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Abstract Background The role of periodontal ligament stem cells (PDLSCs) in repairing periodontal destruction is crucial, but their functions can be impaired by excessive oxidative stress (OS). Nocardamine (NOCA), a cyclic siderophore, has been shown to possess anti-cancer and anti-bacterial properties. This study aimed to investigate the protective mechanisms of NOCA against OS-induced cellular dysfunction in PDLSCs. Methods The cytotoxicity of NOCA on PDLSCs was assessed using a CCK-8 assay. PDLSCs were then treated with hydrogen peroxide (H2O2) to induce OS. ROS levels, cell viability, and antioxidant factor expression were analyzed using relevant kits after treatment. Small molecule inhibitors U0126 and XAV-939 were employed to block ERK signaling and Wnt pathways respectively. Osteogenic differentiation was assessed using alkaline phosphatase (ALP) activity staining and Alizarin Red S (ARS) staining of mineralized nodules. Expression levels of osteogenic gene markers and ERK pathway were determined via real-time quantitative polymerase chain reaction (RT-qPCR) or western blot (WB) analysis. β-catenin nuclear localization was examined by western blotting and confocal microscopy. Results NOCA exhibited no significant cytotoxicity at concentrations below 20 µM and effectively inhibited H2O2-induced OS in PDLSCs. NOCA also restored ALP activity, mineralized nodule formation, and the expression of osteogenic markers in H2O2-stimulated PDLSCs. Mechanistically, NOCA increased p-ERK level and promoted β-catenin translocation into the nucleus; however, blocking ERK pathway disrupted the osteogenic protection provided by NOCA and impaired its ability to induce β-catenin nuclear translocation under OS conditions in PDLSCs. Conclusions NOCA protected PDLSCs against H2O2-induced OS and effectively restored impaired osteogenic differentiation in PDLSCs by modulating the ERK/Wnt signaling pathway.

This study explores the bioactive secondary metabolite profiles of the peels of three major cultivars of bananas (Musa acuminata and Musa balbisiana). These cultivars are primarily grown in Southeast Asia and are widely consumed due to their rich nutritional and fiber content. The research utilizes advanced analytical techniques, specifically HPLC-DAD-q-TOF-MS/MS, in conjunction with both univariate and multivariate statistical analyses, to analyze the ethanolic extracts of the banana peels. This study identifies phenolic acids, flavonoids, and proanthocyanidins as significant contributors to the differentiation of the cultivars. The secondary metabolites rutin, chlorogenic acid, and gentisic acid are pinpointed as the key discriminants. Moreover, the research demonstrates a synergistic contribution of certain phytochemicals to the antioxidant and antibacterial properties of the banana peel extracts. The fingerprint profiling tools introduced in this study offer a reliable method for identifying metabolite biomarkers for the discrimination of banana cultivars.

Allergic diseases like asthma, allergic rhinitis and dermatitis pose a significant global health burden, driving the search for novel therapies. The NLRP3 inflammasome, a key component of the innate immune system, is implicated in various inflammatory diseases. Upon exposure to allergens, NLRP3 undergoes a two-step activation process (priming and assembly) to form active inflammasomes. These inflammasomes trigger caspase-1 activation, leading to the cleavage of pro-inflammatory cytokines (IL-1β and IL-18) and GSDMD. This process induces pyroptosis and amplifies inflammation. Recent studies in humans and mice strongly suggest a link between the NLRP3 inflammasome, IL-1β, and IL-18, and the development of allergic diseases. However, further research is needed to fully understand NLRP3’s specific mechanisms in allergies. This review aims to summarize the latest advances in NLRP3 activation and regulation. We will discuss small molecule drugs and natural products targeting NLRP3 as potential therapeutic strategies for allergic diseases.

The LiFePO4 material continue to suffer from poor rate performance. Nanosized LFP can improve rate performance; however, nanofabrication typically requires expensive organic matter and high-pressure-resistant equipment. The current widely used solid-phase sintering methods employ FePO4 as the precursor, but it is difficult to suppress grain growth. Here, we propose a W–Ti codoping strategy to suppress grain growth during sintering, thereby improving rate performance of Li-ion batteries. W and Ti doping shrinks grains during the sintering process and make the Li-O bond more ionized. Li0.36WO3 accumulates at grain boundaries, hindering grain boundary diffusion and inhibiting grain growth during sintering. The resulting material exhibits refined grains and suppressed polarization growth, resulting in improved rate performance while maintaining a specific capacity of 117 mAh g−1 at a rate of 10 C. After 1000 cycles at a rate of 1 C, 91.0 % of the initial capacity was retained. In summary, this research provides a method for large-scale production of LFP with excellent rate performance.

