Results of a Pilot External Quality Assessment Scheme for Genetic Testing of Newborns with Spinal Muscular Atrophy.

BACKGROUND: This study aims to evaluate the ability of laboratories to perform spinal muscular atrophy (SMA) genetic testing in newborns based on dried blood spot (DBS) samples, and to provide reference data and advance preparation for establishing the pilot external quality assessment (EQA) scheme for SMA genetic testing of newborns in China. METHODS: The pilot EQA scheme contents and evaluation principles of this project were designed by National Center for Clinical Laboratories (NCCL), National Health Commission. Two surveys were carried out in 2022, and 5 batches of blood spots were submitted to the participating laboratory each time. All participating laboratories conducted testing upon receiving samples, and test results were submitted to NCCL within the specified date. RESULTS: The return rates were 75.0% (21/28) and 95.2% (20/21) in the first and second surveys, respectively. The total return rate of the two examinations was 83.7% (41/49). Nineteen laboratories (19/21, 90.5%) had a full score passing on the first survey, while in the second survey twenty laboratories (20/20, 100%) scored full. CONCLUSIONS: This pilot EQA survey provides a preliminary understanding of the capability of SMA genetic testing for newborns across laboratories in China. A few laboratories had technical or operational problems in testing. It is, therefore, of importance to strengthen laboratory management and to improve testing capacity for the establishment of a national EQA scheme for newborn SMA genetic testing.

Stimuli-Responsive Aptamer-Drug Conjugates for Targeted Drug Delivery and Controlled Drug Release.

Chemotherapy has been widely used for cancer therapy but with unsatisfied efficacy, mainly due to the inefficient delivery of anticancer agents. Among the critical "five steps" drug delivery process, internalization into tumor cells and intracellular drug release are two important steps for the overall therapeutic efficiency. Strategy based on active targeting or TME-responsive has been developed individually to improve therapeutic efficiency, but with limited improvement. However, the combination of these two strategies could potentially augment the drug delivery efficiency and therapeutic efficiency, consequently. Therefore, we constructed a library of stimuli-responsive aptamer-drug conjugates (srApDCs), as "dual-targeted" strategy for cancer treatment that enables targeted drug delivery and controlled drug release. Specifically, we used different stimuli-responsive linkers to conjugate a tumor-targeting aptamer (i.e., AS1411) with drugs, forming the library of srApDCs for targeted cancer treatment. Our design hypothesis was validated by the experimental data, which indicated that the aptamer could selectively enhance uptake of the srApDCs and the linkers could be cleaved by pathological cues in the TME to release the drug payload, leading to a significant enhancement of therapeutic efficacy. These results underscore the potential of our approach, providing a promising methodology for cancer therapy. This article is protected by copyright. All rights reserved.

Result of a Pilot External Quality Assessment Scheme for Clinical Diagnosis of Inherited Metabolic Disorders in China.

BACKGROUND: We aimed to evaluate the diagnostic capabilities of Chinese laboratories for inherited metabolic disorders (IMDs) using gas chromatography-mass spectrometry (GC-MS) on urine samples. Meanwhile, based on the result of the pilot external quality assessment (EQA) scheme, we hope to establish a standardized and reliable procedure for future EQA practice. METHODS: We recruited laboratories that participated in the EQA of quantitative analysis of urinary organic acids with GC-MS before joining the surveys. In each survey, a set of five real urine samples was distributed to each participant. The participants should analyze the sample by GC-MS and report the "analytical result", "the most likely diagnosis", and "recommendation for further tests" to the NCCL before the deadline. RESULTS: A total of 21 laboratories participated in the scheme. The pass rates were 94.4% in 2020 and 89.5% in 2021. For all eight IMDs tested, the analytical proficiency rates ranged from 84.7% - 100%, and the interpretational performance rate ranged from 88.2% - 97.0%. The performance on hyperphenylalaninemia (HPA), 3-methylcrotonyl-CoA carboxylase deficiency (MCCD), and ethylmalonic encephalopathy (EE) samples were not satisfactory. CONCLUSIONS: In general, the participants of this pilot EQA scheme are equipped with the basic capability for qualitative organic acid analysis and interpretation of the results. Limited by the small size of laboratories and samples involved, this activity could not fully reflect the state of clinical practice of Chinese laboratories. NCCL will improve the EQA scheme and implement more EQA activities in the future.

Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease.

IgG4-related disease (IgG4-RD) has complex clinical manifestations ranging from fibrosis and inflammation to deregulated metabolism. The molecular mechanisms underpinning these phenotypes are unclear. In this study, by using IgG4-RD patient peripheral blood mononuclear cells (PBMCs), IgG4-RD cell lines and Usp25 knockout mice, we show that ubiquitin-specific protease 25 (USP25) engages in multiple pathways to regulate fibrotic and inflammatory pathways that are characteristic to IgG4-RD. Reduced USP25 expression in IgG4-RD leads to increased SMAD3 activation, which contributes to fibrosis and induces inflammation through the IL-1ß inflammatory axis. Mechanistically, USP25 prevents ubiquitination of RAC1, thus, downregulation of USP25 leads to ubiquitination and degradation of RAC1. Decreased RAC1 levels result in reduced aldolase A release from the actin cytoskeleton, which then lowers glycolysis. The expression of LYN, a component of the B cell receptor signalosome is also reduced in USP25-deficient B cells, which might result in B cell activation deficiency. Altogether, our results indicate a potential anti-inflammatory and anti-fibrotic role for USP25 and make USP25 a promising diagnostic marker and potential therapeutic target in IgG4-RD.

Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever.

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis.

Recent Advances and Perspectives of Metal Halide Perovskite Heteronanocrystals.

Heteronanocrystals that combine multiple semiconductors into a nanoscale heterostructure possess excellent optical performance and flexibility in property engineering compared with their single-component counterparts. The successes in fabricating lead halide perovskite-based heteronanocrystals (PHNCs) have drastically improved the stability and tunability of the optical and electrical properties. However, the epitaxial growth of semiconductor materials on perovskite nanocrystals remains a fundamental challenge because of the mismatch in their surface structure and crystal growth kinetics. Here, we review recent progress in the development of PHNCs with emphasis on their synthesis methods and surface chemistry that led to new insights and reaction protocols for the design and fabrication of PHNCs. In addition, the optical features of different types of PHNCs and nanocomposites and their application perspectives are summarized. Finally, we conclude with a discussion of the remaining issues, challenges, and opportunities in epitaxial growth of Janus and core-shell structure PHNCs.

Core-shell architectured NH2-UiO-66@ZIF-8/multi-walled carbon nanotubes nanocomposite-based sensitive electrochemical sensor towards simultaneous determination of Pb2+ and Cu2.

Amino functionalized zirconium-based metal-organic framework (NH2-UiO-66) and zinc-based zeolitic imidazolate framework (ZIF-8) were integrated to develop a core-shell architectured hybrid material (NH2-UiO-66@ZIF-8, NU66@Z8). The morphology and structure evolutions of core-shell NU6@Z8 were investigated by FE-SEM, XRD, FTIR, and XPS. The NU66@Z8 combined with carboxylated multi-walled carbon nanotubes (CMWCNT) was deposited on a glassy carbon electrode (GCE) for fabricating an electrochemical platform towards detecting Pb2+ and Cu2+. The NU66@Z8/CMWCNT/GCE revealed significantly improved electrochemical performance for determination of Pb2+ and Cu2+ compared with the individual components, which can be attributed to the strong adsorption capacity, unique core-shell structure, and large electrochemical active surface area of NU66@Z8/CMWCNT. Under the optimal conditions, the developed sensor exhibited excellent sensing capability with a low limit of detection (Pb2+,1 nM; Cu2+, 10 nM) and a wide determination range (Pb2+,0.003-70 µM; Cu2+, 0.03-50 µM). The sensor showed high selectivity towards common interfering ions and good repeatability. The real sample recoveries of proposed sensor were in the range 95.0-103% for Pb2+ (RSD ≤ 5.3%) and 94.2-106% for Cu2+ (RSD ≤ 5.9%), suggesting that the NU66@Z8/CMWCNT is suitable for examining trace heavy metals in natural environment.

Exosomal long noncoding RNAs MAGI2-AS3 and CCDC144NL-AS1 in oral squamous cell carcinoma development via the PI3K-AKT-mTOR signaling pathway.

