The role of RNA methylation in tumor immunity and its potential in immunotherapy.

RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating RNA splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of RNA methylation on tumor immunity. The primary types of RNA methylation encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G), and 3-methylcytidine (m3C). Compelling evidence underscores the involvement of RNA methylation in regulating the tumor microenvironment (TME). By affecting RNA translation and stability through the "writers", "erasers" and "readers", RNA methylation exerts influence over the dysregulation of immune cells and immune factors. Consequently, RNA methylation plays a pivotal role in modulating tumor immunity and mediating various biological behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed the mechanisms and functions of several RNA methylations, providing a comprehensive overview of their biological roles and underlying mechanisms within the tumor microenvironment and among immunocytes. By exploring how these RNA modifications mediate tumor immune evasion, we also examine their potential applications in immunotherapy. This review aims to provide novel insights and strategies for identifying novel targets in RNA methylation and advancing cancer immunotherapy efficacy.

Neutral or Detrimental Effects of TREM2 Agonist Antibodies in Preclinical Models of Alzheimer's Disease and Multiple Sclerosis.

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-ß (Aß) pathology (PS2APP) or combined Aß and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.

Quantification of testicular fat content: the value of evaluating testicular function after cryptorchidism surgery.

BACKGROUND: To investigate the correlation between testicular fat content (TFC) and sex hormone levels in patients with cryptorchidism and its value in assessing postsurgical testicular function. METHODS: Pelvic MRI with the mDIXON Quant sequence was performed on 23 cryptorchidism patients and 15 normal controls. The TFC before and after surgery was measured and compared. The correlations between cryptorchid TFC and testosterone (TSTO), follicle-stimulating hormone (FSH), and estradiol (E2) levels were analyzed, as was the specificity of TFC and each hormone for assessing testicular function after surgery. RESULTS: The preoperative cryptorchid TFC (3.06% ± 0.74) was higher than that of the normal controls (1.36% ± 0.49). TSTO was negatively correlated with the cryptorchid TFC (r = -0.698), while FSH and E2 were positively associated with the cryptorchid TFC (r = 0.658, 0.676). Cryptorchid TFC after surgery (2.01% ± 0.55) was lower than the preoperative TFC, but hormone levels were not significantly different. The TFC after surgery (0.864) had a larger AUC value than did TSTO (0.639), FSH (0.597), and E2 (0.586). CONCLUSION: Noninvasive quantification of cryptorchid TFC using the mDIXON Quant sequence is more specific than hormone levels for assessing postsurgical changes in testicular function. IMPACT: The cryptorchid testicular fat content is significantly higher than the normal testicular fat content. Cryptorchid testicular fat content is negatively correlated with presurgical serum TSTO levels and positively correlated with presurgical FSH and E2 levels. Pre- and postoperative changes in cryptorchid testicular fat content change are more sensitive than changes in TSTO, FSH, or E2 levels. Noninvasive cryptorchid testicular fat content quantified by the mDIXON Quant sequence is more specific than serum TSTO, FSH, and E2 levels for assessing changes in testicular function after cryptorchidism surgery.

The comprehensive roles of lncRNA FAM99A/FAM99B in hepatocellular carcinoma: Expressions, regulatory mechanisms and functional pathway analysis.

