Curriculum vitae of CUG binding protein 1 (CELF1) in homeostasis and diseases: a systematic review.

RNA-binding proteins (RBPs) are kinds of proteins with either singular or multiple RNA-binding domains (RBDs), and they can assembly into ribonucleic acid-protein complexes, which mediate transportation, editing, splicing, stabilization, translational efficiency, or epigenetic modifications of their binding RNA partners, and thereby modulate various physiological and pathological processes. CUG-BP, Elav-like family 1 (CELF1) is a member of the CELF family of RBPs with high affinity to the GU-rich elements in mRNA, and thus exerting control over critical processes including mRNA splicing, translation, and decay. Mounting studies support that CELF1 is correlated with occurrence, genesis and development and represents a potential therapeutical target for these malignant diseases. Herein, we present the structure and function of CELF1, outline its role and regulatory mechanisms in varieties of homeostasis and diseases, summarize the identified CELF1 regulators and their structure-activity relationships, and prospect the current challenges and their solutions during studies on CELF1 functions and corresponding drug discovery, which will facilitate the establishment of a targeted regulatory network for CELF1 in diseases and advance CELF1 as a potential drug target for disease therapy.

A comprehensive investigation on the receptor BSG expression reveals the potential risk of healthy individuals and cancer patients to 2019-nCoV infection.

BACKGROUND: Coronavirus disease-2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a newly emerging coronavirus. BSG (basigin) is involved in the tumorigenesis of multiple tumors and recently emerged as a novel viral entry receptor for SARS-CoV-2. However, its expression profile in normal individuals and cancer patients are still unclear. METHODS: We performed a comprehensive analysis of the expression and distribution of BSG in normal tissues, tumor tissues, and cell lines via bioinformatics analysis and experimental verification. In addition, we investigated the expression of BSG and its isoforms in multiple malignancies and adjacent normal tissues, and explored the prognostic values across pan-cancers. Finally, we conducted function analysis for co-expressed genes with BSG. RESULTS: We found BSG was highly conserved in different species, and was ubiquitously expressed in almost all normal tissues and significantly increased in some types of cancer tissues. Moreover, BSG at mRNA expression level was higher than ACE2 in normal lung tissues, and lung cancer tissues. High expression of BSG indicated shorter overall survival (OS) in multiple tumors. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that BSG is mostly enriched in genes for mitochondria electron transport, oxidoreduction-driven active transmembrane transporter activity, mitochondrial inner membrane, oxidative phosphorylation, and genes involving COVID-19. CONCLUSIONS: Our present work emphasized the value of targeting BSG in the treatment of COVID-19 and cancer, and also provided several novel insights for understanding the SARS-CoV-2 pandemic.

Inhibition of TGFß1 activation prevents radiation-induced lung fibrosis.

BACKGROUND: Radiotherapy is the main treatment modality for thoracic tumours, but it may induce pulmonary fibrosis. Currently, the pathogenesis of radiation-induced pulmonary fibrosis (RIPF) is unclear, and effective treatments are lacking. Transforming growth factor beta 1 (TGFß1) plays a central role in RIPF. We found that activated TGFß1 had better performance for radiation pneumonitis (RP) risk prediction by detecting activated and total TGFß1 levels in patient serum. αv integrin plays key roles in TGFß1 activation, but the role of αv integrin-mediated TGFß1 activation in RIPF is unclear. Here, we investigated the role of αv integrin-mediated TGFß1 activation in RIPF and the application of the integrin antagonist cilengitide to prevent RIPF. METHODS: ItgavloxP/loxP ;Pdgfrb-Cre mice were generated by conditionally knocking out Itgav in myofibroblasts, and wild-type mice were treated with cilengitide or placebo. All mice received 16 Gy of radiation or underwent a sham radiation procedure. Lung fibrosis was measured by a modified Ashcroft score and microcomputed tomography (CT). An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum TGFß1 concentration, and total Smad2/3 and p-Smad2/3 levels were determined via Western blotting. RESULTS: Conditional Itgav knockout significantly attenuated RIPF (p < .01). Hounsfield units (HUs) in the lungs were reduced in the knockout mice compared with the control mice (p < .001). Conditional Itgav knockout decreased active TGFß1 secretion and inhibited fibroblast p-Smad2/3 expression. Exogenous active TGFß1, but not latent TGFß1, reversed these reductions. Furthermore, cilengitide treatment elicited similar results and prevented RIPF. CONCLUSIONS: The present study revealed that conditional Itgav knockout and cilengitide treatment both significantly attenuated RIPF in mice by inhibiting αv integrin-mediated TGFß1 activation. HIGHLIGHTS: Activated TGFß1 has a superior capacity in predicting radiation pneumonitis (RP) risk and plays a vital role in the development of radiation-induced pulmonary fibrosis (RIPF). Conditional knock out Itgav in myofibroblasts prevented mice from developing RIPF. Cilengitide alleviated the development of RIPF by inhibiting αv integrin-mediated TGFß1 activation and may be used in targeted approaches for preventing RIPF.

