Efficacy and safety of anti-PD-1/PD-L1-based dual immunotherapies versus PD-1/PD-L1 inhibitor alone in patients with advanced solid tumor: a systematic review and meta-analysis.

INTRODUCTION: Numerous randomized controlled trials (RCTs) have investigated PD-1/PD-L1 inhibitor-based combination therapies. The debate surrounding the potential additive clinical benefits of combination of two immune-oncology (IO) therapies for cancer patients persists. METHODS: Both published and grey sources of randomized clinical trials that compared anti-PD-1/PD-L1-based immunotherapy combinations with monotherapy in patients with advanced or metastatic solid tumors were encompassed. The primary outcome was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). RESULTS: Our analysis encompassed 31 studies comprising 10,341 patients, which covered 12 distinct immune-oncology combination regimens. Across all patients, the immunotherapy combinations exhibited the capability to enhance the ORR (OR = 1.23 [95% CI 1.13-1.34]) and extend PFS (HR = 0.91 [95% CI 0.87-0.95]). However, the observed enhancement in OS (HR = 0.96 [95% CI 0.91-1.01]) was of no significance. Greater benefits in terms of PFS (HR = 0.82 [95% CI 0.72 to 0.93]) and OS (HR = 0.85 [95% CI 0.73 to 0.99]) may be particularly pronounced in cases where PD-L1 expression is negative. Notably, despite a heightened risk of any-grade TRAEs (OR = 1.72 [95% CI 1.40-2.11]) and grade greater than or equal to 3 TRAEs (OR = 2.01 [95% CI 1.67-2.43]), toxicity was generally manageable. CONCLUSIONS: This study suggests that incorporating an additional immunotherapy agent with PD-1/PD-L1 inhibitors can elevate the response rate and reduce the risk of disease progression, all while maintaining manageable toxicity. However, there remains a challenge in translating these primary clinical benefits into extended overall survival.

NAT10-mediated upregulation of GAS5 facilitates immune cell infiltration in non-small cell lung cancer via the MYBBP1A-p53/IRF1/type I interferon signaling axis.

Interactions of tumor cells with immune cells in the tumor microenvironment play an important role during malignancy progression. We previously identified that GAS5 inhibited tumor development by suppressing proliferation of tumor cells in non-small cell lung cancer (NSCLC). Herein, we discovered a tumor-suppressing role for tumor cell-derived GAS5 in regulating tumor microenvironment. GAS5 positively coordinated with the infiltration of macrophages and T cells in NSCLC clinically, and overexpression of GAS5 promoted macrophages and T cells recruitment both in vitro and in vivo. Mechanistically, GAS5 stabilized p53 by directly binding to MYBBP1A and facilitating MYBBP1A-p53 interaction, and enhanced p53-mediated transcription of IRF1, which activated type I interferon signaling and increased the production of downstream CXCL10 and CCL5. We also found that activation of type I interferon signaling was associated with better immunotherapy efficacy in NSCLC. Furthermore, the stability of GAS5 was regulated by NAT10, the key enzyme responsible for N4-acetylcytidine (ac4C) modification, which bound to GAS5 and mediated its ac4C modification. Collectively, tumor cell-derived GAS5 could activate type I interferon signaling via the MYBBP1A-p53/IRF1 axis, promoting immune cell infiltration and potentially correlating with immunotherapy efficacy, which suppressed NSCLC progression. Our results suggested GAS5 as a promising predictive marker and potential therapeutic target for combination therapy in NSCLC. A schematic diagram demonstrating the regulatory effect of GAS5 on immune cell infiltration by activating type I interferon signaling via MYBBP1A-p53/IRF1 axis in non-small cell lung cancer. IFN, interferon.

Lesion Indexes Predict Early Neurologic Deterioration in Lenticulostriate Single Small Subcortical Infarction.

