Integrating Multiple Bacterial Phenotypes and Bayesian Network for Analyzing Health Risks of Pathogens in Plastisphere.

Plastic pollution represents a critical threat to soil ecosystems and even humans, as plastics can serve as a habitat for breeding and refuging pathogenic microorganisms against stresses. However, evaluating the health risk of plastispheres is difficult due to the lack of risk factors and quantification model. Here, DNA sequencing, single-cell Raman-D2O labeling, and transformation assay were used to quantify key risk factors of plastisphere, including pathogen abundance, phenotypic resistance to various stresses (antibiotic and pesticide), and ability to acquire antibiotic resistance genes. A Bayesian network model was newly introduced to integrate these three factors and infer their causal relationships. Using this model, the risk of pathogen in the plastisphere is found to be nearly 3 magnitudes higher than that in free-living state. Furthermore, this model exhibits robustness for risk prediction, even in the absence of one factor. Our framework offers a novel and practical approach to assessing the health risk of plastispheres, contributing to the management of plastic-related threats to human health.

The Effect of Physical Therapy on Somatosensory Tinnitus.

Objective: The objective of this work was to assess the effect of physical therapy in patients with somatosensory tinnitus (ST) and explore the influence of physical therapy on clinical variables obtained before treatment. Methods: A total of 43 patients with ST were randomized to the immediate-start group (n = 20) and delayed-start group (n = 23). All patients received physical therapy for 1 week (seven sessions). Each session lasted 60 min. The Visual Analogue Scale (VAS), Tinnitus Handicap Inventory (THI), and numerical pain rating scale (NPRS) scores were documented at baseline and after treatment (week 1) for all patients. For subjects in the immediate-start group, the THI, VAS, and NPRS scores were measured after therapy (weeks 6, 9, and 12, respectively). Medical history characteristic functional activity scale (HCFA) scores were measured at baseline to assess the association between somatic symptoms and tinnitus. Results: At week 1, VAS, THI, and NPRS scores of patients in the immediate-start group were improved by 1.25 ± 1.59, 11.10 ± 15.10, and 0.95 ± 1.54 points, respectively, and were significantly higher than those in the delayed-start group (p < 0.05). The change in VAS, THI, and NPRS scores in the treatment group was significantly positively correlated with the scores of the HCFA before treatment (r = 0.786, p < 0.001; r = 0.680, p = 0.001; r = 0.796, p < 0.001). There was no significant difference in THI, VAS, and NPRS scores among patients in the immediate-start group between weeks 1, 6, 9, and 12 after treatment (p > 0.05). Conclusions: Although more participants were necessary in the further study, the study implies that physical therapy can reduce physical pain, improve tinnitus symptoms, and quality of life in ST patients without hearing loss, and the short-term curative effect is stable, especially for tinnitus patients with clear somatic symptoms.

Role of gut microbiota in the pathogenesis of castration-resistant prostate cancer: a comprehensive study using sequencing and animal models.

CRPC remains a significant challenge in prostate cancer research. We aimed to elucidate the role of gut microbiota and its specific mechanisms in CRPC using a multidisciplinary approach. We analyzed 16S rRNA sequencing data from mouse fecal samples, revealing substantial differences in gut microbiota composition between CRPC and castration-sensitive prostate cancer mice, particularly in Firmicutes and Bacteroidetes. Functional analysis suggested different bacteria may influence CRPC via the α-linolenic acid metabolism pathway. In vivo, experiments utilizing mouse models and fecal microbiota transplantation (FMT) demonstrated that FMT from healthy control mice could decelerate tumor growth in CRPC mice, reduce TNF-α levels, and inhibit the activation of the TLR4/MyD88/NF-κB signaling pathway. Transcriptome sequencing identified crucial genes and pathways, with rescue experiments confirming the gut microbiota's role in modulating CRPC progression through the TLR4/MyD88/NF-κB pathway. The activation of this pathway by TNF-α has been corroborated by in vitro cell experiments, indicating its role in promoting prostate cancer cell proliferation, migration, and invasion while inhibiting apoptosis. Gut microbiota dysbiosis may promote CRPC development through TNF-α activation of the TLR4/MyD88/NF-κB signaling pathway, potentially linked to α-linolenic acid metabolism.