Electroacupuncture Promotes Nerve Regeneration and Functional Recovery Through Regulating lncRNA GAS5 Targeting miR-21 After Sciatic Nerve Injury.

Although the benefits of electroacupuncture (EA) for peripheral nerve injury (PNI) are well accepted in clinical practice, the underlying mechanism remains incompletely elucidated. In our study, we observed that EA intervention led to a reduction in the expression of the long non-coding RNA growth-arrest-specific transcript 5 (GAS5) and an increased in miR-21 levels within the injured nerve, effectively promoting functional recovery and nerve regeneration following sciatic nerve injury (SNI). In contrast, administration of adeno-associated virus expressing GAS5 (AAV-GAS5) weakened the therapeutic effect of EA. On the other hand, both silencing GAS5 and introducing a miR-21 mimic prominently enhanced the proliferation activity and migration ability of Schwann cells (SCs), while also inhibiting SCs apoptosis. On the contrary, inhibition of SCs apoptosis was found to be mediated by miR-21. Additionally, overexpression of GAS5 counteracted the effects of the miR-21 mimic on SCs. Moreover, SCs that transfected with the miR-21 mimic promoted neurite growth in hypoxia/reoxygenation-induced neurons, which might be prevented by overexpressing GAS5. Furthermore, GAS5 was found to be widely distributed in the cytoplasm and was negatively regulated by miR-21. Consequently, the targeting of GAS5 by miR-21 represents a potential mechanism through which EA enhances reinnervation and functional restoration following SNI. Mechanistically, the GAS5/miR-21 axis can modulate the proliferation, migration, and apoptosis of SCs while potentially influencing the neurite growth of neurons.

Repurposing drugs for solid tumor treatment: focus on immune checkpoint inhibitors.

Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies, such as chemotherapy, radiotherapy, and molecular targeted therapy. Immunotherapy has emerged as a promising therapeutic modality but the efficacy has plateaued, which therefore provides limited benefits to patients with cancer. Identification of more effective approaches to improve patient outcomes and extend survival are urgently needed. Drug repurposing has emerged as an attractive strategy for drug development and has recently garnered considerable interest. This review comprehensively analyses the efficacy of various repurposed drugs, such as transforming growth factor-beta (TGF-ß) inhibitors, metformin, receptor activator of nuclear factor-κB ligand (RANKL) inhibitors, granulocyte macrophage colony-stimulating factor (GM-CSF), thymosin α1 (Tα1), aspirin, and bisphosphonate, in tumorigenesis with a specific focus on their impact on tumor immunology and immunotherapy. Additionally, we present a concise overview of the current preclinical and clinical studies investigating the potential therapeutic synergies achieved by combining these agents with immune checkpoint inhibitors.

Proteomic characteristics of six snake venoms from the Viperidae and Elapidae families in China and their relation to local tissue necrosis.

