Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment.

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.

Estimating disparities of prostate cancer burden and its attributable risk factors for males across the BRICS-plus, 1990-2019: A comparable study of key nations with emerging economies.

BACKGROUNDS: The study aimed to analyze epidemiology burden of male prostate cancer across the BRICS-plus, and identify potential risk factors by assessing the associations with age, period, birth cohorts and sociodemographic index (SDI). METHODS: Data were extracted from the Global Burden of Disease Study 2019. The average annual percent change (AAPC) was calculated to assess long-term trends, and age-period-cohort analysis was used to analyze these three effects on prostate cancer burden. Quantile regression was used to investigate the association between SDI and health outcomes. RESULTS: The higher incidence and mortality were observed in Mercosur and SACU regions, increasing trends were observed in prostate cancer incidence in almost all BRICS-plus countries (AAPC > 0), and EEU's grew by 24.31% (%AAPC range: -0.13-3.03). Mortality had increased in more than half of countries (AAPC > 0), and SACU grew by 1.82% (%AAPC range: 0.62-1.75). Incidence and mortality risk sharply increased with age across all BRICS-plus countries and globally, and the peak was reached in the age group 80-84 years. Rate ratio (RR) of incidence increased with birth cohorts in all BRICS-plus countries except for Kazakhstan where slightly decrease, while mortality RR decreased with birth cohort in most of BRICS-plus countries. SDI presented significantly positive associations with incidence in 50 percentiles. The deaths attributable to smoking declined in most of BRICS-plus nations, and many countries in China-ASEAN-FTA and EEU had higher values. CONCLUSION: Prostate cancer posed a serious public health challenge with an increasing burden among most of BRICS-plus countries. Age had significant effects on prostate cancer burden, and recent birth cohorts suffered from higher incidence risk. SDI presented a positive relationship with incidence, and the smoking-attributable burden was tremendous in China-ASEAN-FTA and EEU region. Secondary prevention should be prioritized in BRICS-plus nations, and health policies targeting important populations should be strengthened based on their characteristics and adaptability.

Monolithic Microparticles Facilitated Flower-Like TiO2 Nanowires for High Areal Capacity Flexible Li-Ion Batteries.

Flexible lithium-ion batteries (FLIBs) are intensively studied using free-standing transition metal oxides (TMOs)-based anode materials. However, achieving high areal capacity TMO-based anode materials is yet to be effectively elucidated owing to the poor adhesion of the active materials to the flexible substrate resulting in low active mass loading, and hence low areal capacity is realized. Herein, a novel monolithic rutile TiO2 microparticles on carbon cloth (ATO/CC) that facilitate the flower-like arrangement of TiO2 nanowires (denoted ATO/CC/OTO) is demonstrated as high areal capacity anode for FLIBs. The optimized ATO/CC/OTO anode exhibits high areal capacity (5.02 mAh cm-2@0.4 mA cm-2) excellent rate capability (1.17 mAh cm-2@5.0 mA cm-2) and remarkable cyclic stability (over 500 cycles). A series of morphological, kinetic, electrochemical, in situ Raman, and theoretical analyses reveal that the rational phase boundaries between the microparticles and nanowires contribute to promoting the Li storage activity. Furthermore, a 16.0 cm2 all-FLIB pouch cell assembled based on the ATO/CC/OTO anode and LiNiCoMnO2 cathode coated on ATO/CC (ATO/CC/LNCM) exhibits impressive flexibility under different folding conditions, creating opportunity for the development of high areal capacity anodes in future flexible energy storage devices.

Endogenous Interfacial Mo-C/N-Mo-S Bonding Regulates the Active Mo Sites for Maximized Li+ Storage Areal Capacity.