Pleural carbohydrate antigen 50 and malignant pleural effusion: a prospective, double-blind diagnostic accuracy test.

Background: Serum carbohydrate antigen 50 (CA50) is an auxiliary diagnostic marker for various solid tumors, but it remains unclear whether CA50 in pleural fluid can assist in the diagnosis of malignant pleural effusion (MPE). This study aimed to evaluate the diagnostic accuracy of pleural fluid CA50 for MPE in pleural effusion patients with undetermined causes. Methods: This study prospectively recruited pleural effusion patients with undetermined causes who visited the Affiliated Hospital of Inner Mongolia Medical University between September 2018 and July 2021. We measured pleural fluid CA50 level with an electrochemiluminescence assay. We analyzed the diagnostic accuracy of CA50 and carcinoembryonic antigen (CEA) for MPE with the receiver operating characteristic (ROC) curve. The net benefits of CA50 and CEA were analyzed using the decision curve analysis (DCA). Results: We enrolled 66 MPEs and 87 benign pleural effusions (BPEs). MPE patients had significantly higher CA50 and CEA than BPE patients. The area under the ROC curve (AUC) of CA50 was 0.72 (95% CI: 0.63-0.80). CA50 had a sensitivity of 0.30 (95% CI: 0.19-0.41) and a specificity of 1.00 (95% CI: 1.00-1.00) at the threshold of 15 IU/mL. The decision curve of CA50 was above the reference line at the calculated risk probability of between 0.30 and 1.00. Venn diagram indicated that some patients with low CEA (<50 or <150 ng/mL) and/or negative cytology can be identified by positive CA50 (>15 IU/mL). Conclusions: Pleural fluid CA50 has moderate accuracy and net benefit for detecting MPE. CA50 >15 IU/mL can be used to diagnose MPE. The combination of CA50 and CEA improves the diagnostic sensitivity for MPE.

Sewage Sludge Promotes the Accumulation of Antibiotic Resistance Genes in Tomato Xylem.

Xylem serves as a conduit linking soil to the aboveground plant parts and facilitating the upward movement of microbes into leaves and fruits. Despite this potential, the composition of the xylem microbiome and its associated risks, including antibiotic resistance, are understudied. Here, we cultivated tomatoes and analyzed their xylem sap to assess the microbiome and antibiotic resistance profiles following treatment with sewage sludge. Our findings show that xylem microbes primarily originate from soil, albeit with reduced diversity in comparison to those of their soil microbiomes. Using single-cell Raman spectroscopy coupled with D2O labeling, we detected significantly higher metabolic activity in xylem microbes than in rhizosphere soil, with 87% of xylem microbes active compared to just 36% in the soil. Additionally, xylem was pinpointed as a reservoir for antibiotic resistance genes (ARGs), with their abundance being 2.4-6.9 times higher than in rhizosphere soil. Sludge addition dramatically increased the abundance of ARGs in xylem and also increased their mobility and host pathogenicity. Xylem represents a distinct ecological niche for microbes and is a significant reservoir for ARGs. These results could be used to manage the resistome in crops and improve food safety.

Serum IgA as a Prognostic Beacon: Anticipating Systemic Therapy Efficacy in Metastatic Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) therapy has revolutionized the treatment landscape for metastatic clear cell renal cell carcinoma (mccRCC); however, the absence of effective biomarkers poses a challenge in predicting the efficacy of these regimens. This study aims to explore the predictive and prognostic value of serum immunoglobulin A (IgA) in mccRCC patients undergoing IO-TKI therapy. METHODS: Ninety-six mccRCC patients treated with IO-TKI therapy from 2019 to 2023 were enrolled and serum IgA levels were assessed at the pretreatment baseline and after 3 months of treatment. RESULTS: Notably, baseline levels of IgA showed no correlation with the objective response rate. However, patients achieving complete or partial responses exhibited a remarkable decrease in IgA levels, while those with stable or progressive disease displayed an increase in IgA levels after 3 months of treatment. Furthermore, the dynamic alteration in IgA levels after 3 months of treatment demonstrated predictive value for both progression-free survival (PFS) and overall survival (OS). The time-dependent receiver operating characteristic curves exhibited outstanding performance in predicting PFS (AUC 0.793) and OS (AUC 0.738). CONCLUSION: Taken together, this study demonstrates that dynamic alteration of serum IgA after 3 months of treatment was significantly correlated with prognosis and therapeutic efficacy in mccRCC patients.

