The efficacy and safety of molidustat for anemia in dialysis-dependent and non-dialysis-dependent chronic kidney disease patients: A systematic review and meta-analysis.

Objective: Molidustat is a novel agent investigated for the treatment of anemia in both dialysisdependent (DD) and non-dialysis-dependent (NDD) patients. Its efficacy and safety are still unclear. Methods: We searched five databases to identify randomized controlled trials comparing molidustat to erythropoiesis-stimulating agents (ESAs) or placebo in patients with anemia. Results: Six studies containing 2025 eligible participants were identified. For NDD patients, the change in Hb levels from baseline (ΔHb) was significantly higher for molidustat than for placebo [mean difference (MD) = 1.47 (95 % CI: 1.18 to 1.75), P < 0.00001] and ΔHb was also significantly higher for molidustat than for ESAs [MD = 0.25 (95 % CI 0.09 to 0.40), P = 0.002]. For NDD patients, Δhepcidin was significantly lower for molidustat than for placebo [MD = -20.66 (95 % CI: -31.67 to -9.66), P = 0.0002] and Δhepcidin was also significantly lower for molidustat than for ESAs [MD = -24.51 (95 % CI: -29.12 to -19.90), P < 0.00001]. For NDD patients, Δiron was significantly lower for molidustat than for ESAs [MD = -11.85 (95 % CI: -15.52 to -8.18), P < 0.00001], and ΔTSAT was also significantly lower for molidustat than for ESAs [MD = -5.29 (95 % CI: -6.81 to -3.78), P < 0.00001]. For NDD patients, Δferritin was significantly lower for molidustat than for placebo [MD = -90.01 (95 % CI: -134.77 to -45.25), P < 0.00001]. However, for DD-CKD patients, molidustat showed an effect similar to that of ESAs on increasing the Hb level [MD = -0.18 (95 % CI: -0.47 to 0.11), P = 0.23], Δiron level [MD = 3.78 (95 % CI: -7.21 to 14.76), P = 0.5], Δferritin level [MD = 25.03 (95 % CI: -34.69 to 84.75), P = 0.41], and Δhepcidin level [MD = 1.20 (95 % CI: -4.36 to 6.76), P = 0.67]. For DD-CKD patients, compared with the placebo or ESA group, molidustat showed a significantly higher level on ΔTSAT[MD = 3.88 (95 % CI: 2.10 to 5.65), P < 0.0001] and a slightly increased level on ΔTIBC level [MD = 1.08 (95 % CI: -0.07 to 2.23), P = 0.07]. There was no significant difference in the incidence of severe adverse events (SAEs), death, and cardio-related adverse events between molidustat and the ESAs groups. Conclusions: Moricizine can effectively improves Hb levels in NDD patients and corrects anemia in DD patients without increasing adverse event incidence.

The mechanisms of ferroptosis in the pathogenesis of kidney diseases.

The pathological features of acute and chronic kidney diseases are closely associated with cell death in glomeruli and tubules. Ferroptosis is a form of programmed cell death characterized by iron overload-induced oxidative stress. Ferroptosis has recently gained increasing attention as a pathogenic mechanism of kidney damage. Specifically, the ferroptosis signaling pathway has been found to be involved in the pathological process of acute and chronic kidney injury, potentially contributing to the development of both acute and chronic kidney diseases. This paper aims to elucidate the underlying mechanisms of ferroptosis and its role in the pathogenesis of kidney disease, highlighting its significance and proposing novel directions for its treatment.

Triggering Receptor Expressed on Myeloid Cells 2 Mediates the Involvement of M2-Type Macrophages in Pulmonary Tuberculosis Infection.

