YAP promotes the early development of temporomandibular joint bony ankylosis by regulating mesenchymal stem cell function.

To explore the role of YAP, a key effector of the Hippo pathway, in temporomandibular joint (TMJ) ankylosis. The temporal and spatial expression of YAP was detected via immunohistochemistry and multiplex immunohistochemistry on postoperative Days 1, 4, 7, 9, 11, 14 and 28 in a sheep model. Isolated mesenchymal stem cells (MSCs) from samples of the Day 14. The relative mRNA expression of YAP was examined before and after the osteogenic induction of MSCs. A YAP-silenced MSC model was constructed, and the effect of YAP knockdown on MSC function was examined. YAP is expressed in the nucleus of the key sites that determine the ankylosis formation, indicating that YAP is activated in a physiological state. The expression of YAP increased gradually over time. Moreover, the number of cells coexpressing of RUNX2 and YAP-with the osteogenic active zone labelled by RUNX2-tended to increase after Day 9. After the osteogenic induction of MSCs, the expression of YAP increased. After silencing YAP, the osteogenic, proliferative and migratory abilities of the MSCs were inhibited. YAP is involved in the early development of TMJ bony ankylosis. Inhibition of YAP using shRNA might be a promising way to prevent or treat TMJ ankylosis.

Effects of neoadjuvant chemotherapy combined with radical laparoscopic surgery with quality nursing care on clinical efficacy and sex hormones in patients with cervical cancer.

OBJECTIVE: To observe the effects of neoadjuvant chemotherapy combined with radical laparoscopic surgery with quality nursing care on the clinical efficacy and sex hormones of cervical cancer patients. METHODS: The clinical data of 107 patients with cervical cancer admitted to Yanan University Affiliated Hospital between January 2017 and January 2020 were retrospectively analyzed in this study. Among them, 50 patients received only laparoscopic radical surgery (surgical group), and the other 57 received neoadjuvant chemotherapy combined with laparoscopic radical surgery (Joint group); patients in both groups received quality nursing care. The baseline and surgical data of the two groups were compared, and the changes in tumor markers and sex hormones before and after treatment were analyzed. Cox regression was used to analyze the independent prognostic factors affecting patients' 2-year survival. RESULTS: The patients in the two groups did not show statistical differences in baseline and surgical data (all P > 0.05). After treatment, the levels of squamous cell carcinoma antigen (SCC-Ag), carcinoembryonic antigen (CEA), and serum glycan antigen 125 (CA125) were significantly reduced in both groups. However, the reduction was more pronounced in the joint group than that in the surgical group (P < 0.0001). Meanwhile, estrogen (E2) levels decreased more significantly in the Joint group, while follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increased more significantly (all P < 0.0001). Multifactorial Cox regression analysis revealed that E2, LH and SCC-Ag were independent prognostic factors affecting 2-year survival (all P < 0.05). CONCLUSION: Neoadjuvant chemotherapy combined with laparoscopic radical surgery is more effective in reducing the levels of tumor markers and significantly affects the levels of sex hormones. E2, LH, and SCC-Ag are the independent prognostic factors for 2-year survival in patients with cervical cancer. This study provides evidence to support the comprehensive treatment of cervical cancer.

Temporal gene expression profiling during early-stage traumatic temporomandibular joint bony ankylosis in a sheep model.

BACKGROUND: Investigating the molecular biology underpinning the early-stage of traumatic temporomandibular joint (TMJ) ankylosis is crucial for discovering new ways to prevent the disease. This study aimed to explore the dynamic changes of transcriptome from the intra-articular hematoma or the newly generated ankylosed callus during the onset and early progression of TMJ ankylosis. METHODS: Based on a well-established sheep model of TMJ bony ankylosis, the genome-wide microarray data were obtained from samples at postoperative Days 1, 4, 7, 9, 11, 14 and 28, with intra-articular hematoma at Day 1 serving as controls. Fold changes in gene expression values were measured, and genes were identified via clustering based on time series analysis and further categorised into three major temporal classes: increased, variable and decreased expression groups. The genes in these three temporal groups were further analysed to reveal pathways and establish their biological significance. RESULTS: Osteoblastic and angiogenetic genes were found to be significantly expressed in the increased expression group. Genes linked to inflammation and osteoclasts were found in the decreased expression group. The various biological processes and pathways related to each temporal expression group were identified, and the increased expression group comprised genes exclusively involved in the following pathways: Hippo signaling pathway, Wnt signaling pathway and Rap 1 signaling pathway. The decreased expression group comprised genes exclusively involved in immune-related pathways and osteoclast differentiation. The variable expression group consisted of genes associated with DNA replication, DNA repair and DNA recombination. Significant biological pathways and transcription factors expressed at each time point postoperatively were also identified. CONCLUSIONS: These data, for the first time, presented the temporal gene expression profiling and reveal the important process of molecular biology in the early-stage of traumatic TMJ bony ankylosis. The findings might contributed to identifying potential targets for the treatment of TMJ ankylosis.