Evolution Characterization and Pathogenicity of an NADC34-like PRRSV Isolated from Inner Mongolia, China.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a pathogen that causes severe abortions in sows and high piglet mortality, resulting in huge economic losses to the pig industry worldwide. The emerging and novel PRRSV isolates are clinically and biologically important, as there are likely recombination and pathogenic differences among PRRSV genomes. Furthermore, the NADC34-like strain has become a major epidemic strain in some parts of China, but the characterization and pathogenicity of the latest strain in Inner Mongolia have not been reported in detail. In this study, an NADC34-like strain (CHNMGKL1-2304) from Tongliao City, Inner Mongolia was successfully isolated and characterized, and confirmed the pathogenicity in pigs. The phylogenetic tree showed that this strain belonged to sublineage 1.5 and had high homology with the strain JS2021NADC34. There is no recombination between CHNMGKL1-2304 and any other domestic strains. Animal experiments show that the CHNMGKL1-2304 strain is moderately virulent to piglets, which show persistent fever, weight loss and high morbidity but no mortality. The presence of PRRSV nucleic acids was detected in both blood, tissues, nasal and fecal swabs. In addition, obvious pathological changes and positive signals were observed in lung, lymph node, liver and spleen tissues when subjected to hematoxylin-eosin (HE) staining and immunohistochemistry (IHC). This report can provide a basis for epidemiological investigations and subsequent studies of PRRSV.

Effectiveness of the acute stroke care map program in reducing in-hospital delay for acute ischemic stroke in a Chinese urban area: an interrupted time series analysis.

Background: Timely intravenous thrombolysis (IVT) is crucial for improving outcomes in acute ischemic stroke (AIS) patients. This study evaluates the effectiveness of the Acute Stroke Care Map (ASCaM) initiative in Shenyang, aimed at reducing door-to-needle times (DNT) and thus improving the timeliness of care for AIS patients. Methods: An retrospective cohort study was conducted from April 2019 to December 2021 in 30 hospitals participating in the ASCaM initiative in Shenyang. The ASCaM bundle included strategies such as EMS prenotification, rapid stroke triage, on-call stroke neurologists, immediate neuroimaging interpretation, and the innovative Pre-hospital Emergency Call and Location Identification feature. An interrupted time series analysis (ITSA) was used to assess the impact of ASCaM on DNT, comparing 9 months pre-intervention with 24 months post-intervention. Results: Data from 9,680 IVT-treated ischemic stroke patients were analyzed, including 2,401 in the pre-intervention phase and 7,279 post-intervention. The ITSA revealed a significant reduction in monthly DNT by -1.12 min and a level change of -5.727 min post-ASCaM implementation. Conclusion: The ASCaM initiative significantly reduced in-hospital delays for AIS patients, demonstrating its effectiveness as a comprehensive stroke care improvement strategy in urban settings. These findings highlight the potential of coordinated care interventions to enhance timely access to reperfusion therapies and overall stroke prognosis.

Acquisition of different transcriptional shear mRNA and biological function of porcine interleukin 18 binding protein in PRRSV infection.

