Deciphering the pharmacological mechanisms of Shenlingbaizhu formula in antibiotic-associated diarrhea treatment: Network pharmacological analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenlingbaizhu (SLBZ) formula, a classical traditional Chinese medicinal (TCM) formula, has been widely used for treating antibiotic-associated diarrhea (AAD). However, the underlying pharmacological mechanisms have not yet been investigated thoroughly. AIM OF THE STUDY: To explore the remission mechanism of SLBZ in the treatment of AAD, we conducted network pharmacological analysis and experimental validation in vitro and in vivo. MATERIALS AND METHODS: In this study, the main compounds of SLBZ were identified by ultra-high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) and online databases. The targets of the active components and AAD-related targets were predicted by network pharmacology, and the potential targets of SLBZ against AAD were obtained. Then the core targets were recognized after Protein-Protein Interaction (PPI) analysis. Based on these, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analyses were conducted, and the key pathway was screened. Subsequently, molecular docking was performed using Auto Dock Vina to find the key components that played a crucial role in that pathway. Molecular dynamics simulation was performed by Gromacs software to detect the binding mode. Finally, the results were confirmed by in vitro and in vivo experiments. RESULTS: A total of 66 active ingredients of SLBZ were detected by UHPLC-MS, and 128 active ingredients were screened out by network pharmacological analysis. Additionally, 935 drug targets and 1686 AAD-related targets were obtained. Seventy-eight intersected genes were selected as potential therapeutic targets and 19 genes were excavated as core targets. Enrichment analysis revealed PI3K-AKT signaling pathway was the key pathway in SLBZ against AAD. Topological analysis further revealed that JAK2, MTOR, TLR4, and SYK were the key targets affected by SLBZ on the PI3K-AKT pathway, and 52 components of SLBZ were associated with them. Molecular docking and dynamics simulation revealed strong binding affinities between MTOR and diosgenin. Subsequently, after SLBZ treatment, the expression levels of JAK2, MTOR, TLR4, and SYK were found significantly upregulated in the AAD model rats (p < 0.05). The cell experiment further validated the good binding ability between MTOR and diosgenin. CONCLUSION: We demonstrate that the therapeutic effect of SLBZ on AAD was achieved in part by inhibiting the PI3K-AKT pathway.

Combined BET and MEK Inhibition synergistically suppresses melanoma by targeting YAP1.

Rationale: The response rate to the MEK inhibitor trametinib in BRAF-mutated melanoma patients is less than 30%, and drug resistance develops rapidly, but the mechanism is still unclear. Yes1-associated transcriptional regulator (YAP1) is highly expressed in melanoma and may be related to MEK inhibitor resistance. The purpose of this study was to investigate the mechanism of YAP1 in MEK inhibitor resistance in melanoma and to screen YAP1 inhibitors to further determine whether YAP1 inhibition reverses MEK inhibitor resistance. Methods: On the one hand, we analyzed paired melanoma and adjacent tissue samples using RNA-seq and found that the Hippo-YAP1 signaling pathway was the top upregulated pathway. On the other hand, we evaluated the transcriptomes of melanoma samples from patients before and after trametinib treatment and investigated the correlation between YAP1 expression and trametinib resistance. Then, we screened for inhibitors that repress YAP1 expression and investigated the mechanisms. Finally, we investigated the antitumor effect of YAP1 inhibition combined with MEK inhibition both in vitro and in vivo. Results: We found that YAP1 expression levels upon trametinib treatment in melanoma patients were correlated with resistance to trametinib. YAP1 was translocated into the nucleus after trametinib treatment in melanoma cells, which could render resistance to MEK inhibition. Thus, we screened for inhibitors that repress YAP1 expression and identified multiple bromodomain and extra-terminal (BET) inhibitors, including NHWD-870, as hits. BET inhibition repressed YAP1 expression by decreasing BRD4 binding to the YAP1 promoter. Consistently, YAP1 overexpression was sufficient to reverse the proliferation defect caused by BRD4 depletion. In addition, the BET inhibitor NHWD-870 acted synergistically with trametinib to suppress melanoma growth in vitro and in vivo. Conclusions: We identified a new vulnerability for MEK inhibitor-resistant melanomas, which activated Hippo pathway due to elevated YAP1 activity. Inhibition of BRD4 using BET inhibitors suppressed YAP1 expression and led to blunted melanoma growth when combined with treatment with the MEK inhibitor trametinib.

