Exome functional risk score and brain connectivity can predict social adaptability outcome of children with autism spectrum disorder in 4 years' follow up.

Introduction: Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder emerging in early childhood, with heterogeneous clinical outcomes across individuals. This study aims to recognize neuroimaging genetic factors associated with outcomes of ASD after a 4-year follow-up. Methods: A total of 104 ASD children were included in this study; they underwent clinical assessments, MRI data acquisition, and the whole exome sequencing (WES). Exome functional risk score (EFRS) was calculated based on WES; and two modalities of brain connectivity were constructed based on MRI data, that is functional connectivity (FC) for functional MRI (fMRI), and individual differential structural covariance network (IDSCN) for structural MRI (sMRI), to explore the neuroimaging genetic biomarker of outcomes of ASD children. Results: Regression analysis found EFRS predicts social adaptability at the 4-year follow-up (Y = -0.013X + 9.29, p = 0.003). We identified 19 pairs of FC associated with autism symptoms severity at follow-up, 10 pairs of FC and 4 pairs of IDSCN associated with social adaptability at follow-up, and 10 pairs of FC associated with ASD EFRS by support vector regression (SVR). Related brain regions with prognostic predictive effects are mainly distributed in superior frontal gyrus, occipital cortex, temporal cortex, parietal cortex, paracentral lobule, pallidum, and amygdala for FC, and temporal cortex, thalamus, and hippocampus for IDSCN. Mediation model showed that ASD EFRS affects the social communication of ASD children through the mediation of FC between left middle occipital gyrus and left pallidum (RMSEA=0.126, CMIN=80.66, DF=42, p< 0.001, CFI=0.867, AIC=152). Discussion: Our findings underscore that both EFRS and brain connectivity can predict social adaptability, and that brain connectivity serving as mediator in the relationship of EFRS and behaviors of ASD, suggesting the intervention targets in the future clinical application.

Metagenomic and Antibiotic Resistance Analysis of the Gut Microbiota in Larus relictus and Anatidae Species Inhabiting the Honghaizi Wetland of Ordos, Inner Mongolia, from 2021 to 2023.

Gut microbes thrive by utilising host energy and, in return, provide valuable benefits, akin to a symbiotic relationship. Here, metagenomic sequencing was performed to characterise and compare the community composition, diversity and antibiotic resistance of the gut microbiota of Relict gull (Larus relictus) and Anatidae species. Alpha diversity analysis revealed that the intestinal microbial richness of L. relictus was significantly lower than that of Anatidae, with distinct differences observed in microbial composition. Notably, the intestines of L. relictus harboured more pathogenic bacteria such as clostridium, which may contribute to the decline in their population and endangered status. A total of 117 strains of Escherichia coli were isolated, with 90.60% exhibiting full susceptibility to 21 antibiotics, while 25.3% exhibited significant biofilm formation. Comprehensive Antibiotic Resistance Database data indicated that glycopeptide resistance genes were the most prevalent type carried by migratory birds, alongside quinolone, tetracycline and lincosamide resistance genes. The abundance of resistance genes carried by migratory birds decreased over time. This metagenomic analysis provides valuable insights into the intestinal microbial composition of these wild bird species, offering important guidance for their conservation efforts, particularly for L. relictus, and contributing to our understanding of pathogen spread and antibiotic-resistant bacteria.

Exacerbated lung inflammation in offspring with high maternal antibody levels following secondary RSV exposure.