Abstract This study evaluated the association between body pH value and preoperative deep vein thrombosis (DVT) in geriatric hip fractures. Older adult patients with hip fractures were screened between January 2015 and September 2019. The demographic and clinical characteristics of the patients were collected. Multivariate binary logistic regression and generalized additive models were used to identify the linear and nonlinear associations between pH value and preoperative DVT. Analyses were performed using EmpowerStats and R software. A total of 1465 patients were included in the study. DVT occurred in 476 (32.6%) of these admitted older adults. We observed a nonlinear association between the serum pH value and preoperative DVT in geriatric patients with hip fractures. A pH value of 7.39 was the inflection point in the curve, with pH highly correlated with DVT at pH 7.39, pH was not correlated with DVT (OR 1.26; 95% CI 0.85–1.86; P = 0.2561), the odds of DVT did not vary with pH, and the highest risk of thrombosis was reached. The body pH value is nonlinearly associated with preoperative DVT in geriatric patients with hip fractures, and it could be considered a predictor of the risk of DVT. Registered information This study is registered in the website of Chinese Clinical Trial Registry (ChiCTR: ChiCTR2200057323).

Background The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial.Methods Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile.Results Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1–49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator.Conclusion Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation.Trial registration number NCT04346381.

The epithelial barrier serves as a critical defense mechanism separating the human body from the external environment, fulfilling both physical and immune functions. This barrier plays a pivotal role in shielding the body from environmental risk factors such as allergens, pathogens, and pollutants. However, since the 19th century, the escalating threats posed by environmental pollution, global warming, heightened usage of industrial chemical products, and alterations in biodiversity have contributed to a noteworthy surge in allergic disease incidences. Notably, allergic diseases frequently exhibit dysfunction in the epithelial barrier. The proposed epithelial barrier hypothesis introduces a novel avenue for the prevention and treatment of allergic diseases. Despite increased attention to the role of barrier dysfunction in allergic disease development, numerous questions persist regarding the mechanisms underlying the disruption of normal barrier function. Consequently, this review aims to provide a comprehensive overview of the epithelial barrier’s role in allergic diseases, encompassing influencing factors, assessment techniques, and repair methodologies. By doing so, it seeks to present innovative strategies for the prevention and treatment of allergic diseases.

Epigallocatechin (EGC) is one of the main bioactive polyphenols in green tea. This study aims to determine the anti-tumor effect of EGC against colorectal cancer. Our results revealed that treatment of EGC led to significant suppression of cell proliferation and apoptosis in three colorectal cancer cells. Western blot confirmed that EGC activated Caspase-3 and PARP, down-regulated the phosphorylation of STAT3 and decreased Bcl-2 expression. Luciferase-reporter-activity assay further determined that EGC suppressed the promoter activity of STAT3 and downregulated the transcription of STAT3. Besides, in vivo study proved that EGC (100 mg/kg) resulted in significant suppression of tumor volume and tumor weight (decreased by 63.7 %) in mice bearing SW620 tumors. Tumor organoid assays demonstrated the inhibitory efficacy of EGC in colorectal organoids. In conclusion, our study present evidence that EGC inhibited colon cancer cell proliferation both in vitro and in vivo by down-regulation phosphorylated STAT3 and activated downstreams.