Interleukin-18 binding protein (IL-18BP), a natural regulator molecule of the pro-inflammatory cytokine interleukin-18 (IL-18), plays an important role in regulating the expression of the cellular immunity factor interferon-γ (IFN-γ). In a previous RNA-seq analysis of porcine alveolar macrophages (PAM) infected with the TIM and TJ strains of porcine reproductive and respiratory syndrome virus (PRRSV), we unexpectedly found that the mRNA expression of porcine interleukin 18-binding protein (pIL-18BP) in PAM cells infected with the TJM strain was significantly higher than that infected with the TJ strain. Studies have shown that human interleukin-18 binding protein (hIL-18bp) plays an important role in regulating cellular immunity in the course of the disease. However, there is a research gap on pIL-18BP. At the same time, PRRSV infection in pigs triggers weak cellular immune response problems. To explore the expression and the role of pIL-18BP in the cellular immune response induced by PRRSV, we strived to acquire the pIL-18BP gene from PAM or peripheral blood mononuclear cell (PBMC) with RT-PCR and sequencing. Furthermore, pIL-18BP and pIL-18 were both expressed prokaryotically and eukaryotically. The colocalization and interaction based on recombinant pIL-18BP and pIL-18 on cells were confirmed in vitro. Finally, the expression of pIL-18BP, pIL-18, and pIFN-γ was explored in pigs with different PRRSV infection states to interpret the biological function of pIL-18BP in vivo. The results showed there were five shear mutants of pIL-18BP. The mutant with the longest coding region was selected for subsequent functional validation. First, it was demonstrated that TJM-induced pIL-18BP mRNA expression was higher than that of TJ. A direct interaction between pIL-18BP and pIL-18 was confirmed through fluorescence colocalization, bimolecular fluorescent complimentary (BIFC), and co-immunoprecipitation (CO-IP). pIL-18BP also can regulate pIFN-γ mRNA expression. Finally, the expression of pIL-18BP, pIL-18, and pIFN-γ was explored in different PRRSV infection states. Surprisingly, both mRNA and protein expression of pIL-18 were suppressed. These findings fill the gap in understanding the roles played by pIL-18BP in PRRSV infection and provide a foundation for further research.IMPORTANCEPRRSV-infected pigs elicit a weak cellular immune response and the mechanisms of cellular immune regulation induced by PRRSV have not yet been fully elucidated. In this study, we investigated the role of pIL-18BP in PRRSV-induced immune response referring to the regulation of human IL-18BP to human interferon-gamma (hIFN-γ). This is expected to be used as a method to enhance the cellular immune response induced by the PRRSV vaccine. Here, we mined five transcripts of the pIL-18BP gene and demonstrated that it interacts with pIL-18 and regulates pIFN-γ mRNA expression. Surprisingly, we also found that both mRNA and protein expression of pIL-18 were suppressed under different PRRSV strains of infection status. These results have led to a renewed understanding of the roles of pIL-18BP and pIL-18 in cellular immunity induced by PRRSV infection, which has important implications for the prevention and control of PRRS.

Aerobic Anoxygenic Phototrophic Bacteria in the Marine Environments Revealed by Raman/Fluorescence-Guided Single-Cell Sorting and Targeted Metagenomics.

Aerobic anoxygenic phototrophic bacteria (AAPB) contribute profoundly to the global carbon cycle. However, most AAPB in marine environments are uncultured and at low abundance, hampering the recognition of their functions and molecular mechanisms. In this study, we developed a new culture-independent method to identify and sort AAPB using single-cell Raman/fluorescence spectroscopy. Characteristic Raman and fluorescent bands specific to bacteriochlorophyll a (Bchl a) in AAPB were determined by comparing multiple known AAPB with non-AAPB isolates. Using these spectroscopic biomarkers, AAPB in coastal seawater, pelagic seawater, and hydrothermal sediment samples were screened, sorted, and sequenced. 16S rRNA gene analysis and functional gene annotations of sorted cells revealed novel AAPB members and functional genes, including one species belonging to the genus Sphingomonas, two genera affiliated to classes Betaproteobacteria and Gammaproteobacteria, and function genes bchCDIX, pucC2, and pufL related to Bchl a biosynthesis and photosynthetic reaction center assembly. Metagenome-assembled genomes (MAGs) of sorted cells from pelagic seawater and deep-sea hydrothermal sediment belonged to Erythrobacter sanguineus that was considered as an AAPB and genus Sphingomonas, respectively. Moreover, multiple photosynthesis-related genes were annotated in both MAGs, and comparative genomic analysis revealed several exclusive genes involved in amino acid and inorganic ion metabolism and transport. This study employed a new single-cell spectroscopy method to detect AAPB, not only broadening the taxonomic and genetic contents of AAPB in marine environments but also revealing their genetic mechanisms at the single-genomic level.

Shape-Selective Alkylation of Toluene with Ethanol over a Twin Intergrowth Structured ZSM-5: Modulation of Acidity and Diffusivity via Interface Engineering.