Easily applicable predictive score for MPR based on parameters before neoadjuvant chemoimmunotherapy in operable NSCLC: a single-center, ambispective, observational study.

BACKGROUND: Neoadjuvant chemoimmunotherapy (NACI) is promising for resectable nonsmall cell lung cancer (NSCLC), but predictive biomarkers are still lacking. The authors aimed to develop a model based on pretreatment parameters to predict major pathological response (MPR) for such an approach. METHODS: The authors enrolled operable NSCLC treated with NACI between March 2020 and May 2023 and then collected baseline clinical-pathology data and routine laboratory examinations before treatment. The efficacy and safety data of this cohort was reported and variables were screened by Logistic and Lasso regression and nomogram was developed. In addition, receiver operating characteristic curves, calibration curves, and decision curve analysis were used to assess its power. Finally, internal cross-validation and external validation was performed to assess the power of the model. RESULTS: In total, 206 eligible patients were recruited in this study and 53.4% (110/206) patients achieved MPR. Using multivariate analysis, the predictive model was constructed by seven variables, prothrombin time (PT), neutrophil percentage (NEUT%), large platelet ratio (P-LCR), eosinophil percentage (EOS%), smoking, pathological type, and programmed death ligand-1 (PD-L1) expression finally. The model had good discrimination, with area under the receiver operating characteristic curve (AUC) of 0.775, 0.746, and 0.835 for all datasets, cross-validation, and external validation, respectively. The calibration curves showed good consistency, and decision curve analysis indicated its potential value in clinical practice. CONCLUSION: This real world study revealed favorable efficacy in operable NSCLC treated with NACI. The proposed model based on multiple clinically accessible parameters could effectively predict MPR probability and could be a powerful tool in personalized medication.

SNX17 Mediates Dendritic Spine Maturation via p140Cap.

Sorting nexin17 (SNX17) is a member of the sorting nexin family, which plays a crucial role in endosomal trafficking. Previous research has shown that SNX17 is involved in the recycling or degradation of various proteins associated with neurodevelopmental and neurological diseases in cell models. However, the significance of SNX17 in neurological function in the mouse brain has not been thoroughly investigated. In this study, we generated Snx17 knockout mice and observed that the homozygous deletion of Snx17 (Snx17-/-) resulted in lethality. On the other hand, heterozygous mutant mice (Snx17+/-) exhibited anxiety-like behavior with a reduced preference for social novelty. Furthermore, Snx17 haploinsufficiency led to impaired synaptic transmission and reduced maturation of dendritic spines. Through GST pulldown and interactome analysis, we identified the SRC kinase inhibitor, p140Cap, as a potential downstream target of SNX17. We also demonstrated that the interaction between p140Cap and SNX17 is crucial for dendritic spine maturation. Together, this study provides the first in vivo evidence highlighting the important role of SNX17 in maintaining neuronal function, as well as regulating social novelty and anxiety-like behaviors.

Hypoxic acclimatization training improves the resistance to motion sickness.

Objective: Vestibular provocation is one of the main causes of flight illusions, and its occurrence is closely related to the susceptibility of motion sickness (MS). However, existing training programs have limited effect in improving the resistance to motion sickness. In this study, we investigated the effects of hypoxia acclimatization training (HAT) on the resistance to motion sickness. Methods: Healthy military college students were identified as subjects according to the criteria. MS model was induced by a rotary chair. Experimental groups included control, HAT, 3D roller training (3DRT), and combined training. Results: The Graybiel scores were decreased in the HAT group and the 3DRT group and further decreased in the combined training group in MS induced by the rotary chair. Participants had a significant increase in blood pressure after the rotary chair test and a significant increase in the heart rate during the rotary chair test, but these changes disappeared in all three training groups. Additionally, LFn was increased, HFn was decreased, and LF/HF was increased accordingly during the rotary chair test in the control group, but the changes of these three parameters were completely opposite in the three training groups during the rotary chair test. Compared with the control group, the decreasing changes in pupillary contraction velocity (PCV) and pupillary minimum diameter (PMD) of the three training groups were smaller. In particular, the binocular PCV changes were further attenuated in the combined training group. Conclusion: Our research provides a possible candidate solution for training military pilots in the resistance to motion sickness.

