Comparison of minimally invasive transforaminal lumbar interbody fusion and midline lumbar interbody fusion in patients with spondylolisthesis.

BACKGROUND: This study aimed to compare surgical outcomes, clinical outcomes, and complications between minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) and midline lumbar interbody fusion (MIDLIF) in patients with spondylolisthesis. METHODS: This study retrospectively compared the patients who underwent MIS TLIF (n = 37) or MIDLIF (n = 50) for spinal spondylolisthesis. Data of surgical outcomes (postoperative one-year fusion rate and time to bony fusion), clinical outcomes (visual analog scale [VAS] for pain and Oswestry Disability Index [ODI] for spine function), and complications were collected and analyzed. RESULTS: There was more 2-level fusion in MIDLIF (46% vs. 24.3%, p = 0.038). The MIS TLIF and MIDLIF groups had similar one-year fusion rate and time to fusion. The MIDLIF group had significantly lower VAS at postoperative 3-months (2.2 vs. 3.1, p = 0.002) and postoperative 1-year (1.1 vs. 2.1, p = < 0.001). ODI was not significantly different. The operation time was shorter in MIDLIF (166.1 min vs. 196.2 min, p = 0.014). The facet joint violation is higher in MIS TLIF (21.6% vs. 2%, p = 0.009). The other complications were not significantly different including rate of implant removal, revision, and adjacent segment disease. CONCLUSION: In this study, postoperative VAS, operation time, and the rate of facet joint violation were significantly higher in the MIS TLIF group. Comparable outcomes were observed between MIDLIF and MIS TLIF in terms of fusion rate, time to fusion, and postoperative ODI score.

Augmentation of hepatocellular carcinoma malignancy by annexin A5 through modulation of invasion and angiogenesis.

BACKGROUND: Hepatocellular carcinoma (HCC) continues to play a substantial role in cancer-related morbidity and mortality, largely owing to its pronounced tumor heterogeneity and propensity for recurrence. This underscores the pressing need for in-depth examination of its highly malignant mechanisms. Annexin A5 (ANXA5), recognized as a hallmark tumor protein, has emerged as a focal point of interest because of its ambiguous function and mechanism in HCC prognosis. This study aimed to provide a comprehensive understanding of the role of ANXA5 in the malignant progression of human HCC cells by employing an integrative approach that combines conventional experimental methods with RNA sequencing. METHODS: Differences in ANXA5 expression between HCC tissues and corresponding nontumor tissues were evaluated using immunofluorescence (n = 25). Correlation analysis was subsequently performed to assess the association between ANXA5 expression and clinicopathological features (n = 65). The role of ANXA5 in human HCC cell lines with ANXA5 gene knockout and overexpression was explored in vitro using migration and invasion assays and Ki-67 indices and in vivo based on node mice xenograft model. A tube formation assay using human umbilical vein endothelial cells (HUVECs) was conducted to demonstrate the angiogenic effects of ANXA5 in HCC. Single-cell and bulk RNA sequencing was used to further investigate the underlying mechanisms involved. RESULTS: This study revealed that ANXA5 is highly expressed in patients with HCC and correlates with poor prognosis. Assays for migration, invasion, and proliferation based on ANXA5 gene knockout and overexpression systems in human HCC cell lines have demonstrated that ANXA5 enhances HCC malignancy in vitro and in vivo. Tube formation assays of HUVECs indicated that ANXA5 facilitates angiogenesis and recruits endothelial cells to HCC cells. Single-cell and bulk RNA sequencing data analysis further confirmed that ANXA5 expression in HCC is associated with hepatocyte metabolism, immune response activation, and various oncogenic signaling pathways. CONCLUSIONS: This study revealed a meaningful association between elevated ANXA5 expression in tumor tissues and an unfavorable prognosis in patients with HCC. In addition, ANXA5 promotes HCC malignancy by promoting invasion and angiogenesis. Thus, ANXA5 has emerged as a promising therapeutic target for HCC and has the potential to improve patient outcomes.

Metabolic Activation and Cytotoxicity of Gramine Mediated by CYP3A in Rats.

