Nickel atom-clusters nanozyme for boosting ferroptosis tumor therapy.

The translation of Fe-based agents for ferroptosis tumor therapy is restricted by the unstable iron valence state, the harsh catalytic environment, and the complex tumor self-protection mechanism. Herein, we developed a stable nickel-based single-atom-metal-clusters (NSAMCs) biocatalyst for efficient tumor ferroptosis therapy. NSAMCs with a nanowire-like nanostructure and hydrophilic functional groups exhibit good water-solubility, colloidal stability, negligible systemic toxicity, and target specificity. In particular, NSAMCs possess excellent peroxidase-like and glutathione oxidase-like activities through the synergistic influence between metal clusters and single atoms. The dual-enzymatic performance enables NSAMCs to synergistically promote efficient ferroptosis of cancer cells through lipid peroxidization aggregation and glutathione peroxidase 4 inactivation. Importantly, NSAMCs highlight the boost of ferroptosis tumor therapy via the synergistic effect between single-atoms and metal clusters, providing a practical and feasible paradigm for further improving the efficiency of ferroptosis tumor treatment.

Association between IL-2 Receptor and Severe Coronary Artery Calcification in Patients with Coronary Artery Disease.

Background: Coronary artery calcification (CAC) is a crucial marker for coronary atherosclerosis, and the extent of CAC is closely linked to the incidence and progression of cardiovascular diseases. The interleukin-2 (IL-2) receptor (IL-2R), which plays a critical role in mediating the proliferation and differentiation of immune cells, may also be involved in the development of CAC. The study aimed to investigate the relationship between IL-2R and CAC, with the goal of providing new insights into cardiovascular diseases. Methods: In this study, we enrolled 606 patients diagnosed with coronary artery disease to assess CAC. Based on coronary artery calcification score (CACS), patients were divided into two groups: the non-severe CAC group (CACS ≤ 400 Agatston units, AU) and the severe CAC group (CACS > 400 AU). Results: The results showed that IL-2R levels were significantly higher in patients with severe CAC compared to those with non-severe CAC (383 vs. 352 pg/mL, p = 0.002). Moreover, the level of IL-2R was positively correlated with the severity of CAC, independent of other clinical risk factors. According to Receiver Operating Characteristic (ROC) curve, the IL-2R prediction model demonstrated a good capability in distinguishing severe CAC with the Area Under the Curve (AUC) value of 0.726. Conclusions: Our study suggests that IL-2R is independently associated with the occurrence of severe CAC in coronary artery disease (CAD) patients. Additionally, IL-2R may play a crucial role in the development of advanced atherosclerosis. Consequently, therapeutic strategies targeting the IL-2/IL-2R pathway may be effective in preventing or treating CAD.

Impacts of Left Atrial Appendage Treatments on Mitral Valve Diseases during Surgical Ablations.

Background: Left atrial appendages (LAAs) play an important role in regulating left atrial function, and much evidence supports the possibility that changes in left atrial structure may cause or worsen mitral regurgitation. This study intended to investigate the outcomes of patients with mitral regurgitation who underwent left atrial appendage closure (resection or endocardial closure) during isolated surgical ablations. Methods: Patients with mild or moderate mitral regurgitation who received isolated surgical ablations for atrial fibrillation (AF) in our center from 2013 to 2022 were referred. During follow-up, each clinical visit was composed of medical interrogation, a 24 h Holter, and echocardiographic evaluation. Death, atrial fibrillation, worsening of mitral regurgitation, and stroke were evaluated as outcomes. Freedom from outcomes whose results were adjusted by inverse probability of treatment weighting for causal effects after acquiring propensity scores. Results: A total of 456 patients were enrolled in this study. During a median follow-up of 48 months, 30 deaths and 11 cases of stroke were observed. After adjustments, no significant differences in terms of death or stroke were observed among the three groups. Patients who underwent resection or endocardial closure during surgical ablations had a higher risk of mitral regurgitation worsening during follow-up (p < 0.05). During the whole follow-up, patients who underwent left atrial appendage interventions showed significantly larger left atrial and mitral annular diameters, as well as lower tethering height than those who had left atrial appendage preserved (all p < 0.05). Conclusions: Mitral regurgitation was more likely to get worse when patients with fundamental mitral diseases underwent LAA interventions during isolated surgical AF ablations. In the absence of LAA, the dilation of the left atrium and mitral annulus may ultimately lead to worsening of regurgitation.

