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Background: Formaldehyde (HCHO) is one of the sources of indoor air pollution and a recognized carcinogenic gas, which sets a huge threat to human health. Therefore, it is urgent to develop a formaldehyde gas sensor with high efficiency, low consumption, and low limit of detection. Methods: With solvothermal and supramolecular assembly methods, we fabricate a nanocomposite of ZnO/5-aminonaphthalene-1-sulfonic acid (ANS)-reduced graphene oxide (rGO) through in situ assembling flower-like ZnO nanoclusters on ANS-modified graphene nanosheets for room temperature formaldehyde detection. Results: The flower-like ZnO/ANS-rGO based gas sensor exhibits high response (32%, 5 ppm), ultra-fast response/recovery times (18/23 s), high selectivity, long-term stability and a low practical limit of detection (pLOD) of 1 ppm toward HCHO at room temperature, offering significant advantages and competitiveness in chemiresistive room temperature HCHO sensors. Conclusion: The unique flower-like nanostructure of ZnO and the functionalization with ANS molecules jointly improved the HCHO sensing performance of the composite at room temperature. This work provides a new approach to designing and preparing high-performance room temperature gas sensing materials.

The influences of the geometrical parameters of interrupted annular groove fin mainly including the annular groove diameter, the groove arc length, and the fin spacing, on the fin side thermal-hydraulic characteristics of a finned circular tube exchanger were numerically investigated by actualizing the custom FORTRAN programing with SIMPLE algorithm in a non-orthogonal curvilinear co-ordinate system, and the regression formulas of average Nusselt number and friction factor with flow parameters and geometrical parameters were obtained. Compared with the referential plain fin, interrupted annular groove fin could significantly improve thermal performance under the same pumping power constraint, and Nusselt number is closely germane to the secondary flow, which implies that the fin side heat transfer is depended entirely on the secondary flow strength. For Nusselt number, the annular groove diameter and the groove arc length have positive effect, while the fin pitch, the groove circumferential and radial locations have negative effect. The dominant parameters influencing on friction factor in turn are the fin pitch, the groove radial location, and the annular groove diameter. The optimal annular groove diameter is screened, and found that the optimal annular groove diameter is closely related with Reynolds number under the same pumping power constraint, while under the same mass-flow rate constraint that is scarcely related with Reynolds number.

Introduction Medulloblastoma (MB) is a malignant pediatric brain tumor that arises in the cerebellar granular neurons. Sonic Hedgehog subtype of MB (SHH‐MB) is one of the major subtypes of MB in the clinic. However, the molecular mechanisms underlying MB tumorigenesis are still not fully understood. Aims Our previous work demonstrated that the receptor for activated C kinase 1 (Rack1) is essential for SHH signaling activation in granule neuron progenitors (GNPs) during cerebellar development. To investigate the potential role of Rack1 in MB development, human MB tissue array and SHH‐MB genetic mouse model were used to study the expression of function of Rack1 in MB pathogenesis. Results We found that the expression of Rack1 was significantly upregulated in the majority of human cerebellar MB tumors. Genetic ablation of Rack1 expression in SHH‐MB tumor mice could significantly inhibit MB proliferation, reduce the tumor size, and prolong the survival of tumor rescue mice. Interestingly, neither apoptosis nor autophagy levels were affected in Rack1‐deletion rescue mice compared to WT mice, but the expression of Gli1 and HDAC2 was significantly decreased suggesting the inactivation of SHH signaling pathway in rescue mice. Conclusion Our results demonstrated that Rack1 may serve as a potential candidate for the diagnostic marker and therapeutic target of MB, including SHH‐MB., Rack1 is essential for GNPs development by activation of Shh signaling. Here, we found that Rack1 was significantly upregulated in some cerebellar MB tumor samples. Genetic ablation of Rack1 in SHH‐subtype medulloblastoma (MB) tumor mice could significantly reduce tumor cell proliferation, reduce the tumor size, and prolong the survival of tumor rescue mice, indicating that Rack1 may serve as a potential novel therapeutic target for SHH‐type MB in the clinic.