The Clinical Characteristic and Management of Patients with Nocardiosis in a Tertiary Hospital in China.

Nocardiosis is an uncommon opportunistic bacterial infection which becomes a significant health problem due to its increasing incidence and high mortality rate. However, many nocardiosis patients are underdiagnosed by physicians. To summarize the clinical characteristics and management of nocardiosis would help with better diagnosis and prognosis of nocardiosis. This retrospective study was conducted based on the medical records of nocardiosis patients between January 2015 and December 2021 in a tertiary hospital in China. Overall, 44 nocardiosis patients with 54 specimens were included. The patients consisted of 26 males and 18 females with a mean age of 50.4 ± 13.2 years. Among 44 patients, 26 (59.1%) were previously given immunosuppressive therapy. Connective tissue diseases (CTDs) were the most common underlying disease (16/44). The most frequent infection sites were the lungs (17/44) and skin or soft tissues (8/44). Common symptoms included cough (23/44), expectoration (18/44), fever (15/44), and subcutaneous abscesses (15/44). Forty-five out of 54 specimens (83.3%) required over 48 hours of culture time for nocardiosis detection. Thirty-six patients were cured or improved, 5 patients were discharged from the hospital due to poor prognosis, and 1 patient died. The average diagnosis time of poor prognosis cases was 19.7 days, which was significantly longer than those of improved or cured patients (7.3 days). Immunosuppressed patients comprise a large part of nocardiosis cases, which is worth attention in clinical practice. Early diagnosis, specifically through prolonged cultivation time of specimen, could help achieve better prognosis of nocardiosis patients.

BRD4 inhibitor suppresses melanoma metastasis via the SPINK6/EGFR-EphA2 pathway.

BET inhibition or BRD4 depletion is a promising and attractive therapy for metastatic melanoma; however, the mechanism is still unclear. Here, we indicated that BET inhibition suppressed melanoma metastasis both in vitro and in vivo and identified a new mechanism by which BET inhibitors suppress melanoma metastasis by blocking the direct interaction of BRD4 and the SPINK6 enhancer. Moreover, we demonstrated that SPINK6 activated the EGFR/EphA2 complex in melanoma and the downstream ERK1/2 and AKT pathways. Thus, these results identified the SPINK6/EGFR-EphA2 axis as a new oncogenic pathway in melanoma metastasis and support the further development of BRD4 inhibitors for the treatment of metastatic melanoma in the clinic.

Qu-Du-San-Jie decoction induces growth inhibition and vascular normalization in NF2-associated vestibular schwannoma.

Background: Neurofibromatosis type 2 (NF2) is a rare genetic syndrome that predisposes individuals to develop bilateral vestibular schwannomas (VSs) causing a high risk of life-threatening neurological complications. Traditional treatment options for NF2-associated VS usually cause neurological damage, and to date, there are no FDA-approved pharmacotherapies for NF2. The aim of this study was to evaluate the antitumor efficacy of Qu-Du-San-Jie (QDSJ) decoction, a traditional Chinese medicine formula, on NF2-associated VS and to investigate the potential underlying mechanisms. Methods: Ultra high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) analysis was performed to identify the components of QDSJ and their targets. To determine the relationships between the putative targets of QDSJ and the differential genes of NF2-associated VS, the drug-disease crossover genes were screened using the UHPLC-MS data combined with our previous gene expression profiling data. The differentially expressed genes were imported into the STRING database to generate a PPI network. Differentially expressed gene targets and pathways were identified using GO and KEGG pathway enrichment analyses. The in vitro and in vivo drug efficacy of QDSJ decoction was tested using a patient-derived schwannoma cell line and a patient-derived xenograft mouse model, respectively. H&E staining, immunochemistry, and immunofluorescence staining were used to evaluate the cell proliferation and tumor vessels. Results: A total of 133 compounds were identified in QDSJ decoction using UHPLC-MS analysis. Network pharmacology showed that the regulation of necroptosis, apoptosis, cell cycle, angiogenesis, adherens junction, and neuroactive ligand-receptor interaction could be associated with the efficacy of QDSJ in treating NF2-associated VS. Treatment with QDSJ induced necrotic cell death and apoptosis of schwannoma cells in vitro and suppressed the tumor growth in vivo. Histopathological analysis revealed areas of cell necrosis and enlarged tumor blood vessels in the QDSJ-treated tumors. The numbers of cells positive for Cyclin D1 and Ki-67 were significantly reduced in QDSJ-treated tumors compared to control tumors. Immunofluorescence staining of CD31 and αSMA showed a decreased number and density of tumor vessels and normalized vessel structure in QDSJ-treated tumors. Conclusion: Our study demonstrates that QDSJ decoction shows significant antitumor activity against NF2-associated schwannoma and is a possible candidate for future clinical trials.