BACKGROUND AND PURPOSE: Early neurologic deterioration (END) often occurs during hospitalization in single small subcortical infarction (SSSI). The objective was to identify imaging predictors of END. MATERIALS AND METHODS: SSSIs in the lenticulostriate artery within 72 hours of stroke onset from January 2015 to June 2021 were consecutively enrolled. The posteriority and laterality indexes were assessed on the second section from the top of the corona radiata section showing the lateral ventricle on DWI. A multivariate logistic analysis was used to explore the predictors of END. RESULTS: A total of 402 patients were included in this study, among whom 93 (23.1%) experienced END. The optimal cutoff points of the posteriority and laterality indexes for predicting END were given by a receiver operating characteristic curve. A multivariate logistic analysis showed that the posteriority index of ≥0.669 (OR: 2.53; 95% CI: 1.41-4.56; P = .002) and the laterality index of ≥0.950 (OR: 2.03; 95% CI: 1.03-4.00; P = .042) were independently associated with the risk of END. Accordingly, the SSSIs were further divided into 4 types: anterior lateral type (AL-type), anterior medial type (AM-type), posterior lateral type (PL-type), and posterior medial type (PM-type). After the multivariate analysis, in comparison with the AL-type, the AM-type (OR: 3.26; 95% CI: 1.10-9.65), PL-type (OR: 4.68; 95% CI: 1.41-15.56), and PM-type (OR: 6.77; 95% CI: 2.53-18.04) carried significantly elevated risks of END. The PM-type was associated with the highest risk of END. CONCLUSIONS: The PM-type was found to be associated with the highest risk of END.

SYVN1 modulates papillary thyroid carcinoma progression by destabilizing HMGB1.

E3 ubiquitin ligase synoviolin (SYVN1) has been reported to participate in many human cancers. This study aimed to investigate SYVN1's roles and molecular pathways in papillary thyroid cancer (PTC). The functions of SYVN1 in PTC were further analyzed using gain- and loss-of-function methods and numerous investigations in cellular function and molecular biology. The findings demonstrated that the overexpression of SYVN1 markedly suppressed the proliferation, migration, and invasion of PTC cell lines (NPA87 and TPC-1). We found that SYVN1 interacted with HMGB1 and promoted its ubiquitination and degradation. In addition, SYVN1 effectively impairs cell proliferation, migration, invasion, and the formation of tumor xenografts in mice models. However, this effect may be partly reversed by overexpressing HMGB1. Thus, SYVN1 may inhibit the proliferation, migration, and invasion of PTC cells by disrupting HMGB1. Consequently, SYVN1 might be considered a promising therapeutic target for PTC.

Adult supratentorial extraventricular anaplastic ependymoma with cerebrospinal fluid dissemination metastases: a case report.

Background: Ependymomas mostly locate in the infratentorial region and often occur in children. Anaplastic ependymomas account for 45-47% of supratentorial and 15-17% of infratentorial ependymomas, also known as malignant ependymomas. Adult supratentorial extraventricular anaplastic ependymoma (SEAE) is rare in clinical practice, and only a few cases have been reported so far, and there is no clinical study with large sample size. We report a case of adult supratentorial extraventricular anaplastic ependymoma in the occipital lobe with cerebrospinal fluid dissemination metastases. Case description: A 58-year-old female patient presented with unexplained pain in multiple parts of the body for the past half a year, mainly manifested as pain in the head, abdomen and chest. On August, 2022, Head MRI of the patient showed abnormal signal shadow in the left occipital lobe, which was considered a malignant lesion. The patient underwent tumor resection under general anesthesia on September 3, 2022. Postoperative pathological examination showed anaplastic ependymoma. The postoperative follow-up head MRI showed multiple cerebrospinal fluid dissemination metastases in the brain. Conclusion: Adult SEAE is a rare tumor with high malignancy and have a tendency to disseminate into the CSF, resulting in drop metastases. Immunohistochemistry is very important for the diagnosis of SEAE. It is recommended to administer adjuvant chemotherapy or radiation therapy appropriately after surgery, based on the tumor being completely resected as much as possible.

Integrative proteomics and metabolomics explore the effect and mechanism of Qiyin granules on improving nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a prominent global health concern, representing a substantial burden within the spectrum of chronic liver diseases. Despite its escalating prevalence, a definitive therapeutic strategy or efficacious pharmacological intervention for NAFLD has yet to receive official approval to date. While Fu Fang Qiyin granules have exhibited efficacy in addressing NAFLD, the intricacies of their underlying mechanism of action remain inadequately elucidated. In this study, we substantiated the ameliorative impact of Qiyin on highfat diet (HFD)induced NAFLD in rat models. The results of metabonomics showed that 108 potential biomarkers in serum and urine related to amino acid metabolism, energy metabolism, and pyrimidine metabolism, have returned to normal levels compared to the model group. Hepatic transcriptomics further indicated that Qiyin potentially confers protective effects against NAFLD by mediating liver inflammation and fibrosis through lumican (LUM) and decorin (DCN). In summation, our investigation provides compelling evidence affirming the therapeutic promise of Qiyin for NAFLD. It elucidates the underlying mechanistic pathways, furnishing a compelling rationale for its prospective clinical application.