Active sites, mass loading, and Li-ion diffusion coefficient are the benchmarks for boosting the areal capacity and storage capability of electrode materials for lithium-ion batteries. However, simultaneously modulating these criteria to achieve high areal capacity in LIBs remains challenging. Herein, MoS2 is considered as a suitable electroactive host material for reversible Li-ion storage and establish an endogenous multi-heterojunction strategy with interfacial Mo-C/N-Mo-S coordination bonding that enables the concurrent regulation of these benchmarks. This strategy involves architecting 3D integrated conductive nanostructured frameworks composed of Mo2 C-MoN@MoS2 on carbon cloth (denoted as C/MMMS) and refining the sluggish kinetics in the MoS2 -based anodes. Benefiting from the rich hetero-interface active sites, optimized Li adsorption energy, and low diffusion barrier, C/MMMS reaches a mass loading of 12.11 mg cm-2 and showcases high areal capacity and remarkable rate capability of 9.6 mAh cm-2 @0.4 mA cm-2 and 2.7 mAh cm-2 @6.0 mA cm-2 , respectively, alongside excellent stability after 500 electrochemical cycles. Moreover, this work not only affirms the outstanding performance of the optimized C/MMMS as an anode material for supercapacitors, underscoring its bifunctionality but also offers valuable insight into developing endogenous transition metal compound electrodes with high mass loading for the next-generation high areal capacity energy storage devices.

Pyoluteorin regulates the biosynthesis of 2,4-DAPG through the TetR family transcription factor PhlH in Pseudomonas protegens Pf-5.

Soil and rhizosphere bacteria act as a rich source of secondary metabolites, effectively fighting against a diverse array of pathogens. Certain Pseudomonas species harbor biosynthetic gene clusters for producing both pyoluteorin and 2,4-diacetylphloroglucinol (2,4-DAPG), which are polyketides that exhibit highly similar antimicrobial spectrum against bacteria and fungi or oomycete. A complex cross talk exists between pyoluteorin and 2,4-DAPG biosynthesis, and production of 2,4-DAPG was strongly repressed by pyoluteorin, yet the underlying mechanism is still elusive. In this study, we find that the TetR family transcription factor PhlH is involved in the cross talk between pyoluteorin and 2,4-DAPG biosynthesis. PhlH binds to a palindromic sequence within the promoter of phlG (PphlG), which encodes a C-C bond hydrolase responsible for degrading 2,4-DAPG. As a signaling molecule, pyoluteorin disrupts the PhlH-PphlG complex by binding to PhlH, leading to decreased levels of 2,4-DAPG. Proteomics data suggest that pyoluteorin regulates multiple physiological processes including fatty acid biosynthesis and transportation of taurine, siderophore, and amino acids. Our work not only reveals a novel mechanism of cross talk between pyoluteorin and 2,4-DAPG biosynthesis, but also highlights pyoluteorin's role as a messenger in the complex communication network of Pseudomonas.IMPORTANCEAntibiosis serves as a crucial defense mechanism for microbes against invasive bacteria and resource competition. These bacteria typically orchestrate the production of multiple antibiotics in a coordinated fashion, wherein the synthesis of one antibiotic inhibits the generation of another. This strategic coordination allows the bacterium to focus its resources on producing the most advantageous antibiotic under specific circumstances. However, the underlying mechanisms of distinct antibiotic production in bacterial cells remain largely elusive. In this study, we reveal that the TetR family transcription factor PhlH detects the secondary metabolite pyoluteorin and mediates the cross talk between pyoluteorin and 2,4-DAPG biosynthesis in the biocontrol strain Pseudomonas protegens Pf-5. These findings hold promise for future research, potentially informing the manipulation of these systems to enhance the effectiveness of biocontrol agents.

HMGA1 chromatin regulators induce transcriptional networks involved in GATA2 and proliferation during MPN progression.