Synergistic Effects between Ambient Air Pollution and Second-Hand Smoke on Inflammatory Skin Diseases in Chinese Adolescents.

Atopic dermatitis (AD), chronic hand eczema (CHE), and urticaria are common inflammatory skin diseases among adolescents and associated with air quality. However, the synergistic effects of ambient air pollution and second-hand smoke (SHS) have been unclear. We conducted a cross-sectional study including 20,138 Chinese college students where dermatological examinations and a questionnaire survey were carried out. A generalized linear mixed model was applied for the association between individualized exposure of O3, CO, NO2, SO2, PM2.5, and PM10 and the prevalence of inflammatory skin diseases. Interactions between air pollutants and SHS were analyzed. As a result, CO, NO2, SO2, PM2.5, and PM10 were positively correlated with the prevalence of AD, CHE, and urticaria. Higher frequency of SHS exposure contributed to increased probabilities of AD (p = 0.042), CHE (p < 0.001), and urticaria (p = 0.002). Of note, CO (OR: 2.57 (1.16−5.69) in third quartile) and NO2 (OR: 2.38 (1.07−5.27) in third quartile) had positive interactions with SHS for AD, and PM2.5 synergized with SHS for CHE (OR: 2.25 (1.22−4.15) for second quartile). Subgroup analyses agreed with the synergistic results. In conclusion, SHS and ambient air pollution are both associated with inflammatory skin diseases, and they have a synergistic effect on the prevalence of AD and CHE.

eEF2K promotes PD-L1 stabilization through inactivating GSK3ß in melanoma.

BACKGROUND: Immune checkpoint blockade (ICB) targeting programmed death ligand-1 (PD-L1)/programmed cell death protein-1 (PD-1) pathway has become an attractive strategy for cancer treatment; however, unsatisfactory efficacy has limited its clinical benefits. Therefore, a more comprehensive understanding of the regulation of PD-L1 expression is essential for developing more effective cancer immunotherapy. Recent studies have revealed the important roles of eukaryotic elongation factor 2 kinase (eEF2K) in promoting epithelial-mesenchymal transition (EMT), angiogenesis, tumor cell migration and invasion; nevertheless, the exact role of eEF2K in the regulation of tumor immune microenvironment (TIME) remains largely unknown. METHODS: In this study, we used a cohort of 38 patients with melanoma who received anti-PD-1 treatment to explore the association between eEF2K expression and immunotherapy efficacy against melanoma. Immunoprecipitation-mass spectrometry analysis and in vitro assays were used to examine the role and molecular mechanism of eEF2K in regulating PD-L1 expression. We also determined the effects of eEF2K on tumor growth and cytotoxicity of CD8+ T cells in TIME in a mouse melanoma model. We further investigated the efficacy of the eEF2K inhibition in combination with anti-PD-1 treatment in vivo. RESULTS: High eEF2K expression is correlated with better therapeutic response and longer survival in patients with melanoma treated with PD-1 monoclonal antibody (mAb). Moreover, eEF2K protein expression is positively correlated with PD-L1 protein expression. Mechanistically, eEF2K directly bound to and inactivated glycogen synthase kinase 3 beta (GSK3ß) by phosphorylating it at serine 9 (S9), leading to PD-L1 protein stabilization and upregulation, and subsequently tumor immune evasion. Knockdown of eEF2K decreased PD-L1 expression and enhanced CD8+ T cell activity, thus dramatically attenuating murine B16F10 melanoma growth in vivo. Clinically, p-GSK3ß/S9 expression is positively correlated with the expressions of eEF2K and PD-L1, and the response to anti-PD-1 immunotherapy. Furthermore, eEF2K inhibitor, NH125 treatment or eEF2K knockdown enhanced the efficacy of PD-1 mAb therapy in a melanoma mouse model. CONCLUSIONS: Our results suggest that eEF2K may serve as a biomarker for predicting therapeutic response and prognosis in patients receiving anti-PD-1 therapy, reveal a vital role of eEF2K in regulating TIME by controlling PD-L1 expression and provide a potential combination therapeutic strategy of eEF2K inhibition with ICB therapy.

