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Non-small cell lung cancer (NSCLC) remains an unsolved challenge in oncology, signifying a substantial global health burden. While considerable progress has been made in recent years through the emergence of immunotherapy modalities, such as immune checkpoint inhibitors (ICIs), monotherapies often yield limited clinical outcomes. The rationale behind combining various immunotherapeutic or other anticancer agents, the mechanistic underpinnings, and the clinical evidence supporting their utilization is crucial in NSCLC therapy. Regarding the synergistic potential of combination immunotherapies, this study aims to provide insights to help the landscape of NSCLC treatment and improve clinical outcomes. In addition, this review article discusses the challenges and considerations of combination regimens, including toxicity management and patient selection.

This study employs a CES production function to construct a theoretical model of labor income share and uses a two-way fixed effects model to test the causal effects of local government debt (LGD) on the labor income share of enterprises. Local government debt governance policies are utilized as exogenous shocks, and a DID (Difference-in-Differences) model is applied for endogeneity testing. The results have passed a series of robustness checks. The findings suggest that LGD decreases the share of firms’ labor income. The mechanism analysis suggests that LGD lowers the labor remuneration of residents, the employment of labor in enterprises, and the size of bank loans mainly; while raising the cost of using funds in enterprises. Moreover, this negative effect is more apparent in non-state-owned enterprises, small and medium-sized enterprises, and enterprises with high financing constraints. This study presents new evidence on how the labor income share of enterprises is affected from the perspective by local governments in China. It has important implications for further deepening local government debt governance and achieving common prosperity.

Cisplatin (DDP) resistance, often leading to first-line chemotherapy failure in non-small cell lung cancer (NSCLC), poses a significant challenge. MiR-219a-5p has been reported to enhance the sensitivity of human NSCLC to DDP. However, free miR-219a-5p is prone to degradation by nucleases in the bloodstream, rendering it unstable. In light of this, our study developed an efficient nanodrug delivery system that achieved targeted delivery of DDP and miR-219a-5p by modifying liposomes with folate (FA). Based on the results of material characterization, we successfully constructed a well-dispersed and uniformly sized (approximately 135.8 nm) Lipo@DDP@miR-219a-5p@FA nanodrug. Agarose gel electrophoresis experiments demonstrated that Lipo@DDP@miR-219a-5p@FA exhibited good stability in serum, effectively protecting miR-219a-5p from degradation. Immunofluorescence and flow cytometry experiments revealed that, due to FA modification, Lipo@DDP@miR-219a-5p@FA could specifically bind to FA receptors on the surface of tumor cells (A549), thus enhancing drug internalization efficiency. Safety evaluations conducted in vitro demonstrated that Lipo@DDP@miR-219a-5p@FA exhibited no significant toxicity to non-cancer cells (BEAS-2B) and displayed excellent blood compatibility. Cellular functional experiments, apoptosis assays, and western blot demonstrated that Lipo@DDP@miR-219a-5p@FA effectively reversed DDP resistance in A549 cells, inhibited cell proliferation and migration, and further promoted apoptosis. In summary, the Lipo@DDP@miR-219a-5p@FA nanodrug, through specific targeting of cancer cells and reducing their resistance to DDP, significantly enhanced the anti-NSCLC effects of DDP in vitro, providing a promising therapeutic option for the clinical treatment of NSCLC.

Chimeric antigen receptor (CAR)-T cell therapy is effective in the treatment of refractory/relapsed (r/r) hematological malignancies (r/r B-cell lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma). In addition, it is being explored as a treatment option for solid tumors. As of 31 March 2022, seven CAR-T therapies for hematological malignancies have been approved worldwide. Although CAR-T therapy is an effective treatment for many malignancies, it also causes adverse effects. The incidence of cytokine release syndrome (CRS), the most common adverse reaction after infusion of CAR-T cells, is as high as 93%.CRS, is the leading risk factor of immune effector cell-associated neurotoxicity syndrome (ICANS), as well as cardiovascular, hematological, hepatorenal, skin, pulmonary, and gastrointestinal toxicity. Severe adverse reactions complicated by CRS severely impede the widespread application of CAR-T therapy. The CAR-T product was initially approved in 2017; however, only limited studies have investigated the adverse reactions owing to CAR-T therapy compared to that of clinically approved drugs. Thus, we aimed to elucidate the mechanisms, risk factors, diagnostic criteria, and treatment of toxicities concurrent with CRS, thereby providing a valuable reference for the safe, effective, and widespread application of CAR-T therapy.