The aerobic photooxidation of sulfides into sulfoxides in eco-friendly solvents, notably water, at room temperature, represents a significant interest in the domain of synthetic chemistry. This study introduces four highly stable hexadentate Ir(III) complexes: [Ir(fpqen)](PF6) (1), [Ir(btqen)](PF6) (2), [Ir(bmpqen)](PF6) (3), and [Ir(bnqen](PF6) (4) (where bfpqen is N,N′-bis(2-(4-fluorophenyl)quinolin-8-yl)ethane-1,2-diamine, btqen is N,N′-bis(2-(4-tolyl)quinolin-8-yl)ethane-1,2-diamine, bmpqen is N,N′-bis(2-(4-methoxyphenyl)quinolin-8-yl)ethane-1,2-diamine, and bnqen is N,N′-bis(2-naphthylquinolin-8-yl)ethane-1,2-diamine). These complexes were synthesized utilizing an in situ inter-ligand C-N cross-coupling photoreaction of the precursors [Ir(L)2(en)](PF6) (L is 2-(4-fluorophenyl)quinoline, (2-(4-tolyl)quinoline, 2-(4-methoxyphenyl)quinoline or 2-naphthylquinoline, and en is 1,2-diamine) under benign conditions. This methodology furnishes a valuable and complementary approach for the in situ generation of multidentate complexes through a post-coordination inter-ligand-coupling strategy under mild conditions. Moreover, these hexadentate Ir(III) complexes exhibit pronounced catalytic activity and chemo-selectivity toward the aerobic photooxidations of sulfides into sulfoxides in aqueous media at room temperature, offering a new avenue for the sustainable synthesis of sulfoxides.

A series of reported Pt(II) carbene complexes possibly have the ability to serve as the new generation of blue emitters in luminescent devices because of their narrow emission spectra, high photoluminescence quantum yields (PLQYs), and rigid molecular skeleton. However, the combination of all carbene ligands with different multidentate structures will affect the overall planarity and horizontal dipole ratio to varying degrees, but the specific extent of this effect has not previously been analyzed in detail. In this work, density functional computation is used to study a class of platinum tetracarbene bidentate complexes with similar absorption and emission band characteristics, which is the main reason for the remarkable difference in quantum efficiency due to subtle differences in electronic states caused by different ligands. From the calculation results, the major reason, which results in significantly decrease in quantum efficiency for [Pt(cyim)2]2+, is that [Pt(cyim)2]2+ can reach the non-radiative deactivation metal-centered d-d excited state through an easier pathway compared with [Pt(meim)2]2+. The result, based on changes in the dihedral angle between ligands, can achieve the goal of improving and designing materials by adjusting the degree of the dihedral angle. (meim: bis(1,1′-dimethyl-3,3′-methylene-diimidazoline-2,2′-diylidene); cyim: bis(1,1′-dicyclohexyl-3,3′-methylene-diimidazoline-2,2′-diylidene).

Objective To investigate the expression of fatty acid binding protein 4 (FABP4) in endometrial cancer and its effects on the proliferation, migration and invasion of endometrial cancer cells line HEC-1-A. Methods The expression level of FABP4 mRNA in endometrial cancer tissues and adjacent normal tissues was detected with RT-qPCR. The correlation between FABP4 mRNA expression and pathological changes of endometrial cancer was analyzed. HEC-1-A cells were cultured in vitro and were randomly divided into control group, FABP4 negative control (si-NC) group and interference FABP4 (si-FABP4) group. RT-qPCR, MTT and Transwell assays were used respectively to detect the FABP4 mRNA expression in HEC-1-A cells, the proliferation, migration and invasion of HEC-1-A cells. Western blot was used to detect the protein expression of FABP4, matrix metalloproteinase (MMP)-2 and MMP-9 of HEC-1-A cells in each group. Results The expression level of FABP4 mRNA in endometrial cancer tissues was significantly higher than that in tissues adjacent to cancer (P＜0.05); The FABP4 mRNA expression was related to tumor TNM staging and lymph node metastasis (P＜0.05).Interference with FABP4 expression could significantly inhibit the proliferation, migration and invasion of endometrial cancer cells. Conclusions Expression of FABP4 is up-regulated in endometrial cancer and interference with FABP4 expression can inhibit the proliferation, migration and invasion of endometrial cancer cells.

Acpuncture as a branch of traditional Chinese medicine is popular in China. It can regulate the running of meridian qi to stimulate the ocular nerve activity and increase blood supply. Periocular acupuncture treatment is very frequent, but it can lead to safety hazards that cannot be ignored. For instance, ocular trauma may develop if done improperly, resulting in impaired vision and even blindness. We report a rare case of perforating ocular injury caused by acupuncture.