Preoperative Ultrasound-Guided Incisional Biopsy Enhances the Pathological Accuracy of Incisional Biopsy of Cutaneous Melanoma: A Prospective Clinical Trial in Chinese Patients.

OBJECTIVES: To assess the feasibility of preoperative ultrasound (US)-guided incisional biopsy through a prospective controlled clinical trial. METHODS: This was a prospective, double-arm, single-center study of Chinese patients. Thirty patients were enrolled in the study. Fourteen patients received incisional biopsies for which the choice of biopsy area relied on a clinical evaluation, and 16 patients received incisional biopsies for which the choice of biopsy area relied on a US-guided evaluation. The following procedure was used in the US-guided incisional biopsy group: 1) clinical and dermoscopic evaluation of skin lesions; 2) US examination; 3) incisional biopsy; 4) surgical excision; and 5) histopathological examination. The same procedure was used in the non-US-guided group except without US examination. RESULTS: In the non-US-guided group, the mean tumor thicknesses obtained from incisional biopsy and postoperative histopathological examination were 2.1 and 4.1 mm, respectively. Seven melanomas were underestimated by incisional biopsy, resulting in margins narrower than currently recommended. In the US-guided group, the mean tumor thicknesses obtained from US, incisional biopsy, and postoperative histopathological examination were 3.4, 2.9, and 2.7 mm, respectively. In only 3 melanomas was the tumor thickness of the incisional biopsy less than that of the postoperative histopathological examination, demonstrating that US-guided biopsy obtains the maximum thickness area. CONCLUSIONS: Preoperative US-guided incisional biopsy can enhance the pathological accuracy of incisional biopsy, which may allow us to better perform surgical excision with safe peripheral surgical margins.

First-line pembrolizumab plus chemotherapy for extensive-stage small-cell lung cancer: a United States-based cost-effectiveness analysis.

BACKGROUND: The clinical trial of Keynote-604 showed that pembrolizumab plus chemotherapy could generate clinical benefits for extensive-stage small-cell lung cancer (ES-SCLC). We aim to assess the efficacy and cost of pembrolizumab combined with chemotherapy in the first-line treatment setting of ES-SCLC from the United States (US) payers' perspective. METHODS: A synthetical Markov model was used to evaluate cost and effectiveness of pembrolizumab plus platinum-etoposide(EP) versus EP in first-line therapy for ES-SCLC from the data of Keynote-604. Lifetime costs life-years(LYs), quality adjusted LYs(QALYs) and incremental cost-effectiveness ratios(ICERs) were estimated. One-way and probabilistic sensitivity analyses were performed. Furthermore, we performed subgroup analysis. RESULTS: Pembrolizumab plus EP resulted in additional 0.18 QALYs(0.32 LYs) and corresponding incremental costs $113,625, resulting an ICER of $647,509 per QALY versus EP. The price of pembrolizumab had a significant impact on ICER. Probabilistic sensitivity analysis indicated that pembrolizumab combined chemotherapy may become a cost-effective option with a probability of 0%. Besides, subgroup analysis suggested that all subgroups were not cost-effective. CONCLUSION: From the perspective of the US payer, pembrolizumab plus EP is not a cost-effective option for first-line treatment patients with ES-SCLC at a WTP threshold of $150,000 per QALY.

Distinguishing Hepatocellular Carcinoma From Hepatic Inflammatory Pseudotumor Using a Nomogram Based on Contrast-Enhanced Ultrasound.

