Network pharmacology and molecular docking to explore the mechanism of a clinical proved recipe for external use of clearing heat and removing dampness in the treatment of immune-related cutaneous adverse events.

Immune-related cutaneous adverse events (ircAEs) will undermine the patients' quality of lives, and interrupt the antitumor therapy. A clinical proved recipe for external use of clearing heat and removing dampness (Qing-Re-Li-Shi Formula, hereinafter referred to as "QRLSF") is beneficial to the treatment of ircAEs in clinical practice. Our study will elucidate the mechanism of QRLSF against ircAEs based on network pharmacology and molecular docking. The active components and corresponding targets of QRLSF were collected through traditional Chinese medicine systems pharmacology database. GeneCards, online Mendelian inheritance in man, and pharmacogenomics knowledgebase were used to screen the targets of ircAEs. The intersecting targets between drug and disease were acquired by venn analysis. Cytoscape software was employed to construct "components-targets" network. Search tool for the retrieval of interacting genes/proteins database was applied to establish the protein-protein interaction network and then its core targets were identified. Gene ontology and Kyoto encyclopedia of genes and genomes analysis was performed to predict the mechanism. The molecular docking verification of key targets and related phytomolecules was accomplished by AutoDock Vina software. Thirty-nine intersecting targets related to QRLSF against ircAEs were recognized. The analysis of network clarified 5 core targets (STAT3, RELA, TNF, TP53, and NFKBIA) and 4 key components (quercetin, apigenin, luteolin, and ursolic acid). The activity of QRLSF against ircAEs could be attributed to the regulation of multiple biological effects via multi-pathways (PI3K-Akt pathway, cytokine-cytokine receptor interaction, JAK-STAT pathway, chemokine pathway, Th17 cell differentiation, IL-17 pathway, TNF pathway, and Toll-like receptor pathway). The binding activities were estimated as good level by molecular docking. These discoveries disclosed the multi-component, multi-target, and multi-pathway characteristics of QRLSF against ircAEs, providing a new strategy for such medical problem.

Current status and future of cancer vaccines: A bibliographic study.

Background: Cancer vaccines are an important component of tumour immunotherapy. An increasing number of studies have shown that cancer vaccines have considerable clinical benefits. With the development of tumour precision medicine, cancer vaccines have become important because of their individualised targeting effects. However, few bibliometric studies have conducted comprehensive systematic reviews in this field. This study aimed to assess the scientific output and trends in cancer vaccine research from a global perspective. Methods: We collected publications on cancer vaccines from the Web of Science Core Collection database, which was limited to articles and reviews in English. Microsoft Excel, VOS Viewer, and CiteSpace V were used for quantitative and visual analyses. Results: A total of 7807 articles were included. From 1991 to 2022, the number of publications increased annually. The United States had the highest number of articles published in this field (48.28 %), the highest citation frequency (183,964 times), and the highest H-index (182). The National Institutes of Health topped the list with 476 articles. Schlom J had the highest number of published articles (128) and was the main investigator in this field. The journal, Cancer Immunology Immunotherapy, had published the highest number of articles in related fields. In recent years, tumour microenvironment, immune checkpoint inhibitors, particle vaccines, tumour antigens, and dendritic cells have become research hotspots related to cancer vaccines. Conclusion: Cancer vaccines are a popular research topic in the field of tumour immunotherapy. Related research and publications will enter a boom stage. "Immune checkpoint inhibitors", "tumour microenvironment" and "dendritic cells" may become future research hotspots, while "T-cell suppressor" is a potential puzzle to be solved.

Clinical Experience of External Application of Clearing Heat and Removing Dampness in Relieving Grade 2 to 3 Rash Caused by Programed Cell Death Protein 1 (PD-1)/Programed Cell Death Ligand 1 (PD-L1) Inhibitors: A Single-Center Retrospective Study.