Background: Macrophage play a significant work in the development of tuberculosis. This study aims to investigate the relationship between TREM2 and macrophage polarization, as well as the related cytokines. Methods: This study involved 43 pulmonary tuberculosis patients and 37 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of M1/M2 macrophage-related cytokines IL-10 and IL-12 in the peripheral blood of pulmonary tuberculosis patients. The relative mRNA expression levels of TREM2, IL-10 and IL-12 were detected using quantitative real-time PCR (qRT-PCR). Additionally, Spearman rank correlation analysis was used to preliminarily assess the correlation between TREM2 and M1 / M2 macrophages. Hematoxylin-eosin (HE) staining was performed to observe the pathological manifestations of pulmonary tuberculosis lesions. Immunohistochemical (IHC) staining was used to observe the localization of the macrophage-specific molecule CD68, the M1 specific molecule iNOS, the M2 specific molecule CD163, and TREM2. Results: The lesions of pulmonary tuberculosis patients showed Langhans multinucleated macrophages and tuberculous granulomas. The ELISA results indicated that the expression levels of IL-10 and IL-12 were significantly increased in peripheral blood of pulmonary tuberculosis patients. Additionally, the relative mRNA expression levels of TREM2, IL-10 and IL-12 were also significantly higher in the pulmonary tuberculosis group. Furthermore, a positive correlation was observed between TREM2 and IL-10, which are secreted by M2 macrophages. IHC revealed significant positivity of TREM2 and macrophage-related markers in tuberculous granuloma. Specifically, TREM2 and M2 macrophage marker CD163 were significantly expressed in the cytoplasm and membrane of Langhans multinucleated macrophages. Conclusion: The role of macrophage polarization in pulmonary tuberculosis is significant, and further investigation is needed to understand relationship between TREM2 and M2 macrophages.

Designing a Novel Wide Bandgap Small Molecule Guest for Enhanced Stability and Morphology Mediation in Ternary Organic Solar Cells with over 19.3% Efficiency.

In this study, a novel wide-bandgap small molecule guest material, ITOA, designed and synthesized for fabricating efficient ternary organic solar cells (OSCs) ITOA complements the absorbance of the PM6:Y6 binary system, exhibiting strong crystallinity and modest miscibility. ITOA optimizes the morphology by promoting intensive molecular packing, reducing domain size, and establishing a preferred vertical phase distribution. These features contribute to improved and well-balanced charge transport, suppressed carrier recombination, and efficient exciton dissociation. Consequently, a significantly enhanced efficiency of 18.62% for the ternary device is achieved, accompanied by increased short-circuit current density (JSC), fill factor (FF), and open-circuit voltage (VOC). Building on this success, replacing Y6 with BTP-eC9 leads to an outstanding PCE of 19.33% for the ternary OSCs. Notably, the introduction of ITOA expedites the formation of the optimized morphology, resulting in an impressive PCE of 18.04% for the ternary device without any postprocessing. Moreover, the ternary device exhibits enhanced operational stability under maximum power point (MPP) tracking. This comprehensive study demonstrates that a rationally designed guest molecule can optimize morphology, reduce energy loss, and streamline the fabrication process, essential for achieving high efficiency and stability in OSCs, paving the way for practical commercial applications.

Deciphering thyroid function and CIMT: a Mendelian randomization study of the U-shaped influence mediated by apolipoproteins.

Background: Carotid Intima-Media Thickness (CIMT) is a key marker for atherosclerosis, with its modulation being crucial for cardiovascular disease (CVD) risk assessment. While thyroid function's impact on cardiovascular health is recognized, the causal relationship and underlying mechanisms influencing CIMT remain to be elucidated. Methods: In this study, Mendelian Randomization (MR) was employed to assess the causal relationship between thyroid function and CIMT. Thyroid hormone data were sourced from the Thyroidomics Consortium, while lipid traits and CIMT measurements were obtained from the UK Biobank. The primary analysis method was a two-sample MR using multiplicative random effects inverse variance weighting (IVW-MRE). Additionally, the study explored the influence of thyroid hormones on lipid profiles and assessed their potential mediating role in the thyroid function-CIMT relationship through multivariate MR analysis. Results: The study revealed that lower levels of Free Thyroxine (FT4) within the normal range are significantly associated with increased CIMT. This association was not observed with free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), or TPOAb. Additionally, mediation analysis suggested that apolipoprotein A-I and B are involved in the relationship between thyroid function and CIMT. The findings indicate a potential U-shaped curve relationship between FT4 levels and CIMT, with thyroid hormone supplementation in hypothyroid patients showing benefits in reducing CIMT. Conclusion: This research establishes a causal link between thyroid function and CIMT using MR methods, underscoring the importance of monitoring thyroid function for early cardiovascular risk assessment. The results advocate for the consideration of thyroid hormone supplementation in hypothyroid patients as a strategy to mitigate the risk of carotid atherosclerosis. These insights pave the way for more targeted approaches in managing patients with thyroid dysfunction to prevent cardiovascular complications.

Molecular imprinting-based Ru@SiO2-embedded covalent organic frameworks composite for electrochemiluminescence detection of cyanidin-3-O-glucoside.