Mitochondrial dysfunction is the main cause of heart failure (HF) postacute myocardial infarction (AMI). Hypoxia acclimation (HA) reduces efficiently the area of AMI caused by ischemia and/or reperfusion and delays HF. Here, we examined whether HA improves mitochondrial structure and function through the hypoxic autophagy receptor FUNDC1 to prevent HF post-AMI. Male adult mice were acclimated in a low-pressure hypoxic animal chamber (11% oxygen (O2)) for 8 h/day for 28 days, and then, an induced HF post-AMI model via left anterior descending (LAD) artery ligation was structured to explore the efficacy and mechanism of HA. Our results showed that HA exposure can improve cardiac structure and function in mice with HF post-AMI and protected myocardial mitochondrial morphology and function. Further studies showed that HA increased the expression of Fundc1 protein and its associated mitophagy protein LC3 in myocardial tissue after infarction. We then established a cellular model of oxygen glucose deprivation (OGD) in vitro, and knockdown of FUNDC1 attenuated the protective effect of HA exposed on cardiomyocyte mitochondria and increased cardiomyocyte apoptosis. In conclusion, the protective effect of HA on HF post-AMI is achieved by regulating Fundc1-mediated mitophagy in myocardial tissue. FUNDC1-mediated mitophagy could be a promising strategy to treat cardiovascular diseases, including HF.

Uncovering the tissue molecular architecture at single-cell resolution could help better understand organisms’ biological and pathological processes. However, bulk RNA-seq can only measure gene expression in cell mixtures, without revealing the transcriptional heterogeneity and spatial patterns of single cells. Herein, we introduce Bulk2Space (https://github.com/ZJUFanLab/bulk2space), a deep learning framework-based spatial deconvolution algorithm that can simultaneously disclose the spatial and cellular heterogeneity of bulk RNA-seq data using existing single-cell and spatial transcriptomics references. The use of bulk transcriptomics to validate Bulk2Space unveils, in particular, the spatial variance of immune cells in different tumor regions, the molecular and spatial heterogeneity of tissues during inflammation-induced tumorigenesis, and spatial patterns of novel genes in different cell types. Moreover, Bulk2Space is utilized to perform spatial deconvolution analysis on bulk transcriptome data from two different mouse brain regions derived from our in-house developed sequencing approach termed Spatial-seq. We have not only reconstructed the hierarchical structure of the mouse isocortex but also further annotated cell types that were not identified by original methods in the mouse hypothalamus.

Rapid, sensitive, and reliable pathogen detection is growing in importance in human health and safety. In this work, we report a stochastic DNA dual-walker-based colorimetric biosensor for bacterial detection. In the presence of target bacteria, two kinds of released multiple walking strands are allowed for continuous walking on the Au nanoparticle (AuNP)-based 3D track, resulting in destabilized aggregation of AuNP-based probes. The induced color change from red to blue can serve as an analytical signal for colorimetric detection of target bacteria. We demonstrated that this mothed enables sensitive and specific bacterial detection within 15 min due to its ultrafast reaction kinetics and sensitive color change, showing a linear response ranging from 100 to 105 CFU/mL with a limit of detection of 1 CFU/mL. Moreover, we also realized analysis of practical samples using this colorimetric biosensor. Given its features of rapid, sensitive, specific, and reliable analysis, our stochastic dual-walker-based colorimetric biosensor shows much promise in point-of-care testing for bacteria detection.