Myeloproliferative neoplasms (MPNs) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although the actionable mechanisms driving progression remain elusive. Here, we elucidate the role of the high mobility group A1 (HMGA1) chromatin regulator as a novel driver of MPN progression. HMGA1 is upregulated in MPN, with highest levels after transformation to MF or AML. To define HMGA1 function, we disrupted gene expression via CRISPR/Cas9, short hairpin RNA, or genetic deletion in MPN models. HMGA1 depletion in JAK2V617F AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F mice, decreasing erythrocytosis, thrombocytosis, megakaryocyte hyperplasia, and expansion of stem and progenitors, while preventing splenomegaly and fibrosis within the spleen and BM. RNA-sequencing and chromatin immunoprecipitation sequencing revealed HMGA1 transcriptional networks and chromatin occupancy at genes that govern proliferation (E2F, G2M, mitotic spindle) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates most phenotypes observed with HMGA1 depletion, whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including proliferation pathways and GATA2, are activated in human MF and MPN leukemic transformation. Importantly, HMGA1 depletion enhances responses to the JAK2 inhibitor, ruxolitinib, preventing MF and prolonging survival in murine models of JAK2V617F AML. These findings illuminate HMGA1 as a key epigenetic switch involved in MPN transformation and a promising therapeutic target to treat or prevent disease progression.

The composition and function of bacterial communities in Bombyx mori (Lepidoptera: Bombycidae) changed dramatically with infected fungi: A new potential to culture Cordyceps cicadae.

Cordyceps cicadae (Hypocreales: Cordycipitaceae) is a renowned entomopathogenic fungus used as herbal medicine in China. However, wild C. cicadae resources have been threatened by heavy harvesting. We hypothesised that Bombyx mori L. (Lepidoptera: Bombycidae) could be a new alternative to cultivate C. cicadae due to the low cost of rearing. Bacterial communities are crucial for the formation of Cordyceps and for promoting the production of metabolites. To better understand the bacterial community structure associated with Cordyceps, three Claviciptaceae fungi were used to explore the pathogenicity of the silkworms. Here, fifth-instar silkworms were infected with C. cicadae, Cordyceps cateniannulata (Hypocreales: Cordycipitaceae) and Beauveria bassiana (Hypocreales: Cordycipitaceae). Subsequently, we applied high-throughput sequencing to explore the composition of bacterial communities in silkworms. Our results showed that all three fungi were highly pathogenic to silkworms, which suggests that silkworms have the potential to cultivate Cordyceps. After fungal infection, the diversity of bacterial communities in silkworms decreased significantly, and the abundance of Staphylococcus increased in mummified larvae, which may play a role in the death process when the host suffers infection by entomopathogenic fungi. Furthermore, there were high similarities in the bacterial community composition and function in the C. cicadae and C. cateniannulata infected samples, and the phylogenetic analysis suggested that these similarities may be related to the fungal phylogenetic relationship. Our findings reveal that infection with different entomopathogenic fungi affects the composition and function of bacterial communities in silkworms and that the bacterial species associated with Cordyceps are primarily host dependent, while fungal infection affects bacterial abundance.

Fine particulate matter 2.5 induces susceptibility to Pseudomonas aeruginosa infection via expansion of PD-L1high neutrophils in mice.

BACKGROUND: Exposure to PM2.5 has been implicated in a range of detrimental health effects, particularly affecting the respiratory system. However, the precise underlying mechanisms remain elusive. METHODS: To address this objective, we collected ambient PM2.5 and administered intranasal challenges to mice, followed by single-cell RNA sequencing (scRNA-seq) to unravel the heterogeneity of neutrophils and unveil their gene expression profiles. Flow cytometry and immunofluorescence staining were subsequently conducted to validate the obtained results. Furthermore, we assessed the phagocytic potential of neutrophils upon PM2.5 exposure using gene analysis of phagocytosis signatures and bacterial uptake assays. Additionally, we utilized a mouse pneumonia model to evaluate the susceptibility of PM2.5-exposed mice to Pseudomonas aeruginosa infection. RESULTS: Our study revealed a significant increase in neutrophil recruitment within the lungs of PM2.5-exposed mice, with subclustering of neutrophils uncovering subsets with distinct gene expression profiles. Notably, exposure to PM2.5 was associated with an expansion of PD-L1high neutrophils, which exhibited impaired phagocytic function dependent upon PD-L1 expression. Furthermore, PM2.5 exposure was found to increase the susceptibility of mice to Pseudomonas aeruginosa, due in part to increased PD-L1 expression on neutrophils. Importantly, monoclonal antibody targeting of PD-L1 significantly reduced bacterial burden, dissemination, and lung inflammation in PM2.5-exposed mice upon Pseudomonas aeruginosa infection. CONCLUSIONS: Our study suggests that PM2.5 exposure promotes expansion of PD-L1high neutrophils with impaired phagocytic function in mouse lungs, contributing to increased vulnerability to bacterial infection, and therefore targeting PD-L1 may be a therapeutic strategy for reducing the harmful effects of PM2.5 exposure on the immune system.