Respiratory syncytial virus (RSV) is the primary cause of bronchiolitis-related hospitalizations among children under 5 years of age, with reinfection being common throughout life. Maternal vaccination has emerged as a promising strategy, delivering elevated antibody levels to newborns for immediate protection. However, limited research has explored the protective efficacy of maternal antibodies (matAbs) against secondary RSV infections in offspring. To address this gap, we employed a mouse model of maternal RSV vaccination and secondary infection of offspring to evaluate lung pathology following RSV reinfection in mice with varying levels of maternal antibody (matAb). Additionally, we aimed to investigate the potential causes of exacerbated lung inflammation in offspring with high matAb levels following secondary RSV exposure. Our findings revealed that offspring with elevated levels of maternal pre-F antibody demonstrated effective protection against lung pathology following the initial RSV infection. However, this protection was compromised upon reinfection, manifesting as heightened weight loss, exacerbated lung pathology, increased expression of RSV-A N genes, eosinophilia, enhanced IL-5, IL-13, MUC5AC, and eosinophils Major Basic Protein (MBP) production in lung tissue compared to offspring lacking matAbs. Importantly, these unexpected outcomes were not attributed to antibody-dependent enhancement (ADE) resulting from declining matAb levels over time. Notably, our findings showed a decline in secretory IgA (sIgA), mucosal IgA, and mucosal IgG levels in offspring with high matAb levels post-primary RSV challenge. We propose that this decline may be a critical factor contributing to the ineffective protection observed during secondary RSV exposure. Overall, these findings offer valuable insights into maternal vaccination against RSV, contributing to a comprehensive understanding and mitigation of potential risks associated with maternal RSV vaccination.

A Zn2+ cross-linked sodium alginate/epigallocatechin gallate hydrogel scaffold for promoting skull repair.

The optimal material for repairing skull defects should exhibit outstanding biocompatibility and mechanical properties. Specifically, hydrogel scaffolds that emulate the microenvironment of the native bone extracellular matrix play a vital role in promoting osteoblast adhesion, proliferation, and differentiation, thereby yielding superior outcomes in skull reconstruction. In this study, a composite network hydrogel comprising sodium alginate (SA), epigallocatechin gallate (EGCG), and zinc ions (Zn2+) was developed to establish an ideal osteogenic microenvironment for bone regeneration. Initially, physical entanglement and hydrogen bonding between SA and EGCG resulted in the formation of a primary network hydrogel known as SA-EGCG. Subsequently, the inclusion of Zn2+ facilitated the creation of a composite network hydrogels named SA-EGCG-Zn2+ via dynamic coordination bonds with SA and EGCG. The engineered SA-EGCG2 %-Zn2+ hydrogels offered an environment mimicking the native extracellular matrix (ECM). Moreover, the sustained release of Zn2+ from the hydrogel effectively enhanced cell adhesion, promoted proliferation, and stimulated osteoblast differentiation. In vitro experiments have shown that SA-EGCG2 %-Zn2+ hydrogels greatly enhance the attachment and growth of osteoblast precursor cells (MC3T3-E1), while also increasing the expression of genes related to osteogenesis in these cells. Additionally, in vivo studies have confirmed that SA-EGCG2 %-Zn2+ hydrogels promote new bone formation and accelerate the regeneration of bone in situ, indicating promising applications in the realm of bone tissue engineering.

The role of sirtuin1 in liver injury: molecular mechanisms and novel therapeutic target.

Liver disease is a common and serious threat to human health. The progression of liver diseases is influenced by many physiologic processes, including oxidative stress, inflammation, bile acid metabolism, and autophagy. Various factors lead to the dysfunction of these processes and basing on the different pathogeny, pathology, clinical manifestation, and pathogenesis, liver diseases are grouped into different categories. Specifically, Sirtuin1 (SIRT1), a member of the sirtuin protein family, has been extensively studied in the context of liver injury in recent years and are confirmed the significant role in liver disease. SIRT1 has been found to play a critical role in regulating key processes in liver injury. Further, SIRT1 seems to cause divers outcomes in different types of liver diseases. Recent studies have showed some therapeutic strategies involving modulating SIRT1, which may bring a novel therapeutic target. To elucidate the mechanisms underlying the role of sirtuin1 in liver injury and its potentiality as a therapeutic target, this review outlines the key signaling pathways associated with sirtuin1 and liver injury, and discusses recent advances in therapeutic strategies targeting sirtuin1 in liver diseases.

Deletion of Tgm2 suppresses BMP-mediated hepatocyte-to-cholangiocyte metaplasia in ductular reaction.