AIMS: The incidence and mortality of liver hepatocellular carcinoma (LIHC) were increasing year by year. The aim of this study was to investigate the comprehensive roles of lncRNA FAM99A and FAM99B in LIHC. MAIN METHODS: According to the data of TCGA and GTEx, the expression levels of FAM99A and FAM99B in LIHC were evaluated, and the overall survival (OS), disease-free survival (DFS), immune cell infiltration and tumor stage were analyzed. The subcellular localization of FAM99A and FAM99B in various cancer cell lines was predicted by lncATLAS database. In addition, we also used ENCORI, KEGG, LinkedOmics, Metascape and other databases. It was verified by in vivo and in vitro experiments. KEY FINDINGS: Compared with adjacent normal tissues, FAM99A and FAM99B were down-regulated in LIHC tissues, and significantly correlated with immune cell infiltration. With the progression of tumor stage and grade, the expression of FAM99A and FAM99B showed a decreasing trend, and the prognosis of patients were also poor. In addition, the biological functions, signaling pathways and protein interactions of FAM99A and FAM99B in LIHC were enriched to study the potential molecular mechanisms. The overlapping RNA binding proteins (RBP) of FAM99A and FAM99B mainly included CSTF2T, BCCIP, RBFOX2 and SF3B4. Finally, experiments showed that overexpression of FAM99A attenuated the proliferation, invasion, colony formation and tumor growth of LIHC cells. SIGNIFICANCE: Taken together, the above studies demonstrated that FAM99A and FAM99B had an inhibitory effect on the progression of LIHC, which might be promising diagnostic biomarkers and therapeutic targets for LIHC patients.

Improving span-based Aspect Sentiment Triplet Extraction with part-of-speech filtering and contrastive learning.

Aspect Sentiment Triple Extraction (ASTE), a subtask of fine-grained sentiment analysis, aims to extract aspect terms, opinion terms, and their corresponding sentiment polarities from sentences. Previous methods often enumerated all possible spans of aspects and opinions as candidate spans that contain many invalid and irrelevant spans. This made the model training and prediction more difficult due to noised spans, leading to poor performance. To address this issue, we first propose a novel span-level approach that explicitly considers prior grammatical knowledge to generate possible candidate spans by part-of-speech filtering. In this way, our approach can make the model easier to be trained and achieve higher performance at the test stage. Besides, the quality of span-level representation of aspects and opinions is crucial for predicting their sentiment relation. To build a high-quality span-level representation of aspects and opinions, we first incorporate the contextual embedding of the entire sequence into span-level representations. Then, we introduce an auxiliary loss based on contrastive learning to make a more compact representation of the same polarities. Experimental evaluations on the 14Lap, 14Res, 15Res, and 16Res datasets demonstrate the effectiveness of our model, achieving state-of-the-art performance in span-based triplet extraction.

Understanding decision curve analysis in clinical prediction model research.

BACKGROUND: Many medical graduate students lack a thorough understanding of decision curve analysis (DCA), a valuable tool in clinical research for evaluating diagnostic models. METHODS: This article elucidates the concept and process of DCA through the lens of clinical research practices, exemplified by its application in diagnosing liver cancer using serum alpha-fetoprotein levels and radiomics indices. It covers the calculation of probability thresholds, computation of net benefits for each threshold, construction of decision curves, and comparison of decision curves from different models to identify the one offering the highest net benefit. RESULTS: The paper provides a detailed explanation of DCA, including the creation and comparison of decision curves, and discusses the relationship and differences between decision curves and receiver operating characteristic curves. It highlights the superiority of decision curves in supporting clinical decision-making processes. CONCLUSION: By clarifying the concept of DCA and highlighting its benefits in clinical decisionmaking, this article has improved researchers' comprehension of how DCA is applied and interpreted, thereby enhancing the quality of research in the medical field.

The closed-loop control method based on dual-port adaptive internal model control for fine image stabilization of space telescopes.

In view of the complex working environment of space astronomical telescopes, the influence of various disturbance sources on the imaging quality cannot be ignored. This paper focuses on compensating for the space telescope line-of-sight (LOS) deviation and suppressing the low-frequency disturbance problem in astronomical observation. A closed-loop control method based on dual-port adaptive internal model control (AIMC) for the fine image stabilization system (FISS) was proposed. To be specific, the fine guidance sensor (FGS) as the high-precision detection unit of the FISS calculates the telescope LOS deviation and sends it to the controller unit in real time. The controller unit drives the large-aperture fast steering mirror (FSM), which performs high-precision two-dimensional rotation to compensate for the telescope LOS deviation, according to the dual-port AIMC control algorithm. Moreover, the dual-port AIMC control method adds an AIMC loop on the basis of the feedback loop and adjusts the filter parameters adaptively according to the target angular velocity of the FSM, achieving higher disturbance suppression capability. The experimental results verify that the control method proposed can effectively compensate for the LOS deviation and suppress the composite frequency disturbance. In the 0-8 Hz frequency band, the power spectral density integral values of the star centroid deviation in the X and Y directions of the FGS are, respectively, suppressed by 97.38% and 98.38%.

TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models.

Heterozygous mutations in the granulin (GRN) gene are a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in TMEM106B have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here, we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency. TMEM106B deletion did not reverse transcriptomic or proteomic profiles in GRN-deficient microglia, with a few exceptions in immune signaling markers. Neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated phenotypes in Grn -/-mice. Furthermore, Tmem106b reduction by antisense oligonucleotide (ASO) was poorly tolerated in Grn -/-mice. These data provide novel insight into TMEM106B and GRN function in microglia cells but do not support lowering TMEM106B levels as a viable therapeutic strategy for treating FTD-GRN.

Activin and Hepatocyte Growth Factor Promotes Colorectal Cancer Stemness and Metastasis through FOXM1/SOX2/CXCR4 Signaling.

Background/Aims: Cancer stem cells (CSCs) are believed to drive tumor development and metastasis. Activin and hepatocyte growth factor (HGF) are important cytokines with the ability to induce cancer stemness. However, the effect of activin and HGF combination treatment on CSCs is still unclear. Methods: In this study, we sequentially treated colorectal cancer cells with activin and HGF and examined CSC marker expression, self-renewal, tumorigenesis, and metastasis. The roles of forkhead box M1 (FOXM1) and sex-determining region Y-box 2 (SOX2), two stemness-related transcription factors, in activin/HGF-induced aggressive phenotype were explored. Results: Activin and HGF treatment increased the expression of CSC markers and enhanced sphere formation in colorectal cancer cells. The tumorigenic and metastatic capacities of colorectal cancer cells were enhanced upon activin and HGF treatment. Activin and HGF treatment preferentially promoted stemness and metastasis of CD133+ subpopulations sorted from colorectal cancer cells. FOXM1 was upregulated by activin and HGF treatment, and the knockdown of FOXM1 blocked activin/HGF-induced stemness, tumorigenesis, and metastasis of colorectal cancer cells. Similarly, SOX2 was silencing impaired sphere formation of activin/HGF-treated colorectal cancers. Overexpression of SOX2 rescued the stem cell-like phenotype in FOXM1-depleted colorectal cancer cells with activin and HGF treatment. Additionally, the inhibition of FOXM1 via thiostrepton suppressed activin/HGF-induced stemness, tumorigenesis and metastasis. Conclusions: Sequential treatment with activin and HGF promotes colorectal cancer stemness and metastasis through activation of the FOXM1/SOX2 signaling. FOXM1 could be a potential target for the treatment of colorectal cancer metastasis.

LOXL4, but not LOXL2, is the critical determinant of pathological collagen cross-linking and fibrosis in the lung.

Idiopathic pulmonary fibrosis is a progressive fibrotic disease characterized by excessive deposition of (myo)fibroblast produced collagen fibrils in alveolar areas of the lung. Lysyl oxidases (LOXs) have been proposed to be the central enzymes that catalyze the cross-linking of collagen fibers. Here, we report that, while its expression is increased in fibrotic lungs, genetic ablation of LOXL2 only leads to a modest reduction of pathological collagen cross-linking but not fibrosis in the lung. On the other hand, loss of another LOX family member, LOXL4, markedly disrupts pathological collagen cross-linking and fibrosis in the lung. Furthermore, knockout of both Loxl2 and Loxl4 does not offer any additive antifibrotic effects when compared to Loxl4 deletion only, as LOXL4 deficiency decreases the expression of other LOX family members including Loxl2. On the basis of these results, we propose that LOXL4 is the main LOX activity underlying pathological collagen cross-linking and lung fibrosis.