Flexible Positive Temperature Coefficient Composites (PVAc/EVA/GP-CNF) with Room Temperature Curie Point.

Polymeric positive temperature coefficient (PTC) materials with low switching temperature points are crucial for numerous electronic devices, which typically function within the room temperature range (0-40 °C). Ideal polymeric PTC materials for flexible electronic thermal control should possess a room-temperature switching temperature, low room-temperature resistivity, exceptional mechanical flexibility, and adaptive thermal control properties. In this study, a novel PTC material with a room-temperature switching temperature and superb mechanical properties has been designed. A blend of a semi-crystalline polymer EVA with a low melting temperature (Tm) and an amorphous polymer (PVAc) with a low glass transition temperature (Tg) was prepared. Low-cost graphite was chosen as the conductive filler, while CNF was incorporated as a hybrid filler to enhance the material's heating stability. PVAc0.4/EVA0.6/GP-3wt.% CNF exhibited the lowest room temperature resistivity, and its PTC strength (1.1) was comparable to that without CNF addition, with a Curie temperature of 29.4 °C. Room temperature Joule heating tests revealed that PVAc0.4/EVA0.6/GP-3wt.% CNF achieved an equilibrium temperature of approximately 42 °C at 25 V, with a heating power of 3.04 W and a power density of 3.04 W/cm2. The Young's modulus of PVAc0.4/EVA0.6/GP-3wt.% CNF was 9.24 MPa, and the toughness value was 1.68 MJ/m3, indicating that the elasticity and toughness of the composites were enhanced after mixing the fillers, and the mechanical properties of the composites were improved by blending graphite with CNF.

MXene-Based Skin-Like Hydrogel Sensor and Machine Learning-Assisted Handwriting Recognition.

Conductive hydrogels are widely used in flexible sensors owing to their adjustable structure, good conductivity, and flexibility. The performance of excellent mechanical properties, high sensitivity, and elastic modulus compatible with human tissues is of great interest in the field of flexible sensors. In this paper, the functional groups of trisodium citrate dihydrate (SC) and MXene form multiple hydrogen bonds in the polymer network to prepare a hydrogel with mechanical properties (Young's modulus (23.5-92 kPa) of similar human tissue (0-100 kPa)), sensitivity (stretched GF is 4.41 and compressed S1 is 5.15 MPa-1), and durability (1000 cycles). The hydrogel is able to sensitively detect deformations caused by strain and stress and can be used in flexible sensors to detect human movement in real time such as fingers, wrists, and walking. In addition, the combination of matrix sensing and machine learning was successfully used for handwriting recognition with an accuracy of 0.9744. The combination of machine learning and flexible sensors shows great potential in areas such as healthcare, information security, and smart homes.

Large-Area Layered Membranes with Precisely Controlled Nano-Confined Channels.

Two-dimensional (2D) nanosheets-based membranes, which have controlled 2D nano-confined channels, are highly desirable for molecular/ionic sieving and confined reactions. However, it is still difficult to develop an efficient method to prepare large-area membranes with high stability, high orientation, and accurately adjustable interlayer spacing. Here, we present a strategy to produce metal ion cross-linked membranes with precisely controlled 2D nano-confined channels and high stability in different solutions using superspreading shear-flow-induced assembly strategy. For example, membranes based on graphene oxide (GO) exhibit interlayer spacing ranging from 8.0±0.1 Što 10.3±0.2 Å, with a precision of down to 1 Å. At the same time, the value of the orientation order parameter (f) of GO membranes is up to 0.95 and GO membranes exhibit superb stability in different solutions. The strategy we present, which can be generalized to the preparation of 2D nano-confined channels based on a variety of 2D materials, will expand the application scope and provide better performances of membranes.