Clinical features and associated factors of coexisting intracerebral hemorrhage in patients with cerebral small vessel disease: a cross-sectional study.

Intracerebral hemorrhage (ICH) is generally considered to be closely related to cerebral small vessel disease (CSVD), leading to a poor prognosis. However, the coexistence of ICH in general CSVD patients and related factors remain underreported. In our cross-sectional study, we screened 414 CSVD patients from a database at the Department of Neurology, First Affiliated Hospital of Zhengzhou University (September 2018 to April 2022). Imaging biomarkers of CSVD and coexisting ICH lesion were assessed. Factors associated with coexisting ICH in CSVD were determined using multivariate logistic regression analysis. ICH was observed in 59 patients (14.3%). Multivariate logistic regression showed that previous history of ischemic stroke or transient ischemic attack (OR 5.189, 95%CI 2.572-10.467, P < 0.001), high-grade perivascular space in the basal ganglia (n > 10) (OR 2.051, 95%CI 1.044-4.027, P = 0.037) and low adjusted calcium-phosphorus product (OR 0.728 per 1 [mmol/L]2 increase, 95%CI 0.531-0.998, P = 0.049) were associated with coexisting ICH in CSVD patients. The considerable proportion of coexisting ICH and revelation of associated factors in general CSVD patients alert physicians of the potential risk of the reoccurrence of ICH, and might have a significant impact on therapeutic strategies.

The Idesia polycarpa genome provides insights into its evolution and oil biosynthesis.

The deciduous tree Idesia polycarpa can provide premium edible oil with high polyunsaturated fatty acid contents. Here, we generate its high-quality reference genome, which is ∼1.21 Gb, comprising 21 pseudochromosomes and 42,086 protein-coding genes. Phylogenetic and genomic synteny analyses show that it diverged with Populus trichocarpa about 16.28 million years ago. Notably, most fatty acid biosynthesis genes are not only increased in number in its genome but are also highly expressed in the fruits. Moreover, we identify, through genome-wide association analysis and RNA sequencing, the I. polycarpa SUGAR TRANSPORTER 5 (IpSTP5) gene as a positive regulator of high oil accumulation in the fruits. Silencing of IpSTP5 by virus-induced gene silencing causes a significant reduction of oil content in the fruits, suggesting it has the potential to be used as a molecular marker to breed the high-oil-content cultivars. Our results collectively lay the foundation for breeding the elite cultivars of I. polycarpa.

Analysis of the lncRNA-miRNA-mRNA network to explore the regulation mechanism in human traumatic brain injury.

Traumatic brain injury (TBI) refers to brain dysfunction with or without traumatic structural injury induced by an external force. Nevertheless, the molecular mechanism of TBI remains undefined. Differentially expressed (DE) lncRNAs, DEmRNAs and DEmiRNAs were selected between human TBI tissues and the adjacent histologically normal tissue by high-throughput sequencing. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis of overlapping DEmRNAs between predicted mRNAs of DEmiRNAs and DEmRNAs. The competitive endogenous RNA (ceRNA) network of lncRNA-miRNA-mRNA was established in light of the ceRNA theory. In the ceRNA network, the key lncRNAs were screened out. Then key lncRNAs related ceRNA subnetwork was constructed. After that, qRT-PCR was applied to validate the expression levels of hub genes. 114 DElncRNAs, 1807 DEmRNAs and 6 DEmiRNAs were DE in TBI. The TBI-related ceRNA network was built with 73 lncRNA nodes, 81 mRNA nodes and 6 miRNAs. According to topological analysis, two hub lncRNAs (ENST00000562897 and ENST00000640877) were selected to construct the ceRNA subnetwork. Subsequently, key lncRNA-miRNA-mRNA regulatory axes constructed by two lncRNAs including ENST00000562897 and ENST00000640877, two miRNAs including miR-6721-5p and miR-129-1-3p, two mRNAs including ketohexokinase (KHK) and cyclic nucleotide-gated channel beta1 (CNGB1), were identified. Furthermore, qRT-PCR results displayed that the expression of ENST00000562897, KHK and CNGB1 were significantly decreased in TBI, while the miR-6721-5p expression levels were markedly increased in TBI. The results of our study reveal a new insight into understanding the ceRNA regulation mechanism in TBI and select key lncRNA-miRNA-mRNA axes for prevention and treatment of TBI.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Enlarged Perivascular Space in the Basal Ganglia is Associated with Cerebral Venous Reflux in Patients with Recent Small Subcortical Infarction.

