Warfarin-related nephropathy: unveiling the hidden dangers of anticoagulation.

Warfarin-related nephropathy (WRN) is defined as acute kidney injury subsequent to excessive anticoagulation with warfarin. Patients with mechanical prosthetic valves require long-term anticoagulant therapy. Nonetheless, warfarin remains the sole available option for anticoagulant therapy. Consequently, patients with mechanical prosthetic valves constitute a special group among the entire anticoagulant population. The present study recorded two cases of patients who had undergone mechanical prosthetic valve surgery and were receiving warfarin therapy. They presented to the hospital with gross hematuria and progressive creatinine levels. Notably, their international normalized ratio (INR) did not exceed three. Subsequent renal biopsies confirmed WRN with IgA nephropathy. The two patients continued to receive warfarin as anticoagulation therapy and were prescribed oral corticosteroids and cyclophosphamide, which resulted in improved renal function during the follow-up. Based on a review of all relevant literature and the present study, we proposed a new challenge: must elevated INR levels be one of the criteria for clinical diagnosis of WRN? Perhaps some inspiration can be drawn from the present article.

Microneedle electrochemical sensor based on disposable stainless-steel wire for real-time analysis of indole-3-acetic acid and salicylic acid in tomato leaves infected by Pst DC3000 in situ.

BACKGROUND: Indole-3-acetic acid (IAA) and salicylic acid (SA), pivotal regulators in plant growth, are integral to a variety of plant physiological activities. The ongoing and simultaneous monitoring of these hormones in vivo enhances our comprehension of their interactive and regulatory roles. Traditional detection methods, such as liquid chromatography-mass spectrometry, cannot obtain precise and immediate information on IAA and SA due to the complexity of sample processing. In contrast, the electrochemical detection method offers high sensitivity, rapid response times, and compactness, making it well-suited for in vivo or real-time detection applications. RESULTS: A microneedle electrochemical sensor system crafted from disposable stainless steel (SS) wire was specifically designed for the real-time assessment of IAA and SA in plant in situ. This sensor system included a SS wire (100 µm diameter) coated with carbon cement and multi-walled carbon nanotubes, a plain platinum wire (100 µm diameter), and an Ag/AgCl wire (100 µm diameter). Differential pulse voltammetry and amperometry were adopted for detecting SA and IAA within the range of 0.1-20 µM, respectively. This sensor was applied to track IAA and SA fluctuations in tomato leaves during PstDC3000 infection, offering continuous data. Observations indicated an uptick in SA levels following infection, while IAA production was suppressed. The newly developed disposable SS wire-based microneedle electrochemical sensor system is economical, suitable for mass production, and inflicts minimal damage during the monitoring of SA and IAA in plant tissues. SIGNIFICANCE: This disposable microneedle electrochemical sensor facilitates in vivo detection of IAA and SA in smaller plant tissues and allows for long-time monitoring of their concentrations, which not only propels research into the regulatory and interaction mechanisms of IAA and SA but also furnishes essential tools for advancing precision agriculture.

Antibiotic susceptibility of Vibrio parahaemolyticus isolated from prawns and oysters marketed in Zhanjiang, China.

To evaluate the antibiotic susceptibility of Vibrio parahaemolyticus from prawns and oysters marketed in Zhanjiang, Guangdong, China. 84 strains of V. parahaemolyticus were isolated from prawns and oysters sampled from 9 major markets. The results showed that 84 V. parahaemolyticus strains had the highest rate of antibiotic resistance to oxytetracycline (69.05 %, 58/84) and the lowest rate of antibiotic resistance to enrofloxacin (1.19 %, 1/84), ciprofloxacin (4.76 %, 4/84) and norfloxacin (7.14 %, 6/84) in quinolone. Meanwhile, 96.42 % of the strains showed multiple antibiotic resistance (MAR). PCR results showed that the resistance phenotype was closely related to the antibiotic resistance genes and efflux pump genes (p < 0.01), and the efflux pump gene was the key causing MAR. The combination of antibiotics significantly eliminated multidrug resistance. In addition, efflux pump inhibitors also reduce MAR. This study may provide information on antibiotic susceptibility, antibiotic resistance and strategies for the control of V. parahaemolyticus.

Identifying the mechanism of polysaccharopeptide against breast cancer based on network pharmacology and experimental verification.