Bushen Huoxue decotion-containing serum prevents chondrocyte pyroptosis in a m6A-dependent manner in facet joint osteoarthritis.

BACKGROUND: Facet joint osteoarthritis (FJOA) is a common lumbar osteoarthritis characterized by degeneration of small joint cartilage. Bushen Huoxue decotion (BSHXD) has good therapeutic effects on OA. Our work aimed to further probe the pharmacological effects of BSHXD-containing serum (BSHXD-CS) on FJOA and define underlying the mechanisms invovled. METHODS: To establish a FJOA cell model, primary rat chondrocytes were treated with LPS. The mRNA and protein expressions were assessed using qRT-PCR and western blot, respectively. The secretion levels of pro-inflammatory cytokines were measured by ELISA. Cell viability was determined by CCK8 assay. The global m6A level was detected by the kit, and NLRP3 mRNA m6A level was determined by Me-RIP assay. The molecular interactions were analyzed by RIP and RNA pull-down assays. RESULTS: BSHXD-CS treatment relieved LPS-induced cell injury, inflammation, NLRP3 inflammasome and pyroptosis in chondrocytes (all p < 0.05). LPS-induced NLRP3 upregulation in chondrocytes was related to its high m6A modification level (p < 0.05). It was also observed that BSHXD-CS reduced LPS-induced m6A modification in chondrocytes via repressing STAT3 (all p < 0.05), suggesting BSHXD-CS could repress NLRP3 expression via m6A-dependent manner. Moreover, DAA, a m6A specific inhibitor, was proved to strengthen the protectively roles of BSHXD-CS on LPS-challenged pytoptosis (all p < 0.05). CONCLUSION: BSHXD-CS inhibited NLRP3 inflammasome activation and pyroptosis in chondrocytes to repress OA progression by reducing RNA m6A modification.

S100A10 promotes cancer metastasis via recruitment of MDSCs within the lungs.

Tumor-derived exosomes bind to organ resident cells, activating S100 molecules during the remodeling of the local immune microenvironment. However, little is known regarding how organ resident cell S100A10 mediates cancer metastatic progression. Here, we provided evidence that S100A10 plays an important role in regulating the lung immune microenvironment and cancer metastasis. S100A10-deficient mice reduced cancer metastasis in the lung. Furthermore, the activation of S100A10 within lung fibroblasts via tumor-derived exosomes increased the expression of CXCL1 and CXCL8 chemokines, accompanied by the myeloid-derived suppressor cells (MDSCs) recruitment. S100A10 inhibitors such as 1-Substituted-4-Aroyl-3-hydroxy-5-Phenyl-1 H-5-pyrrol-2(5 H)-ones inhibit lung metastasis in vivo. Our findings highlight the crucial role of S100A10 in driving MDSC recruitment in order to remodel the lung immune microenvironment and provide potential therapeutic targets to block cancer metastasis to the lung.

Biological pretreatment with white rot fungi for preparing hierarchical porous carbon from Banlangen residues with high performance for supercapacitors and dye adsorption.