Abstract Background In non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs), higher blood tumor mutational burden (bTMB) was usually associated with better progression-free survival (PFS) and objective response rate (ORR). However, the association between bTMB and overall survival (OS) benefit remains undefined. It has been reported that patients harboring a high level of circulating tumor DNA (ctDNA) had poor survival. We hypothesized that ctDNA-adjusted bTMB might predict OS benefit in NSCLC patients receiving ICIs. Methods Our study was retrospectively performed in three cohorts, including OAK and POPLAR cohort (n = 853), Shanghai and Wuhan (SH&WH) cohort (n = 44), and National Cancer Center (NCC) cohort (n = 47). Durable clinical benefit (DCB) was defined as PFS lasting ≥ 6 months. The cutoff value of ctDNA-adjusted bTMB for DCB prediction was calculated based on a receiver operating characteristic curve. Interaction between treatments and ctDNA-adjusted bTMB was assessed. Results The bTMB score was significantly associated with tumor burden, while no association was observed between ctDNA-adjusted bTMB with tumor burden. In the OAK and POPLAR cohort, significantly higher ORR (P = 0.020) and DCB (P

Objective To explore the effects of miR-188 and transforming growth factor α (TGF-α) on the proliferation and migration of osteosarcoma cells. Methods The expressions of miR-188 and TGF-α in human osteosarcoma tissues and adjacent tissues were detected. TGFA was detected as the target gene of miR-188 by TargetScan and dual luciferase reporter gene assay. The migration ability of osteosarcoma cells line MG63 was examined by cell scratch assay. The xenograft model of osteosarcoma was established in nude mice and the effect of miR-188 was observed in a xenograft model of osteosarcoma of nude mice. Results The expression of miR-188 was decreased in osteosarcoma tissues (P＜0.01). miR-188 specifically bound to the 3′-UTR of TGFA and negatively regulated its expression. The transfection of miR-188 mimic could inhibit the migration ability of MG63 cells,while the inhibitor could promoted the migration ability,but the up-regulation of TGF-α and the expression of interfered TGF-α could reduce the inhibition effect. In a nude mouse model of osteosarcoma xenograft,over-expression of miR-188 reduced the inhibitory effect (P＜0.01), while down-regulating the expression of miR-188 expression had the opposite effect. TGF-α expression was significantly increased in osteosarcoma tissues (P＜0.01),while silence protiferation of osteosarcoing was decreased. Conclusions miR-188 may inhibit the proliferation and migration of MG63 cells by targeting the expression of TGF-α.

AAV-mediated gene therapy typically requires a high dose of viral transduction, risking acute immune responses and patient safety, part of which is due to limited understanding of the host-viral interactions, especially post-transduction viral genome processing. Here, through a genome-wide CRISPR screen, we identified SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain 1), an epigenetic modifier, as a critical broad-spectrum restricting host factor for post-entry AAV transgene expression. SMCHD1 knock-down by RNAi and CRISPRi or knock-out by CRISPR all resulted in significantly enhanced transgene expression across multiple viral serotypes, as well as for both single-strand and self-complementary AAV genome types. Mechanistically, upon viral transduction, SMCHD1 effectively repressed AAV transcription by the formation of an LRIF1-HP1-containing protein complex and directly binding with the AAV genome to maintain a heterochromatin-like state. SMCHD1-KO or LRIF1-KD could disrupt such a complex and thus result in AAV transcriptional activation. Together, our results highlight the host factor-induced chromatin remodeling as a critical inhibitory mechanism for AAV transduction and may shed light on further improvement in AAV-based gene therapy. Author summary: Adeno-associated virus (AAV) is one of the most commonly used carrier for gene therapy. However, current approved therapies typically use extremely high doses in order to achieve sufficient beneficial efficiency. This is partially due to a lack of understanding about host reponsese that restrict AAV-mediated gene delivery and expression. In this study, we carried out genome-wide CRISPR screens to identify potential host restricting factors for AAV transduction in human cells and identified SMCHD1 as one of the key epigenetic modifers that formed a complex with LRIF1, bound with HP1-associated AAV genome to form a heterochromatin-like states, and suppressed its transcription. Disruption of the SMCHD1-LRIF1 complex would increase the genome accessibility of AAVs and viral transduction, and significantly increase AAV-mediated transgene expression. Therefore, our results indicated that the host factor-induced chromatin remodeling might be a critical inhibitory mechanism for AAV transduction and may help to further improve AAV-based gene therapy. [ABSTRACT FROM AUTHOR]