Plasma hepatocyte growth factor as a noninvasive biomarker in small cell lung cancer.

BACKGROUND: Hepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine, which is overexpressed and/or activated in multiple malignancies and is reported to be associated with tumor development and inferior survival. At present, the role of HGF in small cell lung cancer (SCLC) has not been fully explored yet. MATERIALS AND METHODS: The expression of HGF and its value in predicting survival in SCLC were explored from GEO database and in pan-cancer analysis. Furthermore, we detected the expression of HGF using tumor tissue and paired plasma samples from a validation cohort of 71 SCLC patients at our institute. Correlation between tumor and plasma HGF expression and the prognostic values were analyzed. RESULTS: GEO database analysis revealed that tumor tissue had lower HGF expression than paired normal tissue in SCLC. At our institute, immunohistochemical staining showed negative expression of HGF in tumor tissue of SCLC at our institute (47/47, 100%). The average baseline plasma HGF was 1.28 (range,0.42-4.35) ng/ml. However, plasma HGF was higher in SCLC patients with patients with N3, M1, liver metastasis (LM) and bone metastasis (BM) disease compared with those N0 - 2 (1.25 vs. 1.75 ng/mL, P = 0.000), M0 (1.26 vs. 1.63 ng/mL, P = 0.003), non-LM (1.32 vs. 2.06 ng/mL, P = 0.009), and non-BM (1.35 vs. 1.77 ng/mL, P = 0.047), respectively. Multivariate analysis revealed plasma HGF was an independent predictor for LM and prognostic factor of OS. CONCLUSION: Our results revealed that plasma HGF rather than tumor HGF exhibited a potential role in predicting metastasis and survival in SCLC. Plasma HGF might be used as a non-invasive detecting and monitoring tool for SCLC.

Mutation status analysis of 58 patients with advanced ALK fusion gene positive non small cell lung cancer.

PURPOSE: To analyze the characteristics and prognostic values of Anaplastic Lymphoma Kinase (ALK) fusion gene partner, gene subtype and abundance in tumor tissues of advanced Non Small Cell Lung Cancer (NSCLC) patients with positive ALK fusion gene and to explore the best treatment mode of ALK-Tyrosine Kinase Inhibitors(TKIs). METHODS: Cases of advanced NSCLC patients with ALK positive confirmed by both Next Generation Sequencing (NGS) and immunohistochemistry were retrospectively collected. The relationships of Overall Survival (OS)/Progression Free Survival (PFS) between different mutation subtypes, mutation abundance, clinicopathological features were analyzed. OS/PFS between different treatment mode of ALK inhibitors were compared. RESULTS: Fifty-eight patients were enrolled. There were diverse fusion partners. Five subtypes of Echinoderm Microtubule-associated protein-Like 4 gene (EML4)-ALK fusion mutation were detected: V1,V2,V3,V5 and V7. The mutation abundance ranged from 0.13 to 27.77%, with a median of 5.34%. The abundance of V2 and V5 was higher than V1 and V3 respectively. There was no difference in OS between the low abundance group(≤ 5.34%) and the high abundance group(>5.34%) (P = 0.434). PFS of second-generation ALK inhibitors as first-line treatment was longer than that of Crizotinib as first-line (P<0.001). Never smokers had longer OS than current smokers(P = 0.001). CONCLUSIONS: There are differences in abundance between different fusion partners and subtypes in advanced NSCLC with positive ALK. OS is not associated with subtypes, mutation abundance and first line treatment option of either generation of ALK inhibitors. Smoking is a poor prognostic factor.

ELAVL4 promotes the tumorigenesis of small cell lung cancer by stabilizing LncRNA LYPLAL1-DT and enhancing profilin 2 activation.