BACKGROUND: Long noncoding RNAs (lncRNAs) are essential and critical components of signal and transduction, regulating the intracellular microenvironment. Serum exosomes (SEs) are involved in rearranging the intercellular functional lncRNAs, which may also play a role in oral squamous cell carcinoma (OSCC). The function of lncRNAs at the transcription level in SEs of patients with OSCC is partially understood. MATERIALS AND METHODS: The lncRNA expression profiles were examined derived from SEs from patients with OSCC with lymph node metastasis (OSCC-LNM), OSCC with no LNM (OSCC-NLNM), postoperative metastasis and recurrence OSCC (rOSCC) and healthy controls (HCs). Bioinformatics analysis was used to analyse differentially expressed lncRNAs (DE lncRNAs) and a total of 150 subjects were enrolled for RT-PCR verifications. The correlations of four lncRNAs and clinicopathologic factors, biochemical indexes were evaluated. MAGI2-AS3 and CCDC144NL-AS1 were overexpressed or silenced in oral cancer (OC) cells. The proliferation, invasion, and migration were evaluated to investigate the effect of MAGI2-AS3 and CCDC144NL-AS1 on the development of OSCC. The related proteins of PI3K-AKT-mTOR signal pathway were also detected. RESULTS: The expressions of the lncRNAs, namely MAGI2-AS3 and CCDC144NL-AS1, were significantly upregulated in rOSCC and OSCC-LNM. MAGI2-AS3 was overexpressed in cancer tissue compared to other control groups. AC109587.1 and AC010978.1 were significantly associated with the clinical stage, and CCDC144NL-AS1 was significantly associated with aging. MAGI2-AS3 and CCDC144NL-AS1 might promote cell proliferation, invasion, and migration in OSCC cells by regulating the PI3K-AKT-mTOR pathway. CONCLUSIONS: our results suggest that MAGI2-AS3 an d CCDC144NL-AS1 may have clinical applications in the treatment of OSCC.

Involvement of MST1/mTORC1/STAT1 activity in the regulation of B-cell receptor signalling by chemokine receptor 2.

BACKGROUND: CCR2 is involved in maintaining immune homeostasis and regulating immune function. This study aims to elucidate the mechanism by which CCR2 regulates B-cell signalling. METHODS: In Ccr2-knockout mice, the development and differentiation of B cells, BCR proximal signals, actin movement and B-cell immune response were determined. Besides, the level of CCR2 in PBMC of SLE patients was analysed by bioinformatics. RESULTS: CCR2 deficiency reduces the proportion and number of follicular B cells, upregulates BCR proximal signalling and enhances the oxidative phosphorylation of B cells. Meanwhile, increased actin filaments aggregation and its associated early-activation events of B cells are also induced by CCR2 deficiency. The MST1/mTORC1/STAT1 axis in B cells is responsible for the regulation of actin remodelling, metabolic activities and transcriptional signalling, specific MST1, mTORC1 or STAT1 inhibitor can rescue the upregulated BCR signalling. Glomerular IgG deposition is obvious in CCR2-deficient mice, accompanied by increased anti-dsDNA IgG level. Additionally, the CCR2 expression in peripheral B cells of SLE patients is decreased than that of healthy controls. CONCLUSIONS: CCR2 can utilise MST1/mTORC1/STAT1 axis to regulate BCR signalling. The interaction between CCR2 and BCR may contribute to exploring the mechanism of autoimmune diseases.

Abelson tyrosine kinase controls BCR signalling and B-cell differentiation by promoting B-cell metabolism.

As a nonreceptor tyrosine kinase, Abelson tyrosine kinase (c-Abl) was first studied in chronic myelogenous leukaemia, and its role in lymphocytes has been well characterised. c-Abl is involved in B-cell development and CD19-associated B-cell antigen receptor (BCR) signalling. Although c-Abl regulates different metabolic pathways, the role of c-Abl is still unknown in B-cell metabolism. In this study, B-cell-specific c-Abl knockout (KO) mice (Mb1Cre+/- c-Ablfl/fl ) were used to investigate how c-Abl regulates B-cell metabolism and BCR signalling. We found that the levels of activation positive BCR signalling proximal molecules, phosphorylated spleen tyrosine kinase (pSYK) and phosphorylated Bruton tyrosine kinase (pBTK), were decreased, while the level of key negative regulator, phosphorylated SH2-containing inositol phosphatase 1 (pSHIP1), was increased in Mb1Cre+/- c-Ablfl/fl mice. Furthermore, we found c-Abl deficiency weakened the B-cell spreading, formation of BCR signalosomes, and the polymerisation of actin during BCR activation, and also impaired the differentiation of germinal center (GC) B-cells both in quiescent condition and after immunisation. Moreover, B-cell mitochondrial respiration and the expression of B-cell metabolism-regulating molecules were downregulated in c-Abl deficiency mice. Overall, c-Abl, which involved in actin remodelling and B-cell metabolism, positively regulates BCR signalling and promotes GC differentiation.