White rot fungi possess superior infiltrability and biodegradability on lignocellulosic substrates, allowing them to form tailored microstructures which are conducive to efficient carbonization and chemical activation. The present research employed white rot fungus pretreatment as a viable approach for preparing porous carbon from Banlangen residues. The resultant F-A-BLGR-PC prepared by pretreating Banlangen residues with white rot fungi followed by carbonization and activation has a hierarchical porous structure with a high specific surface area of 898 m2 g-1, which is 43.4% greater than that of the unprocessed sample (R-BLGR-PC). When used as an electrode for supercapacitors, the F-A-BLGR-PC demonstrated a high specific capacitance of 308 F g-1 at 0.5 A g-1 in 6 M KOH electrolyte in three-electrode configuration. Moreover, the F-A-BLGR-PC based symmetric supercapacitor device achieved a superb cyclic stability with no obvious capacitance decay after 20,000 cycles at 5 A g-1 in 1 M Na2SO4 electrolyte. Additionally, the F-A-BLGR-PC sample was found to be an ideal adsorbent for removing methyl orange (MO) from water, exhibiting an adsorption ability of 173.4 mg g-1 and a maximum removal rate of 86.6%. This study offers a promising method for the preparation of a porous carbon with a high specific surface area in a biological way using white rot fungi pretreatment, and the derived carbon can not only be applied in energy storage but also in environmental remediation, catalysis, and so on.

Tough and elastic hydrogels based on robust hydrophobicity-assisted metal ion coordination for flexible wearable devices.

Flexible wearable sensors that combine excellent flexibility, high elasticity, sensing capabilities, and outstanding biocompatibility are gaining increasing attention. In this study, we successfully develop a robust and elastic hydrogel-based flexible wearable sensor by modulating molecular structures combined with metal ion coordination. We leverage three N-acryloyl amino acid monomers, including N-acryloyl glycine (AG), N-acryloyl alanine (AA), and N-acryloyl valine (AV) with different hydrophobic groups adjacent to the carboxyl group, to copolymerize with acrylamide (AM) in the presence of Zr4+ for hydrogel preparation in one step (P(AM3-AG/AA/AV0.06)-Zr0.034+ hydrogels). Our investigation reveals that the P(AM3-AV0.06)-Zr0.034+ hydrogel with the most hydrophobic side group demonstrates superior mechanical properties (1.1 MPa tensile stress, 3566 kJ m-3 toughness and 1.3 kJ m-2 fracture energy) and resilience to multiple tensile (30% strain, 500 cycles) and compression cycling (50% strain, 500 cycles). Moreover, the P(AM3-AV0.06)-Zr0.034+ hydrogel exhibits good biocompatibility and high conductivity (1.1 S m-1) and responsivity (GF = 16.21), and is proved to be suitable as a flexible wearable sensor for comprehensive human activity monitoring.

Meta-analysis on axillary lymph node metastasis rate in ductal carcinoma in situ with microinvasion.

OBJECTIVE: To address the question of axillary lymph node staging in ductal carcinoma in situ with microinvasion (DCIS-MI), we retrospectively evaluated axillary lymph nodes metastasis (ALNM) rate in a cohort of postsurgical DCIS-MI patients. By analyzing these data, we aimed to generate clinically relevant insights to inform treatment decision-making for this patient population. METHODS: A systematic search was conducted on PubMed, Web of Science, Embase, The Cochrane Library, CNKI, Wanfang Database, Wipe, and China Biomedical Literature Database to identify relevant publications in any language. All the analyses were performed using Stata 16.0 software. RESULTS: Among the 28 studies involving 8279 patients, the pooled analysis revealed an ALNM rate of 8% (95% CI, 7% to 10%) in patients with DCIS-MI. Furthermore, the rates of axillary lymph node macrometastasis, micrometastasis, and ITC in patients with DCIS-MI were 2% (95% CI, 2% to 3%), 3% (95% CI, 2% to 4%), and 2% (95% CI, 1% to 3%), respectively. Moreover, 13 studies investigated the non-sentinel lymph node (Non-SLN) metastasis rate, encompassing a total of 1236 DCIS-MI cases. The pooled analysis identified a Non-SLN metastasis rate of 33% (95% CI, 14% to 55%) in patients with DCIS-MI. CONCLUSION: The SLNB for patients with DCIS-MI is justifiable and could provide a novel therapeutic basis for systemic treatment decisions.

