BACKGROUND:Immune checkpoint inhibitors in combination with chemotherapy have been a common first-line treatment for non-small cell lung cancer (NSCLC), but they do not work for all patients. HDAC inhibitors (HDACis) may synergize with progressive disease (PD)-1 antibodies by inducing and activating cellular immunity. In this phase II study, we assessed the efficacy and tolerability of chidamide and tislelizumab in combination with chemotherapy in NSCLC patients. METHODS:This was a single-arm, prospective study. Driver-gene negative locally advanced and metastatic NSCLC patients without prior systemic treatment were enrolled. Patients received chidamide, tislelizumab, and chemotherapy for 4-6 cycles and were then maintained by tislelizumab and chidamide. The primary endpoint was objective response rate (ORR), and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response, overall survival (OS) and safety. RESULTS:Twenty patients were enrolled in the study and most of them were PD-L1 1%-49% and PD-L1 < 1%. At the data cutoff, ORR was 80% (95% CI, 56.3-94.3), and DCR was 100%. The median follow-up was 23.4 months, the median PFS was 11.0 months (95% CI, 9.1-12.9m), and the median OS was 17.5 months (95% CI, 9.2-25.8m). Eleven patients (55.0%) had ≥ Grade 3 treatment-related adverse events (TRAEs). The most common ≥ Grade 3 TRAEs were leukopenia (25.0%) and neutropenia (20.0%). No patients died from treatment-related adverse events. CONCLUSIONS:The combination of HDACi and tislelizumab with chemotherapy showed promising antitumor effects and manageable toxicity. More studies are needed to further confirm these results. CLINICALTRIALS.GOV IDENTIFIER:ChiCTR2000041542.

Background:Immune checkpoint inhibitors combined with PARP inhibitors and chemotherapy can enhance anti-tumor activity. This phase Ib clinical study was designed to evaluate the safety and efficacy of cisplatin in combination with sintilimab and niraparib in patients with advanced solid tumors. Methods:Patients with advanced solid tumors who had progressed after one or more lines of standard therapy were enrolled in the study, and received cisplatin and sintilimab on day 1 and niraparib from days 1-21 every 3 weeks for up to 4 cycles, followed by maintenance therapy with sintilimab and niraparib (the same doses and schedules as before), until disease progression, death, or intolerable toxicities. During the dose-escalation phase, patients were divided into three dose groups on the basis of a 3 + 3 dose-escalation regimen, and a dose-expansion phase was conducted based on the determined maximum tolerated dose (MTD). The primary endpoint was safety, including treatment-related adverse events (TRAEs), dose-limiting toxicity (DLT), and the recommended phase 2 dose (RP2D), and the secondary endpoint was efficacy. In addition, exploratory endpoints were prespecified to analyze potential biomarkers. Results:From July 31, 2019, to July 1, 2022, a total of 26 patients were enrolled, and no DLTs were observed in the dose-escalation phase. The recommended RP2Ds of cisplatin, sintilimab, and niraparib were 60 mg/m2, 200 mg, and 100 mg every 3 weeks, respectively. All patients experienced TRAEs of varying severity, and a 19.23% (5 patients) incidence of immune-related adverse events (irAEs). With the median follow-up time of 47.9 months (95% CI: 38.8-NA), objective response rate was 26.92% (7 patients, 95% confidence interval [CI], 11.57-47.79), disease control rate was 57.69% (15 patients, 95% CI: 36.92-76.65), the median progression-free survival (PFS) was 3.30 months (95% CI: 2.14-4.46) and the median overall survival (OS) was 8.03 months (95% CI: 3.41-12.66), with PFS rates of 26.92% (seven patients) and 11.54% (three patients) at 6 and 12 months, and OS rates of 69.23%, 34.62% and 11.54% at 6, 12 and 24 months, respectively. Patients with programmed cell death ligand 1 (PD-L1) expression ≥ 1% showed significantly longer PFS (3.93 months, P = 0.032) and OS (14.97 months, P = 0.036) compared to those with PD-L1 expression < 1%. Conclusion:The combination of cisplatin with sintilimab and niraparib showed a manageable safety profile and modest anti-tumor activity in patients with advanced solid tumors. Further validation in larger, histology-specific patients is needed to confirm clinical benefit. Trial registration:https://www.chictr.org.cn/; ID: ChiCTR1900024488.