ZSM-5 zeolites with modified acidity and diffusivity are employed as catalysts for the shape-selective alkylation of toluene with ethanol to para-ethyltoluene (p-ET). To avoid pore blocking and loss of active sites caused by traditional methods of enhancing para-selectivity using modifiers, here, we constructed twin intergrowth structured ZSM-5 (Z5-T), achieving modulation of the inherent acidity and diffusivity through interface engineering. The characterization results demonstrate that due to the intergrowth interface, the Z5-T catalyst forms more inherent Lewis acid sites and also renders more sinusoidal channels opened to the surface. Z5-T with an appropriate acidity and enhanced shape-selectivity inhibits side reactions such as isomerization and coke formation, demonstrating improved p-ET selectivity (>90%) and catalytic stability (>200 h) in the alkylation of toluene with ethanol.

Restructuring Surface Lewis Pairs of FAU Zeolite through N Doping for Boosting the Toluene Side-Chain Alkylation Performance.

Toluene side-chain alkylation with methanol for the styrene monomer formation remains a great challenge. An optimal synergy between acidic and basic sites on zeolites is required for an efficient catalysis process. It is important to modulate the surface Lewis acid-base pairs precisely. Herein, we report a strategy to restructure the surface Lewis acid-base pairs in cesium-modified X zeolite (CsX) by N doping. In the process of toluene side-chain alkylation, the CsX-BN-600 catalyst, where N species is doped into the framework of the X zeolite, exhibits 2.7 times the styrene formation rate and a much better selectivity of 85.7% in comparison to the parent CsX of 70.1% selectivity to styrene at the same reaction conditions. The introduction of N species into zeolites acts as a new Lewis base site and optimizes the Lewis sites due to its ability of electron donation. Meanwhile, the frustrated Lewis pair (FLP) between the deprotonated framework nitrogen in X zeolite and positively polarized C species in the side-chain alkylation reaction is created. Furthermore, the N doping contributes to the generation of the active intermediates of HCOO* and H3CO*. These reasons favor the superiority of the catalyst through N doping.

Lysine methyltransferase SMYD2 enhances androgen receptor signaling to modulate CRPC cell resistance to enzalutamide.

Androgen receptors (ARs) play key roles in prostate cancer (PCa) progression and castration-resistant prostate cancer (CRPC) resistance to drug therapy. SET and MYND domain containing protein 2 (SMYD2), a lysine methyltransferase, has been reported to promote tumors by transcriptionally methylating important oncogenes or tumor repressor genes. However, the role of SMYD2 in CRPC drug resistance remains unclear. In this study, we found that SMYD2 expression was significantly upregulated in PCa tissues and cell lines. High SMYD2 expression indicated poor CRPC-free survival and overall survival in patients. SMYD2 knockdown dramatically inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) potential of 22Rv1 and C4-2 cells. Conversely, ectopic overexpression of SMYD2 promoted these effects in 22Rv1 and C4-2 cells. Mechanistically, SMYD2 methylated and phosphorylated ARs to affect AR ubiquitination and proteasome degradation, which further alters the AR transcriptome in CRPC cells. Importantly, the SMYD2 inhibitor AZ505 had a synergistic therapeutic effect with enzalutamide in CRPC cells and mouse models; however, it could also re-sensitize resistant CRPC cells to enzalutamide. Our findings demonstrated that SMYD2 enhances the methylation and phosphorylation of ARs and affects AR ubiquitination and proteasome degradation to modulate CRPC cell resistance to enzalutamide, indicating that SMYD2 serves as a crucial oncogene in PCa and is an ideal therapeutic target for CRPC.

Long-term seawall barriers lead to the formation of an urban coastal lagoon with increased antibiotic resistome.

Urbanization has increased the spread of antibiotic resistance genes (ARGs) impacting urban aquatic ecosystems and threatening human health. However, an overview of the antibiotic resistome in artificial coastal lagoons formed by coastal seawall construction is unclear. This study investigated the resistome of sediment in a coastal lagoon, established for over 60 years and found that the composition of the resistome in the lagoon sediments associated with the seawall significantly differed from that of marine sediment external to the seawall. Moreover, the diversity, number, relative abundance, and absolute abundance of the antibiotic resistome in the lagoon sediments were significantly higher compared to marine sediment. Network analyses revealed that more co-occurrences were found in lagoon sediment between bacterial communities, ARGs and mobile genetic elements (MGEs) than in marine sediments, suggesting that bacteria in lagoon sediments may be associated with multiple antibiotic resistances. Random forest and structural equation models showed that an increase in the absolute abundance of MGEs had a concomitant effect on the absolute abundance and diversity of ARGs, whereas increasing salinity decreased the absolute abundance of ARGs. This study provides a basis to assess the risk of resistome diffusion and persistence in an artificial coastal lagoon.

