Estimating the viscoelastic anisotropy of human skin through high-frequency ultrasound elastography.

BACKGROUND: The skin is the largest organ of the human body and serves distinct functions in protecting the body. The viscoelastic properties of the skin play a key role in supporting the skin-healing process, also it may be changed due to some skin diseases. PROPOSE: In this study, high-frequency ultrasound (HFUS) elastography based on a Lamb wave model was used to noninvasively assess the viscoelastic anisotropy of human skin. METHOD: Elastic waves were generated through an external vibrator, and the wave propagation velocity was measured through 40 MHz ultrafast HFUS imaging. Through the use of a thin-layer gelatin phantom, HFUS elastography was verified to produce highly accurate estimates of elasticity and viscosity. In a human study involving five volunteers, viscoelastic anisotropy was assessed by rotating an ultrasound transducer 360°. RESULTS: An oval-shaped pattern in the elasticity of human forearm skin was identified, indicating the high elastic anisotropy of skin; the average elastic moduli were 24.90 ± 6.63 and 13.64 ± 2.67 kPa along and across the collagen fiber orientation, respectively. The average viscosity of all the recruited volunteers was 3.23 ± 0.93 Pa·s. CONCLUSIONS: Although the examined skin exhibited elastic anisotropy, no evident viscosity anisotropy was observed.

Knockdown of HSPA13 Inhibits TGFß1-Induced Epithelial-Mesenchymal Transition of RPE by Suppressing the PI3K/Akt Signaling Pathway.

Purpose: This study aimed to explore the impact of HSPA13 on epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells and proliferative vitreoretinopathy (PVR) development, along with its associated molecular mechanisms. Methods: HSPA13 expression was evaluated in epiretinal membranes (ERMs) from patients with PVR using immunohistochemistry. The effects of HSPA13 knockdown on TGFß1-induced EMT in hESC-RPE cells were studied through quantitative PCR (qPCR), Western blot, and wound healing assays. Intracellular Ca2+ levels were measured using Fluo-8/AM incubation. A rat PVR model was induced by the intravitreal injection of RPE cells combined with platelet-rich plasma (PRP). RNA-seq was applied to study the molecular mechanism of HSPA13 knockdown-mediated EMT inhibition. Results: HSPA13 was found in human ERMs and its expression increased with TGFß1 treatment in hESC-RPE cells. Knockdown of HSPA13 inhibited TGFß1-induced EMT and migration. In the PVR rat model, HSPA13 was expressed in the ERMs and its knockdown in RPE cells reduced the development of PVR. Consistent with these observations, RNA-seq showed a global suppression of TGFß1-induced EMT and migration by shHSPA13 in RPE cells. Mechanistically, TGFß1 treatment increased intracellular Ca2+ levels, leading to an upregulation of HSPA13 expression. Downregulation of HSPA13 hindered the phosphorylation of PI3K/Akt in TGFß1-induced RPE cells. Conclusions: Our study revealed the involvement of HSPA13 in PVR development, as well as in TGFß1-induced EMT of RPE through the PI3K/Akt signaling pathway. Targeting HSPA13-related pathways involved in regulating EMT in RPE cells could serve as a novel therapeutic approach for patients with PVR.

Development and validation of a predictive model for pulmonary infection risk in patients with traumatic brain injury in the ICU: a retrospective cohort study based on MIMIC-IV.