Patients envenomed by snakes from the Viperidae and Elapidae families in China often have varying degrees of local tissue necrosis. Due to the relative clinical characteristics of local tissue necrosis and ulceration following envenoming, this study has analyzed the proteome of six snake venoms from the Viperidae and Elapidae family, and the toxin profiles of each snake were compared and correlated with the clinical manifestations that follow cytotoxic envenoming. Deinagkistrodon acutus and Naja atra envenomation induce severe ulceration, which is absent in Bungarus multicinctus envenomation and mild in the other three vipers. It is interesting to note that the proportion of c-type lectins (CTL) (20.63%) in Deinagkistrodon acutus venom was relatively high, which differs from the venom of other vipers. In addition, three-fingered toxin (3FTx) (2.15%) is present in the venom of Deinagkistrodon acutus, but has not been detected in the remaining three vipers. Snake venom metalloprotease (SVMP) (34.4%-44.7%), phospholipase A2 (PLA2) (9.81%-40.83%), and snake venom serine protease (SVSP) (9.44%-16.2%) represent the most abundant families of toxin in Viperidae venom. The Elapidae venom proteome was mainly composed of neurotoxins and cytotoxins, including 3FTx (39.28%-60.08%) and PLA2 (8.24%-58.95%) toxins, however, the proportion of CRISPS (26.36%) in Naja atra venom was relatively higher compared to Bungarus multicinctus venom. Significant differences in SVMP, SVSP, and 3FTx expression levels exist between the Viperidae and the Elapidae family. The main toxins responsible for the development of tissue necrosis and ulcerations following Viperidae envenoming are hematotoxins (SVSMP, SVSP) and myotoxins (PLA2). Deinagkistrodon acutus venom contains high levels of CTL and traces of 3FTx, leading to more severe local necrosis. However, Naja atra venom can also cause severe local necrosis through the effects of myotoxin (3FTx, CRISP, PLA2). Bungarus multicinctus venom does not contain myotoxins, resulting in pure systemic neurological manifestations no obvious necrosis of local tissue in patients.

Dieting alleviates hyperuricemia and organ injuries in uricase-deficient rats via down-regulating cell cycle pathway.

Dieting is a basic treatment for lowering hyperuricemia. Here, we aimed to determine the optimal amount of dietary food that lowers serum uric acid (SUA) without modifying the dietary ingredients in rats. Increased SUA was found in food-deprived 45-day-old uricase-deficient rats (Kunming-DY rats), and the optimal amount of dietary food (75% dietary intake) to lower SUA was established by controlling the amount of food given daily from 25% to 100% for 2 weeks. In addition to lowering SUA by approximately 22.5 ± 20.5%, the optimal amount of dietary food given for 2 weeks inhibited urine uric acid excretion, lowered the uric acid content in multiple organs, improved renal function, lowered serum triglyceride, alleviated organ injuries (e.g., liver, kidney and intestinal tract) at the histological level, and down-regulated the Kyoto Encyclopedia of Genes and Genome (KEGG) pathway of the cell cycle (ko04110). Taken together, these results demonstrate that 75% dietary food effectively lowers the SUA level without modifying dietary ingredients and alleviates the injuries resulting from uricase deficiency or hyperuricemia, the mechanism of which is associated with the down-regulation of the cell cycle pathway.

Radiomics model based on contrast-enhanced computed tomography to predict early recurrence in patients with hepatocellular carcinoma after radical resection.

BACKGROUND: Radical resection remains an effective strategy for patients with hepatocellular carcinoma (HCC). Unfortunately, the postoperative early recurrence (recurrence within 2 years) rate is still high. AIM: To develop a radiomics model based on preoperative contrast-enhanced computed tomography (CECT) to evaluate early recurrence in HCC patients with a single tumour. METHODS: We enrolled a total of 402 HCC patients from two centres who were diagnosed with a single tumour and underwent radical resection. First, the features from the portal venous and arterial phases of CECT were extracted based on the region of interest, and the early recurrence-related radiomics features were selected via the least absolute shrinkage and selection operator proportional hazards model (LASSO Cox) to determine radiomics scores for each patient. Then, the clinicopathologic data were combined to develop a model to predict early recurrence by Cox regression. Finally, we evaluated the prediction performance of this model by multiple methods. RESULTS: A total of 1915 radiomics features were extracted from CECT images, and 31 of them were used to determine the radiomics scores, which showed a significant difference between the early recurrence and nonearly recurrence groups. Univariate and multivariate Cox regression analyses showed that radiomics scores and serum alpha-fetoprotein were independent indicators, and they were used to develop a combined model to predict early recurrence. The area under the receiver operating characteristic curve values for the training and validation cohorts were 0.77 and 0.74, respectively, while the C-indices were 0.712 and 0.674, respectively. The calibration curves and decision curve analysis showed satisfactory accuracy and clinical utilities. Kaplan-Meier curves based on recurrence-free survival and overall survival showed significant differences. CONCLUSION: The preoperative radiomics model was shown to be effective for predicting early recurrence among HCC patients with a single tumour.