Small cell lung cancer (SCLC) is one of the most malignant tumors that has an extremely poor prognosis. RNA-binding protein (RBP) and long noncoding RNA (lncRNA) have been shown to be key regulators during tumorigenesis as well as lung tumor progression. However, the role of RBP ELAVL4 and lncRNA LYPLAL1-DT in SCLC remains unclear. In this study, we verified that lncRNA LYPLAL1-DT acts as an SCLC oncogenic lncRNA and was confirmed in vitro and in vivo. Mechanistically, LYPLAL1-DT negatively regulates the expression of miR-204-5p, leading to the upregulation of PFN2, thus, promoting SCLC cell proliferation, migration, and invasion. ELAVL4 has been shown to enhance the stability of LYPLAL1-DT and PFN2 mRNA. Our study reveals a regulatory pathway, where ELAVL4 stabilizes PFN2 and LYPLAL1-DT with the latter further increasing PFN2 expression by blocking the action of miR-204-5p. Upregulated PFN2 ultimately promotes tumorigenesis and invasion in SCLC. These findings provide novel prognostic indicators as well as promising new therapeutic targets for SCLC.

Longitudinal detection of subcategorized CD44v6+ CTCs and circulating tumor endothelial cells (CTECs) enables novel clinical stratification and improves prognostic prediction of small cell lung cancer: A prospective, multi-center study.

Current management of small cell lung cancer (SCLC) remains challenging. Effective biomarkers are needed to subdivide patients presenting distinct treatment response and clinical outcomes. An understanding of heterogeneous phenotypes of aneuploid CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells (CTECs) may provide novel insights in the clinical management of SCLC. In the present translational and prospective study, increased cancer metastasis-related cell proliferation and motility, accompanied with up-regulated mesenchymal marker vimentin but down-regulated epithelial marker E-cadherin, were observed in both lentivirus infected SCLC and NSCLC cells overexpressing the stemness marker CD44v6. Aneuploid CTCs and CTECs expressing CD44v6 were longitudinally detected by SE-iFISH in 120 SCLC patients. Positive detection of baseline CD44v6+ CTCs and CD44v6+ CTECs was significantly associated with enhanced hepatic metastasis. Karyotype analysis revealed that chromosome 8 (Chr8) in CD44v6+ CTCs shifted from trisomy 8 towards multiploidy in post-therapeutic patients compared to pre-treatment subjects. Furthermore, the burden of baseline CD44v6+ CTCs (t0) or amid the therapy (t1-2), the ratio of baseline CD31+ CTEC/CD31- CTC (t0), and CTC-WBC clusters (t0) were correlated with treatment response and distant metastases, particularly brain metastasis, in subjects with limited disease (LD-SCLC) but not in those with extensive disease (ED-SCLC). Multivariate survival analysis validated that longitudinally detected CD44v6+/CD31- CTCs was an independent prognostic factor for inferior survival in SCLC patients. Our study provides evidence for the first time that comprehensive analyses of CTCs, CTECs, and their respective CD44v6+ subtypes enable clinical stratification and improve prognostic prediction of SCLC, particularly for potentially curable LD-SCLC.

(Tn5-)FISH-based imaging in the era of 3D/spatial genomics.

3D genomics mainly focuses on the 3D position of single genes at the cell level, while spatial genomics focuses more on the tissue level. In this exciting new era of 3D/spatial genomics, half-century old FISH and its derivative methods, including Tn5-FISH, play important roles. In this review, we introduce the Tn5-FISH we developed recently, and present six different applications published by our collaborators and us, based on (Tn5-)FISH, which can be either general BAC clone-based FISH or Tn5-FISH. In these interesting cases, (Tn5-)FISH demonstrated its vigorous ability of targeting sub-chromosomal structures across different diseases and cell lines (leukemia, mESCs (mouse embryonic stem cells), and differentiation cell lines). Serving as an effective tool to image genomic structures at the kilobase level, Tn5-FISH holds great potential to detect chromosomal structures in a high-throughput manner, thus bringing the dawn for new discoveries in the great era of 3D/spatial genomics.

Discovery of YK-029A, a novel mutant EGFR inhibitor targeting both T790 M and exon 20 insertion mutations, as a treatment for NSCLC.