Vitamin D3 mitigates autoimmune inflammation caused by activation of myeloid dendritic cells in SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which defective T cells, immune complex deposition and other immune system alterations contribute to pathological changes of multiple organ systems. The vitamin D metabolite c is a critical immunomodulator playing pivotal roles in the immune system. Epidemiological evidence indicates that vitamin D deficiency is correlated with the severity of SLE. Our aim is to investigate the effects of 1,25(OH)2D3 (VitD3) on the activation of myeloid dendritic cells (mDCs) by autologous DNA-containing immune complex (DNA-ICs), and the effects of VitD3 on immune system balance during SLE. We purified DNA-ICs from the serum of SLE patients and isolated mDCs from normal subjects. In vitro studies showed that DNA-ICs were internalized and consumed by mDCs. VitD3 blocked the effects of DNA-ICs on RelB, IL-10 and TNF-α in mDCs. Further analysis indicated that DNA-ICs stimulated histone acetylation in the RelB promoter region, which was inhibited by VitD3. Knockdown of the histone deacetylase 3 gene (HDAC3) blocked these VitD3-mediated effects. Co-culture of mDCs and CD4+ T cells showed that VitD3 inhibited multiple processes mediated by DNA-ICs, including proliferation, downregulation of IL-10, TGF-ß and upregulation of TNF-α. Moreover, VitD3 could also reverse the effects of DNA-IC-induced imbalance of CD4+ CD127- Foxp3+ T cells and CD4+ IL17+ T cells. Taken together, our results indicated that autologous DNA-ICs stimulate the activation of mDCs in the pathogenesis of SLE, and VitD3 inhibits this stimulatory effects of DNA-ICs by negative transcriptional regulation of RelB gene and maintaining the Treg/Th17 immune cell balance. These results suggest that vitamin D may have therapeutic value for the treatment of SLE.

Radiogenomic analysis of ultrasound phenotypic features coupled to proteomes predicts metastatic risk in primary prostate cancer.

BACKGROUND: Primary prostate cancer with metastasis has a poor prognosis, so assessing its risk of metastasis is essential. METHODS: This study combined comprehensive ultrasound features with tissue proteomic analysis to obtain biomarkers and practical diagnostic image features that signify prostate cancer metastasis. RESULTS: In this study, 17 ultrasound image features of benign prostatic hyperplasia (BPH), primary prostate cancer without metastasis (PPCWOM), and primary prostate cancer with metastasis (PPCWM) were comprehensively analyzed and combined with the corresponding tissue proteome data to perform weighted gene co-expression network analysis (WGCNA), which resulted in two modules highly correlated with the ultrasound phenotype. We screened proteins with temporal expression trends based on the progression of the disease from BPH to PPCWOM and ultimately to PPCWM from two modules and obtained a protein that can promote prostate cancer metastasis. Subsequently, four ultrasound image features significantly associated with the metastatic biomarker HNRNPC (Heterogeneous nuclear ribonucleoprotein C) were identified by analyzing the correlation between the protein and ultrasound image features. The biomarker HNRNPC showed a significant difference in the five-year survival rate of prostate cancer patients (p < 0.0053). On the other hand, we validated the diagnostic efficiency of the four ultrasound image features in clinical data from 112 patients with PPCWOM and 150 patients with PPCWM, obtaining a combined diagnostic AUC of 0.904. In summary, using ultrasound imaging features for predicting whether prostate cancer is metastatic has many applications. CONCLUSION: The above study reveals noninvasive ultrasound image biomarkers and their underlying biological significance, which provide a basis for early diagnosis, treatment, and prognosis of primary prostate cancer with metastasis.

TCF7L2 acts as a molecular switch in midbrain to control mammal vocalization through its DNA binding domain but not transcription activation domain.