Bioactive lipid lysophosphatidic acid species are associated with disease progression in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality. Prognostic biomarkers to identify rapid progressors are urgently needed to improve patient management. Since the lysophosphatidic acid (LPA) pathway has been implicated in lung fibrosis in preclinical models and identified as a potential therapeutic target, we aimed to investigate if bioactive lipid LPA species could be prognostic biomarkers that predict IPF disease progression. LPAs and lipidomics were measured in baseline placebo plasma of a randomized IPF-controlled trial. The association of lipids with disease progression indices were assessed using statistical models. Compared to healthy, IPF patients had significantly higher levels of five LPAs (LPA16:0, 16:1, 18:1, 18:2, 20:4) and reduced levels of two triglycerides species (TAG48:4-FA12:0, -FA18:2) (false discovery rate < 0.05, fold change > 2). Patients with higher levels of LPAs had greater declines in diffusion capacity of carbon monoxide over 52 weeks (P < 0.01); additionally, LPA20:4-high (≥median) patients had earlier time to exacerbation compared to LPA20:4-low (

The Src1-PGC1α-AP1 complex-dependent secretion of substance P induces inflammation and apoptosis in encephalomyocarditis virus-infected mice.

Substance P (SP), a neuropeptide consisting of 11 amino acid residues, is involved in the pathogenesis of encephalomyocarditis virus (EMCV)-induced myocarditis by stimulating the production of proinflammatory cytokines. However, the underlying mechanism that regulates SP production is still unknown. In this study, we report the transcriptional regulation of the Tachykinin Precursor 1 (TAC1) gene that encodes SP by a transcriptional complex composed of Steroid Receptor Coactivator 1 (Src1), Peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC1α), and Activator Protein 1 (AP1) transcription factor. Infection of mice with EMCV induced the accumulation of PGC1α and increased TAC1 expression, thereby promoting the secretion of SP, initiating apoptosis, and elevating proinflammatory cytokine levels. In vitro overexpression of the Src1-PGC1α-AP1 members also induced TAC1 expression, increased the SP concentration, initiated apoptosis, and elevated proinflammatory cytokine concentrations. Depletion or inhibition of the Src1-PGC1α-AP1 complex reversed these effects. The administration of gossypol, an Src1 inhibitor, or SR1892, a PGC1α inhibitor, to EMCV-infected mice attenuated myocarditis. Taken together, our results reveal that the upregulation of TAC1 and the secretion of SP in EMCV-induced myocarditis are dependent on the Src1-PGC1α-AP1 complex. Targeting the Src1-PGC1α-AP1 complex may represent a new therapeutic strategy for myocarditis.

The new 'coN' staging system combining lymph node metastasis and tumour deposit provides a more accurate prognosis for TNM stage III colon cancer.