OBJECTIVE: To develop a nomogram for predicting occurrence of secondary pulmonary infection in patients with critically traumatic brain injury (TBI) during their stay in the intensive care unit, to further optimise personalised treatment for patients and support the development of effective, evidence-based prevention and intervention strategies. DATA SOURCE: This study used patient data from the publicly available MIMIC-IV (Medical Information Mart for Intensive Care IV) database. DESIGN: A population-based retrospective cohort study. METHODS: In this retrospective cohort study, 1780 patients with TBI were included and randomly divided into a training set (n=1246) and a development set (n=534). The impact of pulmonary infection on survival was analysed using Kaplan-Meier curves. A univariate logistic regression model was built in training set to identify potential factors for pulmonary infection, and independent risk factors were determined in a multivariate logistic regression model to build nomogram model. Nomogram performance was assessed with receiver operating characteristic (ROC) curves, calibration curves and Hosmer-Lemeshow test, and predictive value was assessed by decision curve analysis (DCA). RESULT: This study included a total of 1780 patients with TBI, of which 186 patients (approximately 10%) developed secondary lung infections, and 21 patients died during hospitalisation. Among the 1594 patients who did not develop lung infections, only 85 patients died (accounting for 5.3%). The survival curves indicated a significant survival disadvantage for patients with TBI with pulmonary infection at 7 and 14 days after intensive care unit admission (p<0.001). Both univariate and multivariate logistic regression analyses showed that factors such as race other than white or black, respiratory rate, temperature, mechanical ventilation, antibiotics and congestive heart failure were independent risk factors for pulmonary infection in patients with TBI (OR>1, p<0.05). Based on these factors, along with Glasgow Coma Scale and international normalised ratio variables, a training set model was constructed to predict the risk of pulmonary infection in patients with TBI, with an area under the ROC curve of 0.800 in the training set and 0.768 in the validation set. The calibration curve demonstrated the model's good calibration and consistency with actual observations, while DCA indicated the practical utility of the predictive model in clinical practice. CONCLUSION: This study established a predictive model for pulmonary infections in patients with TBI, which may help clinical doctors identify high-risk patients early and prevent occurrence of pulmonary infections.

STING is crucial for the survival of RUNX1::RUNX1T1 leukemia cells.

Even though acute myeloid leukemia (AML) patients with a RUNX1::RUNX1T1 (AE) fusion have a relatively favorable prognosis, approximately 50% relapse within 2.5 years and develop resistance to subsequent chemotherapy [1]. It is therefore imperative to identify novel therapeutic targets for AE leukemia to improve outcomes. In this study, we unveil that targeting STING effectively suppresses the growth of AE leukemia cells. Both genetic and pharmacological inhibition of STING lead to the diminish of AE leukemia cells. Importantly, in a mouse primary AE leukemia model, STING deletion significantly attenuates leukemogenesis and prolongs the animals' lifespan. Blocking the downstream inflammatory pathway of STING yields similar effects to STING inhibition in AE leukemia cells, highlighting the pivotal role of STING-dependent inflammatory responses in sustaining the survival of AE leukemia cells. Moreover, through a genome-wide CRISPR screen, we identified fatty acid desaturase 2 (FADS2) as a non-canonical factor downstream of STING inhibition that mediates cell death. Inhibition of STING releases FADS2 activity, consequently inducing the synthesis of polyunsaturated fatty acids (PUFAs) and triggering lipid peroxidation-associated cell death [2]. Taken together, these findings reveal a critical function of STING in the survival of AE-positive AML cells and suggest STING to be a potential therapeutic target for clinical intervention in these patients.

TFAP2A Activates S100A2 to Mediate Glutamine Metabolism and Promote Lung Adenocarcinoma Metastasis.

BACKGROUND: Lung adenocarcinoma (LUAD) is a fatal disease with metabolic abnormalities. The dysregulation of S100 calcium-binding protein A2 (S100A2), a member of the S100 protein family, is connected to the development of various cancers. The impact of S100A2 on the LUAD occurrence and metastasis, however, has not yet been reported. The functional mechanism of S100A2 on LUAD cell metastasis was examined in this article. METHODS: The expression of TFAP2A and S100A2 in LUAD tissues and cells was analyzed by bioinformatics and qRT-PCR, respectively. The enrichment pathway analysis was performed on S100A2. Bioinformatics analysis determined the binding relationship between TFAP2A and S100A2, and their interaction was validated through dual-luciferase and chromatin immunoprecipitation experiments. Cell viability was determined using cell counting kit-8 (CCK-8). A transwell assay was performed to analyze the invasion and migration of cells. Immunofluorescence was conducted to obtain vimentin and E-cadherin expression, and a western blot was used to detect the expression of MMP-2, MMP-9, GLS, and GLUD1. The kits measured the NADPH/NADP ratio, glutathione (GSH)/glutathione disulfide (GSSG) levels, and the contents of glutamine, α-KG, and glutamate. RESULTS: S100A2 was upregulated in LUAD tissues and cells, and S100A2 mediated glutamine metabolism to induce LUAD metastasis. Additionally, the transcriptional regulator TFAP2A was discovered upstream of S100A2, and TFAP2A expression was upregulated in LUAD, which indicated that TFAP2A promoted the S100A2 expression. The rescue experiment found that upregulation of S100A2 could reverse the inhibitory effects of silencing TFAP2A on glutamine metabolism and cell metastasis. CONCLUSION: In conclusion, by regulating glutamine metabolism, the TFAP2A/S100A2 axis facilitated LUAD metastasis. This suggested that targeting S100A2 could be beneficial for LUAD treatment.