Cyanidin-3-O-glucoside (C3G), a natural antioxidant, plays multiple physiological or pathological roles in maintaining human health; thereby, designing advanced sensors to achieve specific recognition and high-sensitivity detection of C3G is significant. Herein, an imprinted-type electrochemiluminescence (ECL) sensing platform was developed using core-shell Ru@SiO2-CMIPs, which were prepared by covalent organic framework (COF)-based molecularly imprinted polymers (CMIPs) embedded in luminescent Ru@SiO2 cores. The C3G-imprinted COF shell not only helps generate a steady-enhanced ECL signal, but also enables specific recognition of C3G. When C3G is bound to Ru@SiO2-CMIPs with abundant imprinted cavities, resonance energy transfer (RET) behavior is triggered, resulting in a quenched ECL response. The constructed Ru@SiO2-CMIPs nanoprobes exhibit ultra-high sensitivity, absolute specificity, and an ultra-low detection limit (0.15 pg mL-1) for analyzing C3G in food matrices. This study provides a means to construct an efficient and reliable molecular imprinting-based ECL sensor for food analysis.

Proteomic characterization of esophageal squamous cell carcinoma response to immunotherapy reveals potential therapeutic strategy and predictive biomarkers.

Immunotherapy is the first-line therapy for esophageal squamous cell carcinoma (ESCC), yet many patients do not respond due to drug resistance and the lack of reliable predictive markers. We collected 73 ESCC patients (including discovery cohort and validation cohort) without immune thrombocytopenia and undergoing anti-PD1 immunotherapy. Proteomic and phosphoproteomic analysis of 73 ESCC treatment-naive samples by mass spectrometry-based label-free quantification were applied to explore the potential resistant and sensitive mechanisms, and identify predictive markers of ESCC immunotherapy. Comparative analysis found the pathways related to immune and mitochondrial functions were associated with ESCC immunotherapy sensitivity; while platelet activation bioprocess showed negative correlation with CD8+ T cells and related to ESCC immunotherapy non-sensitivity. Finally, we identified 10 ESCC immunotherapy predictive biomarkers with high accuracy (≥ 0.90) to predict the immunotherapeutic response, which was validated in the independent cohort.

Yunvjian decoction mitigates hyperglycemia in rats induced by a high-fat diet and streptozotocin via reducing oxidative stress in pancreatic beta cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Yunvjian (YNJ), a traditional Chinese herbal formula first reported in Jing Yue Quan Shu, is commonly used in the clinical treatment of type 2 diabetes mellitus (T2DM). However, the mechanism by which YNJ affects T2DM remains unclear. AIM OF THE STUDY: This study aimed to assess the therapeutic effects of YNJ on T2DM and explore the potential mechanism involved. MATERIALS AND METHODS: High-performance liquid chromatography (HPLC) was used to identify the chemical compounds of YNJ. The anti-T2DM effects of YNJ were observed in a high-fat diet/streptozotocin induced rat model. The type 2 diabetic rats were prepared as follows: rats were fed a high-fat diet for four weeks and then intraperitoneally injected with a low dose (30 mg/kg) of streptozotocin. YNJ and the positive control metformin were used in these experiments. Biochemical assays were implemented to determine the fasting blood glucose, glucose tolerance, insulin sensitivity, serum lipid levels, and oxidative stress index of the pancreas. Hematoxylin-eosin (H&E) staining was used to assess histopathological alterations in the pancreas. The mechanism by which YNJ affects T2DM was evaluated in INS-1 cells treated with glucose and high sodium palmitate. YNJ-supplemented serum was used in these experiments. Methyl thiazolyl tetrazolium assays, enzyme-linked immunosorbent assays, Nile red staining, flow cytometric analysis, and Western blotting were used to assess apoptosis, insulin secretion, lipid accumulation, reactive oxygen species production, and protein levels. RESULTS: Five major compounds were identified in YNJ. In high-fat diet/streptozotocin-induced diabetic rats, YNJ-M notably decreased fasting blood glucose and lipid levels; ameliorated glucose tolerance, insulin sensitivity, and islet morphology; reduced Malondialdehyde levels; and restored superoxide dismutase activity in the pancreatic islets. Furthermore, the effect of YNJ-M was significantly greater than that of YNJ-L, and YNJ-H had little effect on diabetic rats. In vitro experiments revealed that YNJ-supplemented serum (10%, 15%, and 20%) dramatically suppressed apoptosis, mitigated intracellular lipid accumulation and reduced intracellular oxidative stress levels in a dose-dependent manner. Additionally, YNJ-supplemented serum increased the protein expression of Nuclear factor erythroid 2-related factor 2, Heme oxygenase-1, and superoxide dismutase 1 and inhibited the protein expression of Kelch-like ECH-associated protein 1. CONCLUSION: YNJ ameliorates high-fat diet/streptozotocin induced experimental T2DM. The underlying mechanism involves reducing oxidative stress in pancreatic beta cells. The findings of this study provide scientific justification for the application of the traditional medicine YNJ in treating T2DM.