Young Sca-1+ bone marrow stem cell-derived exosomes preserve visual function via the miR-150-5p/MEKK3/JNK/c-Jun pathway to reduce M1 microglial polarization.

BACKGROUND: Polarization of microglia, the resident retinal immune cells, plays important roles in mediating both injury and repair responses post-retinal ischemia-reperfusion (I/R) injury, which is one of the main pathological mechanisms behind ganglion cell apoptosis. Aging could perturb microglial balances, resulting in lowered post-I/R retinal repair. Young bone marrow (BM) stem cell antigen 1-positive (Sca-1+) cells have been demonstrated to have higher reparative capabilities post-I/R retinal injury when transplanted into old mice, where they were able to home and differentiate into retinal microglia. METHODS: Exosomes were enriched from young Sca-1+ or Sca-1- cells, and injected into the vitreous humor of old mice post-retinal I/R. Bioinformatics analyses, including miRNA sequencing, was used to analyze exosome contents, which was confirmed by RT-qPCR. Western blot was then performed to examine expression levels of inflammatory factors and underlying signaling pathway proteins, while immunofluorescence staining was used to examine the extent of pro-inflammatory M1 microglial polarization. Fluoro-Gold labelling was then utilized to identify viable ganglion cells, while H&E staining was used to examine retinal morphology post-I/R and exosome treatment. RESULTS: Sca-1+ exosome-injected mice yielded better visual functional preservation and lowered inflammatory factors, compared to Sca-1-, at days 1, 3, and 7 days post-I/R. miRNA sequencing found that Sca-1+ exosomes had higher miR-150-5p levels, compared to Sca-1- exosomes, which was confirmed by RT-qPCR. Mechanistic analysis found that miR-150-5p from Sca-1+ exosomes repressed the mitogen-activated protein kinase kinase kinase 3 (MEKK3)/JNK/c-Jun axis, leading to IL-6 and TNF-α downregulation, and subsequently reduced microglial polarization, all of which contributes to reduced ganglion cell apoptosis and preservation of proper retinal morphology. CONCLUSION: This study elucidates a potential new therapeutic approach for neuroprotection against I/R injury, via delivering miR-150-5p-enriched Sca-1+ exosomes, which targets the miR-150-5p/MEKK3/JNK/c-Jun axis, thereby serving as a cell-free remedy for treating retinal I/R injury and preserving visual functioning.

Autophagy gene Atg7 regulates the development of radiation-induced skin injury and fibrosis of skin.

BACKGROUND: Radiation-induced skin injury, which may progress to fibrosis, is a severe side effect of radiotherapy in patients with cancer. However, currently, there is a lack of preventive or curative treatments for this injury. Meanwhile, the mechanisms underlying this injury remain poorly understood. Here, we elucidated whether autophagy is essential for the development of radiation-induced skin injury and the potential molecular pathways and mechanisms involved. METHODS AND RESULTS: We used the myofibroblast-specific Atg7 knockout (namely, conditional Atg7 knockout) mice irradiated with a single electron beam irradiation dose of 30 Gy. Vaseline-based 0.2% rapamycin ointment was topically applied once daily from the day of irradiation for 30 days. On day 30 post irradiation, skin tissues were harvested for further analysis. In vitro, human foreskin fibroblast cells were treated with rapamycin (100 nM) for 24 h and pretreated with 3-MA (5 mM) for 12 h. Macroscopic skin manifestations, histological changes, and fibrosis markers at the mRNA and protein expression levels were measured. Post irradiation, the myofibroblast-specific autophagy-deficient (Atg7Flox/Flox Cre+ ) mice had increased fibrosis marker (COL1A1, CTGF, TGF-ß1, and α-SMA) levels in the irradiated area and had more severe macroscopic skin manifestations than the control group (Atg7Flox/Flox Cre- ) mice. Treatment with an autophagy agonist rapamycin attenuated macroscopic skin injury scores and skin fibrosis marker levels with decreased epidermal thickness and dermal collagen deposition in Atg7Flox/Flox Cre+ mice compared with the vehicle control. Moreover, in vitro experiment results were consistent with the in vivo results. Together with studies at the molecular level, we found that these changes involved the Akt/mTOR pathway. In addition, this phenomenon might also relate to Nrf2-autophagy signaling pathway under oxidative stress conditions. CONCLUSION: In conclusion, Atg7 and autophagy-related mechanisms confer radioprotection, and reactivation of the autophagy process can be a novel therapeutic strategy to reduce and prevent the occurrence of radiodermatitis, particularly skin fibrosis, in patients with cancer.