Effect of Concomitant Use of Analgesics on Prognosis in Patients Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

Background: Drug-drug interactions (DDIs) pose new challenges beyond traditional pharmacodynamics in the context of optimizing the treatment options with immune checkpoint inhibitors (ICIs). To alleviate cancer-related pain, analgesics are of absolute vital importance as chronic medications used by cancer patients. However, the possible outcome of ICI treatment concomitant with analgesics remains unclear. Methods: Original articles describing the possible influence of analgesics use on ICI treatment published before December 1, 2021 were retrieved from PubMed, Embase, and the Cochrane Library. Odds ratio (OR) with 95% confidence interval (CI) for objective response rate (ORR), hazard ratio (HR) with 95% CI for progression-free survival (PFS), and overall survival (OS) were calculated using the random-effects or fixed-effects model, and heterogeneity was assessed using the χ2-based Q-test. Publication bias was examined by funnel plot analysis. Results: A total of 11 studies involving 4,404 patients were included. The pooled OR showed that opioid use decreased the response of opioid users to ICIs compared to non-opioid users (OR = 0.49, 95% CI = 0.37-0.65, p < 0.001). Compared to patients who did not receive opioids, opioid users had an increased risk of progression and mortality (HR = 1.61, 95% CI = 1.37-1.89, p < 0.001; HR = 1.67, 95% CI =1.30-2.14, p < 0.001, respectively). Furthermore, the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) was not significantly associated with differences in ORR, PFS, and OS in patients treated with ICIs (OR = 1.40, 95% CI = 0.84-2.32, p = 0.190; HR = 0.90, 95% CI = 0.77-1.06, p = 0.186; HR = 0.90, 95% CI = 0.71-1.14, p = 0.384, respectively). Conclusion: The concomitant use of opioids during ICI treatment has an adverse effect on patient prognosis, while the use of NSAIDs is not significantly associated with the prognosis in patients treated with ICIs.

Ag nanocubes monolayer-modified PDMS as flexible SERS substrates for pesticides sensing.

A new approach is presented to fabricate flexible surface-enhanced Raman scattering (SERS) substrate of Ag nanocubes monolayer-modified polydimethylsiloxane (Ag NCs/PDMS) through a powerful three-phase interface self-assemble method. The morphologies and crystal structures were characterized by scanning electron microscopy and X-ray diffraction. The self-assembled Ag NCs/PDMS substrate exhibited high SERS activity and good signal homogeneity, which was successfully used for quantitative detection of thiram; the detection limit reached 10 ng/mL, and the linear range is 10-1000 ng/mL. Furthermore, the flexible SERS substrates were successfully employed to detect thiram residues on factual apple samples, and trace amount (1 ng/cm2) of thiram residues was detected on apple peels. The excellent SERS detection ability of self-assembled Ag NCs/PDMS substrate indicated that it will play an important role in pesticide detection in the future.

First-line chemotherapy plus immune checkpoint inhibitors or bevacizumab in advanced non-squamous non-small-cell lung cancer without EGFR mutations or ALK fusions.

Aim: To compare the efficacy and safety of first-line chemotherapy (Chemo) plus immune checkpoint inhibitors (ICIs) or bevacizumab (Bev) in advanced non-squamous non-small-cell lung cancer without EGFR mutations or ALK fusions. Methods: A network meta-analysis was conducted to synthesize relative treatment outcomes. Results: Chemo + ICIs is superior to Chemo + Bev in both overall survival (hazard ratio: 0.92; 95% CI: 0.88-0.96) and progression-free survival (hazard ratio: 0.93; 95% CI: 0.90-0.97), with comparable severe adverse events. However, for patients with liver metastasis, Chemo + Bev has a 59.8% probability of providing better overall survival benefit. For specific regimens, pembrolizumab + Chemo showed an absolute advantage over other regimens. Conclusion: First-line Chemo + ICIs is superior to Chemo + Bev in advanced non-squamous non-small-cell lung cancer except for patients with liver metastasis.