Timed sulfonylurea modulation improves locomotor and sensory dysfunction following spinal cord injury.

Traumatic spinal cord injury (SCI) results in immediate tissue necrosis and delayed secondary expansion of neurological damage, often resulting in lifelong paralysis, neurosensory dysfunction, and chronic pain. Progressive hemorrhagic necrosis (PHN) and excessive excitation are the main sources of secondary neural injury. Recent approaches to attenuate PHN by glibenclamide can improve locomotor function after SCI. However, use of glibenclamide can exacerbate development of SCI-induced chronic pain by inhibiting KATP channels to increase neuronal excitation and glial activation. In this study, we explored a treatment strategy involving administration of glibenclamide, which suppresses PHN, and diazoxide, which protects against neuronal excitation and inflammation, at different time intervals following spinal cord contusion. Our goal was to determine whether this combined approach enhances both sensory and motor function. Contusive SCI was induced at spinal segment T10 in adult rats. We found that KATP channels opener, diazoxide, decreased the hyperexcitability of primary sensory neurons after SCI by electrophysiology. Timed application of glibenclamide and diazoxide following contusion significantly improved locomotor function and mitigated development of SCI-induced chronic pain, as shown by behavioral evidence. Finally, we found that timed application of glibenclamide and diazoxide attenuates the inflammatory activity in the spinal cord and increases the survival of spinal matters following SCI. These preclinical studies introduce a promising potential treatment strategy to address SCI-induced dysfunction.

Ventricular arrhythmias originating from different portions of the communicating vein of the left ventricular summit: electrocardiographic characteristics and catheter ablation.

BACKGROUND: Idiopathic ventricular arrhythmias (IVAs) arising from different portions of the communicating vein of the left ventricular summit (summit-CV) are not a rare phenomenon. Whereas its electrocardiographic (ECG) and electrophysiological characteristics are not fully investigated. OBJECTIVE: This study aimed to identify distinct ECG and electrophysiological features of IVAs originating from different portions of summit-CV. METHODS: Nineteen patients confirmed arising from summit-CV were included in this study. RESULTS: The 19 patients were divided into proximal and distal portion groups based on their target sites in summit-CV. In the proximal portion group, 100% (11/11) VAs showed dominant negative (rs or QS) waves in lead I, while in the distal portion group, 87.5% (7/8) showed dominant positive waves (R, Rs or r) (p < 0.000). In lead V1, 100% (11/11) of the proximal portion group showed dominant positive waves (R or Rs), while 62.50% (5/8) of the distal portion group showed positive and negative bidirectional or negative waves (RS or rS) (p < 0.005). RI>4mV, SI<3.5mV, RV1<13mV, SV1>3.5mV, RI/SI>0.83, and RV1/SV1< 2.6 indicated a distal portion of summit-CV with the predictive value of 0.909, 1.000, 0.653, 0.972, 0.903, 0.966, respectively. A more positive wave in lead I and a more negative wave in lead V1 indicated more distal origin in summit-CV. Target sites in proximal and distal summit-CV groups showed similar electrophysiological characteristics during mapping. CONCLUSIONS: There were significant differences in ECG characteristics of VAs at different portions of summit-CV, which could aid pre-procedure planning and facilitate radiofrequency catheter ablation (RFCA) procedures.