Megalin-targeting and ROS-responsive elamipretide-conjugated polymeric prodrug for treatment of acute kidney injury.

Acute kidney injury (AKI) is associated with both kidney function loss and increased mortality. In the pathological progression of ischemia-reperfusion-induced AKI, the surge of reactive oxygen species (ROS) plays a crucial role. To combat this, mitochondrial-targeted antioxidant therapy shows great promise as mitochondria are the primary source of ROS in AKI. However, most strategies aiming to target mitochondria directly result in nanodrugs that are too large to pass through the glomerular system and reach the renal tubules, which are the main site of damage in AKI. This study focused on synthesizing a Megalin receptor-targeted polymeric prodrug, low molecular weight chitosan-thioketal-elamipretide (LMWC/TK/Ela), to mitigate excessive ROS in renal tubular epithelial cells for AKI. This soluble polymeric prodrug has the ability to successfully reach the tubular site by crossing the glomerular barrier. Once there, it can responsively release elamipretide, which possesses excellent antioxidative properties. Therefore, this research offers a novel approach to actively target renal tubular epithelial cells and intracellular mitochondria for the relief of AKI.

The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment.

The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.

Megalin-targeted acetylcysteine polymeric prodrug ameliorates ischemia-reperfusion-induced acute kidney injury.

Acute kidney injury (AKI), a condition associated with reactive oxygen species (ROS), causes high mortality in clinics annually. Active targeted antioxidative therapy is emerging as a novel strategy for AKI treatment. In this study, we developed a polymeric prodrug that targets the highly expressed Megalin receptor on proximal tubule cells, enabling direct delivery of N-Acetylcysteine (NAC) for the treatment of ischemia reperfusion injury (IRI)-induced AKI. We conjugated NAC with low molecular weight chitosan (LMWC), a biocompatible and biodegradable polymer consisting of glucosamine and N-acetylglucosamine, to enhance its internalization by tubular epithelial cells. Moreover, we further conjugated triphenylphosphonium (TPP), a lipophilic cation with a delocalized positive charge, to low molecular weight chitosan-NAC in order to enhance the distribution of NAC in mitochondria. Our study confirmed that triphenylphosphonium-low molecular weight chitosan-NAC (TLN) exhibits remarkable therapeutic effects on IRI-AKI mice. This was evidenced by improvements in renal function, reduction in oxidative stress, mitigation of pathological progress, and decreased levels of kidney injury molecule-1. These findings suggested that the polymeric prodrug TLN holds promising potential for IRI-AKI treatment.

Continuous infusion versus bolus injection of loop diuretics for acute heart failure.