Vocalization is an essential medium for social signaling in birds and mammals. Periaqueductal gray (PAG) a conserved midbrain structure is believed to be responsible for innate vocalizations, but its molecular regulation remains largely unknown. Here, through a mouse forward genetic screening we identified one of the key Wnt/ß-catenin effectors TCF7L2/TCF4 controls ultrasonic vocalization (USV) production and syllable complexity during maternal deprivation and sexual encounter. Early developmental expression of TCF7L2 in PAG excitatory neurons is necessary for the complex trait, while TCF7L2 loss reduces neuronal gene expressions and synaptic transmission in PAG. TCF7L2-mediated vocal control is independent of its ß-catenin-binding domain but dependent of its DNA binding ability. Patient mutations associated with developmental disorders, including autism spectrum disorders, disrupt the transcriptional repression effect of TCF7L2, while mice carrying those mutations display severe USV impairments. Therefore, we conclude that TCF7L2 orchestrates gene expression in midbrain to control vocal production through its DNA binding but not transcription activation domain.

Narirutin Attenuates Cerebral Ischemia-Reperfusion Injury by Suppressing the TXNIP/NLRP3 Pathway.

Narirutin (Nar) is a flavonoid that is abundantly present in citrus fruits and has attracted considerable attention because of its diverse pharmacological activities and low toxicity. Here, we evaluated the preventive effects of Nar in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice and oxygen-glucose deprivation/reperfusion (OGD/R)-injured bEnd.3 cells. Pretreatment with Nar (150 mg/kg) for 7 days effectively reduced infarct volume, improved neurological deficits, and significantly inhibited neuronal death in the hippocampus and cortex in MCAO/R-injured mice. Moreover, anti-apoptotic effects of Nar (50 µM) were observed in OGD/R-injured bEnd.3 cells. In addition, Nar pre-administration regulated blood-brain barrier function by increasing tight junction-related protein expression after MCAO/R and OGD/R injury. Nar also inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation by reducing the expression of thioredoxin-interacting protein (TXNIP) in vivo and in vitro. Taken together, these results provide new evidence for the use of Nar in the prevention and treatment of ischemic stroke.

Serum sCD25 is an indicator for rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: CD25 (IL-2Rα) is one of IL-2 receptor's polypeptide subunits, and its soluble form is increased in patients with various inflammatory or autoimmune diseases. This study aimed to evaluate the clinical correlation of serum soluble CD25 (sCD25) with interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. METHODS: 294 RA patients, including 72 in the discovery cohort (15 patients with ILD, 57 patients without ILD), 222 in the validation cohort (41 patients with ILD and 181 patients without ILD), and 58 healthy controls (HCs) were recruited. High-resolution computed tomography (HRCT) scan provided evidence and patterns of RA-ILD. Serum sCD25 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory data were recorded and the association with sCD25 was also analysed. RESULTS: In the discovery cohort, 16 RA-related molecules including cytokines, chemokines and functional soluble cell surface proteins were investigated. The results showed that sCD25 was significantly higher in RA-ILD than in RA-no-ILD group (p=0.004). ROC analysis also showed RA-ILD was discriminated with RA-no-ILD by sCD25 (AUC=0.695, 95% CI=0.541-0.849). Logistics regression demonstrated that sCD25 was one of the risk factors of RA-ILD. This result was further confirmed in validation cohort (p<0.001). According to the cut-off value in the discovery cohort, the sensitivity and specificity of sCD25 in RA-ILD were 51.2%, 77.3%, respectively. Compared with RA-no-ILD, serum level of sCD25 was also higher in different HRCT patterns including UIP, NSIP and RA-ILA. The ROC curves revealed sCD25 as diagnostic marker in UIP, NSIP and RA-ILA (with AUCs of 0.730, 0.761, and 0. 694, respectively, p<0.05). The result indicated that sCD25 was a biomarker for RA-ILD subtypes. Although sCD25 was not correlated with HRCT scores, it was significantly higher in consolidation pattern by HRCT. CONCLUSIONS: sCD25 was significantly elevated in RA-ILD (including UIP, NSIP and RA-ILA) compared to RA-no-ILD and HCs, which supports their value as a potential biomarker in RA-ILD screening and assessment.