OBJECTIVE: In China, grade 2 to 3 immune-related rash will probably lead to the interruption of immunotherapy. Corticosteroid (CS) is the main treatment, but not always effective. The external application of clearing heat and removing dampness, which is represented by Qing-Re-Li-Shi Formula (QRLSF), has been used in our hospital to treat immune-related cutaneous adverse events (ircAEs) for the last 5 years. The purpose of this study was to discuss its efficacy and safety in the treatment of grade 2 to 3 rash. METHODS: A retrospective study of patients with grade 2 to 3 immune-related rash in our hospital from December 2019 to December 2022 was conducted. These patients received QRLSF treatment. Clinical characteristics, treatment outcome, and health-related quality of life (HrQoL) were analyzed. RESULTS: Thirty patients with grade 2 to 3 rash (median onset time: 64.5 days) were included. The skin lesions of 24 cases (80%) returned to grade 1 with a median time of 8 days. The accompanying symptoms were also improved with median time of 3 to 4 days. The addition of antihistamine (AH) drug didn't increase the efficacy of QRLSF (AH + QRLSF: 75.00% vs QRLSF: 83.33%, P = .66). No significant difference was observed in the efficacy of QRLSF treatment regardless of whether patients had previously received CS therapy (untreated population: 88.24% vs treated population: 69.23%, P = .36). During 1-month follow-up, 2 cases (8.33%) underwent relapses. In terms of HrQoL, QRLSF treatment could significantly reduce the median scores of all domains of Skindex-16, including symptoms (39.58 vs 8.33, P < .0001), emotions (58.33 vs 15.48, P < .0001), functioning (46.67 vs 13.33, P < .0001) and composite (52.60 vs 14.06, P < .0001). CONCLUSION: External application of clearing heat and removing dampness was proven to be an effective and safe treatment for such patients. In the future, high-quality trials are required to determine its clinical application in the field of ircAEs.

Cutaneous adverse events in patients treated with PD-1/PD-L1 checkpoint inhibitors and their association with survival: a systematic review and meta-analysis.

Immune-related cutaneous adverse events (irCAEs) in patients treated with programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors may be associated with better clinical outcomes. However, the extent to which these results can be extrapolated to all tumour types remains unclear. Herein, we conducted a meta-analysis of patients with cancer receiving anti-PD-1/PD-L1 immunotherapy, to determine the cumulative incidence of irCAEs and their association with survival. We systematically searched six databases (PubMed, Embase, Cochrane, CNKI, CSPD, and CQVIP database) for all cohort studies reporting the relationship between irCAEs and patient survival from the time of database construction to 1 November, 2020. The primary outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), with complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) as secondary outcomes. Patients with irCAEs exhibited higher ORR, and were more likely to report CR and PR and less likely to develop PD than those who did not experience irCAEs. Moreover, the occurrence of irCAEs was significantly associated with both favourable PFS and OS. Therefore, patients with irCAEs have better survival benefit and a significantly lower risk of tumour progression or death. Hence, the occurrence of irCAEs may be a useful marker for predicting the clinical efficacy of anti-PD-1/PD-L1 immunotherapy.

Global research trends on precision cancer medicine-related rashes (2008-2021): A bibliographic study.

Background: Precision cancer medicine-related rashes are a kind of skin and mucous lesions caused by precision therapy. More and more evidences indicated that such events should not be ignored in the course of anti-tumor therapy. Since cancer treatment entered the "Precision Era", there has been a rapid increase in this field. However, there was few bibliometric studies to provide an overall review of this field. This study aims to evaluate the literature output and trends in researches on precision cancer medicine-related rashes from a global perspective. Methods: Collected publications on precision cancer medicine-related rashes from the Web of Science Core Collection database, which were limited to articles and reviews in English. Microsoft Excel, VOS viewer and CiteSpace V were used for quantitative and visual analysis. Results: A total of 1,229 papers were identified. From 2008 to 2021, annual publications increased year by year. The United States published the most papers in this field (44.9%) and ranking first in citation frequency (19,854 times) and H-index (69). The University of Texas system ranks first with 98 papers published. Lacouture M.E and Robert C were the principal investigators. Cancers has the largest number of articles published, with 70 articles. In recent years, there have been research hotspots related to immunotherapy, including ipilimumab, immunotherapy, tumor microenvironment, association, checkpoint inhibitor, and cutaneous adverse event. Conclusion: Precision cancer medicine-related rashes are a hot research topic in oncology. The number of relevant publications will increase dramatically. "Checkpoint inhibitors", "skin adverse events", "associations" and "tumor microenvironment" may become research hotspots in the future.

Aqueous extract of Taxus chinensis var. mairei targeting CD47 enhanced antitumor effects in non-small cell lung cancer.

