Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

Objective This study aims to analyze the factors influencing per capita current health expenditure in Guizhou Province from 2016 to 2022 using the gray correlation analysis method.Methods Based on the"SHA2011"accounting results of current health expenditure in Guizhou Province,as well as data from the"Guizhou Statistical Yearbook"and"Guizhou Health Statistical Yearbook",the gray correlation analysis method was used to analyze the factors influencing per capita current health expenditure in Guizhou Province from 2016 to 2022.Results The factors with the highest correlation to per capita current health expenditure in Guizhou Province were health expenditure(0.829),followed by the number of health technical personnel per thousand people(0.715),the number of practicing(assistant)physicians per thousand people(0.705),and per capita GDP(0.704).The factor with the lowest correlation was the proportion of the tertiary industry to GDP(0.543).Conclusion Health expenditure investment has the strongest correlation with per capita current health expenditure in Guizhou Province.Health re-source investment and health service capacity are the main influencing factors of per capita current health expenditure in Guizhou Province.At the same time,the impact of economic and social factors on current health expenditure should be fully recognized.

Objective This study aims to analyze the factors influencing per capita current health expenditure in Guizhou Province from 2016 to 2022 using the gray correlation analysis method.Methods Based on the"SHA2011"accounting results of current health expenditure in Guizhou Province,as well as data from the"Guizhou Statistical Yearbook"and"Guizhou Health Statistical Yearbook",the gray correlation analysis method was used to analyze the factors influencing per capita current health expenditure in Guizhou Province from 2016 to 2022.Results The factors with the highest correlation to per capita current health expenditure in Guizhou Province were health expenditure(0.829),followed by the number of health technical personnel per thousand people(0.715),the number of practicing(assistant)physicians per thousand people(0.705),and per capita GDP(0.704).The factor with the lowest correlation was the proportion of the tertiary industry to GDP(0.543).Conclusion Health expenditure investment has the strongest correlation with per capita current health expenditure in Guizhou Province.Health re-source investment and health service capacity are the main influencing factors of per capita current health expenditure in Guizhou Province.At the same time,the impact of economic and social factors on current health expenditure should be fully recognized.

Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited signif-icant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degra-dation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

Purpose To investigate the diagnosis and staging performance of 18F-FAPI-42 PET/CT compared to 18F-FDG PET/CT in primary hepatic tumours. Materials and Methods We performed a retrospective study including all primary hepatic tumours patients who underwent both 18F-FAPI-42 and 18F-FDG PET/CT scans within two weeks at the First Affiliated Hospital of Guangzhou Medical University from October 2020 to May 2023. With histopathologic proof (surgical resection and/or percutaneous biopsies) or multimodality radiographic follow-up (CT/MRI-enhanced) as the final diagnostic reference standard. The maximum standard uptake value,tumor-to-background ratio and diagnostic rates (positive lesion/total lesion) between 18F-FAPI-42 and 18F-FDG were compared. Results Thirty-four primary hepatic tumours patients were enrolled in this study,including 27 hepatocellular carcinoma,5 intrahepatic cholangiocarcinoma and 2 combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma. It was found that 18F-FAPI-42 PET/CT significantly outperformed 18F-FDG in diagnosing intrahepatic lesions and lymph node metastases (intrahepatic lesions:93.33％ vs. 52.22％,P<0.001;lymph node metastases:100％ vs. 87.50％,P=0.021). The detection rates for distant metastases were comparable between the two radioactive tracers (100％ vs. 96.20％,P>0.05). 18F-FAPI-42 showed higher maximum standard uptake value and tumor-to-background ratio in intrahepatic lesions,regional lymph node metastases,bone and peritoneal metastases compared to 18F-FDG (Z=-5.261--1.183,all P<0.05). For primary hepatic tumours initial staging,18F-FAPI-42 PET/CT upstaged the T stage in 20.8％ (5/24) of patients,the N stage in 8.3％ (2/24) and the M stage in 8.3％ (2/24) of patients,consistent with multimodal imaging diagnostic results. The evaluation of post-treatment patient outcomes showed that 18F-FAPI-42 had a detection rate of 92.86％ (13/14) for hepatic tumours recurrence,higher than 18F-FDG (64.28％,9/14). 18F-FAPI-42 identified more recurrent primary lesions and intrahepatic metastatic foci,demonstrating greater sensitivity than 18F-FDG. Conclusion The diagnostic efficacy of 18F-FAPI-42 PET/CT for primary hepatic tumours is significantly better than 18F-FDG,showing excellent performance in the staging and restaging of primary hepatic tumours,which suggesting that the application of 18F-FAPI-42 is helpful to improve the clinical management of primary hepatic tumours patients.