BACKGROUND: Hepatocellular carcinoma (HCC) and hepatic iflammatory pseudotumor (IPT) share similar symptoms and imaging features, which makes it challenging to distinguish from each other in clinical practice. This study aims to develop a predictive model based on contrast-enhanced ultrasound (CEUS) and clinical features to discriminate HCC from IPT. METHODS: Sixty-two IPT and 146 HCC patients were enrolled in this study, where pathological diagnosis served as the reference standard for diagnosis. Clinical and ultrasound imaging data including CEUS features: enhancement degree during arterial phase, portal phase and delayed phase, enhancement pattern, early washout within 60 s, feeding artery, peritumoral vessels, peritumoral enhancement, and margin of nonenhanced area were retrospectively collected. Imaging data were reviewed by two experienced ultrasound doctors. Patients were randomly assigned to training and validation sets. Chi-squared test followed by LASSO regression was performed on ultrasonographic features in the training set to identify the most valuable features that distinguish HCC from IPT, based on which the sonographic score formula was generated. With the significant clinical and ultrasonographic indicators, a nomogram was developed. The performance of the nomogram was verified by ROC curve and decision curve analysis (DCA) with the comparison with sonographic score and the ultrasound doctor's diagnosis. RESULTS: The most valuable ultrasonographic features that distinguish between HCC and IPT were enhancement degree during arterial phase, early washout, peritumoral vessels, peritumoral enhancement, and liver background. The sonographic score based on these features was verified to be an independent factor that predicts the diagnosis (p = 0.003). Among the clinical indicators, AFP (p = 0.009) and viral hepatitis infection (p = 0.004) were significant. Sonographic score, AFP, and viral hepatitis were used to construct a predictive nomogram. The AUC of the nomogram was 0.989 and 0.984 in training and validation sets, respectively, which were higher than those of sonographic score alone (0.938 and 0.958) or the ultrasound doctor's diagnosis (0.794 and 0.832). DCA showed the nomogram provided the greatest clinical usefulness. CONCLUSION: A predictive nomogram based on a sonographic signature improved the diagnostic performance in distinguishing HCC and IPT, which may help with individualized diagnosis and treatment in clinical practice.

Cost-Effectiveness Analysis of Durvalumab Plus Chemotherapy in the First-Line Treatment of Extensive-Stage Small Cell Lung Cancer.

BACKGROUND: In the CASPIAN trial, durvalumab + chemotherapy demonstrated significant improvements in overall survival compared with chemotherapy alone in patients with extensive-stage small cell lung cancer (SCLC). We aimed to assess the cost-effectiveness of durvalumab in patients with extensive-stage SCLC from the US healthcare system perspective. PATIENTS AND METHODS: A comprehensive Markov model was adapted to evaluate cost and effectiveness of durvalumab combination versus platinum/etoposide alone in the first-line therapy of extensive-stage SCLC based on data from the CASPIAN study. The main endpoints included total costs, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-e-ectiveness ratios (ICERs). Model robustness was assessed with sensitivity analysis, and additional subgroup analyses were also performed. RESULTS: Durvalumab + chemotherapy therapy resulted in an additional 0.27 LYs and 0.20 QALYs, resulting in an ICER of $464,711.90 per QALY versus the chemotherapy treatment. The cost of durvalumab has the greatest influence on this model. Subgroup analyses showed that the ICER remained higher than $150,000/QALY (the willingness-to-pay threshold in the United States) across all patient subgroups. CONCLUSIONS: Durvalumab in combination with platinum/etoposide is not a cost-effective option in the first-line treatment of patients with extensive-stage SCLC.

Childhood Circumstances and Mental Health in Old Age: A Life Course Survey in China.

Current evidence and research of the life course approach on the association between life experiences and health in old age are fragmentary. This paper empirically examines the "long arm" effect of the childhood circumstances on mental health in later life using a large longitudinal dataset (CHARLS) conducted in 2014 and 2015. We operationalize the childhood circumstances as family economic conditions, community environment, and peer network to include the meaningful content and understand their interaction. The SEM results indicate that effects of those factors contributing to older people's mental health are unequal and vary among age groups and genders. Of those, peer network in childhood determines to a large extent the mental health through the whole life course, while economic conditions and community environment are weakly associated with mental health. Furthermore, we find a distinct interaction mechanism linking those variables. The peer network completely mediates the effect of the community environment on the mental health of older adults and has a partial mediating effect on the economic conditions. Those findings suggest that social policies aimed at promoting older people's mental health in the context of the active ageing and health ageing strategy should go beyond the old age stage and target social conditions early in childhood.

The mechanisms of action of WeiChang'An Pill (WCAP) treat diarrhoea-predominant irritable bowel syndrome (IBS-D) using network pharmacology approach and in vivo studies.