Although traditional EGFR-TKIs have advanced the treatment landscape of NSCLC with sensitive driver mutations (del19 or L858R), some NSCLC patients with EGFR exon 20 insertion mutations have been left with few effective therapies. The development of novel TKIs is still in progress. Herein, we describe the structure-guided design of a novel selective and orally bioavailable inhibitor, YK-029A, which could overcome both the T790 M mutations and exon 20 insertion of EGFR. YK-029A inhibited EGFR signaling, suppressed sensitive mutations and ex20ins of EGFR-driven cell proliferation, and was largely effective with oral administration in vivo. Furthermore, YK-029A exhibited significant antitumor activity in EGFRex20ins-driven patients-derived xenograft (PDX) models, preventing tumor progression or causing tumor regression at well-tolerated dosages. Based on the outcomes of preclinical efficacy and safety studies, YK-029A will enter phase Ⅲ clinical trials for the treatment of EGFRex20ins NSCLC.

Survival Analysis of 159 Patients With Advanced Non-Small-Cell Lung Cancer Resistant to First-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor.

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have limited or no response in some certain patients of non-small-cell lung cancer (NSCLC). However, real-world survival analyses comparing clinical data and EGFR-plasma mutation are still lacking. Methods: In total, 159 patients with advanced NSCLC resistant to first-generation EGFR-TKIs were included for consecutive blood sampling in this study. Super-amplification refractory mutation system (Super-ARMS) was used to detect EGFR-plasma mutations and correlations between survival and circulating tumor DNA (ctDNA) were analyzed. Results: Among 159 eligible patients, the T790M mutation was detected in 27.0% (43/159) of patients. The median progression-free survival (mPFS) was 10.7 months in all patients. Survival analysis revealed that patients with the T790M mutation had shorter progression-free survival (PFS) than those with the T790M wild-type (10.6 months vs 10.8 months, P = .038). Patients who cleared EGFR-plasma mutation had prolonged PFS compared with those with nonclearing EGFR-plasma mutation (11.6 months vs 9.0 months, P = .001). Cox multivariate analysis showed that the nonclearance of EGFR-plasma mutations was an independent risk factor for PFS (RR = 1.745, 95% CI: [1.184, 2.571], P = .005). The T790M mutation was associated with nonclearance of the EGFR-plasma mutation (χ2 = 10.407, P = .001). Conclusion: Patients with advanced NSCLC who were resistant to the first-generation EGFR-TKI had a prolonged PFS with clearance of EGFR-plasma mutation. Those nonclearers were more likely to harbor T790M mutations in plasma.

Post-therapeutic circulating tumor cell-associated white blood cell clusters predict poor survival in patients with advanced driver gene-negative non-small cell lung cancer.

PURPOSE: This study aimed to investigate the clinical utility of diverse aneuploid circulating tumor cell (CTC) subtypes and particularly CTC-associated white blood cell (CTC-WBC) clusters in predicting treatment response, prognosis and real-time monitoring disease progression in advanced driver gene-negative non-small lung cancer (NSCLC) patients. MATERIALS AND METHODS: A total of 74 eligible patients were prospectively enrolled and serial blood samples were collected at pre-treatment(t0), after two cycles of therapy (t1) and at post-four-to-six treatment cycles (t2). Co-detection of diverse subtypes of aneuploid CTCs and CTC-WBC clusters was conducted in advanced NSCLC patients receiving first-line treatment. RESULTS: At baseline, CTCs were detected in 69 (93.24%) patients and CTC-WBC clusters were detected in 23 (31.08%) patients. Patients with CTCs < 5/6ml or with CTC-WBC clusters undetectable exhibited a better treatment response than patients with pre-therapeutic aneuploid CTCs ≥ 5/6ml or harboring CTC-WBC clusters (p = 0.034 and p = 0.012, respectively). Before treatment, patients bearing tetraploid CTCs ≥ 1/6ml showed significantly inferior progression-free survival (PFS) [hazard ratio (HR):2.420, 95% confidence interval (CI): 1.426-4.106; p = 0.001] and overall survival (OS) compared to patients with tetraploid CTCs < 1/6ml (HR:1.907, 95%CI: 1.119-3.251; p = 0.018). A longitudinal study demonstrated that post-therapeutic patients harboring CTC-WBC clusters displayed the reduced PFS and OS compared with those without CTC-WBC clusters, and subgroup analysis showed that the presence of CTC-WBC clusters indicated a worse prognosis in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. After adjusting for multiple significant factors, post-therapeutic CTC-WBC clusters were the only independent predictor of both PFS (HR:2.872, 95% CI: 1.539-5.368; p = 0.001) and OS (HR:2.162, 95% CI: 1.168-4.003; p = 0.014). CONCLUSIONS: In addition to CTCs, longitudinal detection of CTC-WBC clusters provided a feasible tool to indicate initial treatment response, dynamically monitor disease progression and predict survival in driver gene-negative advanced NSCLC patients.