Functional Connectivity Alterations and Molecular Characterization of the Anterior Cingulate Cortex in Tinnitus Pathology without Hearing Loss.

Compared with individuals with hearing loss, tinnitus patients without hearing loss have more psychological or emotional problems. Tinnitus is closely associated to abnormal metabolism and function of the limbic system, a key brain region for emotion experience, but the underlying molecular mechanism remains unknown. Using whole-brain microvasculature dynamics imaging, the anterior cingulate cortex (ACC) is identified as a key brain region of limbic system involve in the onset of salicylate-induced tinnitus in mice. In the tinnitus group, there is enhanced purine metabolism, oxidative phosphorylation, and a distinct pattern of phosphorylation in glutamatergic synaptic pathway according to the metabolome profiles, quantitative proteomic, and phosphoproteomic data of mice ACC tissue. Electroencephalogram in tinnitus patients with normal hearing thresholds show that the functional connectivity between pregenual anterior cingulate cortex and the primary auditory cortex is significantly increased for high-gamma frequency band, which is positively correlated with the serum glutamate level. These findings indicate that ACC plays an important role in the pathophysiology of tinnitus by interacting with the primary auditory cortex and provide potential molecular targets in the ACC for tinnitus treatment.

Prognosis and Clinicopathological Characters of Adult TFEB-Altered Renal Cell Carcinoma: A Single Center Experience of 18 Cases.

INTRODUCTION: TFEB-altered renal cell carcinoma (RCC) is a rare entity characterized by the rearrangement of the TFEB gene or TFEB amplified. The therapeutic implications and long-term survival of TFEB-altered RCC remain unclear, especially for metastatic cases. MATERIALS AND METHODS: The current study initially enrolled 7604 consecutive RCC patients at our center and a total of 248 patients were selected for FISH and immunohistochemistry (IHC) analysis. Eventually, eighteen TFEB-altered RCC patients were identified. We then reported the clinical, morphological, IHC, and radiological features of these cases. RESULTS: The median age at initial diagnosis was 45 years, ranging from 18 years to 66 years. The majority of the TFEB-altered RCC patients were male (61.1%), with localized disease (T1-2N0M0, 77.8%). The median split TFEB fluorescent signal was 24%, ranging from 15%-80%. The morphological characteristics of TFEB-altered RCC were variable, with acinar, papillary, solid, or nest patterns. IHC and magnetic resonance imaging features of TFEB-altered RCC were nonspecific. Nine patients with localized disease received partial nephrectomy and five patients with localized disease received radical nephrectomy. During the median follow-up of 67 months, no signs of recurrence or metastasis were found in these patients. Two patients had distant metastasis and received axitinib plus PD-1 immunotherapy. One of them died at 40-month follow-up and another still alive at 88-month follow-up. CONCLUSION: TFEB-altered RCC is an extremely rare variant, exhibited mixed morphological characteristics. The radiological feature lack specificity, resembling clear cell RCC or papillary RCC. Genetic analyses including FISH analysis is crucial in the diagnosis of TFEB-altered RCC. For localized TFEB-altered RCC, both radical nephrectomy and partial nephrectomy conferred satisfactory prognosis. For metastatic TFEB-altered RCC, immunotherapy-based drug combinations could be a promising treatment strategy.

Machine learning-based prediction of symptomatic intracerebral hemorrhage after intravenous thrombolysis for stroke: a large multicenter study.