ETHNOPHARMACOLOGICAL RELEVANCE: WeiChang'An Pill (WCAP) is used in Traditional Chinese Medicine (TCM) to clinically treat diarrhoea-predominant irritable bowel syndrome (IBS-D); however, the underlying pharmacological mechanisms are unclear to date. AIM OF THE STUDY: To explore the mechanism underlying the therapeutic action of WCAP in IBS-D using a network pharmacology approach and in vivo experiments. MATERIALS AND METHODS: The active compounds of WCAP were selected from the TCM Systems Pharmacology Database and TCM Integrated Database, and the potential targets were identified using the Swiss Target Prediction and Similarity Ensemble Approach (SEA) databases. The targets related to IBS-D were mined from the Therapeutic Target Database (TTD), National Center for Biotechnology Information Search database (NCBI), DrugBank database, and DisGeNET database. The intersecting protein-protein interactions (PPIs) of the drug-disease crossover genes were analysed, and the central PPI network was constructed using the String database, version 11.0, and Cytoscape version 3.7.2. Following Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway analyses, the gene-pathway network was constructed for identifying the key target genes and pathways. Based on the results and existing evidence, it was selected the cyclic adenosine monophosphate (cAMP) signalling pathway for further validation using in vivo experiments. RESULTS: A total of 872 targets were identified from the 77 active compounds in WCAP, which shared 78 targets that were predicted to be related to IBS-D. Twenty-one core targets were identified from the PPI network, which was constructed from the common targets. The results of enrichment analysis revealed that HRT2B, ADRA1A, ADRA1D, and CHRM2 could be the key targets of WCAP in IBS-D, and 11 signalling pathways, including the neuroactive ligand-receptor interaction, calcium signalling, and cAMP signalling pathways, were identified as crucial for the therapeutic activity of WCAP in IBS-D. We also identified the possibility of several interactions and crosstalk between the different pathways. Subsequent molecular biology experiments revealed that the expression levels of cAMP, phospho-(Ser/Thr) protein kinase A substrates (p-PKA), 5-hydroxytryptamine, and proteins in the cAMP signalling pathway, including G protein-coupled receptor (GPCR), adenylyl cyclase 5 (AC5), and cAMP-response element binding protein (CREB), were significantly upregulated in rat models of IBS-D following treatment with WCAP (P < 0.05). However, a reverse trend was observed in the expression of nuclear factor kappa-B (NF-κB) (P < 0.05), which could be attributed to the low-grade inflammation that occurs in IBS-D. CONCLUSION: We demonstrated that WCAP may alleviate the symptoms of diarrhoea and visceral sensitivity in IBS-D by regulating the cAMP signalling pathway.

Development and clinical application of a rapid SARS-CoV-2 antibody test strip: A multi-center assessment across China.

BACKGROUND: The ongoing coronavirus disease 19 (COVID-19) is posing a threat to the public health globally. Serological test for SARS-CoV-2 antibody can improve early diagnosis of COVID-19 and serves as a valuable supplement to RNA detection. METHOD: A SARS-CoV-2 IgG/IgM combined antibody test strip based on colloidal gold immunochromatography assay was developed, with both spike protein and nucleocapsid protein of SARS-CoV-2 antigen used for antibody detection. From 3 medical institutions across China, serum or plasma of 170 patients with confirmed COVID-19 diagnosis and 300 normal controls were collected and tested with the strip. Sensitivity, specificity, kappa coefficient, receiver operating characteristic (ROC) curve, and area under the curve (AUC) were analyzed. Positive rates in different medical centers, age group, gender, and different disease course were compared. RESULTS: 158 out 170 samples from confirmed COVID-19 patients had positive results from the test, and 296 out of 300 samples from normal controls had negative results. The kit was 92.9% sensitive and 98.7% specific. The positive rate was 77.3% during the first week after disease onset, but reached 100% since day 9. AUC and kappa coefficient were 0.958 and 0.926, respectively, which showed the consistency of the test results with the standard diagnosis. Age or gender caused little variations in the kit sensitivity. CONCLUSION: The rapid, easy-to-use SARS-CoV-2 IgG/IgM combined antibody test kit has a superior performance, which can help with accurate diagnosis and thus timely treatment and isolation of COVID-19 patients, that contributes to the better control of the global pandemic.