Role of Platelet/Lymphocyte, Neutrophil/Lymphocyte, and Interleukin-37/Interleukin-17 Ratios in the Occurrence and Treatment of Rheumatoid Arthritis.

This study was designed to investigate the correlation of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and interleukin (IL)-37/IL-17 ratio with the incidence/treatment of rheumatoid arthritis (RA). Firstly, fifty-eight patients with RA treated at the first affiliated hospital of Xinjiang Medical University from January 2018 to January 2019 were selected as the RA group; forty-nine healthy volunteers were enrolled in the control group. RA patients were treated with disease-modifying anti-rheumatic drugs (DMARDs). Next, the NLR, PLR, IL-37, IL-17 and 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) were deleted in two groups. Subsequently, Spearman correlation analysis was adopted for the correlations of various indicators before and after treatment in two groups. According to the analysis results, the levels of NLR, PLR, IL-37, and IL-17 before treatment in the RA group were higher than those in the control group (P < .05), but the difference in the IL-37/IL-17 level between the two groups was not significant (P > .05). After treatment, NLR, PLR, and IL-37/IL-17 levels were significantly reduced in RA patients (P < .05). NLR and PLR were significantly positively correlated with DAS28-ESR, ESR and C-reactive protein (CRP), of which represented the disease activity of RA. NLP was strongly correlated with IL-37/IL-17. Collectively, NLR, PLR, IL-37, and IL-17 are closely related to the occurrence of RA. In addition, NLR and IL-37/IL-17 are more suitable than PLR in reflecting the therapeutic effect. Therefore, IL-37/IL-17 can be considered as a new indicator for reflecting the treatment effectiveness of RA.

Targeting CDK12 obviates the malignant phenotypes of colorectal cancer through the Wnt/ß-catenin signaling pathway.

Colorectal cancer (CRC) is the second most common cause of cancer-related mortality and lies third in terms of morbidity due to the limited number of effective druggable targets. Since cancer stem cells (CSCs) are considered to be one of the roots of tumorigenesis, outgrowth and metastasis, targeting CSCs may be a promising strategy to reverse the malignant phenotypes of CRC. Cyclin-dependent kinase 12 (CDK12) has been reported to be involved in the self-renewal of CSCs in various cancers, rendering it an attractive potential target against CSCs to consequently limit the malignant phenotypes in CRC. In the present study, we aimed to investigate whether CDK12 can be a potential therapeutic target for patients with CRC and clarify its underlying mechanism. We found that CDK12, but not CDK13 is required for CRC survival. CDK12 was found to drive tumor initiation according to the colitis-associated colorectal cancer mouse model. In addition, CDK12 promoted CRC outgrowth and hepatic metastasis in the subcutaneous allograft and liver metastasis mouse models, respectively. In particular, CDK12 was able to induce the self-renewal of CRC CSCs. Mechanistically, the activation of Wnt/ß-catenin signaling mediated by CDK12 was implicated in stemness regulation and malignant phenotype maintenance. These findings indicate that CDK12 is a candidate druggable target in CRC. Therefore, the CDK12 inhibitor SR-4835 warrants clinical trial testing in patients with CRC.

Translation, cultural adaptation, and validation of the Chinese standardized outcomes in nephrology-hemodialysis fatigue (C-SONG-HD fatigue) scale: a study of Chinese patients undergoing hemodialysis.