Gramine (GRM), which occurs in Gramineae plants, has been developed to be a biological insecticide. Exposure to GRM was reported to induce elevations of serum ALT and AST in rats, but the mechanisms of the observed hepatotoxicity have not been elucidated. The present study aimed to identify reactive metabolites that potentially participate in the toxicity. In rat liver microsomal incubations fortified with glutathione or N-acetylcysteine, one oxidative metabolite (M1), one glutathione conjugate (M2), and one N-acetylcysteine conjugate (M3) were detected after exposure to GRM. The corresponding conjugates were detected in the bile and urine of rats after GRM administration. CYP3A was the main enzyme mediating the metabolic activation of GRM. The detected GSH and NAC conjugates suggest that GRM was metabolized to a quinone imine intermediate. Both GRM and M1 showed significant toxicity to rat primary hepatocytes.

Taking SCFAs produced by Lactobacillus reuteri orally reshapes gut microbiota and elicits antitumor responses.

BACKGROUND: Colorectal cancer (CRC) incidence is increasing in recent years due to intestinal flora imbalance, making oral probiotics a hotspot for research. However, numerous studies related to intestinal flora regulation ignore its internal mechanisms without in-depth research. RESULTS: Here, we developed a probiotic microgel delivery system (L.r@(SA-CS)2) through the layer-by-layer encapsulation technology of alginate (SA) and chitosan (CS) to improve gut microbiota dysbiosis and enhance anti-tumor therapeutic effect. Short chain fatty acids (SCFAs) produced by L.r have direct anti-tumor effects. Additionally, it reduces harmful bacteria such as Proteobacteria and Fusobacteriota, and through bacteria mutualophy increases beneficial bacteria such as Bacteroidota and Firmicutes which produce butyric acid. By binding to the G protein-coupled receptor 109A (GPR109A) on the surface of colonic epithelial cells, butyric acid can induce apoptosis in abnormal cells. Due to the low expression of GPR109A in colon cancer cells, MK-6892 (MK) can be used to stimulate GPR109A. With increased production of butyrate, activated GPR109A is able to bind more butyrate, which further promotes apoptosis of cancer cells and triggers an antitumor response. CONCLUSION: It appears that the oral administration of L.r@(SA-CS)2 microgels may provide a treatment option for CRC by modifying the gut microbiota.

Physical Prior Mean Function-Driven Gaussian Processes Search for Minimum-Energy Reaction Paths with a Climbing-Image Nudged Elastic Band: A General Method for Gas-Phase, Interfacial, and Bulk-Phase Reactions.

The climbing-image nudged elastic band (CI-NEB) method serves as an indispensable tool for computational chemists, offering insight into minimum-energy reaction paths (MEPs) by delineating both transition states (TSs) and intermediate nonstationary structures along reaction coordinates. However, executing CI-NEB calculations for reactions with extensive reaction coordinate spans necessitates a large number of images to ensure a reliable convergence of the MEPs and TS structures, presenting a computationally demanding optimization challenge, even with mildly costly electronic-structure methods. In this study, we advocate for the utilization of physically inspired prior mean function-based Gaussian processes (GPs) to expedite MEP exploration and TS optimization via the CI-NEB method. By incorporating reliable prior physical approximations into potential energy surface (PES) modeling, we demonstrate enhanced efficiency in multidimensional CI-NEB optimization with surrogate-based optimizers. Our physically informed GP approach not only outperforms traditional nonsurrogate-based optimizers in optimization efficiency but also on-the-fly learns the reaction path valley during optimization, culminating in significant advancements. The surrogate PES derived from our optimization exhibits high accuracy compared to true PES references, aligning with our emphasis on leveraging reliable physical priors for robust and efficient posterior mean learning in GPs. Through a systematic benchmark study encompassing various reaction pathways, including gas-phase, bulk-phase, and interfacial/surface reactions, our physical GPs consistently demonstrate superior efficiency and reliability. For instance, they outperform the popular fast inertial relaxation engine optimizer by approximately a factor of 10, showcasing their versatility and efficacy in exploring reaction mechanisms and surface reaction PESs.

Modified botulinum toxin type A injections improve symptoms associated with interstitial cystitis/bladder pain syndrome in women: a retrospective cohort study.