Cost-Effectiveness Analysis of Nivolumab Plus Ipilimumab vs. Chemotherapy as First-Line Therapy in Advanced Non-Small Cell Lung Cancer.

Background: The CheckMate 227 trial has indicated that nivolumab plus ipilimumab compared with chemotherapy significantly increases long-term survival in the first-line setting of advanced non-small-cell lung cancer (NSCLC). Methods: A Markov model was built to estimate the cost and effectiveness of nivolumab plus ipilimumab vs. chemotherapy as the first-line therapy in patients with advanced NSCLC based on outcomes data from the CheckMate 227 trial. We calculated the cost and health outcomes at a willingness-to-pay (WTP) threshold of $150,000 per quality adjusted life year (QALY) in populations with different programmed death ligand 1 (PD-L1) expression levels (≥50, ≥1, and <1%) or a high tumor mutational burden (TMB) (≥10 mutations per megabase). Sensitivity analysis were used to test the model stability. Results: The outcomes showed that the incremental costs and QALYs by using nivolumab plus ipilimumab were $124180.76 and 1.16, $70951.42 and 0.53, $144093.63 and 0.83 for the advanced NSCLC patients with a PD-L1 expression ≥50%, ≥1%, and <1%, which led to an incremental cost-effective ratio (ICER) of $107403.72, $133732.20, and $172589.15 per QALY, respectively. For patients with a high TMB, nivolumab plus ipilimumab contributed an extra 2.04 QALYs at a cost of $69182.50 per QALY. Conclusion: Nivolumab plus ipilimumab as first-line therapy makes a better cost-effective strategy than chemotherapy in advanced NSCLC patients with PD-L1 expression levels ≥50% and ≥1% or a high TMB, at a willingness-to-pay threshold of $150,000 per QALY, but not in the patients with a PD-L1 expression <1%.

Prognostic Implications of Metabolism Related Gene Signature in Cutaneous Melanoma.

Metabolic reprogramming is closely related to melanoma. However, the prognostic role of metabolism-related genes (MRGs) remains to be elucidated. We aimed to establish a nomogram by combining MRGs signature and clinicopathological factors to predict melanoma prognosis. Eighteen prognostic MRGs between melanoma and normal samples were identified using The Cancer Genome Atlas (TCGA) and GSE15605. WARS (HR = 0.881, 95% CI = 0.788-0.984, P = 0.025) and MGST1 (HR = 1.124, 95% CI = 1.007-1.255, P = 0.037) were ultimately identified as independent prognostic MRGs with LASSO regression and multivariate Cox regression. The MRGs signature was established according to these two genes and externally validated in the Gene Expression Omnibus (GEO) dataset. Kaplan-Meier survival analysis indicated that patients in the high-risk group had significantly poorer overall survival (OS) than those in the low-risk group. Furthermore, the MRGs signature was identified as an independent prognostic factor for melanoma survival. An MRGs nomogram based on the MRGs signature and clinicopathological factors was developed in TCGA cohort and validated in the GEO dataset. Calibration plots showed good consistency between the prediction of nomogram and actual observation. The receiver operating characteristic curve and decision curve analysis indicated that MRGs nomogram had better OS prediction and clinical net benefit than the stage system. To our knowledge, we are the first to develop a prognostic nomogram based on MRGs signature with better predictive power than the current staging system, which could assist individualized prognosis prediction and improve treatment.

A novel predictive model incorporating immune-related gene signatures for overall survival in melanoma patients.

Melanoma is the most invasive type of skin cancer, in which the immune system plays a vital role. In this study, we aimed to establish a prognostic prediction nomogram for melanoma patients that incorporates immune-related genes (IRGs). Ninety-seven differentially expressed IRGs between melanoma and normal skin were screened using gene expression omnibus database (GEO). Among these IRGs, a two-gene signature consisting of CCL8 and DEFB1 was found to be closely associated with patient prognosis using the cancer genome atlas (TCGA) database. Survival analysis verified that the IRGs score based on the signature gene expressions efficiently distinguished between high- and low-risk patients, and was identified to be an independent prognostic factor. A nomogram integrating the IRGs score, age and TNM stage was established to predict individual prognosis for melanoma. The prognostic performance was validated by the TCGA/GEO-based concordance indices and calibration plots. The area under the curve demonstrated that the nomogram was superior than the conventional staging system, which was confirmed by the decision curve analysis. Overall, we developed and validated a nomogram for prognosis prediction in melanoma based on IRGs signatures and clinical parameters, which could be valuable for decision making in the clinic.