Construction of Interlayer Coupling Diatomic Nanozyme with Peroxidase-Like and Photothermal Activities for Efficient Synergistic Antibacteria.

Pathogenic bacteria are the main cause of bacterial infectious diseases, which have posed a grave threat to public health. Single-atom nanozymes have emerged as promising candidates for antibacterial applications, but their activities need to be further improved. Considering diatomic nanozymes exhibit superior metal loading capacities and enhanced catalytic performance, a new interlayer coupling diatomic nanozyme (IC-DAN) is constructed by modulating the coordination environment in an atomic-level engineering. It is well demonstrated that IC-DAN exhibited superior peroxidase-mimetic activity in the presence of H2 O2 to yield abundant ∙OH and possessed high photothermal conversion ability, which synergistically achieves efficient antibacterial therapy. Therefore, IC-DAN shows great potential used as antibacterial agent in clinic and this study open a new route to developing high-performance artificial enzymes.

Risk factors and predictive model for mortality in patients undergoing allogeneic hematopoietic stem cell transplantation admitted to the intensive care unit.

Hematological malignant tumors represent a group of major diseases carrying a substantial risk to the lives of affected patients. Risk factors for mortality in critically ill patients have garnered substantial attention in recent research endeavors. The present research aimed to identify factors predicting intensive care unit (ICU) mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, the present study analyzed and compared the mortality rate between patients undergoing haploidentical hematopoietic stem cell transplantation (Haplo-SCT) and those undergoing identical sibling donor (ISD) transplantation. A total of 108 patients were included in the present research, 83 (76.9%) of whom underwent Haplo-SCT. ICU mortality was reported in 58 (53.7%) patients, with the values of 55.4 and 48.0% associated with Haplo-SCT and ISD, respectively (P=0.514). The mortality rate of patients undergoing Haplo-SCT was comparable to that of patients undergoing ISD transplantation. The present study found that reduced hemoglobin, elevated total bilirubin, elevated brain natriuretic peptide, elevated fibrinogen degradation products, need for vasoactive drugs at ICU admission, need for invasive mechanical ventilation and elevated APACHE II scores were independent risk factors for ICU mortality. Among patients presenting with 5-7 risk factors, the ICU mortality reached 100%, significantly exceeding that of other patients. The present research revealed that ICU mortality rates remain elevated among patients who underwent allo-HSCT, especially those presenting multiple risk factors. However, the outcome of patients undergoing Haplo-SCT were comparable to those of patients undergoing ISD transplants.

Prospective cohort study on tuberculosis incidence and risk factors in the elderly population of eastern China.

Background: Tuberculosis continues to be a significant public health concern in China, particularly among the elderly population. This study aimed to assess the risk factors of tuberculosis among elderly individuals in China through a cohort study, focusing on this high-risk population. Methods: The population-based census was strategically designed to cover diverse regions and demographics across the city. The survey captured demographic and lifestyle information, as well as a clinical examination. Participants were prospectively followed up over a specified duration to monitor the incidence of tuberculosis cases. Results: After a follow-up period of more than 7 years, 246 individuals developed tuberculosis, resulting in an incidence rate of 92.21 per 100,000 person-years (95 % CI 81.2-104.3). In multivariate analysis, the following factors were found to have significant associations with active tuberculosis. Increasing age correlated with a higher risk of active tuberculosis (AHR = 1.03 per 1-year increase in age, 95%CI: 1.01, 1.04, P < 0.001). Males continued to have a higher risk compared to females (HR = 2.73, 95%CI: 2.08, 3.58, P < 0.001). Individuals with a normal Body Mass Index (BMI) faced nearly three times higher risk compared to their obese counterparts (HR = 2.87, 95 % CI: 1.51, 5.46, P = 0.001). Conversely, those with an underweight BMI had a ten-fold higher risk compared to the obese group (HR = 9.89, 95 % CI: 4.92, 19.85, P < 0.001). Elderly individuals who quit smoking had a 1.35-fold increased risk compared to non-smokers (HR = 1.35, 95%CI: 1.12, 1.64, P < 0.001). Conclusions: Tuberculosis incidence among the elderly population in China remained alarmingly high. This finding emphasizes the urgent need for implementing proactive case detection measures specifically tailored to address the specific needs of this vulnerable demographic, particularly in individuals who are male, have a history of former or current smoking, and have a low BMI. Moreover, we must not underestimate the influence of former smoking on tuberculosis risk.

