWLV. Extensive investigation is needed to elucidate the effects of HER2-targeted tyrosine kinase inhibitors on non-small cell lung cancer with different HER2 insertion subtypes.

Triton X-100 counteracts antibiotic resistance of Enterococcus faecalis: An in vitro study.

OBJECTIVES: The high prevalence of antibiotic-resistant bacteria poses a threat to the global public health. The appropriate use of adjuvants to restore the antimicrobial activity of antibiotics against resistant bacteria could be an effective strategy for combating antibiotic resistance. In this study, we investigated the counteraction of Triton X-100 (TX-100) and the mechanisms underlying the antibiotic resistance of Enterococcus faecalis (E. faecalis). METHODS: Standard, wild-type (WT), and induced antibiotic-resistant E. faecalis strains were used in this study. In vitro antibacterial experiments were conducted to evaluate the antimicrobial activities of gentamicin sulfate and ciprofloxacin hydrochloride in the presence and absence of 0.02 % TX-100 against both planktonic and biofilm bacteria. Transcriptomic and untargeted metabolomic analyses were performed to explore the molecular mechanisms of TX-100 as an antibiotic adjuvant. Additionally, membrane permeability, membrane potential, glycolysis-related enzyme activity, intracellular adenosine triphosphate (ATP), and expression levels of virulence genes were assessed. The biocompatibility of different drug combinations was also evaluated. RESULTS: A substantially low TX-100 concentration improved the antimicrobial effects of gentamicin sulfate or ciprofloxacin hydrochloride against antibiotic-resistant E. faecalis. Mechanistic studies demonstrated that TX-100 increased cell membrane permeability and dissipated membrane potential. Moreover, antibiotic resistance and pathogenicity of E. faecalis were attenuated by TX-100 via downregulation of the ABC transporter, phosphotransferase system (PTS), and ATP supply. CONCLUSIONS: TX-100 enhanced the antimicrobial activity of gentamicin sulfate and ciprofloxacin hydrochloride at a low concentration by improving antibiotic susceptibility and attenuating antibiotic resistance and pathogenicity of E. faecalis. CLINICAL SIGNIFICANCE: These findings provide a theoretical basis for developing new root canal disinfectants that can reduce antibiotic resistance.

Therapeutic effect of phycocyanin on chronic obstructive pulmonary disease in mice.

INTRODUCTION: The prevention and treatment of chronic obstructive pulmonary disease (COPD) is closely tied to antioxidation and anti-inflammation. Phycocyanin (PC) has numerous pharmacological effects, such as antioxidation and anti-inflammation. However, it remains unclear whether PC can play a therapeutic role in COPD. OBJECTIVE: As inflammation and oxidative stress can aggravate COPD, this study is to explore the effect of PC on COPD mice and its mechanisms. METHODS: The COPD mice model was established by exposing them to lipopolysaccharide (LPS) and cigarette smoke (CS); PC was administrated in a concentration of 50 mg/kg for 30 days. On the last day, lung function was measured, and bronchoalveolar lavage fluid (BALF) was obtained and classified for cells. Lung tissue pathological change was analyzed, and organ indices statistics were measured. Based on molecular docking, the mechanism was explored with Western blotting, immunohistochemical, and immunofluorescence in vivo and in vitro. RESULTS: PC significantly ameliorated the pulmonary function of COPD mice and reduced inflammation of the lung (p < 0.05), and hematoxylin and eosin (H&E) staining showed PC depressed lung inflammatory cell accumulation and emphysema. Periodic acid Schiff (PAS) and Masson staining revealed that PC retarded goblet cells metaplasia and collagen deposition (p < 0.05). In addition, in vivo PC regulated Heme oxygenase 1 (HO-1) (p < 0.05) and NAD(P)H dehydrogenase quinone 1 (NQO1) level (p < 0.01) in the lung, as well as NOX2 level in pulmonary macrophages. Molecular docking results indicate that phycocyanobilin (PCB) in PC had a good binding site in Keap1 and NOX2 proteins; the phycocyanobilin-bound phycocyanin peptide (PCB-PC-peptide) was obtained for further studies. In vitro, PCB-PC-peptide could depress the phospho-NF-E2-related factor 2 (p-Nrf2) and NQO1 protein expression in RAW264.7 cells induced by cigarette smoke extract (CSE) (p < 0.05). CONCLUSION: PC exerts beneficial effects on COPD via anti-inflammatory and antioxidative stress, which may be achieved through PCB.