Background: For non-small-cell lung cancer (NSCLC) patients who progressed after first-line chemotherapy, immunotherapy targeting programmed cell death (ligand) 1 has shown promising activity. However, the activity is relatively limited in patients harboring epidermal growth factor receptor (EGFR) mutations. Objectives: This study aimed to evaluate the efficacy and safety of camrelizumab plus famitinib in previously treated patients with locally advanced and metastatic NSCLC. Design: A single-center, single-arm, phase II study. Methods: Previously treated patients with locally advanced and metastatic NSCLC were enrolled to receive camrelizumab (200 mg, administered intravenously every 3 weeks) and famitinib (20 mg, administered orally once daily). Patients harboring EGFR mutation genes had received at least one EGFR tyrosine kinase inhibitor and no more than two lines of chemotherapy regimen before the enrollment. The other patients had progressed on first-line chemotherapy with or without immunotherapy before the enrollment. The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by the investigator. Results: Our study encompassed 23 NSCLC patients between October 2019 and October 2022. For all patients, the confirmed ORR was 30.4%, and the disease control rate was 95.7%. The median progression-free survival (PFS) was 6.9 months (95% CI: 4.9 months–not reached). The median overall survival (OS) was not reached. 1- and 2-year OS rates were 85.6% (95% CI: 71.8%–100.0%) and 56.8% (95% CI: 37.7%–85.7%). Especially, for the 6 patients with EGFR genetic aberrations, the confirmed ORR was 33.3%, the median PFS was 10.3 months (95% CI: 1.8–18.8 months), and the median OS was 20.3 months (95% CI: 0.8–39.8 months). The most common grade 3 and above treatment-related adverse events were platelet count decreased, white blood cell count decreased, and hypertension. No unexpected adverse events were reported. Conclusion: Camrelizumab plus famitinib demonstrated encouraging clinical activity with a manageable safety profile in previously treated patients with locally advanced and metastatic NSCLC. The results warranted further validation. Trial registration: Chinese Clinical Trial Registry identifier: ChiCTR1900026641.

Purpose:To examine the roles and mechanisms of tanshinone IIA (Tan-IIA) in colorectal cancer (CRC) using network pharmacology, molecular docking, and in vitro experiments. Methods:In network pharmacology studies, Tan-IIA targets for treating CRC were identified using public databases. Employing the protein-protein interaction (PPI) network, gene ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the core genes and mechanisms of action of Tan-IIA were obtained. Core targets were validated using Gene Expression Profiling Interactive Analysis, the Human Protein Atlas, DriverDBv3, cBioPortal, and the Tumor Immune Estimation Resource database. Molecular docking validates the binding affinity of Tan-IIA to some key targets. Network pharmacology and molecular docking results were validated via in vitro experiments. Results:Intersecting Tan-IIA and CRC targets led to the identification of 25 potential targets. PPI analysis identified 10 core targets of Tan-IIA for CRC treatment. Database validation revealed that these core targets were expressed at varying levels in both normal and cancer tissues. Their expression could influence patient prognosis and immune cell infiltration levels. GO analysis revealed 170 biological processes, 42 cellular components, and 83 molecular functions. KEGG analysis indicated that Tan-IIA affected CRC through multiple pathways, including the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), cAMP, and TNF signaling pathways, with the PI3K/AKT pathway being the most enriched. Molecular docking results indicated that Tan-IIA effectively binds to PI3K, AKT, and other partial core targets. In vitro experiments revealed that Tan-IIA suppressed the multiplication and migration of HCT116 and SW480 cells, induced apoptosis, and reduced the PI3K/AKT pathway indicator protein expression, which was reversed by the PI3K/AKT pathway agonist insulin-like growth factor-1. Conclusion:Network pharmacology, molecular docking, and in vitro validation confirmed that Tan-IIA contributes to CRC treatment through the PI3K/AKT pathway, providing theoretical and experimental foundations for its potential clinical application.