Chemotherapy plus immune checkpoint inhibitors and chemotherapy plus bevacizumab were both superior to traditional chemotherapy and were recommended as the first-line treatment for advanced non-squamous non-small-cell lung cancer patients without EGFR mutations or ALK fusions. However, the efficacy and safety of these two treatment models have not been comprehensively discussed head-to-head in clinical trials. Therefore, a network meta-analysis was performed to compare efficacy between these two treatment models, especially according to different clinical characteristics, to guide decision making in clinical practice.

Characteristics of the immunogenicity and tumor immune microenvironment in HER2-amplified lung adenocarcinoma.

Objective: Besides breast and gastric cancer, HER2 amplification/mutation are also found in lung adenocarcinoma (LUAD). However, the correlation between HER2 variations and the phenotype of immunogenicity and tumor immune microenvironment (TIME) in LUAD compared with breast and gastric cancer has yet to be fully elucidated. Methods: We integrated public databases (discovery set) and internal data (validated set) of 288 patients representing three distinct HER2-altered tumors. Genomic data were used to identify somatic mutations, copy number variations, and calculate tumor mutational burden (TMB) and microsatellite instability score. RNA sequencing was conducted to estimate immune gene signatures and contents of tumor-infiltrating immune cell populations. Finally, IHC was used to determine PD-L1 expression and the tumoral-infiltration of immune cells in 50 HER2-variant tumor specimens with no prior therapeutic regimens. Results: Compared with HER2-amplified breast and gastric cancers, patients with HER2-amplified LUAD showed higher immunogenicity, mainly manifested in immune checkpoints expression and tissue/blood TMB. Additionally, HER2-amplified LUAD exhibited an inflamed TIME with remarkably increased genes encoding HLAs, T-cell activity and immune cell-type, and accompanied with tumor-infiltrating lymphocytes. In LUAD, patients with HER2 amplification possessed higher tissue TMB than HER2 mutation, whereas no difference was observed in PD-L1 expression. HER2 amplification (primary) was associated with significantly higher PD-L1 expression and TMB than acquired HER2 amplification after resistance to EGFR-TKIs. Conclusion: Patients with HER2-amplified LUAD have better immunogenicity and/or an inflamed TIME among HER2-aberrant tumors. Our study may provide clues for establishing the benefits and uses of ICIs for patients with this disease.

Ultrastretchable and Self-Healing Conductors with Double Dynamic Network for Omni-Healable Capacitive Strain Sensors.

Skin-mountable capacitive-type strain sensors with great linearity and low hysteresis provide inspiration for the interactions between human and machine. For practicality, high sensing performance, large stretchability, and self-healing are demanded but limited by stretchable electrode and dielectric and interfacial compatibility. Here, we demonstrate an extremely stretchable and self-healing conductor via both hard and soft tactics that combine conductive nanowire assemblies with double dynamic network based on π-π attractions and Ag-S coordination bonds. The obtained conductor outperforms the reported stretchable conductors by delivering an elongation of 3250%, resistance change of 223% at 2000% strain, high durability, and multiresponsive self-healability. Especially, this conductor accommodates large strain of 1500% at extremely knotted and twisted deformations. By sandwiching hydrogel conductors with a newly developed dielectric, ultrahigh stretchability and omni-healability are simultaneously achieved for the first time for a capacitive strain sensor inspired by metal-thiolate coordination chemistry, showing great potentials in wearable electronics and soft robotics.

First-line immune-based combination therapies for advanced non-small cell lung cancer: A Bayesian network meta-analysis.