Beneficial effects of postoperative radiotherapy for IIIA­N2 non­small cell lung cancer after radical resection analysed using the propensity score­matching method.

The objective of the present study was to investigate the role of postoperative radiotherapy (PORT) after radical resection of stage IIIA-N2 non-small cell lung cancer (NSCLC). Subgroups of patients who benefited from PORT were evaluated. A retrospective review of 288 consecutive patients with resected pIIIA-N2 NSCLC at Beijing Chest Hospital (Beijing, China) was performed. Of these patients, 61 received PORT. The 288 patients were divided into PORT and non-PORT groups according to the treatment received. The baseline characteristics of the two patient groups were balanced using propensity score-matching (PSM; 1:1 matching). In total, 60 patients in the PORT group and 60 patients in the non-PORT group were matched. After PSM, the median survival time of the matched patients was 53 months. The 1-, 3- and 5-year overall survival (OS) rates of the PORT patient group were 95.0, 63.2 and 48.2%, respectively, while those of the non-PORT group were 86.7, 58.3 and 34.5%, respectively, and there was no significant difference between the two groups (P=0.056). The 5-year local recurrence-free survival (LRFS) rate in the PORT group was significantly improved (P=0.001). The effects of PORT on OS and LRFS rates were analysed in patients with different clinicopathological features. For subgroups with multiple N2 stations, N2 positive lymph nodes ≥4 and squamous cell carcinoma, PORT significantly increased the OS and LRFS rates (P<0.05). In conclusion, there was no statistically significant improvement in the 5-year OS rate with PORT overall, but there may be subgroups, such as patients with multiple N2 stations, N2 positive nodes ≥4 and squamous cell carcinoma histology, that could be explored as potentially benefitting from improved 5-year OS and LRFS rates with PORT.

A single center analysis of first-line treatment in advanced KRAS mutant non-small cell lung cancer: real-world practice.

PURPOSE: For the first-line treatment of KRAS mutant non-small cell lung cancer (NSCLC) patients, immunotherapy or platinum-based chemotherapy are the main treatment method. Here, we investigated the clinical efficacy and prognosis those two regimens as first-line treatment in real-world practice. METHODS: KRAS mutant NSCLC patients received chemotherapy or immunotherapy as first-line treatment from September 2014 to March 2022 were enrolled. Clinical characteristics, treatment scheme, clinical curative effect and follow-up data of enrolled patients were collected for analysis. RESULTS: Fifty patients received immunotherapy and 115 patients received chemotherapy were enrolled. Patients who received immunotherapy (HR = 0.350, 95%CI 0.156-0.781, P = 0.010), or pemetrexed-based regimen (HR = 0.486, 95%CI 0.255-0.928, P = 0.029), or antiangiogenic therapy (HR = 0.355, 95%CI 0.159-0.790, P = 0.011) were at a low risk of disease progression. And patients received antiangiogenic therapy had lower risk of death than those not (HR = 0.333, 95%CI 0.120-0.926, P = 0.035). Subgroup analysis revealed the immunotherapy compared to chemotherapy alone had lower risk of disease progression (HR = 0.377, 95%CI 0.166-0.856, P = 0.020) in PD-L1 expression ≥1% subgroup. And in non-G12C KRAS subgroup, but not in G12C KRAS subgroup, patients who received antiangiogenic therapy had lower risk of disease progression (HR = 0.254, 95%CI 0.098-0.656, P = 0.005) and death than those not (HR = 0.197, 95%CI 0.056-0.692, P = 0.011). In terms of different chemotherapy regimen, platinum-paclitaxel combined with antiangiogenic therapy achieved the highest ORR and DCR (P < 0.05), while the platinum-pemetrexed combined with antiangiogenic therapy had the longest PFS and OS (P < 0.001). CONCLUSION: For the first-line treatment of KRAS mutant NSCLC patients, immunotherapy, antiangiogenic therapy, and pemetrexed-based regimen could obtain more benefits. Subgroup analysis revealed the benefits of immunotherapy compared to chemotherapy were applicable in PD-L1 expression≥1% subgroup, and antiangiogenic therapy could benefit non-G12C KRAS subgroup, but not G12C KRAS subgroup. In terms of different chemotherapy regimen, platinum-pemetrexed combined with antiangiogenic therapy may be the preferred chemotherapy regimen.