Transglutaminase 2 (Tgm2) plays an essential role in hepatic repair following prolonged toxic injury. During cholestatic liver injury, the intrahepatic cholangiocytes undergo dynamic tissue expansion and remodelling, referred to as ductular reaction (DR), which is crucial for liver regeneration. However, the molecular mechanisms governing the dynamics of active cells in DR are still largely unclear. Here, we generated Tgm2-knockout mice (Tgm2-/-) and Tgm2-CreERT2-Rosa26-mTmG flox/flox (Tgm2CreERT2-R26T/Gf/f) mice and performed a three-dimensional (3D) collagen gel culture of mouse hepatocytes to demonstrate how Tgm2 signalling is involved in DR to remodel intrahepatic cholangiocytes. Our results showed that the deletion of Tgm2 adversely affected the functionality and maturity of the proliferative cholangiocytes in DR, thus leading to more severe cholestasis during DDC-induced liver injury. Additionally, Tgm2 hepatocytes played a crucial role in the regulation of DR through metaplasia. We unveiled that Tgm2 regulated H3K4me3Q5ser via serotonin to promote BMP signalling activation to participate in DR. Besides, we revealed that the activation or inhibition of BMP signalling could promote or suppress the development and maturation of cholangiocytes in DDC-induced DR. Furthermore, our 3D collagen gel culture assay indicated that Tgm2 was vital for the development of cholangiocytes in vitro. Our results uncovered a considerable role of BMP signalling in controlling metaplasia of Tgm2 hepatocytes in DR and revealed the phenotypic plasticity of mature hepatocytes.

[Effect of Emotion Regulation on Anxiety/Depression Symptoms in Children With Attention-Deficit/Hyperactivity Disorder: The Mediating Role of Social Problems and the Moderating Role of Family Functioning]. / æƒ ç»ªè°ƒèŠ‚ä¸Žæ³¨æ„ç¼ºé™·å¤šåŠ¨éšœç¢æ‚£å„¿ç„¦è™‘/抑郁症状：社交问题的中介效应和家庭功能的调节.

Objective: To investigate the mediating effect of social problems in the effect pathway of emotional dysregulation influencing anxiety/depression emotions in children with attention-deficit/hyperactivity disorder (ADHD) and to explore the potential moderating effect of family functionality. Methods: A total of 235 children diagnosed with ADHD were enrolled in the study. The paticipants' age ranged from 6 to 12. Emotion Regulation Checklist, Achenbach's Child Behavior Checklist (CBCL) Social Problems Subscale, CBCL Anxious/Depressed Subscale, and Family Assessment Device were used to evaluate the emotional regulation, social problems, anxiety/depression emotions, and family functionality of the participants. A moderated mediation model was employed to analyze whether social problems and family functionality mediate and moderate the relationship between emotional regulation and anxiety/depression emotions. Results: Social problems partially mediated the impact of emotional dysregulation on anxiety/depression emotions in ADHD children, with the direct effect being 0.26 (95% confidence interval [CI]: [0.17, 0.36], P<0.001), the indirect effect being 0.13 (95% CI: [0.07, 0.19], P<0.001), and the mediating effect accounting for 33% of the total effect. Family functionality exhibited a positive moderating effect on the relationship between social problems and anxiety/depression emotions. Conclusion: This study contributes to the understanding of complex factors influencing anxiety/depression in children with ADHD, providing reference for the further development of targeted interventions for children with ADHD and the improvement of prognosis.

An in vitro comparative study on clot lysis efficiency of urokinase and reteplase with the synergy of ultrasound needle.

Objectives: Ultrasound Needle, which is an improved ultrasonic horn device, has shown great potential for promoting the diffusion of thrombolytic drugs within clots and enhancing clot lysis efficiency. However, the clot lysis efficiency of different thrombolytic drugs with the synergy of Ultrasound Needle remains unknown. In this study, we aimed to compare the lysis efficiency of the non-fibrin-specific drug urokinase and fibrin-specific drug reteplase with the synergy of Ultrasound Needle. Materials and methods: Twenty-five milliliters of human blood was incubated for 1.5 h to form in vitro clots and then received the corresponding treatment protocols: control group (normal saline), US group (10 min of Ultrasound Needle treatment), UK group (30000IU of urokinase), r-PA group (2 mg of reteplase), US + UK group, and US + r-PA group. After treatment, the morphological changes of the clots were analyzed by B-mode ultrasound imaging and hematoxylin and eosin (H&E) staining. Lysis efficiency was evaluated based on the relative end weight (final weight/initial weight). The fibrin density of the different groups after treatment was assessed by immunofluorescence staining. Results: Morphological examination and relative end weight analysis showed that combination therapies induced a more thorough dissolution of clots compared with single therapies, and the US + r-PA group exhibited higher lysis efficiency than the US + UK group. In addition, immunofluorescence staining showed that the US + r-PA group had fewer remaining thrombus fibrins than the US + UK group after treatment. Conclusions: The Ultrasound Needle can significantly improve the clot lysis efficiency of both fibrinolytic drugs, and fibrin-specific reteplase exhibited superior lysis efficiency over non-fibrin-specific urokinase with the synergy of the Ultrasound Needle.