OBJECTIVE: Despite controversy over its origin and definition, the significance of tumour deposit (TD) has been underestimated in the tumour node metastasis (TNM) staging system for colon cancer, especially in stage III patients. We aimed to further confirm the prognostic value of TD in stage III colon cancer and to establish a more accurate 'coN' staging system combining TD and lymph node metastasis (LNM). METHODS: Information on stage III colon cancer patients with a definite TD status was retrospectively collected from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2017. The effect of TD on prognosis was estimated using Cox regression analysis. Maximally selected rank statistics were used to select the optimal cut-off value of TD counts. The predictive power of conventional N staging and the new coN staging was evaluated and compared by Akaike's information criterion (AIC), Harrell's concordance index (C-index) and time-dependent receiver operating characteristic (ROC) curves. Clinicopathological data of stage III colon cancer patients in the Xiangya database from 2014 to 2018 were collected to validate the coN staging system. RESULTS: A total of 39,185 patients with stage III colon cancer were included in our study: 38,446 in the SEER cohort and 739 in the Xiangya cohort. The incidence of TD in stage III colon cancer was approximately 30% (26% in SEER and 30% in the Xiangya database). TD was significantly associated with poorer overall survival (OS) (HR = 1.37, 95% CI 1.31-1.44, p < 0.001 in SEER). The optimal cut-off value of TD counts was 4, and the patients were classified into the TD0 (count = 0), TD1 (count = 1-3) and TD2 (count ≥ 4) groups accordingly. The estimated 5-year OS was significantly different among the three groups (69.4%, 95% CI 68.8%-70.0% in TD0; 60.5%, 95% CI 58.9%-62.2% in TD1 and 42.6%, 95% CI 39.2%-46.4% in TD2, respectively, p < 0.001). The coN system integrating LNM and TD was established, and patients with stage III colon cancer were reclassified into five subgroups (coN1a, coN1b, coN2a, coN2b and coN2c). Compared with conventional N staging, the coN staging Cox model had a smaller AIC (197097.581 vs. 197358.006) and a larger C-index (0.611 vs. 0.601). The AUCs of coN staging at 3, 5 and 7 years were also greater than those of conventional N staging (0.6305, 0.6326, 0.6314 vs. 0.6186, 0.6197, 0.6160). Concomitant with the SEER cohort results, the coN staging Cox model of the Xiangya cohort also had a smaller AIC (2883.856 vs. 2906.741) and a larger C-index (0.669 vs. 0.633). Greater AUCs at 3, 5 and 7 years for coN staging were also observed in the Xiangya cohort (0.6983, 0.6774, 0.6502 vs. 0.6512, 0.6368, 0.6199). CONCLUSIONS: Not only the presence but also the number of TDs is associated with poor prognosis in stage III colon cancer. A combined N staging system integrating LNM and TD provides more accurate prognostic prediction than the latest AJCC N staging in stage III colon cancer.

Electric yo-yo centrifugation combining with paper-based microfluidic immunoassay chip for inflammatory biomarkers detection in whole blood.

At present, most countries or regions use commercial centrifuges for centrifugation, but this is out of reaching for limited-resource areas. To overcome this problem, a portable electric yo-yo as centrifuge was firstly proposed to obtain serum, and this device can be combined with paper-based analytical devices for enzyme-linked immunosorbent assay (ELISA) analysis from human whole blood. In this study, inflammatory biomarkers C-reactive protein (CRP) and serum amyloid A (SAA) were used as target biomarker to verify the performance of the proposed method. The results shows good performance and their detection limits were determined to be 580 pg/mL for CRP and 800 pg/mL for SAA, respectively. We believe this method provides a new platform of low cost and fast detection for inflammatory biomarkers in the limited-resource settings.

Systematic pan-cancer analysis identifies RALA as a tumor targeting immune therapeutic and prognostic marker.

Introduction: RALA is a member of the small GTPase Ras superfamily and has been shown to play a role in promoting cell proliferation and migration in most tumors, and increase the resistance of anticancer drugs such as imatinib and cisplatin. Although many literatures have studied the cancer-promoting mechanism of RALA, there is a lack of relevant pan-cancer analysis. Methods: This study systematically analyzed the differential expression and mutation of RALA in pan-cancer, including different tissues and cancer cell lines, and studied the prognosis and immune infiltration associated with RALA in various cancers. Next, based on the genes co-expressed with RALA in pan-cancer, we selected 241 genes with high correlation for enrichment analysis. In terms of pan-cancer, we also analyzed the protein-protein interaction pathway of RALA and the application of small molecule drug Guanosine-5'-Diphosphate. We screened hepatocellular cancer (HCC) to further study RALA. Results: The results indicated that RALA was highly expressed in most cancers. RALA was significantly correlated with the infiltration of B cells and macrophages, as well as the expression of immune checkpoint molecules such as CD274, CTLA4, HAVCR2 and LAG3, suggesting that RALA can be used as a kind of new pan-cancer immune marker. The main functions of 241 genes are mitosis and protein localization to nucleosome, which are related to cell cycle. For HCC, the results displayed that RALA was positively correlated with common intracellular signaling pathways such as angiogenesis and apoptosis. Discussion: In summary, RALA was closely related to the clinical prognosis and immune infiltration of various tumors, and RALA was expected to become a broad-spectrum molecular immune therapeutic target and prognostic marker for pan-cancer.