BACKGROUND: Research has linked enlarged perivascular spaces (EPVS) to cerebral venous reflux (CVR) in patients with hypertensive intracerebral hemorrhage, but it is unclear whether this association exists in recent small subcortical infarct (RSSI) patients. OBJECTIVE: This study aimed to investigate the correlation between EPVS and CVR in patients with RSSI. METHOD: This study included 297 patients, selected from patients with RSSI in the lenticulostriate artery admitted to the Department of Neurology of the First Affiliated Hospital of Zhengzhou University. CVR was assessed by time-of-flight magnetic resonance angiography (TOF-MRA). The relationship between EPVS and CVR was studied using multiple logistic regression analysis. RESULTS: This study included patients with an average age of 59.84±12.27 years, including 201 males (67.7%). CVR was observed in 40 (13.5%) patients. Compared to the group without CVR, the proportions of male patients and patients with a history of smoking and drinking were higher in the CVR group. The proportions of high-grade EPVS in the centrum semiovale region [23 cases (57.5%) vs. 108 cases (42.0%), p =0.067] and the basal ganglia region [30 cases (75.0%) vs. 133 cases (51.8%), p =0.006] were higher in the CVR group. After multiple logistic regression analysis, high-grade EPVS in the basal ganglia region was still associated with CVR (OR, 2.68; 95% CI, 1.22-5.87; p =0.014). CONCLUSION: In the population with RSSI, EPVS in basal ganglia is significantly associated with CVR, suggesting a close relationship between venous dysfunction and the formation of EPVS.

Comparative efficacy and safety of COVID-19 vaccines in phase III trials: a network meta-analysis.

BACKGROUND: Over a dozen vaccines are in or have completed phase III trials at an unprecedented speed since the World Health Organization (WHO) declared COVID-19 a pandemic. In this review, we aimed to compare and rank these vaccines indirectly in terms of efficacy and safety using a network meta-analysis. METHODS: We searched Embase, MEDLINE, and the Cochrane Library for phase III randomized controlled trials (RCTs) from their inception to September 30, 2023. Two investigators independently selected articles, extracted data, and assessed the risk of bias. Outcomes included efficacy in preventing symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the incidence of serious adverse events (SAEs) according to vaccine type and individual vaccines in adults and elderly individuals. The risk ratio and mean differences were calculated with 95% confidence intervals using a Bayesian network meta-analysis. RESULTS: A total of 25 RCTs involving 22 vaccines were included in the study. None of vaccines had a higher incidence of SAEs than the placebo. Inactivated virus vaccines might be the safest, with a surface under the cumulative ranking curve (SUCRA) value of 0.16. BIV1-CovIran showed the highest safety index (SUCRA value: 0.13), followed by BBV152, Soberana, Gam-COVID-Vac, and ZF2001. There were no significant differences among the various types of vaccines regarding the efficacy in preventing symptomatic SARS-CoV-2 infection, although there was a trend toward higher efficacy of the mRNA vaccines (SUCRA value: 0.09). BNT162b2 showed the highest efficacy (SUCRA value: 0.02) among the individual vaccines, followed by mRNA-1273, Abdala, Gam-COVID-Vac, and NVX-CoV2373. BNT162b2 had the highest efficacy (SUCRA value: 0.08) in the elderly population, whereas CVnCoV, CoVLP + AS03, and CoronaVac were not significantly different from the placebo. CONCLUSIONS: None of the different types of vaccines were significantly superior in terms of efficacy, while mRNA vaccines were significantly inferior in safety to other types. BNT162b2 had the highest efficacy in preventing symptomatic SARS-CoV-2 infection in adults and the elderly, whereas BIV1-CovIran had the lowest incidence of SAEs in adults.