Mechanistic Insights into the Discharge Processes of Li-CO2 Batteries.

Li-CO2 batteries facilitate renewable energy storage in a cost-effective, eco-friendly manner. However, an inadequate understanding of their reaction mechanism severely impedes their development. Here we outline recent mechanistic advances in the discharge processes of Li-CO2 batteries, particularly in terms of the theoretical aspect. First, the vital factors affecting the formation of discharge intermediates are highlighted, and a surface lithiation mechanism predominantly applicable to catalysts with weak CO2 adsorption is proposed. Subsequently, the modeling of the chemical potential of Li++e-, which is crucial for the evaluation of the theoretical limiting voltage, is detailed. Finally, challenges and future directions pertaining to the further development of Li-CO2 are discussed. In essence, this concept article seeks to inspire future experimental and theoretical studies in advancing the development of Li-CO2 electrochemical technology.

The efficacy and safety of aspirin-ticagrelor vs. aspirin-clopidogrel in ischemic stroke patients with cerebral artery stenting.

OBJECTIVE: First, the efficacy and safety of aspirin-ticagrelor after cerebral artery stenting in ischemic stroke patients is controversial. Second, there is a gap in the research on guiding two antiplatelet therapy (DAPT) after stenting based on the CYP2C19 genotype. METHODS: This retrospective study included patients who underwent cerebral artery stenting at the First Affiliated Hospital of Chongqing Medical University from January 2019 to February 2023. We divided them into the aspirin-clopidogrel group and aspirin-ticagrelor group and carefully collected baseline information laboratory data and imaging results from the patients. The efficacy outcomes were 30 days recurrent stroke, 90 days recurrent stroke, and 180 days recurrent stroke, and the safety outcome was intracranial hemorrhage. T-tests or Fisher's tests were performed for study outcomes in both groups of patients. OUTCOME: A total of 372 patients were included. For efficacy outcomes, aspirin-ticagrelor was associated with a reduced risk of 180 days recurrent stroke, in patients with CYP2C19 LOF allele (OR = 0.426, CI = 0.184-0.986, P = 0.042) and CYP2C19 intermediate metabolic genotype (OR = 0.237, CI = 0.026-1.034, P = 0.044), compared with aspirin-clopidogrel. There was no significant difference in the rate of intracranial hemorrhage (ICH) between patients with aspirin-clopidogrel and aspirin-ticagrelor, regardless of overall (OR = 1.221, CI = 0.115-7.245, P = 0.683), CYP2C19 LOF allele carriers (OR = 1.226, CI = 0.411-3.658, P = 0.715), or CYP2C19 intermediate metabolizer (OR = 1.221, CI = 0.115-7.245, P = 0.683). No significant differences were found between the two DAPTs on other efficacy and safety outcomes. CONCLUSION: A cohort study found that aspirin-ticagrelor was significantly superior to aspirin-clopidogrel in reducing 180 days recurrent stroke in CYP2C19 LOF allele carriers and CYP2C19 intermediate metabolizers. There was no significant difference between aspirin-ticagrelor and aspirin-clopidogrel in the risk of intracranial hemorrhage in terms of ICH rates.

Enhancement of Tumor Perfusion and Antiangiogenic Therapy in Murine Models of Clear Cell Renal Cell Carcinoma Using Ultrasound-Stimulated Microbubbles.