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma.

BACKGROUND: Chromatin regulators (CRs) are critical epigenetic modifiers and have been reported to play critical roles during the progression of various tumors, but their role in lung adenocarcinoma (LUAD) has not been comprehensively studied. METHODS: Differential expression and univariate Cox regression analyses were conducted to identify the prognostic CRs. Consensus clustering was applied to classify the subtypes of LUAD based on prognostic CRs. LASSO-multivariate Cox regression method was used for construction of a prognostic signature and development of chromatin regulator-related gene index (CRGI). The capacity of CRGI to distinguish survival was evaluated via Kaplan-Meier method in multiple datasets. Relationship between CRGI and tumor microenvironment (TME) was evaluated. Additionally, clinical variables and CRGI were incorporated to create a nomogram. The role of the prognostic gene NPAS2 in LUAD was elucidated via clinical samples validation and a series of in vitro and in vivo experiments. RESULTS: Two subtypes of LUAD were classified based on 46 prognostic CRs via consensus clustering which had significantly different survival and TME. A prognostic signature consisting of six CRs (MOCS, PBK, CBX3, A1CF, NPAS2, and CTCFL) was developed and proved to be an effective survival predictor in multiple independent datasets. The prognostic signature was also demonstrated to be an indicator of TME and sensitivity to immunotherapy and chemotherapy. The nomogram was suggested to be a simple tool that can predict survival accurately. Clinical samples show that NPAS2 is highly expressed in LUAD tissues, and in vitro and in vivo experiments demonstrated that inhibition of NPAS2 impeded malignant progression of LUAD cells. CONCLUSIONS: Our study comprehensively unveiled the functions of CRs in LUAD, developed a classifier to predict survival and response to treatments, and suggested that NPAS2 promoted LUAD progression for the first time.

Analysis of eight types of RNA modification regulators and their correlation with the prognosis in hepatocellular carcinoma.

RNA modification plays important role in the occurrence and development of hepatocellular carcinoma. The best characterized RNA modification is m6A, while other kinds of RNA modifications have not been fully investigated in hepatocellular carcinoma (HCC). In the current study, we investigated the roles of one hundred RNA modification regulators belonging to eight different types of cancer-related RNA modifications in HCC. Expression analysis revealed that nearly 90% RNA regulators exhibited significantly higher expression in tumors than normal tissues. By consensus clustering, we identified two clusters with distinct biological characteristics, immune microenvironment, and prognostic pattern. An RNA modification score (RMScore) was constructed and stratified patients into high- and low-risk group, which showed significantly different prognosis. Moreover, a nomogram including clinicopathologic features and the RMScore could well predict the survival in HCC patients. This study indicated the important role of eight types of RNA modification in HCC and develop a RMScore, which will be a new method to forecast the prognosis of HCC patients.

Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown a moderate response in colorectal cancer (CRC) with deficient mismatch repair (dMMR) functions and poor response in patients with proficient MMR (pMMR). pMMR tumors are generally immunogenically "cold", emphasizing combination strategies to turn the "cold" tumor "hot" to enhance the efficacy of ICIs. ATR inhibitors (ATRi) have been proven to cooperate with radiation to promote antitumor immunity, but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs. This study aimed to investigate the efficacy of combining ATRi, irradiation (IR), and anti-PD-L1 antibodies in CRC mouse models with different microsatellite statuses. METHODS: The efficacy of combining ATRi, IR, and anti-PD-L1 antibodies was evaluated in CRC tumors. The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens. The mechanisms were explored via cell viability assay, flow cytometry, immunofluorescence, immunoblotting, co-immunoprecipitation, and real-time quantitative PCR in multiple murine and human CRC cell lines. RESULTS: Combining ATRi berzosertib and IR enhanced CD8+ T cell infiltration and enhanced the efficacy of anti-PD-L1 therapy in mouse CRC models with different microsatellite statuses. The mechanistic study demonstrated that IR + ATRi could activate both the canonical cGAS-STING-pTBK1/pIRF3 axis by increasing cytosolic double-stranded DNA levels and the non-canonical STING signaling by attenuating SHP1-mediated inhibition of the TRAF6-STING-p65 axis, via promoting SUMOylation of SHP1 at lysine 127. By boosting the STING signaling, IR + ATRi induced type I interferon-related gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment, thus facilitating immunotherapy. CONCLUSIONS: The combination of ATRi and IR could facilitate anti-PD-L1 therapy by promoting STING signaling in CRC models with different microsatellite statuses. The new combination strategy raised by our study is worth investigating in the management of CRC.