Exploration in the Mechanism of Ginsenoside Rg5 for the Treatment of Osteosarcoma by Network Pharmacology and Molecular Docking.

OBJECTIVE: Osteosarcoma is a primary malignancy originating from mesenchymal tissue characterized by rapid growth, early metastasis and poor prognosis. Ginsenoside Rg5 (G-Rg5) is a minor ginsenoside extracted from Panax ginseng C.A. Meyer which has been discovered to possess anti-tumor properties. The objective of current study was to explore the mechanism of G-Rg5 in the treatment of osteosarcoma by network pharmacology and molecular docking technology. METHODS: Pharmmapper, SwissTargetPrediction and similarity ensemble approach databases were used to obtain the pharmacological targets of G-Rg5. Related genes of osteosarcoma were searched for in the GeneCards, OMIM and DrugBank databases. The targets of G-Rg5 and the related genes of osteosarcoma were intersected to obtain the potential target genes of G-Rg5 in the treatment of osteosarccoma. The STRING database and Cytoscape 3.8.2 software were used to construct the protein-protein interaction (PPI) network, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) platform was used to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. AutoDock vina software was used to perform molecular docking between G-Rg5 and hub targets. The hub genes were imported into the Kaplan-Meier Plotter online database for survival analysis. RESULTS: A total of 61 overlapping targets were obtained. The related signaling pathways mainly included PI3K-Akt signaling pathway, Proteoglycans in cancer, Lipid and atherosclerosis and Kaposi sarcoma-associated herpesvirus infection. Six hub targets including PIK3CA, SRC, TP53, MAPK1, EGFR, and VEGFA were obtained through PPI network and targets-pathways network analyses. The results of molecular docking showed that the binding energies were all less than -7 kcal/mol. And the results of survival analysis showed TP53 and VEGFA affect the prognosis of sarcoma patients. CONCLUSION: This study explored the possible mechanism of G-Rg5 in the treatment of osteosarcoma using network pharmacology method, suggesting that G-Rg5 has the characteristics of multi-targets and multi-pathways in the treatment of osteosarcoma, which lays a foundation for the follow-up experimental and clinical researches on the therapeutic effects of G-Rg5 on osteosarcoma.

Bacterial Cytochrome P450 Catalyzed Post-translational Macrocyclization of Ribosomal Peptides.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a fascinating group of natural products that exhibit diverse structural features and bioactivities. P450-catalyzed RiPPs stand out as a unique but underexplored family. Herein, we introduce a rule-based genome mining strategy that harnesses the intrinsic biosynthetic principles of RiPPs, including the co-occurrence and co-conservation of precursors and P450s and interactions between them, successfully facilitating the identification of diverse P450-catalyzed RiPPs. Intensive BGC characterization revealed four new P450s, KstB, ScnB, MciB, and SgrB, that can catalyze the formation of Trp-Trp-Tyr (one C-C and two C-N bonds), Tyr-Trp (C-C bond), Trp-Trp (C-N bond), and His-His (ether bond) crosslinks, respectively, within three or four residues. KstB, ScnB, and MciB could accept non-native precursors, suggesting they could be promising starting templates for bioengineering to construct macrocycles. Our study highlights the potential of P450s to expand the chemical diversity of strained macrocyclic peptides and the range of biocatalytic tools available for peptide macrocyclization.

First-line immunotherapy or angiogenesis inhibitor combined with chemotherapy for advanced non-small cell lung cancer with EGFR exon 20 insertions: Real-world evidence from China.

BACKGROUND: Currently, survival benefit of immunotherapy in advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ex20ins) is controversial, though it generally indicates poor response and activity. Compared with standard chemotherapy in combination with bevacizumab, first-line chemotherapy plus immune checkpoint inhibitor (ICI) in advanced NSCLC with EGFR ex20ins remains elusive and lacks real-world evidence. PATIENTS AND METHODS: A retrospective real-world study was conducted to evaluate clinical outcomes of chemotherapy alone (C), chemotherapy plus ICI (C + I), or chemotherapy plus angiogenesis inhibitors (C + A) as first-line strategies for advanced NSCLC patients with EGFR ex20ins. Investigator-assessed response and survival outcomes were compared between subgroups. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to reveal concomitant alterations and explore the molecular landscape of ex20ins. RESULTS: A total of 164 patients were screened, identifying 35 kinds of ex20ins, and 122 cases treated with C, C + I, and C + A were finally included in the first-line analysis. C + A achieved much better objective response rate (ORR, 38.1% vs. 18.2%) and significant progression-free survival (PFS) benefit compared with C (median, 7.73 vs.5.93 months, HR = 0.60, 95% CI: 0.40-0.90, p = 0.014), and it showed similar ORR (38.1% vs. 40.0%), but higher disease control rate (DCR, 96.8% vs. 80.0%) and numerically longer median PFS (7.73 vs. 6.53 months, HR = 0.83, 95% CI: 0.44-1.56, p = 0.30) than C + I. There was no PFS difference between C + I and C, despite of PD-L1 expression or tumor mutational burden. KEGG analysis revealed concomitant upregulation of PI3K/AKT signaling might mediate intrinsic resistance to ICI in ex20ins. CONCLUSION: First-line chemotherapy plus angiogenesis inhibitors might yield more survival benefits than chemotherapy alone for NSCLC with EGFR ex20ins, whereas, it suggests that chemotherapy in combination with ICI might not obtain a better survival benefit for this subset of patients. Activation of PI3K/AKT signaling might mediate intrinsic immunosuppression in NSCLC with EGFR ex20ins.