OBJECTIVE:To explore the efficacy and safety of immune checkpoint inhibitor (ICI) without pemetrexed as first-line maintenance therapy in driver-gene negative advanced lung adenocarcinoma. METHODS:A retrospective analysis was conducted on patients with advanced lung adenocarcinoma who were treated with pemetrexed and platinum combined with ICI as first-line therapy at PLA General Hospital from January 2019 to December 2023. Clinical data of the patients were collected and followed up. SPSS, GraphPad Prism and R were used to analyze the clinical characteristics and survival of the patients. RESULTS:A total of 138 patients were included in this study, with a median follow-up time of 38.4 months. The median progression-free survival (PFS) of ICI maintenance group and pemetrexed plus ICI (P + ICI) maintenance group were 16.1 months (95%CI 13.9-18.2) and 11.5 months (95%CI 10.0-13.0). No statistically difference was observed between the 2 groups (P = .19). The median overall survival (OS) was 51.1 months (95% CI 32.5-69.6) for the ICI group and 43.6 months (30.4-56.8) for the P + ICI group, with no statistically difference (P = .55). The objective response rate (ORR) was 52.2% (95%CI 40.4-64.0) in the ICI group and 65.2% (95%CI 54.0-76.4) in the P + ICI group. Treatment-related adverse events (TRAEs) occurred in 91.3% and 92.8% of patients, respectively, while grade ≥ 3 events occurred in 27.5% and 30.4%. No grade 5 adverse reactions occurred. CONCLUSION:The maintenance treatment of ICI without pemetrexed showed good therapeutic efficacy and manageable adverse events, which can be an option as the first-line maintenance therapy for patients with driver-gene negative advanced lung adenocarcinoma.

Diabetes related macroangiopathy (DMA) is a major complication of type 2 diabetes (T2D), impacting both morbidity and mortality. This study characterized the gut bacteriome and mycobiome in 179 adults, including 58 with DMA, 71 with T2D, and 50 healthy controls. The gut microbiome of DMA subjects exhibited reduced alpha diversity, and a distinct microbial composition compared with healthy control. Two bacterial families, six bacterial genera, and four bacterial species exhibited significant differences between DMA and T2D subjects. Additionally, in the mycobiome group, Xylariales was significantly decreased in DMA subjects compared with T2D subjects. Disruptions in transkingdom interactions between gut bacteria and fungi supported microbiota dysbiosis in DMA. A diagnostic model combining bacterial and fungal markers achieved an AUC of 94.20%. This work deepens our understanding of the microbial landscape associated with macroangiopathy in diabetes and highlights potential microbial targets for diagnostics and therapeutic intervention.

BACKGROUND:Immune dysfunction is linked to the progression of various diseases. Milk-processed Polygonatum cyrtonema Hua (MPC) is a traditional medicine with nourishing effects in the Qinghai-Tibet Plateau region of China. However, the immune-enhancing effect of MPC and its underlying mechanism remain unclear. PURPOSE:This study aims to investigate the therapeutic effect and underlying mechanism of MPC on immunosuppressed mice. STUDY DESIGN:A cyclophosphamide (CY)-induced immunosuppressive mouse model was established to evaluate the effects of MPC on the gut microbiota, intestinal barrier and immune response. METHODS:The chemical composition of MPC was identified by UPLC-Q-Exactive Orbitrap MS technology. Immune organ weight, body weight, colon length, biochemical parameters, and histopathology were examined. The levels of three short-chain fatty acids (SCFAs) were quantified via HPLC. 16S rRNA sequencing, fecal microbiota transplantation (FMT), antibiotic intervention, and Western blot were applied to explore the mechanism of MPC. RESULTS:MPC significantly enhanced the production of some key cytokines (IL-2, IFN-γ, IL-4, IL-10, and TGF-β3), immunoglobulins (IgM and IgG), and transcription factors (T-bet, GATA-3, RORγt, and Foxp3). Additionally, MPC maintained intestinal mucosal integrity by upregulating tight junction proteins ZO-1, Claudin-1, E-cadherin, and Occludin. 16S rRNA sequencing of fecal samples revealed that MPC increased the relative abundance of beneficial SCFA-producing bacteria, specifically Lachnospiraceae_UCG-006, while decreasing the relative abundance of several pathogenic taxa, including Prevotellaceae, Alloprevotella, and Eubacterium_coprostanoligenes_group. Notably, antibiotic intervention and FMT experiments demonstrated that the immune-enhancing effect of MPC was dependent on the gut microbiota. MPC also increased the levels of three SCFAs including acetate, propionate, and butyrate. Besides, MPC was found to activate the SCFAs/GPR43/Blimp-1 pathway, leading to the production of IL-10, which enhanced the immune response. CONCLUSION:This study demonstrates for the first time that MPC has a significant immune-enhancing effect. The mechanisms include restoring the balance of gut microbiota, promoting the production of SCFAs, repairing intestinal mucosal damage and enhancing immune function. These findings support the potential of MPC as a natural agent for improving gut health and systemic immunity.