Background: Genetic alteration profile of epidermal growth factor receptor ( EGFR ) mutant resected non- small cell lung cancer (NSCLC) and its relationship with clinical outcomes remains to be illustrated and genetic biomarkers that can predict recurrence need to be figured out. Methods: Clinicopathological and follow-up information were collected for 99 EGFR -mutant resected NSCLC. Tumor sections were collected for genetic alteration detection. Targeted next-generation sequencing (NGS) was performed to detect somatic mutations within each sample using a 285-gene panel on the Ion Torrent platform. Results: Concurrent driver gene mutations were detected in 86 participants. Adjuvant therapy was a positive factor in disease-free survival (DFS) period, and patients receiving tyrosine kinase inhibitors (TKIs) gained the longest DFS. A total of 34 concurrent mutant driver genes were found. The median number of mutated driver genes for each sample was 2 (range, 0–12). TP53 and NOTCH1 were the most frequent concurrent mutant driver genes with rates of 53.54% and 25.25% respectively. The number of concurrent mutant genes did not have a significant effect on recurrence. Multivariable analysis found that mutations of ATM (P=0.021), KIT (P=0.002), FGFR2 (P MET (P=0.015), PDGFRA (P=0.042), RB1 (P=0.006), and wildtype NOTCH1 (P=0.032), ERBB4 (P=0.012), FGFR3 (P=0.035) were independent risk factors for the recurrence of resected EGFR mutant NSCLC. Conclusions: TP53 and NOTCH1 was the most common concurrent mutant driver gene. Mutations of ATM, KIT, FGFR2, MET, PDGFRA, RB1 , and wildtype NOTCH1, ERBB4, FGFR3 were independent risk factors for the recurrence of resected EGFR mutant NSCLC.

Dakai Xiao,1,&ast; Qiuhua Deng,1,&ast; Dongyun He,2,&ast; Ying Huang,2 Wenchi Liang,2 Fengnan Wang,2 Haihong Yang2 1Research Center forTranslational Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People’s Republic of China; 2Department of Thoracic Oncology, State Key Laboratory of Respiratory Diseases, National Clinical Research Center of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haihong YangDepartment of Thoracic Oncology, State Key Laboratory of Respiratory Diseases, National Clinical Research Center of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, 510120, People’s Republic of ChinaEmail bjrf2009@yahoo.comBackground: About 20% of patients with ALK-rearranged non-small cell lung cancer (NSCLC) develop acquired resistance to tyrosine kinase inhibitor (TKI) during the first 6 months. This study aimed to examine the molecular mechanisms of early TKI resistance and prognosis in ALK-rearranged NSCLC.Methods: Ten patients with ALK-rearranged NSCLC were included: five who developed rapid resistance to crizotinib (progression-free survival (PFS) ≤ 3 months) and five who exhibited a good response to crizotinib (PFS ≥ 36 months). The tumor specimens were subjected to whole-exome sequencing (WES). The validation cohort included 19 patients with ALK-rearranged NSCLC who received crizotinib; targeted sequencing of 43 selected genes was performed. The effect of the TP53 G245S mutation on crizotinib sensitivity was tested in H3122 cells.Results: Mutations in DNA repair-associated genes were identified in primary resistance to crizotinib. Patients with a poor response to crizotinib harbored a greater burden of somatic mutations than those with a good response [median somatic mutations, 136 (range, 72– 180) vs 31 (range, 10– 48)]. Compared with the patients carrying wild-type TP53 or TP53 exon 3 deletion, 29 patients with TP53 G245S mutation showed a shorter survival time (P < 0.05), with a median PFS of 3 (95% CI: 1.9– 4.1) months and a median overall survival of 7 (95% CI: 3.4– 10.5) months. TP53 mutation promoted the proliferation of EML4-ALK-rearranged H3122 cells by approximately 3 folds (P < 0.001). H3122 cells with TP53 mutant were more sensitive to crizotinib compared with control cells.Conclusion: A higher mutation burden and mutations in DNA repair gene, including TP53, were potentially associated with primary resistance to crizotinib in ALK-rearranged NSCLC. An immune-checkpoint inhibition strategy could be examined, which might overcome primary resistance to crizotinib in ALK-rearranged NSCLC.Keywords: ALK, non-small cell lung cancer, TKI, resistance, prognosis