To investigate the value of CEP55 as a diagnostic marker and independent prognostic factor in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), and to analyze its co-expression genes and related signaling pathways. TCGA database and GEO database were used to analyze the expression of CEP55 in LUAD and LUSC compared with normal tissues. The co-expression genes of CEP55 in LUAD and LUSC were excavated by cBioPortal and enriched by KEGG and GO. Establishing Receiver operating characteristic (ROC) curve to evaluate the value of CEP55 as a diagnostic and prognostic factor. The association between CEP55 expression and the clinicopathological features was evaluated using χ2 tests. ROC curves for diagnosis and prognosis detection were constructed. Prognostic values were analyzed by univariate and multivariate Cox regression models. Compared with normal lung tissues, CEP55 expression was significantly upregulated in both LUAD and LUSC. ROC curve analysis showed that CEP55 could be used as an effective diagnostic target for LUAD (AUC = 0.969) and LUSC (AUC = 0.994). When CEP55 gene was selected as an independent prognostic factor, high expression of CEP55 was more disadvantageous to OS and RFS of LUAD patients (P<0.05), but no significant difference was found in LUSC patients (P>0.05). The number of co-expression genes of CEP55 in LUAD is more than that in LUSC, and is related to cell cycle, DNA replication and P53 signaling pathway. CEP55 can be used as a diagnostic marker for LUAD and LUSC, but only as an independent prognostic factor for LUAD rather than LUSC.

ObjectiveThe ASTRUM-005 trial demonstrated that adding serplulimab to chemotherapy significantly prolonged the survival of patients with extensive-stage small cell lung cancer (SCLC), but also increased the risk of adverse events. Given the high cost of serplulimab compared to chemotherapy, this study aimed to evaluate the cost-effectiveness of serplulimab plus chemotherapy as a first-line treatment for extensive-stage SCLC from the perspective of China’s healthcare system.MethodsA Markov model was developed to simulate the disease process of extensive-stage SCLC and estimate the health outcomes and direct medical costs of patients. Scenario analyses, univariate sensitivity analyses, and probabilistic sensitivity analyses were conducted to explore the impact of different parameters on model uncertainty. The primary model outcomes included costs, life-years (LYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER).ResultsCompared to placebo plus chemotherapy, serplulimab plus chemotherapy resulted in an additional 0.25 life-years and 0.15 QALYs, but also increased costs by $26,402, resulting in an ICER of 179,161 USD/QALY. Sensitivity analysis showed that the ICER was most sensitive to the cost of serplulimab, and the probability that serplulimab was cost-effective when added to chemotherapy was only 0 at the willingness-to-pay threshold of 37,423 USD/QALY. Scenario analysis revealed that price discounts on serplulimab could increase its probability of being cost-effective.ConclusionSerplulimab plus chemotherapy is not a cost-effective strategy for first-line treatment of extensive-stage SCLC in China. Price discounts on serplulimab can enhance its cost-effectiveness.

γδ T cells, a subgroup of T cells based on the γδ TCR, when compared with conventional T cells (αβ T cells), make up a very small proportion of T cells. However, its various subgroups are widely distributed in different parts of the human body and are attractive effectors for infectious disease immunity. γδ T cells are activated and expanded by nonpeptidic antigens (P-Ags), major histocompatibility complex (MHC) molecules, and lipids which are associated with different kinds of pathogen infections. Activation and proliferation of γδ T cells play a significant role in diverse infectious diseases induced by viruses, bacteria, and parasites and exert their potential effector function to effectively eliminate infection. It is well known that many types of infectious diseases are detrimental to human life and health and give rise to high incidence of illnesses and death rate all over the world. To date, there is no comprehensive understanding of the correlation between γδ T cells and infectious diseases. In this review, we will focus on the various subgroups of γδ T cells (mainly Vδ1 T cells and Vδ2 T cells) which can induce multiple immune responses or effective functions to fight against common pathogen infections, such as Mycobacterium tuberculosis, Listeria monocytogenes, influenza viruses, HIV, EBV, and HBV. Hopefully, the gamma-delta T cell study will provide a novel effective way to treat infectious diseases.

Objective: Cholinesterase inhibitor (ChEIs) is the first-line drug for Alzheimer’s disease (AD). Understanding torsade de pointes (TdP)/QT prolongation with different ChEIs is essential for its safe and rational administration. This study aimed to evaluate the correlation between different ChEIs and TdP/QT prolongation. Methods: All ChEIs related TdP/QT prolongation cases were retrieved from the FAERS database using standard MedDRA query (SMQ) from the first quarter of 2004 to the third quarter of 2022. Disproportionality and sensitivity analysis were used to determine the signal of TdP/QT prolongation related to ChEIs. Results: 557 cases of TdP/QT prolongation related to 3 ChEIs were searched by SMQ. The patients were mostly elderly people, with markedly more female than male. The signals of TdP/QT prolongation for ChEIs were detected by disproportionality analysis, and the signal of Donepezil was the strongest. The sensitivity analysis results indicate a robust and stable correlation between these signals with ChEIs. TdP/QT prolongation usually occurs within 1 month after taking ChEIs. The drug with the highest frequency of combination with donepezil and galantamine is citalopram, and the drug with the highest frequency of combination with rivastigmine is atorvastatin. Conclusion: The signals of TdP/QT prolongation related to ChEIs were strong and stable. It is necessary to be vigilant about the TdP/QT prolongation of various ChEIs, especially in elderly women, the initial stage after taking ChEIs, and when ChEIs combining with drugs that could prolong the QT interval.