Alterations in 3D chromatin conformation may disrupt the interplay between promoters and distal enhancers. How gene regulatory circuits are reshaped during ionizing radiation-induced tumorigenesis remains unclear, and little is known about the mediators that drive these processes. To decipher the chromatin alterations in radiation-induced lung cancer, we performed ATAC-seq, RNA-seq and Hi-C analyses of human bronchial epithelial cells and corresponding radiation-induced malignantly transformed cell lines. We found that this malignant transformation is accompanied by chromatin switching from the inactive B compartment to the active A compartment, an increased number of TADs and gained ATAC-seq peaks that mediate new distal chromatin contacts. We identified tumour protein 63 (TP63) as a mediator of new chromatin-accessible sites that anchor tumour-specific chromatin contacts in radiation-induced tumour cells. A TP63-mediated accessible chromatin site anchors a tumour-specific TAD boundary and multiple tumour-specific chromatin loops, which might underlie MYC oncogene activation during malignant transformation.

Although immunotherapy combined with chemotherapy (ICT) is the standard treatment for advanced non-small cell lung cancer (NSCLC), identification of reliable prognostic biomarkers remains challenging. In this multicenter study, we performed next-generation sequencing of tumor samples from 162 patients receiving first-line ICT at the Chinese PLA General Hospital and collected their pathological image information. First, we established a model to predict the risk of tumor progression based on genomic characteristics. Furthermore, a deep learning method was employed to recognize different cell types from pathological images, which significantly improved the accuracy of progression-free survival (PFS) and overall survival (OS) prediction. In summary, we constructed a Prognostic Multimodal Classifier for Progression (PMCP) that possesses the capability to precisely forecast PFS and OS. Patients with the PMCP1 subtype exhibit a low risk of progression and demonstrate a higher proportion of epithelial cells. PMCP highlighted the potential value of multimodal biomarkers in guiding clinical decisions regarding ICT. The area under curve (AUC) for predicting PFS was 0.807. This study revealed the importance of integrating genomic and pathological data to improve prognostic accuracy and enable personalized treatment for patients with advanced NSCLC.

This study utilized TCGA database to explore the role of m6A modification and immune infiltration in AML. Through unsupervised clustering and WGCNA analysis, 8 hub genes were identified, and a risk model with EHBP1L1 and ZNF385A was established using LASSO regression. A nomogram incorporating hub gene risk score and age showed satisfactory prognostic prediction. External validation of GEO confirmed the model’s effectiveness. TME analysis revealed correlations with monocytes and Treg cells, while immune checkpoints and HLA genes were associated with risk scores. Drug sensitivity analysis suggested potential responses to specific chemotherapy drugs. TIDE analysis indicated reduced ICI treatment benefit in high-risk patients. RT-qPCR validations revealed the significance of prognosis and risk stratification of ZNF385A. The noticeable trend of EHBP1L1 was observed. In addition, the accurate predictive capability of the risk model has been validated by clinical samples. Therefore, the risk model enables a quantitative evaluation of disease severity and progression risk in AML patients, based on their clinical and biological characteristics. This precise prediction not only informs treatment decisions but also guides the selection of chemotherapy regimens, overall improving patient outcomes.

center dot Pemigatinib has demonstrated significant efficacy as a second-line treatment for patients with FGFR abnormalities in advanced cholangiocarcinoma. center dot There are currently no proven drugs specifically targeting FGFR aberration in patients with advanced NSCLC. center dot The results suggest that pemigatinib could be considered for patients with FGFR-aberrant advanced lung cancer and further research is warranted to identify the specific FGFR aberrations that may be more responsive to pemigatinib.