The effect of high-altitude (HA) on venous thromboembolism (VTE) and its mechanism remains ambiguous. To clarify this, we aimed to conduct a meta-analysis and systematic review to evaluate the incidence of VTE at HA and comparatively low altitude (LA) and figure out the intrinsic risk factors such as susceptibility genes of patients with VTE at HA.We selected studies that explored the risk factors for HA and VTE by searching PubMed, Embase, and Web of Science to analyze the impact of HA on VTE. All relevant studies before August 2021 were screened using the terms ([high altitude] OR [plateau] OR [mountain]) AND ([venous thromboembolism] OR [deep vein thrombosis] OR [pulmonary embolism]). Latest studies on the gene of HA-VTE patients were also summarized and analyzed.Fifteen studies were eventually assessed, and the overall numbers of subjects with and without VTE were 1475 and 286,926 respectively. The overall incidence of VTE, deep vein thrombosis (DVT) and pulmonary embolism (PE) in the HA group was significantly higher than that in the LA group (P0.01). The overall incidence of VTE, DVT and PE in the HA group was significantly higher than that in the LA group at 30 days post operation (P0.05, P0.05 and P0.01, respectively). At 90 days post operation, incidence of VTE and PE in the HA group was higher than that in the LA group (P0.01and P0.01, respectively), but there was no difference in the incidence of DVT (P = 0.07). Regarding endogenous factors, the analysis of genes in patients with HA-VTE revealed numerous targeted genes such as ANG, ACE, lncRNA-LINC00 659/UXT-AS1 and GP4.We observed a significant association between HA and the overall incidence of VTE and that at 30/90 days post operation, indicating that HA may be a risk factor for VTE.

Opioid-induced nausea and vomiting are common side effects of patient-controlled intravenous analgesia (PCIA). This study aimed to explore the inhibitory effect of a naloxone admixture on the incidence of sufentanil-induced postoperative nausea and vomiting (PONV).A total of 132 Uyghur American Society of Anesthesiologists I and II patients scheduled to undergo elective gynecological laparoscopic surgery were recruited; among these, 120 patients were enrolled and randomly allocated into 4 groups: patients receiving PCIA but no naloxone were included in the control group (group A); patients receiving PCIA with a low-dose naloxone admixture at 0.2 μg·kg-1·h-1 were included in group B; patients receiving PCIA with naloxone admixture at 0.4 μg·kg-1·h-1 were included in group C; patients receiving PCIA with naloxone admixture at 0.6 μg·kg-1·h-1 were included in group D. All patients were administered sufentanil at 0.04 kg-1·h-1, butorphanol at 2 kg-1·h-1, and dexmedetomidine at 0.08 kg-1·h-1 using a PCIA device within 2 days of surgery. The occurrence of nausea and vomiting, visual analogue scores for pain intensity, mean arterial pressure, heart rate, oxygen saturation, pruritus, lethargy, respiratory depression, etc, was recorded at 2, 8, 12, 24, and 48 hours postoperatively.There was a significant difference in the PONV scores between the groups at 8, 12, and 24 hours after surgery (P0.01). At 8 and 12 hours, the score of group C/D was significantly lower than that of group A/B (P0.01). At 24 hours after surgery, the PONV score of group B/C/D was significantly lower than that of group A (P0.01). No significant difference was observed in the general data and visual analogue scores for postoperative pain between the 4 groups.Naloxone admixture administered at 0.4 to 0.6 μg·kg-1·h-1 can exert an effective inhibitory effect on the incidence and intensity of PONV in gynecological laparoscopic surgery.