OBJECTIVE: This study aimed to translate and culturally adapt the standardized outcomes in nephrology-hemodialysis fatigue (SONG-HD fatigue) scale and to assess the psychometric properties of the Chinese version of the SONG-HD fatigue (C-SONG-HD fatigue) scale. METHODS: Forward and back translations were used to translate the SONG-HD fatigue scale into Chinese. We used the C-SONG-HD fatigue scale to survey Chinese patients undergoing hemodialysis (HD) in China. We examined the distribution of responses and floor and ceiling effects. Cronbach's alpha and McDonald's omega coefficient, intraclass coefficients, and Spearman correlations were used to assess internal consistency reliability, test-retest reliability, and convergent validity, respectively. Responsiveness was also evaluated. RESULTS: In total, 489 participants across southeast China, northwest China, and central China completed the study. The C-SONG-HD fatigue scale had good internal consistency (Cronbach's alpha coefficient 0.861, omega coefficient 0.916), test-retest reliability (intraclass correlation coefficient 0.695), and convergent validity (Spearman correlation 0.691). The analysis of all first-time HD patients did not show notable responsiveness, and only patients with temporary vascular access had good responsiveness with an effect size (ES) of 0.54, a standardized response mean (SRM) of 0.85, and a standard error of measurement (SEM) of 0.77. CONCLUSION: The Chinese version of the SONG-HD fatigue scale showed satisfactory reliability and validity in patients undergoing hemodialysis (HD) in China. It could be used as a tool to measure the fatigue of Chinese HD patients.

Clear cell hidradenoma of the breast with MAML2 gene rearrangement.

Clear cell hidradenoma is a rare benign tumor of the breast, its origin and pathogenesis are controversial. We have experienced a case of breast clear cell hidradenoma with mastermind like transcriptional coactivator 2 (MAML2) gene rearrangement. The patient found a painless mass with a hard texture in the left breast areola without nipple discharge. Microscopically, the tumor was cystic and solid, locally arranged in a glandular structure, covered by single cuboidal cells; it was composed of clear cells, epidermoid cells, and basaloid cells; there were no necrosis or mitotic figures. Immunohistochemical staining showed that the tumor cells positively expressed low-molecular cytokeratin 7, low-molecular cytokeratins (Cam5.2), high-molecular cytokeratin 5/6, cytokeratin 14, CD117, and p63; and did not express calponin, and smooth muscle myosin heavy chain. The cuboidal cells were positive for SOX10 but negative for p63. Additionally, periodic acid-Schiff reaction showed purple-red granules in the tumor cytoplasm, but Alcian blue staining showed no blue mucus in the cytoplasm. The split signals of MAML2 gene were detected by fluorescence in situ hybridization. Subtle histological and immunophenotypical differences may help to distinguish breast clear cell hidradenoma from common breast tumors. Furthermore, the MAML2 gene rearrangement may be a molecular genetic characteristic of breast clear cell hidradenoma.

The Impact of Serum Uric Acid Levels on Hypertensive Disorders of Pregnancy in Advanced Maternal Age Women: A Retrospective Study from a Single Center in China.

BACKGROUND In many countries, including China, women are delaying pregnancy until later in life; therefore, hypertensive disorders of pregnancy (HDP) are increasing. This retrospective study from a single center in China aimed to evaluate the association between serum uric acid (SUA) levels and HDP in 288 women of advanced maternal age >35 years. MATERIAL AND METHODS A total of 780 pregnant women of advanced maternal age were included in the study - 288 were had HDP (including gestational hypertension and preeclampsia) and 492 had normal blood pressure using 1: 2 (84: 168) propensity score matching. SUA (collected before 20 weeks' gestation) and HDP incidence in advanced maternal age women were assessed using multivariate logistic modeling and 3 propensity score-based methods. RESULTS Median patient age was 37 years. The risk of developing HDP increases with higher SUA (30.19% vs 13.65%, P<0.001). In the PS-matched cohort, the risk ratio (OR) for HDP with high uric acid after adjusting for confounders was 2.88 (95% CI: 1.44-5.75, P=0.0027). It has been demonstrated that high uric acid is strongly associated with HDP incidence in both the crude population (OR=3.43, 95% CI: 2.01-4.66, P<0.0001) and the weighted cohorts (OR=3.62, 95% CI: 2.81-4.66, P<0.0001). As a successive variable, after adjusting for the clinical confounders, a 1-SD increase in SUA was related to a 135% increased risk of HDP (OR=2.35; 95% CI: 1.57-3.50; P<0.0001) based on the fully adjusted model. There were similar conclusions in the sensitivity analysis. CONCLUSIONS There was a significant association between SUA and HDP in women of advanced maternal age, supporting the importance of early detection of SUA in pregnant women.