Introduction: Ji-Ni-De-Xie (JNDX) is a traditional herbal preparation in China. It is widely used to treat type 2 diabetes mellitus (T2DM) in traditional Tibetan medicine system. However, its antidiabetic mechanisms have not been elucidated. The aim of this study is to elucidate the underlying mechanism of JNDX on bile acids (BAs) metabolism and FXR/FGF15 signaling pathway in T2DM rats.Methods: High-performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-QQQ-MS) and UPLC-Q-Exactive Orbitrap MS technology were used to identify the constituents in JNDX. High-fat diet (HFD) combined with streptozotocin (45 mg∙kg−1) (STZ) was used to establish a T2DM rat model, and the levels of fasting blood-glucose (FBG), glycosylated serum protein (GSP), homeostasis model assessment of insulin resistance (HOMA-IR), LPS, TNF-α, IL-1β, IL-6, TG, TC, LDL-C, HDL-C, and insulin sensitivity index (ISI) were measured to evaluate the anti-diabetic activity of JNDX. In addition, metagenomic analysis was performed to detect changes in gut microbiota. The metabolic profile of BAs was analyzed by HPLC-QQQ-MS. Moreover, the protein and mRNA expressions of FXR and FGF15 in the colon and the protein expressions of FGF15 and CYP7A1 in the liver of T2DM rats were measured by western blot and RT-qPCR.Results: A total of 12 constituents were identified by HPLC-QQQ-MS in JNDX. Furthermore, 45 chemical components in serum were identified from JNDX via UPLC-Q-Exactive Orbitrap MS technology, including 22 prototype components and 23 metabolites. Using a T2DM rat model, we found that JNDX (0.083, 0.165 and 0.33 g/kg) reduced the levels of FBG, GSP, HOMA-IR, LPS, TNF-α, IL-1β, IL-6, TG, TC, and LDL-C, and increased ISI and HDL-C levels in T2DM rats. Metagenomic results demonstrated that JNDX treatment effectively improved gut microbiota dysbiosis, including altering some bacteria (e.g., Streptococcus and Bacteroides) associated with BAs metabolism. Additionally, JNDX improved BAs disorder in T2DM rats, especially significantly increasing cholic acid (CA) levels and decreasing ursodeoxycholic acid (UDCA) levels. Moreover, the protein and mRNA expressions of FXR and FGF15 of T2DM rats were significantly increased, while the expression of CYP7A1 protein in the liver was markedly inhibited by JNDX.Discussion: JNDX can effectively improve insulin resistance, hyperglycemia, hyperlipidemia, and inflammation in T2DM rats. The mechanism is related to its regulation of BAs metabolism and activation of FXR/FGF15 signaling pathway.

Globally, metabolic diseases are becoming a major public health problem. Herbal medicines are medicinal materials or preparations derived from plants and are widely used in the treatment of metabolic diseases due to their good curative effects and minimal side effects. Recent studies have shown that gut microbiota plays an important role in the herbal treatment of metabolic diseases. However, the mechanisms involved are still not fully understood. This review provides a timely and comprehensive summary of the interactions between herbal medicines and gut microbiota in metabolic diseases. Mechanisms by which herbal medicines treat metabolic diseases include their effects on the gut microbial composition, the intestinal barrier, inflammation, and microbial metabolites (e.g., short-chain fatty acids and bile acids). Herbal medicines can increase the abundance of beneficial bacteria (e.g., Akkermansia and Blautia), reduce the abundance of harmful bacteria (e.g., Escherichia–Shigella), protect the intestinal barrier, and alleviate inflammation. In turn, gut microbes can metabolize herbal compounds and thereby increase their bioavailability and bioactivity, in addition to reducing their toxicity. These findings suggest that the therapeutic effects of herbal medicines on metabolic diseases are closely related to their interactions with the gut microbiota. In addition, some methods, and techniques for studying the bidirectional interaction between herbal medicines and gut microbiota are proposed and discussed. The information presented in this review will help with a better understanding of the therapeutic mechanisms of herbal medicines and the key role of gut microbiota.

ImportanceBoth pembrolizumab and sintilimab have been approved by the Chinese State Drug Administration (NMPA) for the first-line treatment of patients with advanced squamous lung cancer. The differences of the two drugs in efficacy and safety are unclear. ObjectivesTo compare the real-world efficacy and safety of first-line treatments in patients with advanced squamous lung cancer. Materials and methodsThis was a retrospective review of patients with advanced squamous carcinoma who received sintilimab or pembrolizumab in combination with chemotherapy as first-line therapy between June 2018 and April 2022 in the Chinese PLA Hospital. The primary objective was to compare the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) between the two groups. Secondary objectives were to compare the disease control rate (DCR) and to analyze adverse events (AEs) between the two groups. ResultsA total of 164 patients were enrolled, including 63 patients (38.4%) in the sintilimab-combined chemotherapy group and 101 patients (61.6%) in the pembrolizumab-combined chemotherapy group. The ORR was 65.10% in the sintilimab group and 61.40% in the pembrolizumab group (P=0.634). The DCR was 92.10% and 92.10% in the sintilimab and pembrolizumab groups, respectively (P=0.991). The median PFS was 22.2 months for patients treated with sintilimab group compared with 16.5 months for patients treated with pembrolizumab group[hazard ratio (HR) = 0.743; 95% confidence interval (CI): 0.479-1.152; P = 0.599]. Patients treated with pembrolizumab did not achieve a median OS, and patients treated with sintilimab had a median OS of 30.7 months. In the sintilimab group, the incidence of all treatment-related adverse events (TRAEs) was 92.1% (58/63), and the incidence of grade 3-4 TRAEs of 42.9% (27/63). In the pembrolizumab group, the incidence of all TRAEs was 90.1% (91/101), and the incidence of grade 3-4 TRAEs was 37.6% (38/101). ConclusionIn the clinical treatment of Chinese patients with advanced squamous lung cancer, first-line treatment with sintilimab in combination with chemotherapy provided similar efficacy to pembrolizumab in combination with chemotherapy, and the treatment-related adverse effect profiles were comparable between the two groups, including similar rates of grade 3-4 and all adverse events.