Secondary KIT gene amplification leads to tyrosine kinase inhibitor resistance in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC). The presence of the 4q12 amplicon causes the activation of downstream mast/stem cell growth factor receptor Kit (c-Kit) or platelet-derived growth factor receptor α (PDGFRA) signaling pathways. Therefore, in the present study, the association between the functional proteins phosphorylated c-Kit (p-c-Kit) and phosphorylated PDGFRA (p-PDGFRA) and the prognosis of ALK fusion NSCLC was investigated. Advanced stage NSCLC samples with ALK fusion were tested for their p-c-Kit and p-PDGFRA content by immunohistochemical staining, and for its association with crizotinib efficacy and the survival of the patients. Of 64 eligible ALK-positive patients with NSCLC, 30 (46.9%) were p-c-Kit-positive and 10 (15.7%) were p-PDGFRA-positive. Brain metastases were more common in ALK-positive cases that were p-PDGFRA-positive compared with those who were p-PDGFRA-negative. ALK-positive patients treated with crizotinib, who exhibited high levels of p-c-Kit had significantly lower progression-free survival times than those with low levels. In addition, the patients with high levels of p-c-Kit exhibited lower overall survival times than those with low levels. Furthermore, multivariate analysis indicated that high levels of p-c-Kit in patients with ALK fusion was the only significant predictive factor for crizotinib efficacy and was a prognostic factor for poor overall survival time. However, no statistically significant difference was observed in the survival of patients with different p-PDGFRA levels. p-PDGFRA was more frequently expressed in the ALK-positive cases with brain metastasis. c-Kit signaling activation may be associated with poor efficacy of crizotinib and poor prognosis in advanced ALK fusion NSCLC.

A superselective isothermal amplification technique, termed circularized blocker-displacement amplification, was developed for multiplex analysis of rare DNA variants.

The polysaccharides from blackcurrant (Ribes nigrum L.) fruits were degraded by ultrasonic irradiation. Results showed that viscosity-average molecular weight decreased with increasing ultrasonic time or power. The degradation was fitted to the second-order kinetics model and midpoint chain scission model. Gas chromatographic analysis demonstrated that the native polysaccharide and three degraded polysaccharides were composed of the same monosaccharides but in different ratios. Fourier transform infrared and nuclear magnetic resonance spectroscopic analyses revealed the presence of α-, β-pyranose rings and the same six sugar residues in the four blackcurrant polysaccharides. Compared to the native polysaccharide, three degraded polysaccharides displayed better rheological properties and stronger protective effects against erythrocyte hemolysis. Collectively, the results support the potential utility of blackcurrant polysaccharides as natural antioxidants.

Advances in single-cell RNA sequencing (scRNA-seq) have furthered the simultaneous classification of thousands of cells in a single assay based on transcriptome profiling. In most analysis protocols, single-cell type annotation relies on marker genes or RNA-seq profiles, resulting in poor extrapolation. Here, we introduce scDeepSort (https://github.com/ZJUFanLab/scDeepSort), a reference-free cell-type annotation tool for single-cell transcriptomics that uses a deep learning model with a weighted graph neural network. Using human and mouse scRNA-seq data resources, we demonstrate the feasibility of scDeepSort and its high accuracy in labeling 764,741 cells involving 56 human and 32 mouse tissues. Significantly, scDeepSort outperformed reference-dependent methods in annotating 76 external testing scRNA-seq datasets, including 126,384 cells (85.79%) from ten human tissues and 134,604 cells from 12 mouse tissues (81.30%). scDeepSort accurately revealed cell identities without prior reference knowledge, thus potentially providing new insights into mechanisms underlying biological processes, disease pathogenesis, and disease progression at a single-cell resolution.

An acidic heteropolysaccharide HEP-2 was obtained from blue honeysuckle berry extracts after purification using Sepharose 6B and Sephadex G-200 column chromatography. The molecular weight of HEP-2, determined with high-performance gel permeation chromatography, was 3.01 × 106 Da. Fourier transform infrared spectroscopy, gas chromatography and nuclear magnetic resonance analyses revealed the presence of α-, β-pyranose ring and six sugar residues in HEP-2. Amorphous aggregates of HEP-2 with irregular shape and lacking the triple helical structure were detected using the Congo red test, scanning electron and atomic force microscopy, and X-ray diffraction studies. Rheological characterization showed typical shear-thinning behavior and viscoelastic property of the polysaccharide. HEP-2 exerted significant inhibitory effects on α-amylase and α-glucosidase and displayed competitive inhibition kinetics. The collective results support the potential utility of HEP-2 as a hypoglycemic agent for enzyme-targeted treatment of diabetes or functional food.