BACKGROUND: Acute heart failure (AHF) is new onset of, or a sudden worsening of, chronic heart failure characterised by congestion in about 95% of cases or end-organ hypoperfusion in 5% of cases. Treatment often requires urgent escalation of diuretic therapy, mainly through hospitalisation. This Cochrane review evaluated the efficacy of intravenous loop diuretics strategies in treating AHF in individuals with New York Heart Association (NYHA) classification III or IV and fluid overload. OBJECTIVES: To assess the effects of intravenous continuous infusion versus bolus injection of loop diuretics for the initial treatment of acute heart failure in adults. SEARCH METHODS: We identified trials through systematic searches of bibliographic databases and in clinical trials registers including CENTRAL, MEDLINE, Embase, CPCI-S on the Web of Science, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry platform (ICTRP), and the European Union Trials register. We conducted reference checking and citation searching, and contacted study authors to identify additional studies. The latest search was performed on 29 February 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving adults with AHF, NYHA classification III or IV, regardless of aetiology or ejection fraction, where trials compared intravenous continuous infusion of loop diuretics with intermittent bolus injection in AHF. We excluded trials with chronic stable heart failure, cardiogenic shock, renal artery stenosis, or end-stage renal disease. Additionally, we excluded studies combining loop diuretics with hypertonic saline, inotropes, vasoactive medications, or renal replacement therapy and trials where diuretic dosing was protocol-driven to achieve a target urine output, due to confounding factors. DATA COLLECTION AND ANALYSIS: Two review authors independently screened papers for inclusion and reviewed full-texts. Outcomes included weight loss, all-cause mortality, length of hospital stay, readmission following discharge, and occurrence of acute kidney injury. We performed risk of bias assessment and meta-analysis where data permitted and assessed certainty of the evidence. MAIN RESULTS: The review included seven RCTs, spanning 32 hospitals in seven countries in North America, Europe, and Asia. Data collection ranged from eight months to six years. Following exclusion of participants in subgroups with confounding treatments and different clinical settings, 681 participants were eligible for review. These additional study characteristics, coupled with our strict inclusion and exclusion criteria, improve the applicability of the body of the evidence as they reflect real-world clinical practice. Meta-analysis was feasible for net weight loss, all-cause mortality, length of hospital stay, readmission, and acute kidney injury. Literature review and narrative analysis explored daily fluid balance; cardiovascular mortality; B-type natriuretic peptide (BNP) change; N-terminal-proBNP change; and adverse incidents such as ototoxicity, hypotension, and electrolyte imbalances. Risk of bias assessment revealed two studies with low overall risk, four with some concerns, and one with high risk. All sensitivity analyses excluded trials at high risk of bias. Only narrative analysis was conducted for 'daily fluid balance' due to diverse data presentation methods across two studies (169 participants, the evidence was very uncertain about the effect). Results of narrative analysis varied. For instance, one study reported higher daily fluid balance within the first 24 hours in the continuous infusion group compared to the bolus injection group, whereas there was no difference in fluid balance beyond this time point. Continuous intravenous infusion of loop diuretics may result in mean net weight loss of 0.86 kg more than bolus injection of loop diuretics, but the evidence is very uncertain (mean difference (MD) 0.86 kg, 95% confidence interval (CI) 0.44 to 1.28; 5 trials, 497 participants; P < 0.001, I2 = 21%; very low-certainty evidence). Importantly, sensitivity analysis excluding trials with high risk of bias showed there was insufficient evidence for a difference in bodyweight loss between groups (MD 0.70 kg, 95% CI -0.06 to 1.46; 3 trials, 378 participants; P = 0.07, I2 = 0%). There may be little to no difference in all-cause mortality between continuous infusion and bolus injection (risk ratio (RR) 1.53, 95% CI 0.81 to 2.90; 5 trials, 530 participants; P = 0.19, I2 = 4%; low-certainty evidence). Despite sensitivity analysis, the direction of the evidence remained unchanged. No trials measured cardiovascular mortality. There may be little to no difference in the length of hospital stay between continuous infusion and bolus injection of loop diuretics, but the evidence is very uncertain (MD -1.10 days, 95% CI -4.84 to 2.64; 4 trials, 211 participants; P = 0.57, I2 = 88%; very low-certainty evidence). Sensitivity analysis improved heterogeneity; however, the direction of the evidence remained unchanged. There may be little to no difference in the readmission to hospital between continuous infusion and bolus injection of loop diuretics (RR 0.85, 95% CI 0.63 to 1.16; 3 trials, 400 participants; P = 0.31, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show insufficient evidence for a difference in the readmission to hospital between groups. There may be little to no difference in the occurrence of acute kidney injury as an adverse event between continuous infusion and bolus injection of intravenous loop diuretics (RR 1.02, 95% CI 0.70 to 1.49; 3 trials, 491 participants; P = 0.92, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show that continuous infusion may make little to no difference on the occurrence of acute kidney injury as an adverse events compared to the bolus injection of intravenous loop diuretics. AUTHORS' CONCLUSIONS: Analysis of available data comparing two delivery methods of diuretics in acute heart failure found that the current data are insufficient to show superiority of one strategy intervention over the other. Our findings were based on trials meeting stringent inclusion and exclusion criteria to ensure validity. Despite previous reviews suggesting advantages of continuous infusion over bolus injections, our review found insufficient evidence to support or refute this. However, our review, which excluded trials with clinical confounders and RCTs with high risk of bias, offers the most robust conclusion to date.