Cost-Effectiveness Analysis of Atezolizumab Plus Chemotherapy in the First-Line Treatment of Metastatic Non-Squamous Non-Small Cell Lung Cancer.

INTRODUCTION: The purpose of this study was to estimate the cost-effectiveness of atezolizumab plus chemotherapy in patients with metastatic non-squamous non-small cell lung cancer (NSCLC) from the United States (US) payers' perspective in the first-line treatment. METHODS: A mathematical Markov model was developed to estimate cost and effectiveness of atezolizumab combination therapy versus carboplatin plus nab-paclitaxel alone in the first-line therapy of metastatic non-squamous NSCLC from the data of IMpower130. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were analyzed, and model robustness was assessed by sensitivity analysis. Additional subgroup analyses were performed as well. RESULTS: Compared to chemotherapy, treatment with atezolizumab plus chemotherapy yields an increase of 0.16 QALYs with an increase in cost of $109,809.13, resulting in an ICER of $670,309.66 per QALY. The most influential factor in this model was the cost of atezolizumab. Probabilistic sensitivity analysis showed that there was 0% probability that atezolizumab plus chemotherapy was cost-effective at willingness-to-pay (WTP) values of $150,000 per QALY. The results of subgroup analyses showed that the ICER remained greater than $150,000/QALY across the all patient subgroups. CONCLUSION: First-line treatment with atezolizumab in combination with carboplatin plus nab-paclitaxel is not a cost-effective option in patients with metastatic non-squamous NSCLC.

Laparoscopic versus open gastrectomy for gastric cancer.

BACKGROUND: Compared with open gastrectomy (OG), laparoscopic gastrectomy (LG) for gastric cancer has achieved rapid development and popularities in the past decades. However, lack of comprehensive analysis in long-term oncological outcomes such as recurrence and mortality hinder its full support as a valid procedure. Therefore, there are still debates on whether one of these options is superior. AIM: To evaluate the primary and secondary outcomes of laparoscopic versus open gastrectomy for gastric cancer patients METHODS: Two authors independently extracted study data. Risk ratio (RR) with 95% confidence interval (CI) was calculated for binary outcomes, mean difference (MD) or the standardized mean difference (SMD) with 95% CI for continuous outcomes, and the hazard ratio (HR) for time-to-event outcomes. Review Manager 5.3 and STATA software were used for the meta-analysis. RESULTS: Seventeen randomized controlled trials (RCTs) involving 5204 participants were included in this meta-analysis. There were no differences in the primary outcomes including the number of lymph nodes harvested during operation, severe complications, short-term and long-term recurrence, and mortality. As for secondary outcomes, compared with the OG group, longer operative time was required for patients in the LG group (MD = 58.80 min, 95% CI = [45.80, 71.81], P < 0.001), but there were less intraoperative blood loss (MD = - 54.93 ml, 95% CI = [- 81.60, - 28.26], P < 0.001), less analgesic administration (frequency: MD = - 1.73, 95% CI = [- 2.21, - 1.24], P < 0.001; duration: MD = - 1.26 days, 95% CI = [- 1.40, - 1.12], P < 0.001), shorter hospital stay (MD = - 1.37 days, 95% CI = [- 2.05, - 0.70], P < 0.001), shorter time to first flatus (MD = - 0.58 days, 95% CI = [- 0.79, - 0.37], P < 0.001), ambulation (MD = - 0.50 days, 95% CI = [- 0.90, - 0.09], P = 0.02) and oral intake (MD = - 0.64 days, 95% CI = [- 1.24, - 0.03], P < 0.04), and less total complications (RR = 0.81, 95% CI = [0.71, 0.93], P = 0.003) in the OG group. There was no difference in blood transfusions (number, quantity) between these two groups. Subgroup analysis, sensitivity analysis, and the adjustment of Duval's trim and fill methods for publication bias did not change the conclusions. CONCLUSION: LG was comparable to OG in the primary outcomes and had some advantages in secondary outcomes for gastric cancer patients. LG is superior to OG for gastric cancer patients.