BACKGROUND: Genetic alteration profile of epidermal growth factor receptor (EGFR) mutant resected non-small cell lung cancer (NSCLC) and its relationship with clinical outcomes remains to be illustrated and genetic biomarkers that can predict recurrence need to be figured out. METHODS: Clinicopathological and follow-up information were collected for 99 EGFR-mutant resected NSCLC. Tumor sections were collected for genetic alteration detection. Targeted next-generation sequencing (NGS) was performed to detect somatic mutations within each sample using a 285-gene panel on the Ion Torrent platform. RESULTS: Concurrent driver gene mutations were detected in 86 participants. Adjuvant therapy was a positive factor in disease-free survival (DFS) period, and patients receiving tyrosine kinase inhibitors (TKIs) gained the longest DFS. A total of 34 concurrent mutant driver genes were found. The median number of mutated driver genes for each sample was 2 (range, 0–12). TP53 and NOTCH1 were the most frequent concurrent mutant driver genes with rates of 53.54% and 25.25% respectively. The number of concurrent mutant genes did not have a significant effect on recurrence. Multivariable analysis found that mutations of ATM (P=0.021), KIT (P=0.002), FGFR2 (P

Normal neurodevelopment relies on intricate signaling pathways that balance neural stem cell (NSC) self-renewal, maturation and survival. Disruptions lead to neurodevelopmental disorders including microcephaly. Here, we implicate the inhibition of NSC senescence as an additional mechanism that controls neurogenesis and corticogenesis. We report that the receptor for activated C kinase (Rack1), a family member of WD40-repeat (WDR) proteins, is highly enriched in NSCs in the early developmental brain. Deletion of Rack1 in NSCs leads to an extreme microcephaly phenotype, including impaired corticogenesis, severe hippocampal hypoplasia, and extensive corpus callosum defects. Strikingly, the absence of Rack1 decreased neurogenesis and significantly promoted a cellular senescence phenotype in NSCs. Mechanistically, the senescence-related p21 signaling pathway was dramatically activated in Rack1-depleted NSCs, and simultaneous deletion of p21 significantly rescued the Rack1-knockout phenotype in vivo. Finally, Rack1 directly interacts with Smad3 to suppress the activation of TGF-β/Smad signaling pathway, which plays a critical role in p21-mediated senescence. Our data implicate Rack1-driven inhibition of NSC senescence as a critical mechanism behind normal cortical development. Deregulation of p21-induced senescence of NSCs may be a contributing factor in the pathology of microcephaly.

Advances in single-cell RNA sequencing (scRNA-seq) have furthered the simultaneous classification of thousands of cells in a single assay based on transcriptome profiling. In most analysis protocols, single-cell type annotation relies on marker genes or RNA-seq profiles, resulting in poor extrapolation. Still, the accurate cell-type annotation for single-cell transcriptomic data remains a great challenge. Here, we introduce scDeepSort (https://github.com/ZJUFanLab/scDeepSort), a pre-trained cell-type annotation tool for single-cell transcriptomics that uses a deep learning model with a weighted graph neural network (GNN). Using human and mouse scRNA-seq data resources, we demonstrate the high performance and robustness of scDeepSort in labeling 764 741 cells involving 56 human and 32 mouse tissues. Significantly, scDeepSort outperformed other known methods in annotating 76 external test datasets, reaching an 83.79% accuracy across 265 489 cells in humans and mice. Moreover, we demonstrate the universality of scDeepSort using more challenging datasets and using references from different scRNA-seq technology. Above all, scDeepSort is the first attempt to annotate cell types of scRNA-seq data with a pre-trained GNN model, which can realize the accurate cell-type annotation without additional references, i.e. markers or RNA-seq profiles.