A glimpse into novel acylations and their emerging role in regulating cancer metastasis.

Metastatic cancer is a major cause of cancer-related mortality; however, the complex regulation process remains to be further elucidated. A large amount of preliminary investigations focus on the role of epigenetic mechanisms in cancer metastasis. Notably, the posttranslational modifications were found to be critically involved in malignancy, thus attracting considerable attention. Beyond acetylation, novel forms of acylation have been recently identified following advances in mass spectrometry, proteomics technologies, and bioinformatics, such as propionylation, butyrylation, malonylation, succinylation, crotonylation, 2-hydroxyisobutyrylation, lactylation, among others. These novel acylations play pivotal roles in regulating different aspects of energy mechanism and mediating signal transduction by covalently modifying histone or nonhistone proteins. Furthermore, these acylations and their modifying enzymes show promise regarding the diagnosis and treatment of tumors, especially tumor metastasis. Here, we comprehensively review the identification and characterization of 11 novel acylations, and the corresponding modifying enzymes, highlighting their significance for tumor metastasis. We also focus on their potential application as clinical therapeutic targets and diagnostic predictors, discussing the current obstacles and future research prospects.

TPN10475 Constrains Effector T Lymphocytes Activation and Attenuates Experimental Autoimmune Encephalomyelitis Pathogenesis by Facilitating TGF-ß Signal Transduction.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by immune cells, in which auto-reactive CD4+ T cells have been implicated as a major driver in the pathogenesis of the disease. In this study, we aimed to investigate whether the artemisinin derivative TPN10475 could alleviate experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS and its possible mechanisms. TPN10475 effectively resisted the reduction of TGF-ß signal transduction induced by TCR stimulation, suppressed the activation and function of effector CD4+ T cells in vitro, and restricted the differentiation of pathogenic Th1 and Th17 cells. It was also found to negatively regulate the inflammatory response in EAE by reducing the peripheral activation drive of auto-reactive helper T lymphocytes, inhibiting the migration of inflammatory cells into the CNS to attenuate EAE. The above results suggested that the upregulation of TGF-ß signal transduction may provide new ideas for the study of MS pathogenesis and have positive implications for the development of drugs for the treatment of autoimmune diseases.

Covalent organic frameworks-derived carbon nanospheres based nanoplatform for tumor specific synergistic therapy via oxidative stress amplification and calcium overload.

Combinational therapy in cancer treatment that integrates the merits of different therapies is an effective approach to improve therapeutic outcomes. Herein, a simple nanoplatform (N-CNS-CaO2-HA/Ce6 NCs) that synergized chemodynamic therapy (CDT), photodynamic therapy (PDT), photothermal therapy (PTT), and Ca2+ interference therapy (CIT) has been developed to combat hypoxic tumors. With high photothermal effect, excellent peroxidase-like activity, and inherent mesoporous structure, N-doped carbon nanospheres (N-CNSs) were prepared via in situ pyrolysis of an established nanoscale covalent organic frameworks (COFs) precursor. These N-CNSs acted as PTT/CDT agents and carriers for the photosensitizer chlorin e6 (Ce6), thereby yielding a minimally invasive PDT/PTT/CDT synergistic therapy. Hyaluronic acid (HA)-modified CaO2 nanoparticles (CaO2-HA NPs) coated on the surface of the nanoplatform endowed the nanoplatform with O2/H2O2 self-supply capability to respond to and modulate the tumor microenvironment (TME), which greatly facilitated the tumor-specific performance of CDT and PDT. Moreover, the reactive oxygen species (ROS) produced during PDT and CDT enhanced the Ca2+ overloading due to CaO2 decomposition, amplifying the intracellular oxidative stress and leading to mitochondrial dysfunction. Notably, the HA molecules not only increased the cancer-targeting efficiency but also prevented CaO2 degradation during blood circulation, providing double insurance of tumor-selective CIT. Such a nanotherapeutic system possessed boosted antitumor efficacy with minimized systemic toxicity and showed great potential for treating hypoxic tumors.