Peritoneal B1 and B2 cells respond differently to LPS and IL-21 stimulation.

Peritoneal B cells can be divided into B1 cells (CD11b+CD19+) and B2 cells (CD11b-CD19+) based on CD11b expression. B1 cells play a crucial role in the innate immune response by producing natural antibodies and cytokines. B2 cells share similar traits with B1 cells, influenced by the peritoneal environment. However, the response of both B1 and B2 cells to the same stimuli in the peritoneum remains uncertain. We isolated peritoneal B1 and B2 cells from mice and assessed differences in Interleukin-10(IL-10) secretion, apoptosis, and surface molecule expression following exposure to LPS and Interleukin-21(IL-21). Our findings indicate that B1 cells are potent IL-10 producers, possessing surface molecules with an IgMhiCD43+CD21low profile, and exhibit a propensity for apoptosis in vitro. Conversely, B2 cells exhibit lower IL-10 production and surface markers characterized as IgMlowCD43-CD21hi, indicative of some resistance to apoptosis. LPS stimulates MAPK phosphorylation in B1 and B2 cells, causing IL-10 production. Furthermore, LPS inhibits peritoneal B2 cell apoptosis by enhancing Bcl-xL expression. Conversely, IL-21 has no impact on IL-10 production in these cells. Nevertheless, impeding STAT3 phosphorylation permits IL-21 to increase IL-10 production in peritoneal B cells. Moreover, IL-21 significantly raises apoptosis levels in these cells, a process independent of STAT3 phosphorylation and possibly linked to reduced Bcl-xL expression. This study elucidates the distinct functional and response profiles of B1 and B2 cells in the peritoneum to stimuli like LPS and IL-21, highlighting their differential roles in immunological responses and B cell diversity.

Early evaluation of circulating tumor DNA as marker of therapeutic efficacy and prognosis in breast cancer patients during primary systemic therapy.

BACKGROUND: We assessed the potential role of serial circulating tumor DNA (ctDNA) as a biomarker to monitor treatment response to primary systemic therapy (PST) in breast cancer and evaluated the predictive value of ctDNA to further identify patients with residual disease. METHODS: We prospectively enrolled 208 plasma samples collected at three time points (before PST, after 2 cycles of treatment, before surgery) of 72 patients with stage Ⅱ-III breast cancer. Somatic mutations in plasma samples were identified using a customized 128-gene capture panel with next-generation sequencing. The correlation between early change in ctDNA levels and treatment response or long-term clinical outcomes was assessed. RESULTS: 37 of 72 (51.4%) patients harbored detectable ctDNA alterations at baseline. Patients with complete response showed a larger decrease in ctDNA levels during PST. The median relative change of variant allele fraction (VAF) was -97.4%, -46.7%, and +21.1% for patients who subsequently had a complete response (n = 11), partial response (n = 11), and no response (n = 15) (p = 0.0012), respectively. In addition, the relative change of VAF between the pretreatment and first on-treatment blood draw exhibited the optimal predictive value to tumor response after PST (area under the curve, AUC = 0.7448, p = 0.02). More importantly, early change of ctDNA levels during treatment have significant prognostic value for patients with BC, there was a significant correlation between early decrease of VAF and longer recurrence-free survival compared to those with an VAF increase (HR = 12.54; 95% CI, 2.084 to 75.42, p = 0.0063). CONCLUSION: Early changes of ctDNA are strongly correlated with therapeutic efficacy to PST and clinical outcomes in BC patients. The integration of preoperative ctDNA evaluation could help improving the perioperative management for BC patients receiving PST.

Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere.