OBJECTIVE: To explore the effect of ultrasound-stimulated microbubble cavitation (USMC) on enhancing antiangiogenic therapy in clear cell renal cell carcinoma. MATERIALS AND METHODS: We explored the effects of USMC with different mechanical indices (MIs) on tumor perfusion, 36 786-O tumor-bearing nude mice were randomly assigned into four groups: (i) control group, (ii) USMC0.25 group (MI = 0.25), (iii) USMC1.4 group (MI = 1.4) (iv) US1.4 group (MI = 1.4). Tumor perfusion was assessed by contrast-enhanced ultrasound (CEUS) before the USMC treatment and 30 min, 4h and 6h after the USMC treatment, respectively. Then we evaluated vascular normalization(VN) induced by low-MI (0.25) USMC treatment, 12 tumor-bearing nude mice were randomly divided into two groups: (i) control group (ii) USMC0.25 group. USMC treatment was performed, and tumor microvascular imaging and blood perfusion were analyzed by MicroFlow imaging (MFI) and CEUS 30 min after each treatment. In combination therapy, a total of 144 tumor-bearing nude mice were randomly assigned to six groups (n = 24): (i) control group, (ii) USMC1.4 group, (iii) USMC0.25 group, (iv) bevacizumab(BEV) group, (v) USMC1.4 +BEV group, (vi) USMC0.25 +BEV group. BEV was injected on the 6th, 10th, 14th, and 18th d after the tumors were inoculated, while USMC treatment was performed 24 h before and after every BEV administration. We examined the effects of the combination therapy through a series of experiments. RESULTS: Tumor blood perfusion enhanced by USMC with low MI (0.25)could last for more than 6h, inducing tumor VN and promoting drug delivery. Compared with other groups, USMC0.25+BEV combination therapy had the strongest inhibition on tumor growth, led to the longest survival time of the mice. CONCLUSION: The optimized USMC is a promising therapeutic approach that can be combined with antiangiogenic therapy to combat tumor progression.

Natural diterpenoid EKO activates deubiqutinase ATXN3 to preserve vascular endothelial integrity and alleviate diabetic retinopathy through c-fos/focal adhesion axis.

Diabetic retinopathy (DR) is one of the most prevalent severe diabetic microvascular complications caused by hyperglycemia. Deciphering the underlying mechanism of vascular injury and finding ways to alleviate hyperglycemia induced microvascular complications is of great necessity. In this study, we identified that a compound ent-9α-hydroxy-15-oxo-16-kauren-19-oic acid (EKO), the diterpenoid isolated and purified from Pteris semipinnata L., exhibited good protective roles against vascular endothelial injury associated with diabetic retinopathy in vitro and in vivo. To further uncover the underlying mechanism, we used unbiased transcriptome sequencing analysis and showed substantial impairment in the focal adhesion pathway upon high glucose and IL-1ß stimulation. EKO could effectively improve endothelial focal adhesion pathway by enhancing the expression of two focal adhesion proteins Vinculin and ITGA11. We found that c-fos protein was involved in regulating the expression of Vinculin and ITGA11, a transcription factor component that was downregulated by high glucose and IL-1ß stimulation and recovered by EKO. Mechanically, EKO facilitated the binding of deubiquitylation enzyme ATXN3 to c-fos protein and promoted its deubiquitylation, thereby elevating its protein level to enhance the expression of Vinculin and ITGA11. Besides, EKO effectively suppressed ROS production and restored mitochondrial function. In vivo studies, we confirmed EKO could alleviate some of the indicators of diabetic mice. In addition, protein levels of ATXN3 and focal adhesion Vinculin molecule were also verified in vivo. Collectively, our findings addressed the endothelial protective role of natural diterpenoid EKO, with emphasize of mechanism on ATXN3/c-fos/focal adhesion signaling pathway as well as oxygen stress suppression, implicating its therapeutic potential in alleviating vascular endothelium injury and diabetic retinopathy.

Review on Frontal Polymerization Behavior for Thermosetting Resins: Materials, Modeling and Application.