Colo-colonic intussusception as a rare complication of colonoscopy with polypectomy: Two case reports.

BACKGROUND: Colonoscopy is the most frequently used diagnostic and therapeutic tool for the treatment of colorectal diseases. Although the complication rate is low, it can be potentially serious. Intussusception is a rare and severe complication often associated with polypectomy. Only a handful of post-colonoscopy intussusception cases have been reported, making this study a valuable addition to the medical literature. CASE SUMMARY: Case 1: A 61-year-old man underwent colonoscopy with polypectomy for chronic abdominal pain. The patient experienced abdominal pain 11 hours later but was still discharged after pain management. He was readmitted due to recurring pain. Computed tomography (CT) showed colo-colonic intussusception. Initial conservative management and attempts at endoscopic reduction failed; therefore, laparoscopic right hemicolectomy was performed. Histopathological examination revealed tubular adenomas in the polyps and inflammation in the resected specimens. Case 2: A 59-year-old woman underwent colonoscopy with polypectomy for a polyp in the transverse colon. She experienced upper abdominal pain, fever, nausea, and vomiting 9 hours after the procedure. Emergency CT and blood tests revealed a colo-colonic intussusception near the hepatic flexure and an elevated white blood cell count. Initial attempts at endoscopic reduction failed and conservative treatment showed no improvement. She underwent successful laparoscopic reduction and recovered uneventfully. Histopathological examination of the resected polyp revealed hyperplasia. CONCLUSION: Post-colonoscopy intussusception in adults is rare, and polypectomy may contribute to its occurrence. Early diagnosis is crucial, with prompt CT examination serving as key. After excluding malignancies, conservative management and reduction of intussusception should be considered before surgical bowel resection.

Feasibility of a modified hybrid glubran-supported single-proglide technique for access closure during endovascular aneurysm repair.

Objective: This study aimed to evaluate the feasibility of a hybrid Glubran-supported single-Proglide technique for large bore femoral access closure during percutaneous access endovascular aneurysm repair (EVAR). Methods: A retrospective cohort study was performed for all percutaneous EVARs at our center from January 2023 to June 2023. All patients received the hybrid Glubran-supported single-Proglide technique involving a mixture of surgical glue and Lipiodol injection after single suture placement for femoral access closure. Technical success was defined as achieving complete hemostasis without a bailout strategy. Vascular complications and bleeding were defined by Valve Academic Research Consortium-3 (VARC-3) criteria. Vascular access changes and 30-day mortality were recorded. Results: The technique success rate for the entire study population was 100% (55 femoral access in 37 patients; median age: 72; 78% males). The mean sheath size was 20.4 ± 2.3F. The mean manual compression time was 3.5 ± 1.4 min, the mean hemostasis time was 9.0 ± 2.5 min, and the mean procedural time was 103.9 ± 34.7 min. One patient (1.6%) developed an access site infection and recovered conservatively. No VARC-3 vascular complications and access changes were observed. No 30-day mortality happened. Conclusions: The hybrid Glubran-supported single-Proglide technique is feasible for large bore access closure during EVAR and may be a viable alternative; however, larger prospective studies are required to confirm its efficacy.

Nitrogen-fixing bacteria promote growth and bioactive components accumulation of Astragalus mongholicus by regulating plant metabolism and rhizosphere microbiota.