Hub genes, a diagnostic model, and immune infiltration based on ferroptosis-linked genes in schizophrenia.

Background: Schizophrenia (SCZ) is a prevalent and serious mental disorder, and the exact pathophysiology of this condition is not fully understood. In previous studies, it has been proven that ferroprotein levels are high in SCZ. It has also been shown that this inflammatory response may modify fibromodulin. Accumulating evidence indicates a strong link between metabolism and ferroptosis. Therefore, the present study aims to identify ferroptosis-linked hub genes to further investigate the role that ferroptosis plays in the development of SCZ. Material and methods: From the GEO database, four microarray data sets on SCZ (GSE53987, GSE38481, GSE18312, and GSE38484) and ferroptosis-linked genes were extracted. Using the prefrontal cortex expression matrix of SCZ patients and healthy individuals as the control group from GSE53987, weighted gene co-expression network analysis (WGCNA) was performed to discover SCZ-linked module genes. From the feed, genes associated with ferroptosis were retrieved. The intersection of the module and ferroptosis-linked genes was done to obtain the hub genes. Then, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and Gene Set Enrichment Analysis (GSEA) were conducted. The SCZ diagnostic model was established using logistic regression, and the GSE38481, GSE18312, and GSE38484 data sets were used to validate the model. Finally, hub genes linked to immune infiltration were examined. Results: A total of 13 SCZ module genes and 7 hub genes linked to ferroptosis were obtained: DECR1, GJA1, EFN2L2, PSAT1, SLC7A11, SOX2, and YAP1. The GO/KEGG/GSEA study indicated that these hub genes were predominantly enriched in mitochondria and lipid metabolism, oxidative stress, immunological inflammation, ferroptosis, Hippo signaling pathway, AMP-activated protein kinase pathway, and other associated biological processes. The diagnostic model created using these hub genes was further confirmed using the data sets of three blood samples from patients with SCZ. The immune infiltration data showed that immune cell dysfunction enhanced ferroptosis and triggered SCZ. Conclusion: In this study, seven critical genes that are strongly associated with ferroptosis in patients with SCZ were discovered, a valid clinical diagnostic model was built, and a novel therapeutic target for the treatment of SCZ was identified by the investigation of immune infiltration.

Discovery and identification of interspecies peptide biomarkers in the seahorse species using liquid chromatography tandem mass spectrometry and chemometrics.

Seahorses have important edible and medicinal values including strengthening the body, tonifying the liver and kidneys, and reducing swelling. And there are abundant seahorse species on Earth. Many seahorses have large price differences due to the scarcity of resources, and some seahorses with similar appearances appear to be confused for use. While in market trading, Hippocampus is susceptible to loss of specialized morphology characteristics, making it difficult to distinguish between specific species. Here we report an effective method based on peptide biomarkers for the identification of seahorse species. Peptide biomarkers for each species were predicted using nano-liquid chromatography-tandem mass spectrometry (Nano-LC-MS/MS) combined with chemometrics software. One unique biomarker peptide for each species was synthesized and verified, and finally developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) multiple reaction monitoring method. The results indicate that the method has great potential for species-specific identification of seahorses and their preparations, among others.

Family-based genetic analysis in schizophrenia by whole-exome sequence to identify rare pathogenic variants.