Immunoglobulin protein CD47 is overexpressed in malignant tumor cells, allowing them to evade host immunity mainly by inhibiting macrophage-mediated phagocytosis. Taxus chinensis var. mairei (TC) exhibits high antitumor efficacy with low toxicity and notable cost-effectiveness. However, it is unknown whether aqueous extract of TC (AETC) is an immunomodulator that mediates antitumor efficacy. In this study, we aimed to elucidate the critical role of CD47 degradation in the treatment of AETC in non-small cell lung cancer (NSCLC) cells. A mouse Lewis lung carcinoma model was developed to determine whether the administration of AETC, as an anti-CD47 antibody, in combination with anti-PD-1 could synergistically inhibit tumor growth and promote a peripheral immune response. AETC treatment downregulated CD47 levels in NSCLC cells and Lewis tumor xenograft mice. Furthermore, treatment enhanced immunity against NSCLC by triggering CD47 ubiquitination and degradation, promoting macrophage-mediated tumor cell phagocytosis, and activating CD8+ T cells. The present study empirically demonstrated, for the first time, that AETC exerts antitumor properties as an immunomodulator. Our findings present AETC as a promising alternative or adjuvant treatment in lung cancer therapy.

Study on the Molecular Mechanism of the Herbal Couple Sparganii Rhizoma-Curcumae Rhizoma in the Treatment of Lung Cancer Based on Network Pharmacology.

BACKGROUND: Lung cancer has a poor prognosis and a high mortality rate, and patients may develop multidrug resistance. Sparganii Rhizoma-Curcumae Rhizoma (HCSC), the classic herbal drug combination of traditional Chinese medicine (TCM), is commonly used in treating tumors, but its molecular mechanism is still unclear. METHOD: We explored the possible mechanisms underlying the antitumor effect of HCSC using network pharmacology. The bioactive components of HCSC and their targets were collected from the TCM Systems Pharmacology (TCMSP) database and PharmMapper. Gene Ontology (GO) and KEGG enrichment analyses were performed; the GeneMANIA platform was used for the functional enrichment analysis of the core targets and their neighboring genes. Molecular docking was performed between the bioactive components and core targets. HCSC freeze-dried powder was prepared, and the bioactive components were verified by liquid chromatography- (LC-) mass spectrometry (MS). Human lung adenocarcinoma H1975 cells were cultured to verify in vitro the molecular mechanism of action of HCSC in treating lung cancer, as predicted by network pharmacology. Finally, we used the Symmap database to predict the relationship between the herb and TCM syndrome. RESULT: A total of seven bioactive components were identified by network pharmacological analysis. Through enrichment analyses, it was found that the mechanism of action mainly involved mitochondrial-mediated caspase-dependent cell apoptosis signaling pathways. The results of molecular docking showed that the bioactive components in HCSC have a good affinity with the target proteins (ALB, BCL2L1, ESR1, HRAS, MAP2K1, MAPK14, and SIRT1). LC-MS confirmed that formononetin and bisdemethoxycurcumin were present in the HCSC freeze-dried powder, consistent with the prediction. The results of in vitro experiments on NCI-H1975 cells confirmed that HCSC can upregulate the mitochondrial-mediated caspase-dependent apoptosis signaling pathway by inducing the cleavage of caspase-3, caspase-9, and PARP, consistent with the network pharmacology prediction. Further, the qi deficiency and blood stasis associated with TCM syndrome can be treated with HCSC.

Neoadjuvant therapy of cetuximab combined with chemoradiotherapy in rectal cancer: A single-arm meta-analysis of noncomparative clinical studies and randomized controlled trials.

OBJECTIVE: Preoperative chemoradiotherapy combined with radical resection has reduced local recurrence rates in rectal cancer. Cetuximab shows improvement in rectal cancer treatment. But the role for neoadjuvant therapy of cetuximab combined with chenmoradiotherapy in rectal cancer remains unclear. The present study aimed to use meta-analytical techniques to assess its benefit and risk. MATERIALS AND METHODS: We searched PubMed, the Cochrane Library, Embase to identify the correlational non-comparative clinical studies and randomized controlled trials (RCTs). The primary endpoints of interest were pathological complete response (pCR), complete response (CR), partial response (PR), stable disease, progressive disease (PD), R0-resection, R1-resection, and R2-resection. The secondary included any grade of toxicity. RESULTS: Eleven investigations (9 noncomparative open-label cohort studies and 2 randomized controlled trials) involving 550 patients were ultimately included. The pooled estimates of pCR was 10% (95% confidence interval [CI]: 7%-13%, I2 = 55.9%). Simultaneously, only a small amount of patients achieved CR (11%, 95% CI: 7%-15%, I2 = 44.0%), which was consistent with pCR. Besides, R0 resection (93%, 95% CI: 90%-96%, I2 = 16.5%) seemed to be increased but need further exploration. The safety was also calculated, and most of the toxicities were moderate. CONCLUSION: Neoadjuvant therapy of cetuximab combined with chemoradiotherapy could not improve pCR. The raise of R0-resection rate needed to be verified by more high-quality and well-designed RCTs. Meanwhile, the morbidity of toxicity was relatively mild and acceptable.