BACKGROUND: The excessive application of chemical fertilizers in the cultivation of Astragalus mongholicus Bunge results in a reduction in the quality of the medicinal plant and compromises the sustainable productivity of the soil. PGPB inoculant is a hot topic in ecological agriculture research. In the cultivation of Astragalus mongholicus, the screened nitrogen-fixing bacteria can promote plant growth, however, whether it can promote the accumulation of main bioactive components remains unknown. In this study, mixed inoculants containing 5 strains of growth promoting bacteria (Rhizobium T16 , Sinorhizobium T21 , Bacillus J1 , Bacillus G4 and Arthrobacter J2) were used in the field experiment. The metabolic substances in the root tissues of Astragalus mongholicus were identified during the harvest period by non-targeted metabolomics method, and the differential metabolites between groups were identified by statistical analysis. Meanwhile, high-throughput sequencing was performed to analyze the changes of rhizosphere soil and endophytic microbial community structure after mixed microbial treatment. RESULTS: The results of non-targeted metabolism indicated a significant increase in the levels of 26 metabolites after treatment including 13 flavonoids, 3 saponins and 10 other components. The contents of three plant hormones (abscisic acid, salicylic acid and spermidine) also increased after treatment, which presumed to play an important role in regulating plant growth and metabolism. Studies on endosphere and rhizosphere bacterial communities showed that Rhzobiaceae, Micromonosporaceae, and Hypomicrobiaceae in endophytic, and Oxalobactereae in rhizosphere were significantly increased after treatment. These findings suggest their potential importance in plant growth promotion and secondary metabolism regulation. CONCLUSIONS: This finding provides a basis for developing nitrogen-fixing bacteria fertilizer and improving the ecological planting efficiency of Astragalus mongholicus.

[Research progress of deep learning applications in mass spectrometry imaging data analysis].

Mass spectrometry imaging (MSI) is a promising method for characterizing the spatial distribution of compounds. Given the diversified development of acquisition methods and continuous improvements in the sensitivity of this technology, both the total amount of generated data and complexity of analysis have exponentially increased, rendering increasing challenges of data postprocessing, such as large amounts of noise, background signal interferences, as well as image registration deviations caused by sample position changes and scan deviations, and etc. Deep learning (DL) is a powerful tool widely used in data analysis and image reconstruction. This tool enables the automatic feature extraction of data by building and training a neural network model, and achieves comprehensive and in-depth analysis of target data through transfer learning, which has great potential for MSI data analysis. This paper reviews the current research status, application progress and challenges of DL in MSI data analysis, focusing on four core stages: data preprocessing, image reconstruction, cluster analysis, and multimodal fusion. The application of a combination of DL and mass spectrometry imaging in the study of tumor diagnosis and subtype classification is also illustrated. This review also discusses trends of development in the future, aiming to promote a better combination of artificial intelligence and mass spectrometry technology.

Vancomycin-Loaded Sol-Gel System for In Situ Coating of Artificial Bone to Prevent Surgical Site Infections.

Surgical site infections (SSIs) related to implants have always been a major challenge for clinical doctors and patients. Clinically, doctors may directly apply antibiotics into the wound to prevent SSIs. However, this strategy is strongly associated with experience of doctors on the amount and the location of antibiotics. Herein, an in situ constructable sol-gel system is developed containing antibiotics during surgical process and validated the efficacy against SSIs in beagles. The system involves chitosan (CS), ß-glycerophosphate (ß-GP) and vancomycin (VAN), which can be adsorbed onto porous hydroxyapatite (HA) and form VAN-CS/ß-GP@HA hydrogel in a short time. The VAN concentration from VAN-CS/ß-GP@HA hydrogel is higher than minimum inhibitory concentration (MIC) against Staphylococcus aureus (S. aureus) at the 21st day in vitro. In an in vivo canine model for the prevention of SSIs in the femoral condyle, VAN-CS/ß-GP@HA exhibits excellent biocompatibility, antimicrobial properties, and promotion of bone healing. In all, the CS/ß-GP instant sol-gel system is able to in situ encapsulate antibiotics and adhere on artificial bone implants during the surgery, effectively preventing SSIs related to implants.

Esophageal button battery impactions in children: an analysis of 89 cases.