BACKGROUND: Immune-based combination therapies have revolutionized the first-line treatment for advanced non-small cell lung cancer (NSCLC). However, for the efficacy and safety, the best treatment option is still uncertain. METHODS: We conducted a Bayesian network meta-analysis of randomized controlled trials (RCTs) to evaluate first-line immune-based combination therapies for advanced NSCLC. RESULTS: Fourteen trials involving 8467 patients were included. For the programmed cell death-ligand 1 (PD-L1) expression non-selective patients, there were no significant differences among all the treatment modes for overall survival (OS), but the ranking profiles indicated that Immunotherapy + Immunotherapy + Chemotherapy (IO + IO + Chemo) was most likely to be the best mode (probability = 68%). Immunotherapy + Immunotherapy + Anti-angiogenic therapy + Chemotherapy (IO + Anti-angio + Chemo) was significantly better than most other treatment modes for progression-free survival (PFS) with better objective response rate (ORR) and more obvious grade ≥3 treatment-related adverse events (TRAEs). In PD-L1-high cohort, IO + Anti-angio + Chemo seemed to be the best mode for OS, PFS, and ORR according to the ranking profiles. In PD-L1-intermediate and PD-L1-negative cohort, IO + IO + Chemo was inclined to be ranked first for prolonging OS (probability = 78%; 37%) and IO + Anti-angio + Chemo was most likely to provide best PFS (probability = 96%; 100%). CONCLUSION: IO + IO + Chemo has great potential to improve the OS regardless of histology type, especially in PD-L1-intermediate and PD-L1-negative cohort. IO + Anti-angio + Chemo shows great superiority in improving the short-term survival accompanied by increasing grade ≥3 TRAEs.

An Indirect Comparison Between Nivolumab + Ipilimumab + Two Cycles of Chemotherapy vs. Pembrolizumab + Chemotherapy as First-Line Treatment for Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: Nivolumab + ipilimumab + two cycles chemotherapy (N-I + chemo, intensive immunotherapy but chemo-light) and pembrolizumab + chemotherapy (Pem + chemo) were both recommended as first-line treatment for metastatic non-small cell lung carcinoma (NSCLC) patients. We conducted this indirect comparison to compare the efficacy of and safety between these two treatments for providing reference for decision making. METHODS: Relevant databases were searched for eligible trials. A well-accepted adjusted indirect treatment comparison (ITC) approach was selected to pool efficacy results and safety outcomes. Subgroup analyses were stratified according to PD-L1 expression and clinical characteristics. RESULTS: Four eligible randomized trials (CheckMate9LA, KEYNOTE-021G, KEYNOTE 189, KEYNOTE 407) involving 2017 patients were available to analyze. The ITC results suggested that N-I + chemo is comparable to Pem + chemo in OS (HR 1.03, 95% CI 0.82-1.30) and ORR (RR 0.81, 95% CI 0.62-1.06), but tended to yield inferior PFS (HR 1.28, 95% CI 1.04-1.59) than did Pem + chemo. As for safety profiles, N-I + chemo showed no significant difference relative to Pem + chemo in any grade adverse events: (RR 1.03, 95% CI 0.99-1.10), but demonstrated reduced toxicity in chemo-related adverse events, such as anemia (RR 0.63, 95% CI 0.49-0.81), neutropenia (RR0.51, 95% CI 0.33-0.79), and thrombocytopenia (RR 0.38, 95% CI 0.21-0.69). CONCLUSIONS: N-I + chemo is a promising treatment option for providing comparable OS related to Pem + chemo. However, for never smoker female patients, Pem + chemo is preferable to choose for demonstrating favorable OS benefit than N-I + chemo.

Circ-SKA3 Enhances Doxorubicin Toxicity in AC16 Cells Through miR-1303/TLR4 Axis.

Doxorubicin (DOX) is a widely used anticancer drug, but its cardiotoxicity largely limits its clinical utilization. Circular RNA spindle and kinetochore-associated protein 3 (circ-SKA3) were found to be differentially expressed in heart failure patients. In this study, we investigated the role and mechanism of circ-SKA3 in DOX-induced cardiotoxicity.The quantitative real-time polymerase chain reaction and western blot assays were applied to measure the expression of circ-SKA3, microRNA (miR) -1303, and toll-like receptor 4 (TLR4). The viability and apoptosis of AC16 cells were analyzed using cell counting kit-8, flow cytometry, and western blot assays. The interaction between miR-1303 and circ-SKA3 or TLR4 was verified using dual-luciferase reporter and RNA immunoprecipitation assays. Exosomes were collected from culture media by the use of commercial kits and then qualified by transmission electron microscopy.The expression of circ-SKA3 and TLR4 was increased, whereas miR-1303 expression was decreased in DOX-treated AC16 cells. DOX treatment promoted cell apoptosis and inhibited cell viability in AC16 cells in vitro, which was partially reversed by circ-SKA3 knockdown, TLR4 silencing, or miR-1303 overexpression. Mechanistically, circ-SKA3 served as a sponge for miR-1303 to upregulate TLR4, which was confirmed to be a target of miR-1303. Additionally, circ-SKA3 contributed to DOX-induced cardiotoxicity through the miR-1303/TLR4 axis. Further studies suggested that circ-SKA3 was overexpressed in exosomes extracted from DOX-mediated AC16 cells, which could be internalized by surrounding untreated AC16 cells.Circ-SKA3 enhanced DOX-induced toxicity in AC16 cells through the miR-1303/TLR4 axis. Extracellular circ-SKA3 was packaged into exosomes, and exosomal circ-SKA3 could function as a mediator in intercellular communication between AC16 cells.