Objective Oncogenic alternation in RET is one of the important targets of non-small cell lung cancer (NSCLC). Pralsetinib has shown great efficacy in RET fusion-positive NSCLC, but a series of adverse reactions will inevitably occur in the meantime. We aimed to explore the clinical characteristics of patients with pneumonia and recognition it in early stage, so patients could longer benefit from pralsetinib. Methods This is a multicenter, retrospective study. RET fusion-positive advanced NSCLC patients who developed pneumonia during pralsetinib treatment from January 2020 to December 2022 were included. Clinical data, time to onset of pneumonia, methods of pneumonia diagnosis, treatment with pneumonia, prognosis of pneumonia, and the effect of pneumonia on the efficacy of pralsetinib. Results A total of 8 patients with pneumonia were included in the study, most of which were non-smoking female patients and the main fusion gene was KIF5B (87.5%), which was consistent with the general characteristics of RET fusion population. The median occurrence time of pralsetinib-associated pneumonia was 2.15 (range 1.1–6.63) months. All patients were infected by opportunistic pathogens, and the most common pathogen was human herpesviruses and pneumospora yerbii. Fever was always the first symptom, and timely anti-infective treatment including antibiotics, antiviral drugs, and antifungal drugs was effective. Until February 28, 2023, the median follow-up time was 18.7 months, the mean PFS of patients was 17.4 months, and the median PFS was not reached. Fortunately, patients who restarted pralsetinib after infection control continued to benefit. Conclusions Opportunistic infection may be a unique adverse effect of pralsetinib. During the treatment of pralsetinib, we should be vigilant about the occurrence of pneumonia and achieve early recognition and timely treatment.

The Coronavirus Diseases 2019 (COVID-19) has been rapidly spreading globally and has caused severe harm to the health of people and a substantial social burden. In response to this situation, experts around the world have considered various treatments, including the use of traditional medicine. Traditional Tibetan medicine (TTM), one of the traditional medicines in China, has played an important role in the treatment of infectious diseases in history. It has formed a solid theoretical foundation and accumulated rich experience in the treatment of infectious diseases. In this review, we provide a comprehensive introduction to the basic theory, treatment strategies, and commonly used drugs of TTM for the treatment of COVID-19. In addition, the efficacies and potential mechanisms of these TTM drugs against COVID-19 are discussed based on available experimental data. This review may provide important information for the basic research, clinical application and drug development of traditional medicines for the treatment of COVID-19 or other infectious diseases. More pharmacological studies are needed to reveal the therapeutic mechanisms and active ingredients of TTM drugs in the treatment of COVID-19.