Schizophrenia (SCZ) is influenced by a combination of genetic and environmental factors. Although several studies have been conducted to identify the causative loci and genes, few of these loci or genes can be repeated due to the high phenotypic and genetic heterogeneity of disease, and their mechanisms are not fully understood. There may be some "missing heritability" that has not yet been found. In order to investigate the deleterious heritable mutations, whole-exome sequencing (WES) in pedigrees with SCZ was used in the current work. Two unrelated pedigrees with SCZ were recruited to perform WES. Genetic analysis was next performed to find potential variants in accordance with the prioritized strategy. Followed by genetic analysis to detect candidate variants according to the prioritized strategy. Next, a series of algorithms was used to predict the pathogenicity of variants. Sanger sequencing was finally conducted to verify the co-segregation. Recessive mutations in six genes (TFEB, SNAI2, TFAP2B, PRKDC, ST18 in Pedigree 1 and PKHD1L1 in Pedigree 2) that co-segregated with SCZ in two families were discovered through genetic analysis by WES. Sanger sequencing verified that all of the mutations in the affected siblings were homozygous. These results corroborated the hypothesis that SCZ exhibits strong heterogeneity and complex inheritance patterns. The newly discovered homozygous variations deepen our understanding of the mutation spectrum and offer more proof for the involvement of TFEB, SNAI2, TFAP2B, PRKDC, ST18, and PKHD1L1 in the development of SCZ.

A multivalent polyphenol-metal-nanoplatform for cascade amplified chemo-chemodynamic therapy.

Chemodynamic therapy (CDT), as an emerging therapeutic strategy, kills cancer cells by converting intracellular hydrogen peroxide (H2O2) into cytotoxic oxidizing hydroxyl radicals (⋅OH). However, the therapeutic efficiency of CDT is compromised due to the insufficient endogenous H2O2 and metal catalysts in tumor cells. The use of multivalent polyphenols with multiple hydroxyl functions provides a facile yet robust means for efficient CDT augmentation. For this purpose, we reported herein the construction of polyphenol-metal nanoparticles (NPs) via a phenol-metal coordination strategy. The uniqueness of this study is the preparation of only one polymer construct with multivalency that can afford various supramolecular interactions for simultaneous "one-pot" loading of different therapeutic species, i.e., doxorubicin (DOX), glucose oxidases (GOD), and Fe3+ and further co-self-assembly into a stabilized nanomedicine for cascade amplified chemo-chemodynamic therapy. Specifically, the tumor intracellular acidic pH-triggered DOX release could serve for chemotherapy as well as enhance the intracellular H2O2 level. Together with the extra H2O2 and gluconic acid produced by the GOD-triggered glucose consumption, DOX@POAD-Fe@GOD NPs promoted Fe3+participation in the Fe-mediated Fenton reaction for cascade amplified chemo-chemodynamic therapy. Notably, this formulation displayed a greater anti-tumor effect with a tumor inhibition ratio 1.6-fold higher than that of free DOX in a BALB/c mice model bearing 4T1 tumors. Overall, the multivalent polyphenol-metal nanoplatform developed herein integrates chemotherapy, starvation therapy, and CDT for synergistic enhanced anticancer efficiency, which shows great potential for clinical translations. STATEMENT OF SIGNIFICANCE: Chemodynamic therapy (CDT) generally suffers from compromised therapeutic efficiency due to insufficient endogenous H2O2 and metal catalysts in tumor cells. To develop a facile yet robust strategy for efficient CDT augmentation, we reported herein construction of a multivalent polyphenol-metal nanoplatform, DOX@POAD-Fe@GOD nanoparticles (NPs) via a phenol-metal coordination strategy. This nanoplatform integrates multiple supramolecular dynamic interactions not only for simultaneously safe encapsulation of doxorubicin (DOX), Fe3+, and glucose oxidases (GOD), but also for cascade amplified chemo-chemodynamic therapy. Specifically, the intracellular acidic pH-triggered dissociation of DOX@POAD-Fe@GOD NPs promoted the release of Fe3+, DOX, and GOD for significantly increased ROS levels that can accelerate Fenton reactions for cascaded chemotherapy, starvation therapy, and CDT with amplified antitumor efficiency in vivo.

Precision nephrotoxicity testing using 3D in vitro models.

Nephrotoxicity is a significant concern during the development of new drugs or when assessing the safety of chemicals in consumer products. Traditional methods for testing nephrotoxicity involve animal models or 2D in vitro cell cultures, the latter of which lack the complexity and functionality of the human kidney. 3D in vitro models are created by culturing human primary kidney cells derived from urine in a 3D microenvironment that mimics the fluid shear stresses of the kidney. Thus, 3D in vitro models provide more accurate and reliable predictions of human nephrotoxicity compared to existing 2D models. In this review, we focus on precision nephrotoxicity testing using 3D in vitro models with human autologous urine-derived kidney cells as a promising approach for evaluating drug safety.