The traditional curing methods for thermosetting resins are energy-inefficient and environmentally unfriendly. Frontal polymerization (FP) is a self-sustaining process relying on the exothermic heat of polymerization. During FP, the external energy input (such as UV light input or heating) is only required at the initial stage to trigger a localized reaction front. FP is regarded as the rapid and energy-efficient manufacturing of polymers. The precise control of FP is essential for several manufacturing technologies, such as 3D printing, depending on the materials and the coupling of thermal transfer and polymerization. In this review, recent progress on the materials, modeling, and application of FP for thermosetting resins are presented. First, the effects of resin formulations and mixed fillers on FP behavior are discussed. Then, the basic mathematical model and reaction-thermal transfer model of FP are introduced. After that, recent developments in FP-based manufacturing applications are introduced in detail. Finally, this review outlines a roadmap for future research in this field.

Influence of protonic acid on the structure and properties of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) in oxidation polymerization.

Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is widely used because of its excellent performance. We report the synthesis of two PEDOT:PSS dispersions. The two dispersions differ by the addition of additional protonic acid in the oxidative polymerization system. Although there are examples of the introduction of acids into the polymerization system, the effects of acid on the structure and properties of these materials, in particular their mechanisms of action, have not been elucidated. We describe the chemical structure and molecular weight of two PEDOT polymers using Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, UV-vis-NIR spectroscopy, and density functional theory calculations. The carrier concentration, carrier mobility, and surface morphology of the composites are characterized by UV-vis-NIR spectroscopy, electron spin resonance, Raman spectra, Hall effect measurements, and atomic force microscopy. The crystallinity of PEDOT:PSS was measured by X-ray diffraction patterns. We show that the addition of a proper amount of protonic acid to the oxidative polymerization system can effectively reduce the formation of the terminal carbonyl group of PEDOT chains, which is conducive to the growth of polymer chains, and further improve the carrier concentration, which leads to an improvement of conductivity. Our results highlight the optimization of the chemical structure of PEDOT in order to increase its molecular weight and ultimately its conductivity.

Association between physical activity and diet quality of obese and non-obese MAFLD.

BACKGROUND AND AIM: Clinical data on the prevalence of metabolic-associated fatty liver disease (MAFLD) in obese and non-obese individuals within a diverse US population is scarce. Furthermore, the influence of physical activity (PA) and dietary quality (DQ) on MAFLD risk remains unclear. This study aims to assess the prevalence and clinical features of MAFLD and examine the relationship between PA and DQ with the risk of developing MAFLD. METHODS AND RESULTS: A cross-sectional analysis of data from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) was conducted. The overall MAFLD prevalence was 41.9%, with 28.6% of participants being obese and 13.4% non-obese. Among those with MAFLD, 67.1% (95% confidence interval (CI): 59.1%-75.1%) were obese, and 32.9% (95% CI: 29.1%-36.7%) were non-obese. Non-obese MAFLD was more frequent in Asians (27.2%), while obese MAFLD was more prevalent in Blacks (66.3%). Metabolic comorbidities were more common in individuals with obese MAFLD, who also exhibited more advanced fibrosis. A high-quality diet (HQD) and increased PA were linked to reduced odds of both obese and non-obese MAFLD (odds ratio (OR) and 95% CI: 0.67 [0.51-0.88] and 0.57 [0.47-0.69]; 0.62 [0.43-0.90] and 0.63 [0.46-0.87], respectively). PA and HQD significantly decreased the risk of obese and non-obese MAFLD (OR and 95% CI: 0.46 [0.33-0.64] and 0.42 [0.31-0.57]). CONCLUSION: A substantial proportion of the US population is affected by both obese and non-obese MAFLD. A strong association exists between a lower risk of both types of MAFLD and adherence to an HQD and engagement in PA.

BiTiS3 bio-transducer with explosive on-demand generation of NO gas for synergetic cancer therapy.