Siah1 promotes the proliferation of NSCLC cells through ubiquitinating and stabilizing Notch1.

Seven in absentia homolog 1 (Siah1) has been shown plays important roles in the pathogenesis and development of multiple cancers. However, the functions and mechanisms of Siah1 in non-small cell lung cancer (NSCLC) remain unclear. In our study, we found that knock down of Siah1 could inhibit the proliferation of NSCLC cells, while over-expression of Siah1 had the opposite effects. Molecularly, the bioinformatics analysis determined that notch receptor 1 (Notch1) might be the potential target of Siah1. Subsequently, we identified that Siah1 acted as an E3 ligase to promote the ubiquitination and stabilization of Notch1 through the proteasome pathway. Furthermore, the results showed that the Siah1 expression was directly correlated with CTR9 in human NSCLC tissues. Finally, Siah1 could promote Akt phosphorylation through regulating Notch1, thus promoting the proliferation of NSCLC cells. In conclusion, our study demonstrated that Siah1 acts as an oncogene, can ubiquitinate and stabilize Notch1 by proteasome pathway, which promotes Akt phosphorylation and ultimately leads to NSCLC cell proliferation.

Compound Ipratropium Bromide plus Budesonide Inhalation in the Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease and Its Effect on Heparin-Binding Protein.

Objective: To analyze the clinical effect of compound ipratropium bromide combined with budesonide atomization inhalation on acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and its effect on the heparin-binding protein. Methods: A total of 110 patients with AECOPD who were admitted to our hospital between January 2020 and January 2021 were enrolled and assigned into control group (conventional treatment + compound ipratropium bromide) and combined group (conventional treatment + compound ipratropium bromide + budesonide) in a 1 : 1 ratio according to different treatment methods. The clinical effects, pulmonary function indexes, and heparin-binding protein levels before and after treatment were compared between the two groups. Results: The treatment with oxygen-driven nebulization of ipratropium bromide combined with budesonide led to a significantly higher total effective rate versus the treatment with ipratropium bromide alone (P < 0.001). After treatment, remarkably higher arterial oxygen partial pressure (PaO2), arterial oxygen saturation (SaO2), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and FEV1/FVC in the combined group vs. the control group were observed (P < 0.001). The carbon dioxide partial pressure (PaCO2) levels in the two groups were significantly lower than those before treatment, and the decrease in the combined group was greater (P < 0.001). A significantl reduction was observed in heparin-binding protein in both groups after treatment, and the decrease in the combined group was greater versus the control group (P < 0.001). Conclusion: Compound ipratropium bromide plus budesonide via aerosol inhalation therapy might be a preferable approach for AECOPD patients. It exhibits a synergistic effect on inhibiting inflammatory mediators and cytokine networks, significantly reduces airway hyperresponsiveness, and improves blood gas indicators and lung function.