Purpose To investigate the diagnosis and staging performance of 18F-FAPI-42 PET/CT compared to 18F-FDG PET/CT in primary hepatic tumours. Materials and Methods We performed a retrospective study including all primary hepatic tumours patients who underwent both 18F-FAPI-42 and 18F-FDG PET/CT scans within two weeks at the First Affiliated Hospital of Guangzhou Medical University from October 2020 to May 2023. With histopathologic proof (surgical resection and/or percutaneous biopsies) or multimodality radiographic follow-up (CT/MRI-enhanced) as the final diagnostic reference standard. The maximum standard uptake value,tumor-to-background ratio and diagnostic rates (positive lesion/total lesion) between 18F-FAPI-42 and 18F-FDG were compared. Results Thirty-four primary hepatic tumours patients were enrolled in this study,including 27 hepatocellular carcinoma,5 intrahepatic cholangiocarcinoma and 2 combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma. It was found that 18F-FAPI-42 PET/CT significantly outperformed 18F-FDG in diagnosing intrahepatic lesions and lymph node metastases (intrahepatic lesions:93.33％ vs. 52.22％,P<0.001;lymph node metastases:100％ vs. 87.50％,P=0.021). The detection rates for distant metastases were comparable between the two radioactive tracers (100％ vs. 96.20％,P>0.05). 18F-FAPI-42 showed higher maximum standard uptake value and tumor-to-background ratio in intrahepatic lesions,regional lymph node metastases,bone and peritoneal metastases compared to 18F-FDG (Z=-5.261--1.183,all P<0.05). For primary hepatic tumours initial staging,18F-FAPI-42 PET/CT upstaged the T stage in 20.8％ (5/24) of patients,the N stage in 8.3％ (2/24) and the M stage in 8.3％ (2/24) of patients,consistent with multimodal imaging diagnostic results. The evaluation of post-treatment patient outcomes showed that 18F-FAPI-42 had a detection rate of 92.86％ (13/14) for hepatic tumours recurrence,higher than 18F-FDG (64.28％,9/14). 18F-FAPI-42 identified more recurrent primary lesions and intrahepatic metastatic foci,demonstrating greater sensitivity than 18F-FDG. Conclusion The diagnostic efficacy of 18F-FAPI-42 PET/CT for primary hepatic tumours is significantly better than 18F-FDG,showing excellent performance in the staging and restaging of primary hepatic tumours,which suggesting that the application of 18F-FAPI-42 is helpful to improve the clinical management of primary hepatic tumours patients.

The perception of motion is an important function of vision. Neural wiring diagrams for extracting directional information have been obtained by connectome reconstruction. Direction selectivity in Drosophila is thought to originate in T4/T5 neurons through integrating inputs with different temporal filtering properties. Through genetic screening based on synaptic distribution, we isolated a new type of TmY neuron, termed TmY-ds, that form reciprocal synaptic connections with T4/T5 neurons. Its neurites responded to grating motion along the four cardinal directions and showed a variety of direction selectivity. Intriguingly, its direction selectivity originated from temporal filtering neurons rather than T4/T5. Genetic silencing and activation experiments showed that TmY-ds neurons are functionally upstream of T4/T5. Our results suggest that direction selectivity is generated in a tripartite circuit formed among these three neurons-temporal filtering, TmY-ds, and T4/T5 neurons, in which TmY-ds plays a role in the enhancement of direction selectivity in T4/T5 neurons.
Animals ; Neurites ; Drosophila ; Neurons ; Connectome

Pulmonary fibrosis (PF) is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration (LAR). Here, we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells (AEC2s). The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells (AEC1s). We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s, which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK, two critical kinases supporting LAR, leading to LAR failure. TRIB3, a stress sensor, interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination. Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF. Our study reveals a mechanism of the TRIB3-MDM2-SLUG-SLC34A2 axis causing the LAR failure in PF, which confers a potential strategy for treating patients with fibroproliferative lung diseases.

Chromodomain-helicase-DNA-binding protein 1 (CHD1) deletion is among the most common mutations in prostate cancer (PCa), but its role remains unclear. In this study, RNA sequencing was conducted in PCa cells after clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9)-based CHD1 knockout. Gene set enrichment analysis (GSEA) indicated upregulation of hypoxia-related pathways. A subsequent study confirmed that CHD1 deletion significantly upregulated hypoxia-inducible factor 1α (HIF1α) expression. Mechanistic investigation revealed that CHD1 deletion upregulated HIF1α by transcriptionally downregulating prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase catalyzing the hydroxylation of HIF1α and thus promoting its degradation by the E3 ligase von Hippel-Lindau tumor suppressor (VHL). Functional analysis showed that CHD1 deletion promoted angiogenesis and glycolysis, possibly through HIF1α target genes. Taken together, these findings indicate that CHD1 deletion enhances HIF1α expression through PHD2 downregulation and therefore promotes angiogenesis and metabolic reprogramming in PCa.
Male ; Humans ; Von Hippel-Lindau Tumor Suppressor Protein/metabolism* ; DNA-Binding Proteins/metabolism* ; Prolyl Hydroxylases/metabolism* ; Hypoxia ; Prostatic Neoplasms/pathology* ; Glycolysis ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Cell Line, Tumor ; DNA Helicases/metabolism*

The cell cycle inhibitor P21 has been implicated in cell senescence and plays an important role in the injury-repair process following lung injury. Pulmonary fibrosis (PF) is a fibrotic lung disorder characterized by cell senescence in lung alveolar epithelial cells. In this study, we report that P21 expression was increased in alveolar epithelial type 2 cells (AEC2s) in a time-dependent manner following multiple bleomycin-induced PF. Repeated injury of AEC2s resulted in telomere shortening and triggered P21-dependent cell senescence. AEC2s with elevated expression of P21 lost their self-renewal and differentiation abilities. In particular, elevated P21 not only induced cell cycle arrest in AEC2s but also bound to P300 and β-catenin and inhibited AEC2 differentiation by disturbing the P300-β-catenin interaction. Meanwhile, senescent AEC2s triggered myofibroblast activation by releasing profibrotic cytokines. Knockdown of P21 restored AEC2-mediated lung alveolar regeneration in mice with chronic PF. The results of our study reveal a mechanism of P21-mediated lung regeneration failure during PF development, which suggests a potential strategy for the treatment of fibrotic lung diseases.