OBJECTIVE: To investigate the efficacy and safety of modified botulinum toxin type A (BoNT-A) injections (with additional periurethral injection [PUI] of BoNT-A) for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: This single-center, retrospective cohort study included 52 adult female patients with IC/BPS, with 24 patients receiving conventional BoNT-A injections and 28 receiving modified BoNT-A injections. The primary outcome measure was patient-reported global response assessment (GRA). Secondary outcomes included daytime frequency, nocturia, number of urinary urgency episodes in the voiding diary, pain visual analog score, O'Leary-Sant Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, pelvic pain and urgency/frequency scores, risk factors for recurrence, and postoperative recurrence-free time. RESULTS: The median duration of follow-up was 16.0 months (interquartile range 11.75-21 months). Patients who underwent modified BoNT-A injections showed significant improvement in postoperative GRA, symptom questionnaires, and pain assessment compared with those who underwent conventional surgery. A statistically significant difference was observed between the two groups in terms of recurrence-free time (12.5 vs. 18.0 months, P=0.02). Subgroup analysis suggested that additional PUI of BoNT-A was more effective in patients with combined severe periurethral pain. No serious complications occurred in both groups, and all minor postoperative complications were temporary. CONCLUSIONS: Modified BoNT-A injection is an effective treatment for IC/BPS that significantly reduces pain and improves voiding symptoms. It is particularly effective in patients with combined periurethral pain. In such patients, PUI of BoNT-A should be added to the routine intravesical injection of BoNT-A.

Transformation of dissolved organic matter during groundwater arsenite removal using air cathode iron electrocoagulation.

Dissolve organic matters (DOM) usually showed negative effect on the removal of inorganic arsenic (As) in groundwater by electrochemical approaches, yet which parts of sub-component within DOM played the role was lack of evidence. Herein, we investigated the effects of land-source humic-like acid (HA) on groundwater As(III) removal using air cathode iron electrocoagulation, based on the parallel factor analysis of three-dimensional excitation-emission matrix and statistical methods. Our results showed that the land-source HA contained five kinds of components and all components presented significantly negative correlations with the removal of both As(III) and As(V). However, the high aromatic fulvic-like acid and low aromatic humic-like acid components of land-source HA presented the opposite correlations with the concentration of As(III) during the reaction. The high aromaticity fulvic-like components of land-source HA (Sigma-Aldrich HA, SAHA) produced during the reaction facilitated the oxidation of As(III) due to its high electron transfer capacities and good solubility in wide pH range, but the low aromaticity humic-like ones worked against the oxidation of As(III). Our findings offered the novel insights for the flexible activities of DOM in electron Fenton system.

FDG PET/CT in a Case of Solitary Mixed Squamous Cell and Glandular Papilloma of the Lung With High CEA Level.

ABSTRACT: Solitary mixed squamous cell and glandular papilloma of the lung is an extremely rare benign neoplasm. We describe FDG PET/CT findings in a case of solitary mixed squamous cell and glandular papilloma of the lung with high serum carcinoembryonic antigen level (63.3 ng/mL; reference, <5 ng/mL). The tumor showed intense FDG uptake with SUVmax of 23.8 mimicking lung cancer.

USP39 Promotes the Viability and Migration of Head and Neck Squamous Cell Carcinoma Cell by Regulating STAT1.

Objective: Ubiquitin-specific peptidase 39 (USP39) plays a carcinogenic role in many cancers, but little research has been conducted examining whether it is involved in head and neck squamous cell carcinoma (HNSCC). Therefore, this study explored the functional role of USP39 in HNSCC. Method: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify differentially expressed proteins (DEPs) between the HNSCC tumor and adjacent healthy tissues. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to assess the functional enrichment of DEPs. Immunohistochemistry was used to detect protein expression. The viability and migration of two HNSCC cell lines, namely CAL27 and SCC25, were detected using the cell counting kit-8 assay and a wound healing assay, respectively. Quantitative real-time PCR was used to detect the expression level of signal transducer and activator of transcription 1 (STAT1) mRNA. Results: LC-MS/MS results identified 590 DEPs between HNSCC and adjacent tissues collected from 4 patients. Through GO and KEGG pathway analyses, 34 different proteins were found to be enriched in the spliceosome pathway. The expression levels of USP39 and STAT1 were significantly higher in HNSCC tumor tissue than in adjacent healthy tissue as assessed by LC-MS/MS analysis, and the increased expression of USP39 and STAT1 protein was confirmed by immunohistochemistry in clinical samples collected from 7 additional patients with HNSCC. Knockdown of USP39 or STAT1 inhibited the viability and migration of CAL27 and SCC25 cells. In addition, USP39 knockdown inhibited the expression of STAT1 mRNA in these cells. Conclusion: Our findings indicated that USP39 knockdown may inhibit HNSCC viability and migration by suppressing STAT1 expression. The results of this study suggest that USP39 may be a potential new target for HNSCC clinical therapy or a new biomarker for HNSCC.