Glucosinolates (GSLs) are not only a unique flavor substance from leaf B. juncea but also a major secondary metabolite produced in response to abiotic stresses. Cold stress is one of the most common abiotic stresses in leaf B. juncea; however, the metabolic response pattern of GSLs in leaf B. juncea under cold stress has not yet been reported. In the present study, we analyzed the GSLs content of leaf B. juncea under cold stress and found that it increased and subsequently decreased. According to RNA-seq data, genes related to the synthesis of aliphatic GSLs were significantly upregulated following 24 h of cold stress; genes related to the synthesis of indole GSLs were significantly upregulated following 48 h of cold stress; and BjBGLU25 and BjBGLU27 were significantly upregulated. Further analysis of the correlation between transcription factors and GSLs content revealed that MYB, ERF, IQD, and bHLH may be involved in regulating the GSLs response pattern in leaf B. juncea under cold stress. In particular, an unreported transcription factor, BjMYBS3 (BjuVA05G33250), was found to play a possible role in the synthesis of aliphatic GSLs. And the external application of GSLs increased the ability of leaf B. juncea to cope with cold stress.

Pro-inflammatory factors may be associated with abnormalities in functional brain networks, which may be a mechanism in the pathogenesis of major depressive disorder (MDD). Electroencephalogram (EEG) microstates reflect the functioning of brain networks. However, the relationship between pro-inflammatory factors and the microstate abnormalities in patients with MDD is poorly understood. 24 MDD patients and 24 age-and sex-matched healthy controls (HC) were recruited. Montgomery-Asberg Depression Rating Scale(MADRS) were assessed. Serum (interleukin- 2(IL- 2), tumor necrosis factor-α (TNF-α) and hs-C-reactive protein (CRP)and EEG data were collected. K-means clustering was performed to characterize different microstates. For each microstate, duration, occurrence and coverage were estimated. Four microstates (e.g. A, B, C, D) were characterized, MDD group showed lower duration, occurrence and coverage of microstate B and microstate D, while higher duration of microstate A and microstate C and levels of IL-2, TNF-α, hs-CRP than HC group. The duration, occurrence and coverage of microstate D were negatively correlated with levels of pro-inflammatory factors (IL-2, TNF- α and hs- CRP) (all P

Expanded porphyrin systems are capable of binding a variety of substrates due to their increased cavity size and aromatic nature, holding important applications as magnetic resonance imaging contrast agents and as sensitizers for photodynamic therapy. It is there of fundamental interest to know the photoelectrical properties of expanded porphyrins using quantum chemistry calculations. In this work, we theoretically designed and screened a series of expanded porphyrins by incorporating terthiophene (TTH) and dithienothiophene (DTT) moieties. Our calculations showed that all the designed molecules exhibit excellent optoelectronic performance than the reference molecule. It is suggested that the porphyrin molecule with TTH moiety has better stability than the one with DTT moiety. Finally, we demonstrated that molecule 2 features with TTH moiety and the inverted selenophene ring outperform other molecules because it exhibits increased HOMO-LUMO gap, planar geometry, and strengthened aromaticity. We expect that this work can provide theoretical guidelines for the design of novel porphyrin materials.

During the rapid urbanisation of Beijing in the past two decades, the original natural underlying surface has been changed, and the groundwater recharge and discharge processes had undergone great changes. Therefore, whether these natural and human factors affect the evolution of groundwater chemical composition, and how these influences evolve, need to be studied urgently. In this study, the Daxing District was taken as a typical area to understand the evolution rules of the chemical characteristics of shallow groundwater in the plain areas of Beijing. By collecting monitoring data on shallow groundwater from 2006 to 2016, the spatiotemporal evolution trends of the chemical characteristics and influencing factors of shallow groundwater in Daxing District were studied using the hydrochemical analysis methods and principal component analysis–partial connection number method. The results show the following: 1) The cations and anions of groundwater in the study area increased with time, indicating that the groundwater quality tends to deteriorate. 2) The hydrochemical type and anion and cation components changed accordingly with the change in NO3−, indicating the profound impact of NO3− on the evolution of groundwater components. 3) The groundwater has always been affected by human factors and natural factors. Natural factors have dominated, but the influence of human factors on hydrochemical components has been increasing. From the spatial distribution of the impact of human factors and natural factors on groundwater composition, regions with higher urbanisation degrees are highly affected by human factors and vice versa. This study can provide a theoretical and methodological reference for regional groundwater management and industrial layout.