First-in-human study of PSMA-targeting agent, [18F]AlF-P16-093: dosimetry and initial evaluation in prostate cancer patients.

PURPOSE: This is a first-in-human study to evaluate the radiation dosimetry of a new prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, [18F]AlF-P16-093, and also initial investigation of its ability to detect PSMA-positive tumors using PET scans in a cohort of prostate cancer (PCa) patients. METHODS: The [18F]AlF-P16-093 was automatically synthesized with a GE TRACERlab. A total of 23 patients with histopathologically proven PCa were prospectively enrolled. Dosimetry and biodistribution study investigations were carried out on a subset of six (6) PCa patients, involving multiple time-point scanning. The mean absorbed doses were estimated with PMOD and OLINDA software. RESULTS: [18F]AlF-P16-093 was successfully synthesized, and radiochemical purity was > 95%, and average labeling yield was 36.5 ± 8.3% (decay correction, n = 12). The highest tracer uptake was observed in the kidneys, spleen, and liver, contributing to an effective dose of 16.8 ± 1.3 µSv/MBq, which was ~ 30% lower than that of [68Ga]Ga-P16-093. All subjects tolerated the PET examination well, and no reportable side-effects were observed. The PSMA-positive tumors displayed rapid uptake, and they were all detectable within 10 min, and no additional lesions were observed in the following multi-time points scanning. Each patient had at least one detectable tumor lesion, and a total of 356 tumor lesions were observed, including intraprostatic, lymph node metastases, bone metastases, and other soft tissue metastases. CONCLUSIONS: We report herein a streamlined method for high yield synthesis of [18F]AlF-P16-093. Preliminary study in PCa patients has demonstrated its safety and acceptable radiation dosimetry. The initial diagnostic study indicated that [18F]AlF-P16-093 PET/CT is efficacious and potentially useful for a widespread application in the diagnosis of PCa patients.

Effect of esketamine on postpartum depression after labor analgesia and potential mechanisms: a randomized, double-blinded controlled trial.

BACKGROUND: To evaluate the effect of esketamine combined with ropivacaine hydrochloride on the occurrence of postpartum depression (PPD) after labor analgesia under epidural analgesia pump and explore the possible mechanisms. METHODS: A total of 120 women aged 24 to 36 years old who underwent labor analgesia by epidural analgesia pump, with American Society of Anesthesiologists (ASA) physical status II were enrolled. According to the formula of epidural analgesia pump, all participants were randomly divided into two groups: esketamine group (Group E) and control group (Group C). Epidural anaesthesia were operated in all women between L2 and L3 after cervical dilation up to 2 ~ 3 cm. After successful puncture, the epidural catheter was placed 3.5 cm toward the head and 1% lidocaine was injected for 3 ml. The epidural analgesia pump was connected. Esketamine (0.2 mg/kg) combined with 0.75% ropivacaine hydrochloride (20 ml) were diluted by normal saline up to 100 ml in Group E, when only the equal dose of ropivacaine hydrochloride was used in Group C. The visual analogue scale (VAS) before analgesia (T1), 5 (T2), 10 (T3) and 20 (T4) minutes after analgesia were measured. The duration of the first and second stage of labor, the Apgar score of fetus at delivery, postpartum hemorrhage, consumption of esketamine and ropivacaine were recorded. The incidence of PPD was recorded at 1 week and 6 weeks after delivering. The occurrence of side effects such as nausea and vomiting, dizziness, and nightmares were also recorded for 48 h after delivering. The levels of leptin, norepinephrine(NE), and epinephrine(E) in the peripheral venous blood were measured before labor analgesia and at 24 h, 1 week, and 6 weeks after delivering. RESULTS: Compared with Group C, the VAS score at T2, T3 and T4 were significantly lower in Group E (P < 0.01). Compared with Group C, the incidence of PPD was significantly lower at 1 week and 6 weeks after delivering in Group E (P < 0.01). Compared with Group C, the levels of leptin were significantly higher at 24 h and 1 week after delivering in Group E (P < 0.01), while NE and E (P < 0.01) were lower at the same time (P < 0.01). There were no significant difference of the duration of the first and second stage of labor, the Apgar score of fetus at delivery, postpartum hemorrhage, consumption of ropivacaine and the side effects for 48 h after delivering between the two groups. CONCLUSION: Esketamine combined with ropivacaine hydrochloride used in labor analgesia can significantly reduce the incidence of postpartum depression after delivering without increasing related side effects, which may be related to the regulation of leptin, norepinephrine, and epinephrine in the serum. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry on 30/05/2022 (CTRI registration number-ChiCTR2200060387). URL of registry: https://www.chictr.org.cn/bin/home .