Effect of Immune-Related Adverse Events and Pneumonitis on Prognosis in Advanced Non-Small Cell Lung Cancer: A Comprehensive Systematic Review and Meta-analysis.

OBJECTIVE: The correlation between immune-related adverse events (irAEs) and prognosis remains controversial in advanced non-small cell lung cancer (NSCLC). The aim of this study was to systematically evaluate the effect of irAEs, especially checkpoint inhibitor pneumonitis (CIP), on the survival and treatment response in advanced NSCLC. METHODS: The primary outcomes were overall survival (OS) and objective response rate (ORR). Databases were searched for relevant studies, and meta-analysis was conducted with RevMan. RESULTS: A total of 51 studies involving 12,600 participants were included. The development of irAEs had an advantageous effect on OS and ORR in advanced NSCLC (OS: hazard ratio [HR], 0.56 [95% confidence interval [CI] 0.46 to 0.67]; ORR: odds ratio [OR], 3.13 [2.41 to 4.06]). The occurrence of endocrine and skin irAEs had advantageous effects on both OS and ORR (endocrine OS, HR, 0.47 [-0.37 to 0.59]; endocrine ORR: OR, 1.90 [1.27 to 2.84]; skin OS: HR, 0.48 [0.38 to 0.61]; skin ORR: OR, 4.30 [2.68 to 6.91]). Severe-grade irAEs resulted in shorter OS than low-grade irAEs (HR, 1.49 [1.06, 2.09]), and multiple irAEs resulted in better ORR compared with 1 irAE (OR, 2.04 [1.41 to 2.94]). The occurrence of CIP had no significant effect on OS (HR, 1.14 [0.70 to 1.86]), but it was associated with better ORR (OR, 2.12 [1.06 to 4.25]). Severe-grade CIP had no effect on OS or ORR, but CIP leading to treatment discontinuation resulted in shorter OS (HR, 2.35 [1.17 to 4.72]). CONCLUSION: The development of irAEs had advantageous effects on survival and response in advanced NSCLC. CIP had no effect on survival, but it predicted better response.

The Novel Tumor Suppressor Gene ZNF24 Induces THCA Cells Senescence by Regulating Wnt Signaling Pathway, Resulting in Inhibition of THCA Tumorigenesis and Invasion.

OBJECT: Clinically, the effective treatment options available to thyroid cancer (THCA) patients are very limited. Elucidating the features of tumor suppressor genes (TSGs) and the corresponding signal transduction cascade may provide clues for the development of new strategies for targeted therapy of THCA. Therefore, this paper aims to explore the mechanism of ZNF24 underlying promoting THCA cell senescence at molecular level. METHODS: We performed RT-PCR and Western Blotting for evaluating associated RNA and protein expression. CCK8, colony forming, wound healing and Transwell chamber assays were conducted to examine THCA cell proliferation, invasion and migration. ß-galactosidase staining assay was performed to detect THCA cells senescence. The size and volume of xenotransplanted tumors in nude mice are calculated to asses ZNF24 effect in vivo. RESULTS: Ectopic expression of ZNF24 significantly inhibited the cell viability, colony forming, migration and invasion abilities of THCA cell lines (K1/GLAG-66i and BCPAPi) (P < 0.05). ZNF24 induced BCPAPi cells senescence through regulating Wnt signaling pathway. ZNF24 inhibited Wnt signaling pathway activition by competitively binding ß-catenin from LEF1/TCF1-ß-catenin complex. In nude mice, both Ectopic expression of ZNF24 and 2,4-Da (the strong ß-catenin/Tcf-4 inhibitor) treatment significantly decreased both the size and weight of xenotransplanted tumors when compared with control mice (P < 0.05). CONCLUSION: Results obtained in vivo and in vitro reveal the role of ZNF24 in significantly suppressing THCA tumorigenesis and invasion by regulating Wnt signaling pathway.