Nivolumab, recently proven in a phase 3 clinical trial (CheckMate 901) to enhance survival when combined with gemcitabine-cisplatin for advanced urothelial carcinoma. This study aimed to assess its cost-effectiveness against gemcitabine-cisplatin alone, from US and Chinese payers' perspectives. A partitioned survival model was established to assess the life-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) of nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone as first-line treatment for advanced urothelial carcinoma. Univariate, two-way, and probabilistic sensitivity analyses were conducted to assess the model's robustness. Additionally, subgroup analyses were performed. Nivolumab plus gemcitabine-cisplatin and gemcitabine-cisplatin achieved survival benefits of 4.238 life-years and 2.979 life-years for patients with advanced urothelial carcinoma, respectively. Compared with gemcitabine-cisplatin, nivolumab plus gemcitabine-cisplatin resulted in ICERs of $116,856/QALY in the US and $51,997/QALY in China. The probabilities of achieving cost-effectiveness at the current willingness-to-pay thresholds were 77.5% in the US and 16.5% in China. Cost-effectiveness could be reached if the price of nivolumab were reduced to $920.87/100mg in China. Subgroup analyses indicated that the combination had the highest probability of cost-effectiveness in patients under 65 or with an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 in the US and China. Nivolumab plus gemcitabine-cisplatin first-line treatment for advanced urothelial carcinoma results in longer life expectancy than gemcitabine-cisplatin, but is not cost-effective in China at current price. However, cost-effectiveness is likely to be achieved in most patient subgroups in the US.

Background: Drug-induced interstitial lung disease (DILD) is an increasingly common cause of morbidity and mortality. However, due to the lack of specificity, DILD detection remains an unsolved public health challenge. Objectives: For the first time, we aimed to examine DILD reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to identify demographic characteristics and top drugs associated with DILD at a group level (including age, sex, drug class, and country stratification) and individual drug level. Design: A retrospective analysis of the FAERS database was examined by disproportionality analysis. Methods: We reviewed the FAERS database from 2004 to 2021, using search terms ‘interstitial lung disease’ and sorting cases by generic drug name. The reporting odds ratio, proportional reporting ratio, and Bayesian confidence propagation neural network were calculated as the measure of strength of association. Results: There were 32,821 DILD reports in the FAERS. After excluding reports without age, sex, or country data according to the specific measurement, the median age of patients was 68 (interquartile range: 59), 54.77% were male, and 46.00% of reports came from Japan. The top drug classes related to DILD in the FAERS were antineoplastic, followed by cardiovascular and antirheumatic agents, in varying order in different sexes. Fam-trastuzumab deruxtecan-nxki, ramucirumab, and eribulin were the top three drugs with the highest strength of association. We also found some drugs without DILD in the labels, such as amiodarone, temsirolimus, and ursodiol. There are significant differences in DILD reports in various countries. For example, the United States and France reported more cardiovascular agents, whereas Canada reported more antirheumatic agents. Conclusion: We found the top drugs and drug classes that were associated with DILD in the FAERS, which provides a real-world window for different ages, sexes, and countries to formulate precise pharmacovigilance policies. Plain language summary A study on drug-induced interstitial lung disease Introduction: The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database is the largest public database for spontaneous reporting of adverse events, any undesirable experiences that occur while taking a medication. The FDA designed the FAERS database to allow them to track the safety of drugs once they are released on the market. This study aims to explore drug-induced interstitial lung disease (DILD) reporting trends, demographic characteristics, most commonly reported drugs, and high strength of association drugs using the FAERS database. Methods: We retrieved the term ‘interstitial lung disease’ to extract DILD reports in the FAERS database from 2004 to 2021. Then, we not only counted basic patient information, including age, gender, and reporting country, but also analyzed the drug class, the reporting frequency of drug, and the degree of relevance. Results: We identified a total of 32,821 DILD reports. DILD reports had a persistent increase from 2004 to 2021. The top three drug classes related to DILD in the FAERS were antineoplastic, cardiovascular and antirheumatic agents. The top three reported drugs associated with DILD were methotrexate, doxorubicin, and pembrolizumab. The top three drugs with the highest strength of association were fam-trastuzumab deruxtecan-nxki, ramucirumab, and eribulin. Various countries have significant differences in drugs related to DILD. Conclusion: By analyzing data from the FAERS database, we identified the top drugs, drug classes, and some unexpected drugs without DILD in the labels. Our findings provide additional insight into DILD to inform clinicians to enhance monitor related to drugs of potential importance.