Summary Normal neurodevelopment relies on intricate signaling pathways that balance neural stem cell (NSC) self-renewal, maturation, and survival. Disruptions lead to neurodevelopmental disorders, including microcephaly. Here, we implicate the inhibition of NSC senescence as a mechanism underlying neurogenesis and corticogenesis. We report that the receptor for activated C kinase (Rack1), a family member of WD40-repeat (WDR) proteins, is highly enriched in NSCs. Deletion of Rack1 in developing cortical progenitors leads to a microcephaly phenotype. Strikingly, the absence of Rack1 decreases neurogenesis and promotes a cellular senescence phenotype in NSCs. Mechanistically, the senescence-related p21 signaling pathway is dramatically activated in Rack1 null NSCs, and removal of p21 significantly rescues the Rack1-knockout phenotype in vivo. Finally, Rack1 directly interacts with Smad3 to suppress the activation of transforming growth factor (TGF)-β/Smad signaling pathway, which plays a critical role in p21-mediated senescence. Our data implicate Rack1-driven inhibition of p21-induced NSC senescence as a critical mechanism behind normal cortical development.

Brain metastases (BMs) are frequently occurred in lung adenocarcinoma with driver mutation. There is a need to explore multi-discipline treatments and prognostic factors in those patients with most frequent driver mutations: EGFR mutation and ALK fusion. In the retrospective study, different therapies and prognostic factors were compared between EGFR and ALK-driven lung adenocarcinoma with BMs. 516 patients with EGFR mutation and 76 with ALK fusion were screened for this study, 303 (58.7%) and 34 (44.7%) had BM respectively. In multivariate analyses, the pretreatment factors including delayed BMs and asymptomatic BMs, treatment strategies including the first-generation tyrosine kinase inhibitor (TKI) and cranial radiotherapy (RT) treatment, were associated with much better OS in EGFR mutation patients. Moreover, we found EGFR-mutation patients receiving erlotinib would achieve better survival than those receiving gefitinib (P = 0.032). However, BM patients with ALK fusion treated by only the first generation TKI (HR = 0.23, P = 0.036) or cranial RT (HR = 0.12, P = 0.003), had better OS. After balancing of baseline characteristics of the two groups, there was no significant difference in the survival between BM patients with EGFR mutation and ALK fusion. And only cranial RT was associated with better survival in those patients (HR = 0.52, P

The development of the cerebellum depends on intricate processes of neurogenesis, migration, and differentiation of neural stem cells (NSCs) and progenitor cells. Defective cerebellar development often results in motor dysfunctions and psychiatric disorders. Understanding the molecular mechanisms that underlie the complex development of the cerebellum will facilitate the development of novel treatment options. Here, we report that the receptor for activated C kinase (Rack1), a multifaceted signaling adaptor protein, regulates mammalian cerebellar development in a cell type-specific manner. Selective deletion of Rack1 in mouse NSCs or granule neuron progenitors (GNPs), but not Bergmann glial cells (BGs), causes severe defects in cerebellar morphogenesis, including impaired folia and fissure formation. NSCs and GNPs lacking Rack1 exhibit enhanced Wnt/β-catenin signaling but reduced Sonic hedgehog (Shh) signaling. Simultaneous deletion of β-catenin in NSCs, but not GNPs, significantly rescues the Rack1 mutant phenotype. Interestingly, Rack1 controls the activation of Shh signaling by regulating the ubiquitylation and stability of histone deacetylase 1 (HDAC1)/HDAC2. Suppression of HDAC1/HDAC2 activity in the developing cerebellum phenocopies the Rack1 mutant. Together, these results reveal a previously unknown role of Rack1 in controlling mammalian cerebellar development by opposite regulation of Wnt/β-catenin and Shh signaling pathways.