A Health Education Program for Home Emergency Management of Acute Complications of Diabetes in the Elderly / 中国医学科学院学报

Objective To establish a health education program for home emergency management of acute complications of diabetes in the elderly.Methods The program was drafted by literature review and panel discussion.The final draft was formed after two rounds of correspondence from 13 experts.Results The recovery rate of the two rounds of expert correspondence was 100%,and the expert authority coefficient was 0.98.The Kendall's harmony coefficients of the two rounds of correspondence were 0.263 and 0.212 respectively(both P<0.001).The established health education program included indicators of three categories:early stage of acute complications of diabetes at home(understanding the inducing factors),emergency warning(quick and early identification in case of emergency),and emergency treatment at home.Conclusion The contents of the health education program are systematic and reliable and meet the needs of health education for home emergency management of the elderly with diabetes.

“Liquid seal to detoxification – drying and puffing” of two stage processing technology design and pharmacodynamic study of aconite (Aconiti Lateralis Radix Praeparata) processed by microwave / 药学学报

Establish a production line with controllable process and high intelligence, contribute to improve the quality and production efficiency of aconite processed by microwave, and promote the transformation and application of aconite processed by microwave. According to the principle of aconite detoxification and the characteristics of industrial microwave equipment, an industrial production line of aconite processed by microwave was established with diester alkaloids and monoester alkaloids as indicators, and pilot production was carried out. At the same time, the content of active constituents and efficacy were compared with that of the main processed products, such as Shengfupian, Baifupian and Heishunpian. The results showed that the industrial production of aconite processed by microwave can be divided into two stages: "Liquid seal to detoxification - drying and puffing". The content of monoester alkaloids in 10 batches of aconite processed by microwave was 0.071%-0.166% and the content of diester alkaloids was 0.004%-0.016%, which met the relevant requirements of the Chinese Pharmacopoeia in 2020. Compared with Heishunpian and Baifupian, the retention rate of the effective components of aconite processed by microwave was higher. Pharmacological experiments showed that aconite processed by microwave not only retained the anti-inflammatory and analgesic activities of Heishunpian and Baifupian, but also significantly increased the levels of leukocytes and lymphocytes in mice with liver cancer chemotherapy, enhanced the CD4/CD8 ratio in spleen cells of mice (P < 0.05), thus regulating the body's immunity. However, this effect of Baifupian was weak, while Heishunpian and Shengfupian had no such effect. Through the above research, this study established microwave processing line with controllable process and high intelligence, as well produced the aconite processed by microwave with low toxicity and stable quality. It laid a foundation for the industrialized continuous production and clinical positioning of aconite by microwave processed, and provided scientific support for the development and application of microwave technology in the field of traditional Chinese medicine. All animal experiments in this study were reviewed and approved by the Experimental Animal Ethics Committee of Chengdu University of Traditional Chinese Medicine before being carried out (Approval No. 2020-28).

Effect of speech imagery therapy on dysarthria in children with cerebral palsy / 中国康复理论与实践

ObjectiveTo investigate the effect of speech imagery therapy combined with traditional dysarthria training on dysarthria in children with cerebral palsy. MethodsFrom August to December, 2022, 21 children with cerebral palsy combined with dysarthria in Wuhu Fifth People's Hospital were randomly divided into three groups A, B and C. Group A was given traditional dysarthria training for 30 minutes everytime, group B was given implantable speech imagery combined with traditional dysarthria training for 40 minutes everytime, and group C was given additional speech imagery combined with traditional dysarthria training for 40 minutes everytime, five days a week, for three weeks. Articulation and Phonology Assessment Scale, Mouth Sensory-Motor Assessment Scale, and mandibular distance, tongue distance and vowel space area (VSA) were evaluated before and after treatment. ResultsThere was no significant difference in all the indexes among three groups before treatment (F < 1.247, P > 0.05). After treatment, the scores of phonological function and sensory-motor assessment scale increased (|t| > 2.575, P < 0.05), and the mandibular distance and VSA increased in groups A and B (|t| > 2.632, P < 0.05). The d-value of phonological function before and after treatment was more in groups B and C than in group A (P < 0.05), and no difference was found in the d-value of other indexes before and after treatment among three groups (P > 0.05). ConclusionBoth speech imagery therapies are effective in improving diction clarity, oral range of motion, and motion control ability in children with cerebral palsy, and are more effective in improving articulatory clarity than traditional speech-language training.