Molecularly defined and functionally distinct cholinergic subnetworks.

Cholinergic neurons in the medial septum (MS) constitute a major source of cholinergic input to the forebrain and modulate diverse functions, including sensory processing, memory, and attention. Most studies to date have treated cholinergic neurons as a single population; as such, the organizational principles underling their functional diversity remain unknown. Here, we identified two subsets (D28K+ versus D28K-) of cholinergic neurons that are topographically segregated in mice, Macaca fascicularis, and humans. These cholinergic subpopulations possess unique electrophysiological signatures, express mutually exclusive marker genes (kcnh1 and aifm3 versus cacna1h and gga3), and make differential connections with physiologically distinct neuronal classes in the hippocampus to form two structurally defined and functionally distinct circuits. Gain- and loss-of-function studies on these circuits revealed their differential roles in modulation of anxiety-like behavior and spatial memory. These results provide a molecular and circuitry-based theory for how cholinergic neurons contribute to their diverse behavioral functions.

Gut dysbiosis impairs hippocampal plasticity and behaviors by remodeling serum metabolome.

Accumulating evidence suggests that gut microbiota as a critical mediator of gut-brain axis plays an important role in human health. Altered gut microbial profiles have been implicated in increasing the vulnerability of psychiatric disorders, such as autism, depression, and schizophrenia. However, the cellular and molecular mechanisms underlying the association remain unknown. Here, we modified the gut microbiome with antibiotics in newborn mice, and found that gut microbial alteration induced behavioral impairment by decreasing adult neurogenesis and long-term potentiation of synaptic transmission, and altering the gene expression profile in hippocampus. Reconstitution with normal gut flora produced therapeutic effects against both adult neurogenesis and behavioral deficits in the dysbiosis mice. Furthermore, our results show that circulating metabolites changes mediate the effect of gut dysbiosis on hippocampal plasticity and behavior outcomes. Elevating the serum 4-methylphenol, a small aromatic metabolite produced by gut bacteria, was found to induce autism spectrum disorder (ASD)-like behavior impairment and hippocampal dysfunction. Together our finding demonstrates that early-life gut dysbiosis and its correlated metabolites change contribute to hippocampal dysfunction and behavior impairment, hence highlight the potential microbiome-mediated therapies for treating psychiatric disorders.

Combined application of bevacizumab and PD-1 blockade displays durable treatment effects by increasing the infiltration and cytotoxic function of CD8+ T cells in lung cancer.

Aim: VEGF/VEGFR inhibitors may help immune checkpoint inhibitors expand the population that will benefit from treatment. The authors investigated the efficacy of combined bevacizumab and PD-1 antibody. Materials & methods: C57BL/6J mice were injected subcutaneously with 1 × 106 Lewis lung carcinoma cells. The mice were intraperitoneally injected with 0.25 mg anti-PD-1 inhibitors and/or 15 mg/kg bevacizumab. Tumor tissues were harvested. The authors reported that a non-small cell lung cancer patient received 200 mg PD-1 antibody combined with 7.5 mg/kg bevacizumab as fourth-line treatment. Results: Bevacizumab combined with PD-1 antibody induced a strong and durable antitumor effect. Bevacizumab combined with PD-1 antibody improved abnormal tumor vessels and enhanced the cytotoxic function and infiltration of T lymphocytes. The patient's survival time was significantly prolonged. Conclusion: Bevacizumab combined with anti-PD-1 antibody induces a durable antitumor effect by increasing the infiltration and cytotoxic function of CD8+ T cells in lung cancer.

Immune checkpoint inhibitors can improve long-term survival in advanced non-small-cell lung cancer, but the promising clinical benefit was only observed in a minority of patients. The combination of VEGF/VEGFR inhibitors and immune checkpoint inhibitors has become an attractive strategy. In this study, lung carcinoma mouse models were used to investigate the therapeutic efficacy of combined bevacizumab and anti-PD-1 antibody. The authors demonstrated that the combined application of bevacizumab and PD-1 blockade displays durable treatment effects by increasing the infiltration and cytotoxic function of CD8⁺ T cells. This study also reports a non-small-cell lung cancer patient who benefited from this treatment regimen as fourth-line therapy.