Lnc-ABCA12-8 confers acquired resistance to gefitinib in non-small cell lung cancer by regulating the alternative splicing of fibronectin 1 in the IIICS region.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, has dramatically impaired the clinical outcomes in non-small cell lung cancer (NSCLC) patients, but the mechanisms are still unclear in substantial cases. In our previous study, we demonstrated that a novel long non-coding RNA (lncRNA), lnc-ABCA12-8, was overexpressed in gefitinib-resistant NSCLC cells, but the exact function is unknown. In this study, we confirmed that lnc-ABCA12-8 was significantly upregulated both in NSCLC cell lines and the plasma samples of NSCLC patients with acquired resistance to gefitinib. Downregulation of lnc-ABCA12-8 could reverse gefitinib resistance both in vitro and in vivo. Mechanistically, lnc-ABCA12-8 interacted with alternative splicing factor/splicing factor 2 (ASF/SF2), promoted the binding of ASF/SF2 to the IIICS exon of fibronectin 1 (FN1) gene and enhanced the IIICS region inclusion during fibronectin 1 (FN1) alternative splicing, resulting in the upregulation of entire IIICS region, and enhanced cell proliferation, migration, invasion, and adhesion. Taken together, our study suggest that lnc-ABCA12-8 is involved in the acquired resistance to gefitinib, and may be a novel biomarker and therapeutic target for monitoring and overcoming gefitinib resistance in NSCLC.

Stress-induced vesicular assemblies of dual leucine zipper kinase are signaling hubs involved in kinase activation and neurodegeneration.

Mitogen-activated protein kinases (MAPKs) drive key signaling cascades during neuronal survival and degeneration. The localization of kinases to specific subcellular compartments is a critical mechanism to locally control signaling activity and specificity upon stimulation. However, how MAPK signaling components tightly control their localization remains largely unknown. Here, we systematically analyzed the phosphorylation and membrane localization of all MAPKs expressed in dorsal root ganglia (DRG) neurons, under control and stress conditions. We found that MAP3K12/dual leucine zipper kinase (DLK) becomes phosphorylated and palmitoylated, and it is recruited to sphingomyelin-rich vesicles upon stress. Stress-induced DLK vesicle recruitment is essential for kinase activation; blocking DLK-membrane interaction inhibits downstream signaling, while DLK recruitment to ectopic subcellular structures is sufficient to induce kinase activation. We show that the localization of DLK to newly formed vesicles is essential for local signaling. Inhibition of membrane internalization blocks DLK activation and protects against neurodegeneration in DRG neurons. These data establish vesicular assemblies as dynamically regulated platforms for DLK signaling during neuronal stress responses.

Effects of Nursing Intervention Based on Health Belief Model on Self-Perceived Burden, Drug Compliance, and Quality of Life of Renal Transplant Recipients.

Objective: To explore the effects of nursing intervention based on health belief model (HBM) on self-perceived burden, drug compliance, and quality of life of renal transplant recipients. Methods: Sixty patients with renal transplantation treated in our hospital from February 2019 to July 2021 were enrolled. The patients were randomly assigned to control group and study group. The former received routine nursing and the latter received nursing intervention based on HBM. Results: The nursing satisfaction in the study group was higher compared to the control group (P < 0.05). Secondly, we compared the scores of self-burdens. Before nursing, they exhibited no significant difference (P > 0.05); after nursing, they decreased. Moreover, the physical burden, economic burden, and emotional burden of the study group were lower compared to the control group (P < 0.05). In terms of drug compliance, the rates of no missed medication, noncontinuous missed medication, timely medication, dose-by-dose medication, and non-self-stopping medication in the study group were higher compared to the control group (P < 0.05). The scores of SAS and SDS exhibited no significant difference before nursing (P > 0.05). After nursing, they decreased. Furthermore, the scores of SAS and SDS of the study group were lower compared to the control group (P < 0.05). The self-management ability exhibited no significant difference before nursing (P > 0.05); after nursing, it increased. Moreover, the self-management ability of the study group at discharge and 1 month, 3 months, and 6 months after discharge was higher compared to the control group (P < 0.05). Finally, we compared the scores of quality of life. Before nursing, there was no significant difference (P > 0.05). The scores of physiological function, psychological function, social function, and health self-cognition in the study group were lower compared to the control group (P < 0.05). Conclusion: The nursing intervention based on HBM can enhance the medication compliance of renal transplant recipients, and the intervention effect is long-lasting. Meanwhile, it can effectively enhance the negative emotion of patients, reduce the burden of self-feeling, promote the quality of life, strengthen the self-management of patients, and facilitate the prognosis.