VP5 protein of oncolytic herpes simplex virus type 2 induces apoptosis in A549 cells through TP53I3 protein.

Oncolytic virotherapy stands out as a burgeoning and promising therapeutic paradigm, harnessing the intrinsic cytotoxicity of oncolytic viruses for selective replication and dissemination within tumors. The primary mode of action revolves around the direct eradication of tumor cells. In our previous investigations, we formulated an oncolytic herpes simplex virus type 2 (OH2) and substantiated its anti-tumor efficacy both in vivo and in vitro. Subsequently, we embarked on a phase I/II clinical trial in China (NMPA, 2018L02743) and the USA (FDA, IND 27137) to assess OH2's safety, biodistribution, and anti-tumor activity as a standalone agent in patients with advanced solid tumors. In this investigation, our primary focus was to comprehend the influence of the major capsid protein VP5 of OH2 on its efficacy as an antitumor agent. Our findings underscore that the VP5 protein significantly amplifies OH2's oncolytic impact on A549 cells. Additionally, we observed that VP5 actively promotes the induction of apoptosis in A549 cells, both in vivo and in vitro. Through comprehensive transcriptional sequencing, we further authenticated that the VP5 protein triggers apoptosis-related signaling pathways and Gene Ontology (GO) terms in A549 cells. Moreover, we scrutinized differentially expressed genes in the p53-dependent apoptosis pathway and conducted meticulous in vitro validation of these genes. Subsequently, we delved deeper into unraveling the functional significance of the TP53I3 gene and conclusively affirmed that the VP5 protein induces apoptosis in A549 cells through the TP53I3 gene. These revelations illuminate the underlying mechanisms of OH2's antitumor activity and underscore the pivotal role played by the VP5 protein. The outcomes of our study harbor promising implications for the formulation of effective oncolytic virotherapy strategies in cancer treatment.

Deubiquitinase PSMD14 promotes tumorigenicity of glioblastoma by deubiquitinating and stabilizing ß-catenin.

The deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14), a member of the JAB1/MPN/Mov34 metalloenzyme (JAMM) family, has been shown to function as an oncogene in various human cancers. However, the function of PSMD14 in glioma and the underlying mechanism remain unclear. In this study, our findings reveal a dramatic upregulation of PSMD14 in GBMs, which is associated with poor survival outcomes. Knocking down PSMD14 is associated with decreased proliferation and invasion of GBM cells in vitro and inhibited tumor growth in a xenograft mouse model. Mechanistically, PSMD14 directly interacts with ß-catenin, leading to a decrease in the K48-linked ubiquitination of ß-catenin and subsequent ß-catenin stabilization. Increased ß-catenin expression significantly reverses the inhibitory effects of PSMD14 knockdown on the migration, invasion, and tumor growth of GBM cells. Moreover, we observed a significant correlation between PSMD14 and ß-catenin expression in human GBM samples. In summary, our results reveal that PSMD14 is a crucial deubiquitinase that is responsible for stabilizing the ß-catenin protein, highlighting its potential for use as a therapeutic target for GBM.

Next-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity.

The clinical applications of immunocytokines are severely restricted by dose-limiting toxicities. To address this challenge, here we propose a next-generation immunocytokine concept involving the design of LH05, a tumor-conditional anti-PD-L1/interleukin-15 (IL-15) prodrug. LH05 innovatively masks IL-15 with steric hindrance, mitigating the "cytokine sink" effect of IL-15 and reducing systemic toxicities associated with wild-type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within the tumor microenvironment, LH05 releases an active IL-15 superagonist, exerting potent antitumor effects. Mechanistically, the antitumor efficacy of LH05 depends on the increased infiltration of CD8+ T and natural killer cells by stimulating the chemokines CXCL9 and CXCL10, thereby converting cold tumors into hot tumors. Additionally, the tumor-conditional anti-PD-L1/IL-15 can synergize with an oncolytic virus or checkpoint blockade in advanced and metastatic tumor models. Our findings provide a compelling proof of concept for the development of next-generation immunocytokines, contributing significantly to current knowledge and strategies of immunotherapy.