Combined photothermal therapy and nitric oxide (NO)-mediated gas therapy has shown great potential as a cancer treatment. However, the on-demand release of NO at a high concentration presents a challenge owing to the lack of an ideal bio-transducer with a high loading capacity of NO donors and sufficient energy to induce NO release. Here, we present a new 2D BiTiS3 nanosheet that is synthesized, loaded with the NO donor (BNN6), and conjugated with PEG-iRGD to produce a multifunctional bio-transducer (BNN6-BiTiS3-iRGD) for the on-demand production of NO. The BiTiS3 nanosheets not only have a high loading capacity of NO donors (750%), but also exhibit a high photothermal conversion efficiency (59.5%) after irradiation by a 1064-nm laser at 0.5 W/cm2. As a result of the above advantages, the temporal-controllable generation of NO within a large dynamic range (from 0 to 344 µM) is achieved by adjusting power densities, which is among the highest efficiency values reported for NO generators so far. Moreover, the targeted accumulation of BNN6-BiTiS3-iRGD at tumor sites leads to spatial-controllable NO release. In vitro and in vivo assessments demonstrate synergistic NO gas therapy with mild photothermal therapy based on BNN6-BiTiS3-iRGD. Our work provides insights into the design and application of other 2D nanomaterial-based therapeutic platforms.

Heat shock induces HuR-dependent MKP-1 posttranslational regulation through the p38 MAPK signaling cascade.

Previous studies demonstrated that phosphatases play a pivotal role in modulating inflammation-associated signal transduction, particularly in the context of heat shock, where Mitogen-Activated Protein Kinase Phosphatase-1 (MKP-1) appears to have a central role. Recently, Human Antigen R (HuR) has also been identified as a factor that enhances stress-response protein MKP-1 levels. Consequently, we have directed our interest towards elucidating the mechanisms by which heat shock induces MKP-1 mRNA stabilization, dependent on HuR via the p38 MAPK Signaling Cascade. In this study, we subjected Mouse Embryonic Fibroblast (Mef) cells to heat shock treatment, resulting in a potent stabilization MKP-1 mRNA. The RNA-binding protein HuR, known to influence mRNA, was observed to bind to the MKP-1 AU-rich 3 ´untranslated region. Transfection of p38 wild-type Mef cells with a flag-HuR plasmid resulted in a significant increase in MKP-1 mRNA stability. Interestingly, transfection of the siRNA for HuR into Mef cells resulted in diminished MKP-1 mRNA stability following heat shock, inhibition of p38 MAPK activity effectively curtailed heat shock-mediated MKP-1 mRNA stability. Immunofluorescence analyses further revealed that the translocation of HuR was contingent on p38 MAPK Signaling Cascade. Collectively, these findings underscore the regulatory role of heat shock in MKP-1 gene expression at posttranscriptional levels. The mechanisms underlying the observed increased MKP-1 mRNA stability are shown to be partially dependent on HuR through the p38 MAPK Signaling Cascade.

Ultrasound-Induced Tumor Perfusion Changes and Doxorubicin Delivery: A Study on Pulse Length and Pulse Repetition Frequency.

OBJECTIVES: To investigate the appropriate combination of pulse length (PL) and pulse repetition frequency (PRF) when performing ultrasound stimulated microbubble (USMB) to enhance doxorubicin (DOX) delivery to tumors. METHODS: A total of 48 tumor-bearing mice were divided into four groups, namely groups A-D. The mice in groups B-D were treated with chemotherapy and USMB treatment with different combinations of PL and PRF, and group A was control. Contrast-enhanced ultrasound imaging was conducted to analyze tumor blood perfusion. Fluorescence microscopy and high-performance liquid chromatography were used to qualitatively and quantitatively analyse DOX release. The structural changes of tumors were observed under light microscope and transmission electron microscope. Furthermore, another 24 tumor-bearing mice were treated with sonochemotherapy and some related inflammatory factors were measured to explore the underlying mechanism. RESULTS: With PL of three cycles and PRF of 2 kHz, the tumor perfusion area ratio increased by 26.67%, and the DOX concentration was 4.69 times higher than the control (P < .001). With PL of 34.5 cycles and PRF of 200 Hz, the tumor perfusion area ratio decreased by 12.7% and DOX did not exhibit increased extravasation compared with the control. Microvascular rupture and hemorrhage were observed after long PL and low PRF treatment. While vasodilation and higher levels of some vasodilator inflammatory factors were found after treatment with short PL and high PRF. CONCLUSIONS: USMB treatment using short PL and high PRF could enhance tumor blood perfusion and increase DOX delivery, whereas long PL and low PRF could not serve the same purpose.

Clinical sonochemotherapy of inoperable pancreatic cancer using diagnostic ultrasound and microbubbles: a multicentre, open-label, randomised, controlled trial.