Efficacy and safety of first-line PD-1/PD-L1 inhibitor combinations for extensive-stage small-cell lung cancer: a Bayesian network meta-analysis.

Objectives: Several randomized controlled trials (RCTs) indicated that first-line programmed cell death protein-1/death-ligand 1 inhibitors plus chemotherapy (PD-1/PD-L1 + chemo) led to survival benefits in extensive-stage small-cell lung cancer (ES-SCLC) compared with platinum-based chemotherapy. This study aims to identify the optimal PD-1/PD-L1 + chemo combination strategy. Methods: We included RCTs comparing PD-1/ PD-L1 + chemo versus chemo alone in ES-SCLC. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade ⩾3 treatment-related adverse events were considered. Odds ratios (ORs), hazard ratios (HRs), and their 95% confidence intervals (CIs) were extracted. Results: Six RCTs with 2600 patients were analyzed in this Bayesian network meta-analysis. Results showed that adding PD-1/PD-L1 inhibitors to chemotherapy led to significant benefits in OS (HR = 0.72, 95% CI: 0.66-0.79), PFS (HR = 0.69, 95% CI: 0.63-0.75), and ORR (OR = 1.32, 95% CI: 1.12-1.56), and no differences in toxicity were found (OR = 1.09, 95% CI: 0.92-1.30). Serplulimab plus chemotherapy was found to provide the best OS (HR = 0.63, 95% CI: 0.49-0.82), the best PFS (HR = 0.47, 95% CI: 0.38-0.59), and the best ORR (OR = 1.7, 95% CI: 1.15-2.53). Moreover, although there were no difference between PD-L1 + chemo and PD-1 + chemo regarding OS (HR = 0.99, 95% CI: 0.91-1.08) and ORR (OR = 1.27, 95% CI: 0.91-1.78), PD-1 + chemo showed a significant benefit in PFS (HR = 0.82, 95% CI: 0.68-0.98) compared with PD-L1 + chemo. Conclusions: Serplulimab plus chemotherapy seems to be superior first-line immunotherapy combination for patients with ES-SCLC. PD-1 + chemo seems to outperform PD-L1 + chemo in PFS.

Risk factors for symptomatic malignant pleural effusion recurrence in patients with actionable mutations in advanced lung adenocarcinoma.

Background: Malignant pleural effusion (MPE) comes generally with high mortality and poor prognosis. Recurrence of symptomatic MPE is always accompanied by poor survival quality. In lung adenocarcinoma, researchers speculate whether patients with actionable mutation or without are applicable to different management models for MPE. Under the background of the high mutation probability and the encouraging therapeutic response in Asians, researches on the risk factors of MPE are in need. Methods: This retrospective review included 343 metastatic lung adenocarcinoma patients with MPE. Recurrence was defined as recurrent symptomatic MPE requiring the second thoracentesis to relieve symptoms within 300 days after the first thoracentesis. Univariable and multivariable Cox regression analysis were utilized to investigate independent risk factors for MPE recurrence. Results: Of the 343 patients involved, 139 experienced MPE recurrence within 300 days; 34.3% in 201 patients with actionable mutations and 51.2% in 129 patients without actionable mutations are in the recurrence. The median recurrence-free survival (RFS) of the group without mutations was 161 days. The median RFS of the other group with mutations was 300 days. Patients with actionable mutations showed a significantly lower hazard of MPE recurrence on univariate analysis. The multivariate analysis indicated that receiving targeted therapy after the first thoracentesis within 30 days, lower neutrophil-to-lymphocyte ratio (NLR) level, lower serum lactate dehydrogenase (s-LDH) level, and lower serum carcinoembryonic antigen (s-CEA) level were independent protective factors. In subgroup analysis, risk factors differed. Receiving targeted therapy after the first thoracentesis within 30 days remained an independent factor in the mutated patients. Conclusions: The findings herein indicated the characteristics of specific patients at high risk for MPE recurrence in lung adenocarcinoma. Patients with actionable mutations benefit more in MPE recurrence and could benefit from targeted therapy and active intrapleural management.

Expert consensus on the diagnosis and treatment of RET gene fusion non-small cell lung cancer in China.

The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell-surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non-small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second-generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first-generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET-targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.