Background: This study aimed to compare the performance of different machine learning models in predicting symptomatic intracranial hemorrhage (sICH) after thrombolysis treatment for ischemic stroke. Methods: This multicenter study utilized the Shenyang Stroke Emergency Map database, comprising 8,924 acute ischemic stroke patients from 29 comprehensive hospitals who underwent thrombolysis between January 2019 and December 2021. An independent testing cohort was further established, including 1,921 patients from the First People's Hospital of Shenyang. The structured dataset encompassed 15 variables, including clinical and therapeutic metrics. The primary outcome was the sICH occurrence post-thrombolysis. Models were developed using an 80/20 split for training and internal validation. Performance was assessed using machine learning classifiers, including logistic regression with lasso regularization, support vector machine (SVM), random forest, gradient-boosted decision tree (GBDT), and multilayer perceptron (MLP). The model boasting the highest area under the curve (AUC) was specifically employed to highlight feature importance. Results: Baseline characteristics were compared between the training cohort (n = 6,369) and the external validation cohort (n = 1,921), with the sICH incidence being slightly higher in the training cohort (1.6%) compared to the validation cohort (1.1%). Among the evaluated models, the logistic regression with lasso regularization achieved the highest AUC of 0.87 (95% confidence interval [CI]: 0.79-0.95; p < 0.001), followed by the MLP model with an AUC of 0.766 (95% CI: 0.637-0.894; p = 0.04). The reference model and SVM showed AUCs of 0.575 and 0.582, respectively, while the random forest and GBDT models performed less optimally with AUCs of 0.536 and 0.436, respectively. Decision curve analysis revealed net benefits primarily for the SVM and MLP models. Feature importance from the logistic regression model emphasized anticoagulation therapy as the most significant negative predictor (coefficient: -2.0833) and recombinant tissue plasminogen activator as the principal positive predictor (coefficient: 0.5082). Conclusion: After a comprehensive evaluation, the MLP model is recommended due to its superior ability to predict the risk of symptomatic hemorrhage post-thrombolysis in ischemic stroke patients. Based on decision curve analysis, the MLP-based model was chosen and demonstrated enhanced discriminative ability compared to the reference. This model serves as a valuable tool for clinicians, aiding in treatment planning and ensuring more precise forecasting of patient outcomes.

Nucleophosmin 1 cooperates with BRD4 to facilitate c-Myc transcription to promote prostate cancer progression.

Nucleophosmin 1 (NPM1) is a multifunctional protein that promotes tumor progression in various cancers and is associated with a poor prognosis of prostate cancer (PCa). However, the mechanism by which NPM1 exerts its malignant potential in PCa remains elusive. Here, we showed that NPM1 is overexpressed in PCa cell lines and tissues and that the dysregulation of NPM1 promotes PCa proliferation. We also demonstrated that NPM1 transcriptionally upregulates c-Myc expression in PCa cells that is diminished by blockade of bromodomain-containing protein 4 (BRD4). Furthermore, we detected a correlation between NPM1 and c-Myc in patient PCa specimens. Mechanistically, NPM1 influences and cooperates with BRD4 to facilitate c-Myc transcription to promote PCa progression. In addition, JQ1, a bromodomain and extra-terminal domain (BET) inhibitor, in combination with NPM1 inhibition suppresses PCa progression in vitro and in vivo. These results indicate that NPM1 promotes PCa progression through a c-Myc -mediated pathway via BRD4, and blockade of the NPM1-c-Myc oncogenic pathway may be a therapeutic strategy for PCa.

A systematic pan-cancer analysis identifies TRIM28 as an immunological and prognostic predictor and involved in immunotherapy resistance.

Tripartite motif-containing protein 28 (TRIM28), as a transcriptional cofactor, has pleiotropic biological effects, such as silencing genes, promoting cellular proliferation and differentiation, and facilitating DNA repair. It is reported that TRIM28 is also correlated with immune infiltration in liver cancer that highlights an unnoticed function of TRIM28 in immune system. However, the prognostic and immunotherapeutic role of TRIM28 in human cancer has not been elucidated. In this study, we conducted a systematic pan-cancer analysis and partial experimental validation of TRIM28 as an immunological and prognostic predictor and its involvement in immunotherapy resistance. We found that TRIM28 expression was higher in various tumor tissues than in normal tissues. Higher TRIM28 expression was associated with poorer prognosis in multiple cancers. The expression of TRIM28 was positively correlated with the presence of T cells, macrophages and neutrophils, and TRIM28 also promoted the infiltration of a series of immune cell. Moreover, TRIM28 affected a wide range of cancer-related scores, and the abnormal expression of TRIM28 was also involved in tumor mutational burden, drug sensitivity, and microsatellite instability in cancer. The results suggest that TRIM28 is a potentially valuable immune response indicator and a molecular biomarker for predicting the prognosis of cancer patients.