OBJECTIVES: Sonochemotherapy, which uses microbubble (MB)-assisted ultrasound (US) to deliver chemotherapeutic agents, has the potential to enhance tumour chemotherapy. The combination of US and MB has been demonstrated to prolong the survival of patients with pancreatic cancer. This phase 2 clinical trial aimed to determine the clinical efficacy and safety of sonochemotherapy for inoperable pancreatic ductal adenocarcinoma by using US and MB. METHODS: Eighty-two patients with stage III or IV pancreatic cancer were recruited from July 2018 to March 2021 and followed up until September 2022. US treatment was performed with a modified diagnostic US scanner for 30 min after chemotherapeutic infusion. The primary endpoint was overall survival (OS), and the secondary endpoints were Eastern Cooperative Oncology Group (ECOG) status < 2, progression-free survival (PFS), disease control rate (DCR), and adverse events. RESULTS: Seventy-eight patients were randomly allocated (40 to chemotherapy and 38 to sonochemotherapy). The median OS was longer with sonochemotherapy than with chemotherapy (9.10 vs. 6.10 months; p = 0.037). The median PFS with sonochemotherapy was 5.50 months, compared with 3.50 months (p = 0.080) for chemotherapy. The time of ECOG status < 2 was longer with sonochemotherapy (7.20 months) than with chemotherapy (5.00 months; p = 0.029). The DCR was 73.68% for sonochemotherapy compared with 42.50% for the control (p = 0.005). The incidence of overall adverse events was balanced between the two groups. CONCLUSIONS: The use of sonochemotherapy can extend the survival and well-being time of stage III or IV pancreatic cancer patients without any increase in serious adverse events. TRIAL REGISTRATION: ChineseClinicalTrials.gov ChiCTR2100044721 CLINICAL RELEVANCE STATEMENT: This multicentre, randomised, controlled trial has proven that sonochemotherapy, namely, the combination of diagnostic ultrasound, microbubbles, and chemotherapy, could extend the overall survival of patients with end-stage pancreatic ductal adenocarcinoma from 6.10 to 9.10 months without increasing any serious adverse events. KEY POINTS: • This is the first multicentre, randomised, controlled trial of sonochemotherapy for clinical pancreatic cancer treatment using ultrasound and a commercial ultrasound contrast agent. • Sonochemotherapy extended the median overall survival from 6.10 (chemotherapy alone) to 9.10 months. • The disease control rate increased from 42.50% with chemotherapy to 73.68% with sonochemotherapy.

Activated Tim-3/Galectin-9 participated in the development of multiple myeloma by negatively regulating CD4 T cells.

The interaction between Tim-3 on T cells and its ligand Galectin-9 negatively regulates the cellular immune response. However, the regulation of Tim-3/Galectin-9 on CD4 T cell subsets in multiple myeloma (MM) remains unclear. The aim of this study was to investigate the relationship between the regulation of CD4 T cell subsets by the Tim-3/Galectin-9 pathway and clinical prognostic indicators in MM. Tim-3/Galectin-9 were detected by flow cytometry, PCR and ELISA in 60 MM patients and 40 healthy controls, and its correlation with clinical prognostic parameters was analyzed. The expressions of Tim-3 on CD4 T cells, Galectin-9 mRNA in PBMC and level of Galectin-9 protein in serum were significantly elevated in MM patients, especially those with poor prognostic indicators. In MM patients, Tim-3 was highly expressed on the surfaces of Th1, Th2, and Th17 cells, but lowly expressed on Treg. Moreover, level of cytokine IFN-γ in serum was negatively correlated with Tim-3+Th1 cell and Galectin-9mRNA, Galectin-9 protein level. In addition, cell culture experiments showed that the anti-tumor effect and the ability to secrete IFN-γ were restored by blocking the Tim-3/Galectin-9 pathway. In MM patients, Tim-3/Galectin-9 is elevated and associated with disease progression, by inhibiting the cytotoxic function of Th1, and also promoting Th2 and Th17 to be involved in immune escape of MM. Therefore, Tim-3/Galectin-9 may serve as a new immunotherapeutic target for MM patients.