e21058 Background: Currently, the standard first-line treatment for driver gene-negative advanced lung adenocarcinoma (LUAD) is chemotherapy plus immune checkpoint inhibitor (ICI) therapy followed by pemetrexed and ICI. However, pemetrexed is prone to certain adverse reactions and needs to be pretreated. At present, there is no relevant study on the efficacy between pemetrexed combined with ICI and ICI monotherapy in maintenance treatment. The object of this study is to explore the efficacy and safety of ICI as maintenance therapy in such patients. Methods: The study retrospectively analyzed patients with driver gene-negative advanced LUAD in PLA General Hospital from January 2019 to June 2022. These patients had received pemetrexed and platinum-based chemotherapy combined with ICI for 4-6 cycles. Patients who didn’t progress were subsequently entered into maintenance stage. The primary endpoint was progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was objective response rate (ORR) and safety. Results: A total of 93 patients with advanced LUAD who received first-line chemotherapy combined with ICI were collected, including 39 patients receiving pemetrexed plus ICI of maintenance therapy, 30 patients receiving ICI maintenance therapy, and 24 patients who failed to enter the maintenance treatment. Baseline characteristics of ICI group and pemetrexed plus ICI group were as follows: median age, 61.5 (42~81) years vs. 63 (35~74) years; male, 66.7% (20/30) vs. 79.5% (31/39); Smoking history, 63.3% (19/30) vs. 74.4% (29/39); Brain metastases, 10% (3/30) vs. 23.1% (9/39). ORR was 60.0% (95%CI 42.5-77.5) in the ICI monotherapy group and 69.2% (95%CI 54.7~83.7) in the pemetrexed plus ICI group. By November 30, 2022, the median follow-up time was 19.2 months. The median PFS of the two groups were 15.8 months (95%CI 9.84-21.70) in ICI group and 22.8 months (95%CI 4.57-40.97) in pemetrexed plus ICI group and there was no statistical difference between the two groups (P = 0.50). Neither group achieved OS. The incidence of all grade treatment-related adverse events (TRAEs) was 90.0% (27/30) in ICI monotherapy group and 92.3% (36/39) in pemetrexed plus ICI group. Grade 3/4 TRAEs occurred in 23.3% (7/30) and 23.1% (9/39) of each cohort and no grade 5 TRAE occurred. Conclusions: ICI maintenance therapy without pemetrexed showed great therapeutic efficacy in first-line maintenance stage and can be a feasible regimen in advanced lung adenocarcinoma.

Metabolic diseases, such as type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD) and obesity, have become a major public health problem worldwide. In recent years, most research on the role of gut microbes in metabolic diseases has focused on bacteria, whereas fungal microbes have been neglected. This review aims to provide a comprehensive overview of gut fungal alterations in T2DM, obesity, and NAFLD, and to discuss the mechanisms associated with disease development. In addition, several novel strategies targeting gut mycobiome and/or their metabolites to improve T2DM, obesity and NAFLD, including fungal probiotics, antifungal drugs, dietary intervention, and fecal microbiota transplantation, are critically discussed. The accumulated evidence suggests that gut mycobiome plays an important role in the occurrence and development of metabolic diseases. The possible mechanisms by which the gut mycobiome affects metabolic diseases include fungal-induced immune responses, fungal-bacterial interactions, and fungal-derived metabolites. Candida albicans, Aspergillus and Meyerozyma may be potential pathogens of metabolic diseases because they can activate the immune system and/or produce harmful metabolites. Moreover, Saccharomyces boulardii, S. cerevisiae, Alternaria, and Cochliobolus fungi may have the potential to improve metabolic diseases. The information may provide an important reference for the development of new therapeutics for metabolic diseases based on gut mycobiome.

Background Hyper progressive disease (HPD) describes the phenomenon that patients can’t benefit from immunotherapy but cause rapid tumor progression. HPD is a particular phenomenon in immunotherapy but lacks prediction methods. Our study aims to screen the factors that may forecast HPD and provide a predictive model for risky stratifying. Methods We retrospectively reviewed advanced-stage tumor patients who received immune checkpoint inhibitors (ICI) in the General PLA Hospital. Subsequently, we calculated the tumor growth kinetics ratio (TGKr) and identified typical HPD patients. Differences analysis of clinical characteristics was performed, and a predictive binary classification model was constructed. Results 867 patients with complete image information were screened from more than 3000 patients who received ICI between January 2015 and January 2020. Among them, 36 patients were identified as HPD for TGKr > 2. After the propensity score matched, confounding factors were limited. Survival analysis revealed that the clinical outcome of HPD patients was significantly worse than non-HPD patients. Besides, we found that Body Mass Index (BMI), anemia, lymph node metastasis in non-draining areas, pancreatic metastasis, and whether combined with anti-angiogenesis or chemotherapy therapy were closely connected with the HPD incidence. Based on these risk factors, we constructed a visualised predicted nomogram model, and the Area Under Curve (AUC) is 0.850 in the train dataset, whereas 0.812 in the test dataset. Conclusion We carried out a retrospective study for HPD based on real-world patients and constructed a clinically feasible and practical model for predicting HPD incidence, which could help oncologists to stratify risky patients and select treatment strategies.