Nesprins comprise a family of multi-isomeric scaffolding proteins, forming the linker of nucleoskeleton-and-cytoskeleton complex with lamin A/C, emerin and SUN1/2 at the nuclear envelope. Mutations in nesprin-1/-2 are associated with Emery-Dreifuss muscular dystrophy (EDMD) with conduction defects and dilated cardiomyopathy (DCM). We have previously observed sarcomeric staining of nesprin-1/-2 in cardiac and skeletal muscle, but nesprin function in this compartment remains unknown. In this study, we show that specific nesprin-2 isoforms are highly expressed in cardiac muscle and localize to the Z-disc and I band of the sarcomere. Expression of GFP-tagged nesprin-2 giant spectrin repeats 52 to 53, localized to the sarcomere of neonatal rat cardiomyocytes. Yeast two-hybrid screening of a cardiac muscle cDNA library identified telethonin and four-and-half LIM domain (FHL)-2 as potential nesprin-2 binding partners. GST pull-down and immunoprecipitation confirmed the individual interactions between nesprin-2/telethonin and nesprin-2/FHL-2, and showed that nesprin-2 and telethonin binding was dependent on telethonin phosphorylation status. Importantly, the interactions between these binding partners were impaired by mutations in nesprin-2, telethonin, and FHL-2 identified in EDMD with DCM and hypertrophic cardiomyopathy patients. These data suggest that nesprin-2 is a novel sarcomeric scaffold protein that may potentially participate in the maintenance and/or regulation of sarcomeric organization and function.

Anisotropic Hardening and Plastic Evolution Characterization on the Pressure-Coupled Drucker Yield Function of ZK61M Magnesium Alloy.

This paper studies the plastic behavior of the ZK61M magnesium alloy through a combination method of experiments and theoretical models. Based on a dog-bone specimen under different loading directions, mechanical tests under uniaxial tension were carried out, and the hardening behavior was characterized by the Swift-Voce hardening law. The von Mises yield function and the pressure-coupled Drucker yield function were used to predict the load-displacement curves of the ZK61M magnesium alloy under various conditions, respectively, where the material parameters were calibrated by using inverse engineering. The experimental results show that the hardening behavior of the ZK61M magnesium alloy has obvious anisotropy, but the effect of the stress state is more important on the strain hardening behavior of the alloy. Compared with the von Mises yield function, the pressure-coupled Drucker yield function is more accurate when characterizing the plastic behavior and strain hardening in different stress states of shear, uniaxial tension, and plane strain tension for the ZK61M alloy.

Near-infrared II theranostic agents for the diagnosis and treatment of Alzheimer's disease.

BACKGROUND: Near-infrared II theranostic agents have gained great momentum in the research field of AD owing to the appealing advantages. Recently, an array of activatable NIR-II fluorescence probes has been developed to specifically monitor pathological targets of AD. Furthermore, various NIR-II-mediated nanomaterials with desirable photothermal and photodynamic properties have demonstrated favorable outcomes in the management of AD. METHODS: We summerized amounts of references and focused on small-molecule probes, nanomaterials, photothermal therapy, and photodynamic therapy based on NIR-II fluorescent imaging for the diagnosis and treatment in AD. In addition, design strategies for NIR-II-triggered theranostics targeting AD are presented, and some prospects are also addressed. RESULTS: NIR-II theranostic agents including small molecular probes and nanoparticles have received the increasing attention for biomedical applications. Meanwhile, most of the theranostic agents exhibited the promising results in animal studies. To our surprise, the multifunctional nanoplatforms also show a great potential in the diagnosis and treatment of AD. CONCLUSIONS: Although NIR-II theranostic agents showed the great potential in diagnosis and treatment of AD, there are still many challenges: 1) Faborable NIR-II fluorohpores are still lacking; 2) Biocompatibility, bioseurity and dosage of NIR-II theranostic agents should be further revealed; 3) New equipment and software associated with NIR-II imaging system should be explored.