The Efficacy and Safety of the Shouzu Ning Decoction Treatment for Multi-Kinase Inhibitors-Associated Severe Hand-Foot Skin Reaction.

BACKGROUND: Multi-kinase inhibitors (MKIs) treatment plays an important role in cancer therapy, but still suffers from a high incidence of hand-foot skin reaction (HFSR), leading to MKIs dose modification or termination. Thus, there is a high need for therapeutic strategy for HFSR. PATIENTS AND METHODS: This prospective analysis included twenty patients, who were continuously administered with MKIs treatment and presented with a grade 3 HFSR during January 2018 to December 2019. All the patients were treated with the Shouzu Ning Decoction (SND) twice a day, in addition to the MKIs treatment. Grading of HFSR was assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Pain intensity was evaluated using the numerical rating scale (NRS). Quality of life was assessed using the Hand-Foot Quality of Life Scale (HF-QoLS). RESULTS: The median time from MKIs initiation to onset of grade 3 HFSR was 26.2 days. Following the SND treatment, seventeen (17/20) patients displayed grade 2 HFSR with a median time of 5.1 days. Among whom, seven (7/17) finally transformed to grade 1 with a median time of 9.9 days. While all of the grade 1 patients (7/7) had local recurrence, and retreatment of the SND was effective. In addition, after the SND treatment, the score of NRS and HF-QoLS decreased to 1.60 ± 1.14 (P < 0.01) and 26.75 ± 11.76 (P < 0.01), respectively. CONCLUSION: The SND treatment could alleviate symptoms, relieve pain and improve quality of life in HFSR patients. The SND treatment was proved to be an effective and well-tolerated treatment for MKIs-associated grade 3 HFSR patients for the first time. Indeed, further randomized controlled trails with large-scale, multi-center are require to fully determine the clinical application of the SND in MKIs-associated HFSR.

Mutation of the OsSAC1 Gene, which Encodes an Endoplasmic Reticulum Protein with an Unknown Function, Causes Sugar Accumulation in Rice Leaves.

Sugars are the most abundant organic compounds produced by plants, and can be used to build carbon skeletons and generate energy. The sugar accumulation 1 (OsSAC1) gene encodes a protein with an unknown function that exhibits four N-terminal transmembrane regions and two conserved domains of unknown function, DUF4220 and DUF594. OsSAC1 was found to be poorly and specifically expressed at the bottoms of young leaves and in the developing leaf sheaths. Subcellular location results showed that OsSAC1 was co-localized with ER:mCherry and targeted the endoplasmic reticulum (ER). OsSAC1 has been found to affect sugar partitioning in rice (Oryza sativa). I2/KI starch staining, ultrastructure observations and starch content measurements indicated that more and larger starch granules accumulated in ossac1 source leaves than in wild-type (WT) source leaves. Additionally, higher sucrose and glucose concentrations accumulated in the ossac1 source leaves than in WT source leaves, whereas lower sucrose and glucose concentrations were observed in the ossac1 young leaves and developing leaf sheaths than in those of the WT. Much greater expression of OsAGPL1 and OsAGPS1 (responsible for starch synthesis) and significantly less expression of OscFBP1, OscFBP2, OsSPS1 and OsSPS11 (responsible for sucrose synthesis) and OsSWEET11, OsSWEET14 and OsSUT1 (responsible for sucrose loading) occurred in ossac1 source leaves than in WT source leaves. A greater amount of the rice plasmodesmatal negative regulator OsGSD1 was detected in ossac1 young leaves and developing leaf sheaths than in those of the WT. These results suggest that ER-targeted OsSAC1 may indirectly regulate sugar partitioning in carbon-demanding young leaves and developing leaf sheaths.