Dietary knowledge-attitude-practice status in hemodialysis patients: a latent profile analysis.

BACKGROUND: Hemodialysis patients require a reasonable dietary intake to manage their disease progression effectively. However, there is limited research on these patients' overall dietary knowledge, attitude, and practice (KAP) status. This study aimed to investigate the dietary KAP status and latent profiles in hemodialysis patients and identify sociodemographic and disease-related factors associated with these profiles and dietary practice. METHODS: A multicenter cross-sectional study involving 425 hemodialysis patients was conducted. A dietary KAP questionnaire in hemodialysis patients was used to evaluate the dietary KAP of the patients. A structural equation model was employed to analyze the correlations between dietary knowledge, attitude, and practice. Multiple linear regression analysis was used to identify factors associated with dietary practice scores. Latent profile analysis was conducted to determine the latent profiles of dietary KAP, and binary logistic regression was used to explore the sociodemographic and disease-related characteristics associated with each KAP profile in hemodialysis patients. RESULTS: The normalized average scores for dietary knowledge, attitude, and practice in hemodialysis patients were 0.58, 0.82, and 0.58, respectively. The structural equation model revealed significant positive correlations between dietary knowledge and attitude, and attitude and practice. Attitude played an indirect effect between knowledge and practice. Gender, cerebrovascular disease, and dietary attitude scores were identified as independent influencing factors for dietary practice scores. Two dietary KAP profiles were developed: a profile with general knowledge and attitude but low practice (40.2%) and a profile with general knowledge and attitude and high practice (59.8%). Binary logistic regression analysis indicated gender and monthly income per household significantly predicted membership in each KAP profile. CONCLUSIONS: The dietary practice of hemodialysis patients requires improvement. It is necessary to develop more individualized dietary interventions for these patients. Further exploration is needed to understand the motivation of patients to change their dietary behavior.

Comparison of remimazolam tosilate and propofol during induction and maintenance of general anesthesia in patients undergoing laparoscopic cholecystectomy: a prospective, single center, randomized controlled trial.

BACKGROUND: Remimazolam tosilate (RT) is a new, ultrashort-acting benzodiazepine. Here, we investigated the efficacy and safety of RT for general anesthesia in patients undergoing Laparoscopic Cholecystectomy (LC). METHODS: In this study, 122 patients undergoing laparoscopic cholecystectomy were randomly allocated to receive either remimazolam tosilate (Group RT) or propofol group (Group P). RT was administered as a slow bolus of 0.3 mg kg- 1 for induction, followed by 1.0-2.0 mg kg- 1 h- 1 for maintenance of general anesthesia. Propofol was started at 2 mg kg- 1 and followed by 4-10 mg kg- 1 h- 1 until the end of surgery. The primary outcome was the time to bispectral index (BIS) ≤ 60. The secondary outcome included the time to loss of consciousness (LoC), and the time to extubation. Adverse events were also assessed. RESULTS: A total of 112 patients were recruited for study participation. Among them, the time to BIS ≤ 60 in Group RT was longer than that in Group P (Group RT: 89.3 ± 10.7 s; Group P: 85.9 ± 9.7 s, P > 0.05). While the time to LoC comparing remimazolam and propofol showed no statistical significance (Group RT: 74.4 ± 10.3 s; Group P: 74.7 ± 9.3 s, P > 0.05). The time to extubation in Group RT was significantly longer than that in Group P (Group RT: 16.0 ± 2.6 min; Group P: 8.8 ± 4.3 min, P < 0.001). Remimazolam tosilate had more stable hemodynamics and a lower incidence of hypotension during general anesthesia. CONCLUSIONS: Remimazolam tosilate can be safely and effectively used for general anesthesia in patients undergoing Laparoscopic Cholecystectomy. It maintains stable hemodynamics during induction and maintenance of general anesthesia compared with propofol. Further studies are needed to validate the findings. TRIAL REGISTRATION: Chictr.org.cn ChiCTR2300071256 (date of registration: 09/05/2023).