The intelligent detection technology driven by X-ray images and deep learning represents the forefront of advanced techniques and development trends in flaw detection and automated evaluation of light alloy castings. However, the efficacy of deep learning models hinges upon a substantial abundance of flaw samples. The existing research on X-ray image augmentation for flaw detection suffers from shortcomings such as poor diversity of flaw samples and low reliability of quality evaluation. To this end, a novel approach was put forward, which involves the creation of the Interpolation-Deep Convolutional Generative Adversarial Network (I-DCGAN) for flaw detection image generation and a comprehensive evaluation algorithm named TOPSIS-IFP. I-DCGAN enables the generation of high-resolution, diverse simulated images with multiple appearances, achieving an improvement in sample diversity and quality while maintaining a relatively lower computational complexity. TOPSIS-IFP facilitates multi-dimensional quality evaluation, including aspects such as diversity, authenticity, image distribution difference, and image distortion degree. The results indicate that the X-ray radiographic images of magnesium and aluminum alloy castings achieve optimal performance when trained up to the 800th and 600th epochs, respectively. The TOPSIS-IFP value reaches 78.7% and 73.8% similarity to the ideal solution, respectively. Compared to single index evaluation, the TOPSIS-IFP algorithm achieves higher-quality simulated images at the optimal training epoch. This approach successfully mitigates the issue of unreliable quality associated with single index evaluation. The image generation and comprehensive quality evaluation method developed in this paper provides a novel approach for image augmentation in flaw recognition, holding significant importance for enhancing the robustness of subsequent flaw recognition networks. [ABSTRACT FROM AUTHOR]

Abstract. In recent years, the research of immune checkpoint inhibitors has made a great breakthrough in lung cancer treatment. Currently, a variety of immune checkpoint inhibitors have been applied into clinical practice, including antibodies targeting the programmed cell death-1, programmed cell death-ligand 1, and cytotoxic T-lymphocyte antigen 4, and so on. However, not all patients can benefit from the treatment. Abnormal antigen presentation, functional gene mutation, tumor microenvironment, and other factors can lead to primary or secondary resistance. In this paper, we reviewed the molecular mechanism of immune checkpoint inhibitor resistance and various combination strategies to overcome resistance, in order to expand the beneficial population and enable precision medicine.

ObjectivesTranscutaneous auricular vagus nerve stimulation (taVNS) has been reported to be effective for chronic insomnia (CI). However, the appropriate population for taVNS to treat insomnia is unclear.MethodsTotal twenty-four patients with CI and eighteen health controls (HC) were recruited. Rest-state functional magnetic resonance imaging (Rs-fMRI) was performed before and after 30 min' taVNS at baseline. The activated and deactivated brain regions were revealed by different voxel-based analyses, then the seed-voxel functional connectivity analysis was calculated. In the CI group, 30 min of taVNS were applied twice daily for 4 weeks. Pittsburgh Sleep Quality Index (PSQI) and Flinders Fatigue Scale (FFS) were also assessed before and after 4 weeks of treatment in the CI group. The HC group did not receive any treatment. The correlations were estimated between the clinical scales' score and the brain changes.ResultsThe scores of PSQI (p < 0.01) and FFS (p < 0.05) decreased after 4 weeks in the CI group. Compared to the HC group, the first taVNS session up-regulated left dorsolateral prefrontal cortex (dlPFC) and decreased the functional connectivity (FCs) between dlPFC and bilateral medial prefrontal cortex in the CI group. The CI groups' baseline voxel wised fMRI value in the dlPFC were negatively correlated to the PSQI and the FFS score after 4 weeks treatment.ConclusionsIt manifests that taVNS has a modulatory effect on the prefrontal cortex in patients with CI. The initial state of dlPFC may predict the efficacy for taVNS on CI.