EGFR uncommon alterations in advanced non-small cell lung cancer and structural insights into sensitivity to diverse tyrosine kinase inhibitors.

Background: Approximately 10% of patients with non-small cell lung cancer (NSCLC) harbor uncommon epidermal growth factor receptor (EGFR) alterations. This study aims to investigate the therapeutic responses and predict the binding activity of different tyrosine kinase inhibitors (TKIs) for EGFR uncommon alterations. Methods: Between May 2014 and June 2021, clinical outcomes of NSCLC patients harboring EGFR uncommon alterations who received diverse treatment modalities: first-generation (1G) EGFR-TKI, second-generation (2G) EGFR-TKI afatinib, chemotherapy, and 1G TKI in combination with chemotherapy as the initial therapy were retrospectively analyzed, and structural analysis for the binding activity of major uncommon subtypes G719A, S768I, and L861Q to different TKIs were predicted. Results: A total of 102 NSCLC patients harboring EGFR uncommon alterations with treatment and survival outcomes were included and analyzed. The majority of patients presented compound mutations (54.9%), and G719X plus S768I was the predominant subtype (n = 33, 32.3%). There was a significant difference in median progression-free survival (mPFS) between therapeutic patterns (p = 0.015) and EGFR alteration subtypes (p = 0.017). Rather than almonertinib and furmonertinib, afatinib, dacomitinib and osimertinib revealed favorable binding activity to G719A mutation. In contrast, S768I and L861Q mutation indicated an unaffected binding activity to these diverse kinds of EGFR TKIs. Conclusion: Together with afatinib, 1G-TKIs combined with chemotherapy might be another effective option for NSCLC patients harboring EGFR uncommon alterations. Based on computational findings, afatinib, dacomitinib, and osimertinib might confer favorable activity to G719A, S768I, and L861Q, whereas almonertinib and furmonertinib revealed less activity to G719A.

GNG12 as A Novel Molecular Marker for the Diagnosis and Treatment of Glioma.

Purpose: GNG12 influences a variety of tumors; however, its relationship with glioma remains unclear. The aim of this study was to comprehensively investigate the relationship between GNG12 and the clinical characteristics and prognosis of glioma patients and reveal the mechanisms causing the malignant process of GNG12. Materials and Methods: We obtained information on clinical samples from multiple databases. The expression level of GNG12 was validated using a RT-qPCR and IHC. KM curves were used to assess the correlation between the GNG12 expression and OS of glioma patients. An ROC curve was drawn to assess the predictive performance of GNG12. Univariate and multivariate Cox analyses were performed to analyze the factors affecting the prognosis of patients with glioma. GSEA and TIMER databases were used to estimate the relationship between GNG12 expression, possible molecular mechanisms, and immune cell infiltration. CMap analysis was used to screen candidate drugs for glioma. Subsequent in vitro experiments were used to validate the proliferation and migration of glioma cells and to explore the potential mechanisms by which GNG12 causes poor prognosis in gliomas. Results: GNG12 was overexpressed in glioma patients and GNG12 expression level correlated closely with clinical features, including age and histological type, etc. Subsequently, the K-M survival analysis indicated that the expression level of GNG12 was relevant to the prognosis of glioma, and the ROC curve implied that GNG12 can predict glioma stability. Univariate and multivariate analyses showed that GNG12 represents a risk factor for glioma occurrence. GNG12 expression is closely associated with some immune cells. Additionally, several in vitro experiments demonstrated that down-regulation of GNG12 expression can inhibits the proliferation and migration capacity of glioma cells. Ultimately, the results for the GSEA and WB experiments revealed that GNG12 may promote the malignant progression of gliomas by regulating the cell adhesion molecule cell signaling pathway. Conclusion: In this study, we identified GNG12 as a novel oncogene elevated in gliomas. Reducing GNG12 expression inhibits the proliferation and migration of glioma cells. In summary, GNG12 can be used as a novel biomarker for the early diagnosis of human gliomas and as a potential therapeutic target.