A methylation-related signature for predicting prognosis and sensitivity to first-line therapies in gastric cancer.

Background: Methylation modification patterns play a crucial role in human cancer progression, especially in gastrointestinal cancers. We aimed to use methylation regulators to classify patients with gastric adenocarcinoma and build a model to predict prognosis, promoting the application of precision medicine. Methods: We obtained RNA sequencing data and clinical data from The Cancer Genome Atlas (TCGA) database (n=335) and Gene Expression Omnibus (GEO) database (n=865). Unsupervised consensus clustering was used to identify subtypes of gastric adenocarcinoma. We performed functional enrichment analysis, immune infiltration analysis, drug sensitivity analysis, and molecular feature analysis to determine the clinical application for different subtypes. The univariate Cox regression analysis and the LASSO regression analysis were subsequently used to identify prognosis-related methylation regulators and construct a risk model. Results: Through unsupervised consensus clustering, patients were divided into two subtypes (cluster A and cluster B) with different clinical outcomes. Cluster B included patients with a better prognosis outcome and who were more likely to respond to immunotherapy. We then successfully built a predictive model and found five methylation-related genes (CHAF1A, CPNE8, PHLDA3, SPARC, and EHF) potentially significant to the prognosis of patients. The 1-, 3-, and 5-year areas under the curve of the risk model were 0.712, 0.696, and 0.759, respectively. The risk score was an independent prognostic factor and had the highest concordance index among common clinical indicators. Meanwhile, the tumor microenvironment, sensitivity of chemotherapeutic drugs, molecular features, and oncogenic dedifferentiation differed significantly across the risk groups and subtypes. Conclusions: We classified patients with gastric adenocarcinoma based on methylation regulators, which has positive implications for first-line clinical treatment. The prognostic model could predict the prognosis of patients and help to promote the development of precision medicine.

Multi-omics consensus portfolio to refine the classification of lung adenocarcinoma with prognostic stratification, tumor microenvironment, and unique sensitivity to first-line therapies.

Background: Molecular classification of lung adenocarcinoma (LUAD) based on transcriptomic features has been widely studied. The complementarity of data obtained from multilayer molecular biology could help the LUAD classification via combining multi-omics information. Methods: We successfully divided samples from the The Cancer Genome Atlas (TCGA) (n=437) into four subtypes (CS1, CS2, CS3 and CS4) by 10 comprehensive multi-omics clustering methods in the "movics" R package. Meanwhile, external validation sets from different sequencing technologies proved the robustness of the grouping model. The relationship between subtypes, prognosis, molecular features, tumor microenvironment and response to first-line therapy was further analyzed. Next we used univariate Cox regression analysis and Lasso regression analysis to explore the application of biomarkers in clinical prognosis and constructed a prognostic model. Results: CS1 showed the worst overall survival (OS) among all four clusters, possibly related to its poor immune infiltration, higher tumor mutation and worse chromosomal stability. Patients in different subtypes differed significantly in cancer stem cell characteristics, activation of cancer-related pathways, sensitivity to chemotherapy and immunotherapy. The prognostic model showed good predictive performance. The 1-, 2- and 3-year areas under the curve of risk score were 0.779, 0.742 and 0.678, respectively. Seven genes (DKK1, TSPAN7, ID1, DLGAP5, HHIPL2, CD40 and SEMA3C) used to build the model may be potential therapeutic targets for LUAD. Conclusions: Four LUAD subtypes with different molecular characteristics and clinical implications were identified successfully through bioinformatic analysis. Our results may contribute to precision medicine and inform the development of rational clinical strategies for targeted and immune therapies.