OBJECTIVE: To analyze the clinical characteristics of esophageal button battery impactions in children and explore safe and effective treatment methods. METHODS: This retrospective cohort study was conducted at a single tertiary care center, Shenzhen Children's Hospital, encompassing 89 children diagnosed with esophageal button battery impactions between January 2013 and January 2023. To minimize esophageal mucosal corrosion, prompt removal of the button battery with a first-aid fast track rigid esophagoscopy under general anesthesia was performed within thirty minutes of diagnosis. The clinical features and complications were recorded and analyzed. RESULTS: Button battery as esophageal foreign body was prevalent among children under 3 years old (79.8%), with boys exhibiting a higher incidence rate (56.2%) compared to girls (43.8%), and an average age of 25.8 months. The median duration from ingestion to hospital admission was 3 h (range: 0.5 h to 3 months). Common symptoms included vomiting and dysphagia, with early stage vomiting of brown foamy secretions being a characteristic presentation of esophageal button battery impactions. The majority (77.5%) of batteries were lodged in the upper esophagus. The larger batteries were verified to be more prone to complications. All 89 cases exhibited varying degrees of esophageal mucosal erosion, with 31 cases (34.8%) experiencing severe complications, including esophageal stenosis in 11 cases (35.5%), esophageal perforation in 9 cases (29%) with 4 cases of tracheoesophageal fistula, vocal cord paralysis in 6 cases (19.4%), hemorrhage in 2 cases (6.5%), mediastinitis in 2 cases (6.5%), and periesophageal abscess in 1 case (3.2%). Despite the severity of these complications, none of the patients died after emergency surgery. CONCLUSION: Esophageal button battery impactions can lead to significant damage to the esophageal mucosa due to its strong corrosiveness. Prompt action is crucial to mitigate the risk of complications. For the first time, we implement a first-aid fast track surgical intervention following diagnosis is imperative to minimize the incidence of adverse outcomes.

Engineering Glucosamine-6-Phosphate Synthase to Achieve Efficient One-Step Biosynthesis of Glucosamine.

As an important functional monosaccharide, glucosamine (GlcN) is widely used in fields such as medicine, food nutrition, and health care. Here, we report a distinct GlcN biosynthesis method that utilizes engineered Bacillus subtilis glucosamine-6-phosphate synthase (BsGlmS) to convert D-fructose to directly generate GlcN. The best variant obtained by using a combinatorial active-site saturation test/iterative saturation mutagenesis (CAST/ISM) strategy was a quadruple mutant S596D/V597G/S347H/G299Q (BsGlmS-BK19), which has a catalytic activity 1736-fold that of the wild type toward D-fructose. Upon using mutant BK19 as a whole-cell catalyst, D-fructose was converted into GlcN with 65.32% conversion in 6 h, whereas the wild type only attained a conversion rate of 0.31% under the same conditions. Molecular docking and molecular dynamics simulations were implemented to provide insights into the mechanism underlying the enhanced activity of BK19. Importantly, the BsGlmS-BK19 variant specifically catalyzes D-fructose without the need for phosphorylated substrates, representing a significant advancement in GlcN biosynthesis.

Divergent Synthesis of Scabrolide A and Havellockate via an exo-exo-endo Radical Cascade.

Here we report a concise and divergent synthesis of scabrolide A and havellockate, representative members of polycyclic marine natural product furano(nor)cembranoids. The synthesis features a highly efficient exo-exo-endo radical cascade. Through the generation of two rings, three C-C bonds, and three contiguous stereocenters in one step, this remarkable transformation not only assembles the bowl-shaped, common 6-5-5 fused ring system from simple building blocks but also precisely installs the functionalities at desired positions and sets the stage for further divergent preparation of both target molecules. Further studies reveal that the robust and unusual 6-endo radical addition in the cascade is likely facilitated by the rigidity of the substrate.

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Two new withanolides from Physalis minima L.

Two new withanolides named physaminilides L (1) and M (2), together with four known ones (3-6) were isolated from the Physalis minima L. The structures were established by analysis of the HR ESIMS, IR and NMR spectroscopic data. The absolute configurations were determined through NOESY and ECD spectra. For compounds 1-5 assayed at 20 µM and compound 6 at 10 µM, inhibition rates of hepatic fibrosis were 22.19%, 15.29%, 37.07%, 9.27%, 12.45%, and 37.03%, respectively.

Uric acid-lowering effect of harpagoside and its protective effect against hyperuricemia-induced renal injury in mice.

Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1ß in the kidney. Harp was a promising anti-HUA agent.

Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy.

Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N6-methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels.

Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.