Determining the optimal pharmacokinetic modelling and simplified quantification method of [18F]AlF-P16-093 for patients with primary prostate cancer (PPCa).

PURPOSE: This paper discusses the optimization of pharmacokinetic modelling and alternate simplified quantification method for [18F]AlF-P16-093, a novel tracer for in vivo imaging of prostate cancer. METHODS: Dynamic PET/CT scans were conducted on eight primary prostate cancer patients, followed by a whole-body scan at 60 min post-injection. Time-activity curves (TACs) were obtained by drawing volumes of interest for primary prostatic and metastatic lesions. Optimal kinetic modelling involved evaluating three compartmental models (1T2K, 2T3K, and 2T4K) accounting for fractional blood volume (Vb). The simplified quantification method was then determined based on the correlation between the static uptake measure and total distribution volume (Vt) obtained from the optimal pharmacokinetic analysis. RESULTS: In total, 17 intraprostatic lesions, 10 lymph nodes, and 36 osseous metastases were evaluated. Visually, the contrast of the tumor increased and showed the steepest incline within the first few minutes, whereas background activity decreased over time. Full pharmacokinetic analysis revealed that a reversible two-compartmental (2T4K) model is the preferred kinetic model for the given tracer. The kinetic parameters K1, k3, Vb, and Vt were all significantly higher in lesions when compared with normal tissue (P < 0.01). Several simplified protocols were tested for approximating comprehensive dynamic quantification in tumors, with image-based SURmean (the ratio of tumor SUVmean to blood SUVmean) within the 28-34 min window found to be sufficient for approximating the total distribution Vt values (R2 = 0.949, P < 0.01). Both Vt and SURmean correlated significantly with the total serum prostate-specific antigen (tPSA) levels (P < 0.01). CONCLUSIONS: This study introduced an optimized pharmacokinetic modelling approach and a simplified acquisition method for [18F]AlF-P16-093, a novel PSMA-targeted radioligand, highlighting the feasibility of utilizing one static PET imaging (between 30 and 60 min) for the diagnosis of prostate cancer. Note that the image-derived input function in this study may not reflect the true corrected plasma input function, therefore the interpretation of the associated kinetic parameter estimates should be done with caution.

Autologous stem cell transplant for refractory and relapsed peripheral T-cell lymphoma: a retrospective study in China.

Objective To evaluate the efficacy and prognostic factors of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) in treating refractory and relapsed peripheral T-cell lymphoma (R/R PTCL). Methods We included medical records from 48 R/R PTCL patients treated with HDT/ASCT at the Beijing Cancer Hospital from January 2003 to December 2021, and these patients were followed up. Results We followed up with patients for a median of 71.0 months (interquartile range 48.8-124.4 months). The progression-free survival (PFS) at five years was 43.4%, and the five-year overall survival (OS) was 54.7. The five-year PFS and subgroups were as follows: 14 patients with anaplastic large-cell lymphoma (57.1%, 62.9%), 14 patients with NK/T-cell lymphoma (NKTCL) (28.6%, 28.6%), nine with angioimmunoblastic T-cell lymphoma (44.4%, 51.9%), and 11 with PTCL not otherwise specified (41.6%, 80.8%). Univariate analysis revealed that females had a better PFS than males (hazard ratio [HR] = 0.301, 95% confidence interval [CI] 0.091-0.996, P = 0.049); the NKTCL type had worse OS than the non-NKTCL type (HR = 0.292, 95% CI 0.122-0.698, P = 0.006); the patients with the relapsed disease did better than those with refractory disease (HR for PFS: 0.161, 95% CI 0.072-0.357, P < 0.001; HR for OS: 0.171, 95% CI 0.066-0.444, P < 0.001). The PIT score was significantly better for T-cell lymphoma with score = 0 than for score ≥ 1 group (HR for PFS: 0.261, 95% CI 0.109-0.625, P = 0.003; HR for OS: 0.305, 95% CI 0.111-0.842, P = 0.022). The pre-transplantation disease status also influences survival. Patients who achieved complete response (CR) did better (HR for PFS: 0.104, 95% CI 0.044-0.247, P < 0.001; HR for OS: 0.139, 95% CI 0.050-0.383, P < 0.001). Pre-transplantation status was an independent influencing factor associated with PFS and OS (better survival in those achieving CR) (HR for PFS: 0.126, 95% CI 0.030-0.530, P = 0.005; HR for OS: 0.154, 95% CI 0.040-0.603, P = 0.007); the pathological classification independently influenced OS (better in the those with non-NKTCL) (HR = 0.210, 95% CI 0.081-0.549, P = 0.001). CR, with a PIT score of 0 (n = 17), was associated with more prolonged PFS. None of the 48 patients experienced HDT/ASCT-related deaths. Conclusion HDT/ASCT as a salvage therapy for R/R PTCL patients can partially improve outcomes with a favorable safety profile. Prospective, randomized, and controlled studies are necessary to validate the value of HDT/ASCT for patients with diverse pathological subtypes and pre-transplantation states.