FDG PET/CT Findings of Primary Pulmonary Choriocarcinoma in a Postmenopausal Woman.

ABSTRACT: Choriocarcinomas usually occur in the genital tracts of reproductive-age women after a gestational event. Primary pulmonary choriocarcinoma is very rare. We describe FDG PET/CT findings of primary pulmonary choriocarcinoma with multiple intrapulmonary metastases in a postmenopausal woman with elevated serum beta human chorionic gonadotropin level. On FDG PET/CT, the large primary lung tumor showed intense FDG uptake (SUVmax, 46), and the small intrapulmonary metastases showed variable FDG uptake (SUVmax, 27). Primary pulmonary choriocarcinoma should be included in the differential diagnosis of FDG-avid pulmonary lesions with elevated serum beta human chorionic gonadotropin levels, including metastatic choriocarcinoma and lung cancer.

Tackling Antibiotic Resistance: Exploring 5-Fluorouracil as a Promising Antimicrobial Strategy for the Treatment of Streptococcus suis Infection.

Streptococcus suis (S. suis) is a zoonotic pathogen with a global distribution, which causes serious diseases in both humans and animals and economic losses in the swine industry. As antibiotic resistance increases, there is an urgent imperative to explore novel antibacterial alternatives. In the present study, we selected the anticancer drug 5-fluorouracil (5-FU) approved by the Food and Drug Administration (FDA) as a candidate drug to treat S. suis infections. The results showed that various pathogens, especially S. suis, are more sensitive to 5-FU. Moreover, the cytotoxicity of 5-FU is relatively low. Extensive in vitro assays demonstrated the pronounced bacteriostatic and bactericidal efficacy of 5-FU against susceptible and multidrug-resistant S. suis strains. Its mechanisms of action include damage to the bacterial cell walls and membranes, resulting in the leakage of intracellular components, and the inhibition of thymidylate synthase (TS), leading to a depletion of deoxythymidine triphosphate (dTTP) pools, ultimately causing thymine-less death and lethal DNA damage in bacteria. Gene-knockout experiments further showed that 5-FU played a role by inhibiting the thyA gene-encoding thymidine synthase. Finally, we determined that S. suis infections can be alleviated by 5-FU in the mouse infection model. This study emphasizes the antibacterial potential of 5-FU against S. suis and provides evidence for its targeting of bacterial membrane damage and DNA damage. In summary, 5-FU can control S. suis infection and is expected to become a new alternative to antibiotics.

Genetic and phenotypic profiling of single living circulating tumor cells from patients with microfluidics.

Accurate prediction of the efficacy of immunotherapy for cancer patients through the characterization of both genetic and phenotypic heterogeneity in individual patient cells holds great promise in informing targeted treatments, and ultimately in improving care pathways and clinical outcomes. Here, we describe the nanoplatform for interrogating living cell host-gene and (micro-)environment (NICHE) relationships, that integrates micro- and nanofluidics to enable highly efficient capture of circulating tumor cells (CTCs) from blood samples. The platform uses a unique nanopore-enhanced electrodelivery system that efficiently and rapidly integrates stable multichannel fluorescence probes into living CTCs for in situ quantification of target gene expression, while on-chip coculturing of CTCs with immune cells allows for the real-time correlative quantification of their phenotypic heterogeneities in response to immune checkpoint inhibitors (ICI). The NICHE microfluidic device provides a unique ability to perform both gene expression and phenotypic analysis on the same single cells in situ, allowing us to generate a predictive index for screening patients who could benefit from ICI. This index, which simultaneously integrates the heterogeneity of single cellular responses for both gene expression and phenotype, was validated by clinically tracing 80 non-small cell lung cancer patients, demonstrating significantly higher AUC (area under the curve) (0.906) than current clinical reference for immunotherapy prediction.

Investigation of Metabolic and Inflammatory Disorder in the Aging FGF21 Knockout Mouse.

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36-40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36-40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism.

Comprehensive bioremediation effect of phosphorus-mineralized bacterium Enterobacter sp. PMB-5 on cadmium contaminated soil-crop system.