DRAXIN as a Novel Diagnostic Marker to Predict the Poor Prognosis of Glioma Patients.

An increasing number of evidences have shown that the carcinogenic effect of DRAXIN plays an important role in the malignant process of tumors, but the mechanism of its involvement in glioma has not yet been revealed. The main aim of this study is to explore the relationship between DRAXIN and the prognosis and pathogenesis of glioma through a large quality of data analysis. Firstly, thousands of tissue samples with clinical information were collected based on various public databases. Then, a series of bioinformatics analyses were performed to mine data from information of glioma samples extracted from several reputable databases to reveal the key role of DRAXIN in glioma development and progression, with the confirmation of basic experiments. Our results showed that high expression of the oncogene DRAXIN in tumor tissue and cells could be used as an independent risk factor for poor prognosis in glioma patients and was strongly associated with clinical risk features. The reverse transcription-quantitative PCR technique was then utilized to validate the DRAXIN expression results we obtained. In addition, co-expression analysis identified, respectively, top 10 genes that were closely associated with DRAXIN positively or negatively. Finally, in vitro experiments demonstrated that knockdown of DRAXIN significantly inhibited proliferation and invasion of glioma cell. To sum up, this is the first report of DRAXIN being highly expressed in gliomas and leading to poor prognosis of glioma patients. DRAXIN may not only benefit to explore the pathogenesis of gliomas, but also serve as a novel biological target for the treatment of glioma.

CDC7 as a novel biomarker and druggable target in cancer.

Due to the bottlenecks encountered in traditional treatment for tumor, more effective drug targets need to be developed. Cell division cycle 7 kinase plays an important role in DNA replication, DNA repair and recombination signaling pathways. In this review, we first describe recent studies on the role of CDC7 in DNA replication in normal human tissues, and then we integrate new evidence focusing on the important role of CDC7 in replication stress tolerance of tumor cells and its impact on the prognosis of clinical oncology patients. Finally, we comb through the CDC7 inhibitors identified in recent studies as a reference for further research in clinical practice.

Specific HER2 Exon 20 Gly776 Deletion-Insertions in Non-Small Cell Lung Cancer: Structural Analysis and Sensitivity to HER2-Targeted Tyrosine Kinase Inhibitors.

Background: HER2 exon 20 insertions remain a subset heterogeneous alterations in lung cancer, with currently unmet need for precision targeted therapy. G776delinsVC, a typical HER2 exon 20 deletion-insertion at codon Gly776, was reported to respond discrepantly to afatinib compared with the predominant insertion A775_G776insYVMA (YVMA). However, it lacks structural evidence to illustrate the possible mechanism and predict the binding activities of its similar variants over YVMA insertion to HER2-targered tyrosine kinase inhibitors (TKIs). Methods: Real-world cohort study was performed to investigate clinical outcomes with HER2-targeted TKI afatinib and pyrotinib, and structural analysis for exon 20 Gly776 deletion-insertions G776delinsVC, G776delinsLC and G776delinsVV, and YVMA by molecular dynamics simulation and cellular kinase inhibition assay were provided for full exploration. Results: Afatinib revealed low objective response rate (ORR) of 0-9.5% and short median progression-free survival (mPFS) of 2.8-3.2 months for YVMA, but with higher ORR of 20-28.6% and longer mPFS of 4.3-7.1 months for G776delinsVC. Pyrotinib presented significantly improved PFS benefit than afatinib for G776delinsVC and YVMA as first-line (median, 6.8 vs. 3.4 months, p = 0.010) or second-line therapy (median, 5.8 vs. 2.8 months, p < 0.001). No significant difference was observed on drug binding pocket and TKI binding activity between G776delinsVC, G776delinsLC and G776delinsVV, and both afatinib and pyrotinib showed favorable binding activity. YVMA insertion significantly affected the loop region with altering HER2 protein secondary structure and forming steric hindrance to binding of afatinib. Pyrotinib showed the best selectivity to HER2, with more favorable activity to YVMA than afatinib indicated by cellular inhibition assay. Conclusion: Both afatinib and pyrotinib showed favorable activity for NSCLC patients with HER2 exon 20 Gly776 deletion-insertions. Pyrotinib revealed more potent activity to A775_G776insYVMA insertion than afatinib due to the steric binding hindrance induced by YVMA.