Flagellar hook protein FlgE promotes macrophage activation and atherosclerosis by targeting ATP5B.

BACKGROUND AND AIMS: Pseudomonas aeruginosa (P. aeruginosa) infections are strongly linked to the development of cardiovascular disease and atherosclerosis; however, the underlying mechanisms remain unclear. We previously confirmed that the flagellar hook protein FlgE in P. aeruginosa has immunostimulatory effects. This study investigated the effects and mechanisms of action of FlgE on atherogenesis. METHODS: ApoE-/- mice were intravenously challenged with FlgE or FlgEM recombinant proteins for eight weeks. A murine model of chronic lung colonization was established using beads containing either mutable- or wild-type bacteria. Aortic sinus sections were stained to assess atherosclerosis progression. THP-1 macrophages exposed to FlgE or FlgEM were evaluated for their effects on lipid uptake and inflammation in vitro. Western blotting and pull-down assays were used to identify the binding proteins and signaling pathways involved, and specific blocking experiments were performed to confirm these effects. RESULTS: FlgE accelerated atherosclerosis progression by triggering lipid deposition and inflammatory responses in high-fat diet (HFD)-fed ApoE-/- mice. In comparison to infection with wild-type PAO1, infection with PAO1/flgEΔBmF resulted in reduced atherosclerosis. Mechanistic analysis indicated that FlgE exacerbated lipoprotein uptake and foam cell formation by upregulating SR-A1 expression. Moreover, FlgE activated NF-κB and MAPK signaling, which subsequently led to inflammatory responses in THP-1-derived macrophages. Pull-down assays revealed that FlgE directly interacted with ATP5B, whereas blocking ATP5B attenuated FlgE-induced responses in macrophages. CONCLUSIONS: FlgE induces macrophage lipid uptake and pro-inflammatory responses mediated by ATP5B/NF-kB/AP-1 signaling, which eventually results in atherosclerosis. These findings support the development of therapeutic strategies for P. aeruginosa infection-induced atherosclerosis.

Manganese Exacerbates ConA-Induced Liver Inflammation via the cGAS-STING Signaling Pathway.

There is a potential association between the dysregulation of trace elements and impaired liver function. Elevated levels of manganese, an essential metal ion, have been observed in liver-related diseases, and excessive intake of manganese can worsen liver damage. However, the specific mechanisms underlying manganese-induced liver injury are not well understood. The aim of our study was to investigate the effects of excess manganese on autoimmune hepatitis (AIH) and elucidate its mechanisms. Our findings revealed that manganese exacerbates liver damage under ConA-induced inflammatory conditions. Transcriptomic and experimental data suggested that manganese enhances inflammatory signaling and contributes to the inflammatory microenvironment in the liver of AIH mice. Further investigations demonstrated that manganese exacerbates liver injury by activating the cGAS-STING signaling pathway and its downstream pro-inflammatory factors such as IFN[Formula: see text], IFN[Formula: see text], TNF[Formula: see text], and IL-6 in the liver of AIH mice. These results suggest that manganese overload promotes the progression of AIH by activating cGAS-STING-mediated inflammation, providing a new perspective for the treatment and prognosis of AIH.