Phosphate-mineralizing bacteria (PMBs) have been widely studied by inducing phosphate heavy metal precipitation, but current researches neglect to study their effects on soil-microbe-crop systems on cadmium (Cd) contaminated. Based on this, a strain PMB, Enterobacter sp. PMB-5, was inoculated into Cd contaminated pots to detect soil characteristics, Cd occurrence forms, soil biological activities, plant physiological and biochemical indicators. The results showed that the inoculation of strain PMB-5 significantly increased the available phosphorus content (85.97%-138.64%), Cd-residual fraction (11.04%-29.73%), soil enzyme activities (31.94%-304.63%), plant biomass (6.10%-59.81%), while decreased the state of Cd-HOAc (11.50%-31.17%) and plant bioconcentration factor (23.76%-44.24%). These findings indicated that strain PMB-5 could perform the function of phosphorus solubilization to realize the immobilization of Cd in the complex soil environment. Moreover, SEM-EDS, FTIR, XPS, and XRD analysis revealed that strain PMB-5 does not significantly alter the soil morphology, structure, elemental distribution, and chemical composition, which suggested that remediation of Cd contamination using strain PMB-5 would not further burden the soil. This research implies that PMB-5 could be a safe and effective bioinoculant for remediating Cd-contaminated soils, contributing to the sustainable management of soil health in contaminated environments.

A Novel Network Pharmacology Strategy Based on the Universal Effectiveness-Common Mechanism of Medical Herbs Uncovers Therapeutic Targets in Traumatic Brain Injury.

Purpose: Many herbs can promote neurological recovery following traumatic brain injury (TBI). There must lie a shared mechanism behind the common effectiveness. We aimed to explore the key therapeutic targets for TBI based on the common effectiveness of the medicinal plants. Material and methods: The TBI-effective herbs were retrieved from the literature as imputes of network pharmacology. Then, the active ingredients in at least two herbs were screened out as common components. The hub targets of all active compounds were identified through Cytohubba. Next, AutoDock vina was used to rank the common compound-hub target interactions by molecular docking. A highly scored compound-target pair was selected for in vivo validation. Results: We enrolled sixteen TBI-effective medicinal herbs and screened out twenty-one common compounds, such as luteolin. Ten hub targets were recognized according to the topology of the protein-protein interaction network of targets, including epidermal growth factor receptor (EGFR). Molecular docking analysis suggested that luteolin could bind strongly to the active pocket of EGFR. Administration of luteolin or the selective EGFR inhibitor AZD3759 to TBI mice promoted the recovery of body weight and neurological function, reduced astrocyte activation and EGFR expression, decreased chondroitin sulfate proteoglycans deposition, and upregulated GAP43 levels in the cortex. The effects were similar to those when treated with the selective EGFR inhibitor. Conclusion: The common effectiveness-based, common target screening strategy suggests that inhibition of EGFR can be an effective therapy for TBI. This strategy can be applied to discover core targets and therapeutic compounds in other diseases.

Abrogation of USP9X is a potential strategy to decrease PEG10 levels and impede tumor progression in cutaneous T-cell lymphoma.

Advanced-stage cutaneous T-cell lymphomas (CTCL) are notorious for its highly aggressive behavior, resistance to conventional treatments and poor prognosis, particularly when large-cell transformation (LCT) occurs. Paternally expressed gene 10 (PEG10) has been recently proposed as a potent driver for LCT in CTCL. However, the targeting of PEG10 continues to present a formidable clinical challenge that has yet to be addressed. Here we report an important post-translational regulatory mechanism of PEG10 in CTCL. Ubiquitin-specific protease 9X (USP9X), a deubiquitinase, interacted with and deubiquitinated PEG10, thereby stabilizing PEG10. Knockdown of USP9X or pharmacological targeting of USP9X resulted in a prominent downregulation of PEG10 and its downstream pathway in CTCL. Moreover, USP9X inhibition conferred tumor cell growth disadvantage and enhanced apoptosis in vitro, an effect that occurred in part through its regulation on PEG10. Furthermore, we demonstrated that inhibition of USP9X obviously restrained CTCL tumor growth in vivo, and that high expression of USP9X is associated with poor survival in CTCL patients. Collectively, our findings uncover USP9X as a key post-translational regulator in the stabilization of PEG10 and suggest that targeting PEG10 stabilization through USP9X inhibition may represent a promising therapeutic strategy for advanced-stage CTCL.