First-line immunotherapy or angiogenesis inhibitor plus chemotherapy for HER2-altered NSCLC: a retrospective real-world POLISH study.

BACKGROUND: There have been no comprehensive large-scale studies that have evaluated the benefits of chemotherapy-based regimens in addressing HER2-altered advanced non-small-cell lung cancer (NSCLC) in a first-line setting. Data on HER2 alteration subtypes and concomitant alterations are also limited. Accordingly, our retrospective, real-world POLISH study assesses the efficacy of first-line chemotherapy alone (C) as well as combinations with immune checkpoint inhibitors (C + I) or angiogenesis inhibitors (C + A) for HER2-altered NSCLC; molecular features are also reported. METHODS: HER2-altered NSCLC patients who received a first-line treatment between November 2015 and September 2021 were screened. Patients treated with C, C + I, or C + A were included in our final efficacy analysis. Progression-free survival (PFS) was compared between the subgroups. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed to evaluate concomitant alterations. RESULTS: A total of 293 patients were screened, with an identification of HER2 amplification and 37 distinct HER2 mutations, and 210 cases treated with C, C + I, or C + A were ultimately included. C + A achieved longer PFS than C (5.63 vs 4.03 months, hazard ratio: 0.64, 95% confidence interval [CI]: 0.46-0.88, p = 0.006). C + I did not improve median PFS compared to C + A or C (both p > 0.05), despite the programmed cell death ligand-1 (PD-L1) expression or tumor mutational burden. KEGG analysis revealed that concomitant upregulation of PI3 K/AKT pathway signaling was common in HER2-altered NSCLC. CONCLUSION: Chemotherapy plus angiogenesis inhibitors may yield a greater survival benefit than chemotherapy alone in a first-line setting for HER2-altered NSCLC, whereas an immune-based combination therapy may not be superior to a sole chemotherapy regimen. Activation of PI3 K/AKT signaling may mediate immunosuppression in HER2-altered NSCLC.

EN1 Regulates Cell Growth and Proliferation in Human Glioma Cells via Hedgehog Signaling.

Glioblastoma is an aggressive cancer of the nervous system that accounts for the majority of brain cancer-related deaths. Through cross-species transcriptome studies, we found that Engrailed 1 (EN1) is highly expressed in serum-free cultured glioma cells as well as glioma tissues, and increased expression level predicts a worse prognosis. EN1 controls glioma cell proliferation, colony formation, migration, and tumorigenic capacity in vivo. It also influences sensitivity of glioma cells to γ-ray irradiation by regulating intracellular ROS levels. Mechanistically, EN1 influences Hedgehog signaling by regulating the level of Gli1 as well as primary cilia length and the primary cilia transport-related protein TULP3. In conclusion, we demonstrate that EN1 acts as an oncogenic regulator that contributes to glioblastoma pathogenesis and could serve as a diagnostic/prognostic marker and therapeutic target for glioblastoma.

Tannic acid-polypyrrole multifunctional coating layer enhancing the interface effect and efficient Li-ion transport of a phosphorus anode.

Phosphorus has been considered a promising anode material for lithium-ion batteries because of its high specific capacity of 2596 mA h g-1 and safe lithiation voltage of 0.7 V. However, the practical application of the phosphorus anode is challenged by its poor cyclability associated with the dissolution of phosphorus intermediates, the enormous volume expansion and the sluggish lithiation reaction kinetics during the cycling process. Herein, a multifunctional coating layer is designed and fabricated on the surface of a phosphorus-carbon nanotube (P-CNT) electrode via the facile in situ polymerization of plant-derived tannic acid (TA) and pyrrole (Py). This coating layer shows strong adsorption of phosphorus and its derivatives, buffers the volumetric expansion of phosphorus and facilitates efficient Li-ion transport, thus enhancing phosphorus utilization during the cycling process. As a result, the P-CNT@TA-PPy hybrid exhibits a stable coulombic efficiency of 99.0% at 520 mA g-1 after 100 cycles and a reduced volumetric expansion of 50% at 260 mA g-1, superior to P-CNT with its unstable coulombic efficiency and large electrode expansion of 329%. This study sheds light on the rational design of advanced phosphorus-based anodes for alkali metal-ion batteries.