Polysaccharopeptide (PSP) is a potential active component in traditional Chinese medicine because of its anticancer effects on a variety of cancer cells and as immune enhancers of the immune system. Previous studies on the role of PSP in breast cancer have been limited, and the mechanism has not been clarified. This study is based on network pharmacology and molecular docking technology to predict the possible target of PSP treatment of breast cancer, and use experiments to verify the effect and mechanism of PSP on breast cancer. In this study, 287 PSP targets were obtained using SwissTargetPrediction database and PharmMapper database, and 183 breast cancer targets were obtained using DisGenNET database. By intersections of PSP targets and breast cancer targets, a total of 10 intersections were obtained. GO functional enrichment, KEGG pathway enrichment and molecular docking of these 10 target genes were performed to obtain the potential targets of PSP on breast cancer. In vitro experiments, we found that PSP significantly inhibited the proliferation and induced apoptosis of breast cancer cell lines MDA-MB-231, SUM-159 and MCF-7. Western Blot results showed that PSP could down-regulate the expression of p-JAK2 and p-STAT3 proteins. Similarly, the results of in vivo experiments showed that PSP can directly inhibit the tumor of MDA-MB-231 tumor-bearing mice, and the mechanism of action is mainly to inhibit the JAK2-STAT3 pathway. The above results were consistent with the results of network pharmacology, which provides a scientific basis for the clinical application of PSP in breast cancer patients.

Total Synthesis of a PSGL-1 Glycopeptide Analogue for Targeted Inhibition of P-Selectin.

The high affinity interaction between P-selectin glycoprotein ligand-1 (PSGL-1) and P-selectin is mediated by a multimotif glycosulfopeptide (GSP) recognition domain consisting of clustered tyrosine sulfates and a Core 2 O-glycan terminated with sialyl LewisX (C2-O-sLeX). These distinct GSP motifs are much more common than previously appreciated within a wide variety of functionally important domains involved in protein-protein interactions. However, despite the potential of GSPs to serve as tools for fundamental studies and prospects for drug discovery, their utility has been limited by the absence of chemical schemes for synthesis on scale. Herein, we report the total synthesis of GSnP-6, an analogue of the N-terminal domain of PSGL-1, and potent inhibitor of P-selectin. An efficient, scalable, hydrogenolysis-free synthesis of C2-O-sLeX-Thr-COOH was identified by both convergent and orthogonal one-pot assembly, which afforded this crucial building block, ready for direct use in solid phase peptide synthesis (SPPS). C2-O-sLeX-Thr-COOH was synthesized in 10 steps with an overall yield of 23% from the 4-O,5-N oxazolidinone thiosialoside donor. This synthesis represents an 80-fold improvement in reaction yield as compared to prior reports, achieving the first gram scale synthesis of SPPS ready C2-O-sLeX-Thr-COOH and enabling the scalable synthesis of GSnP-6 for preclinical evaluation. Significantly, we established that GSnP-6 displays dose-dependent inhibition of venous thrombosis in vivo and inhibits vaso-occlusive events in a human sickle cell disease equivalent microvasculature-on-a-chip system. The insights gained in formulating this design strategy can be broadly applied to the synthesis of a wide variety of biologically important oligosaccharides and O-glycan bearing glycopeptides.

Analysis of Clinicopathological Characteristics of Malignancy Patients with Membranous Nephropathy and Literature Review.

Purpose: In recent years, the incidence of malignancy patients with membranous nephropathy (MN) has gradually increased, but the clinical and pathological characteristics of these patients are still unclear. Our study aims at elucidating the clinical and pathological characteristics of malignancy patients with MN, especially the expression patterns of MN-specific antigens in both kidney and tumor tissue. Patients and Methods: A retrospective analysis was performed to summarize the clinical and pathological data of MN patients with malignancy at Beijing Anzhen Hospital from January 1, 2012, to December 31, 2022, followed by a thorough review of relevant literature published between May 1, 2000 to May 1, 2023 and case aggregation. Results: 19 patients in our center's MN cohort and 21 patients from literature review were diagnosed with malignancy either before or after being diagnosed with MN. Among them, 16 (40.0%) and 17 (42.5%) patients tested PLA2R-only and THSD7A-only positive in renal tissue, respectively. And 16 of 26 patients showed similar staining in tumor and kidney tissues. Compared to the idiopathic membranous nephropathy (IMN) patients at our center, patients with malignancy were older, had a lower estimated glomerular filtration rate, and had a lower rate of partial or complete response to treatment. Renal tissue from MN patients with concomitant malignancy was less frequently PLA2R-positive, more frequently THSD7A-positive, and more often glomerular IgG subclass IgG2 (P = 0.033) but less frequently IgG4 (P < 0.001). Conclusion: The clinical and pathological characteristics of MN patients with concomitant malignancy are different from those of IMN patients. Active screening for malignancy should be performed in non-PLA2R-positive elderly MN patients with a poor therapeutic response. Staining for MN target antigens in kidney and tumor tissues may be inconsistent, and the role of MN target antigens needs to be further explored.

Spalling Criterion of Hard Brittle Rock Mass Based on Dilatation Lateral Strain.

Spalling failure is a typical failure phenomenon after excavation and unloading of a deep, hard brittle rock mass, which seriously threatens the safe construction of deep roadways (tunnels) and other projects. From the engineering viewpoint, it is essential to accurately evaluate the range and depth of surrounding rock spalling failure. From the perspective of the laboratory and engineering site, the strength and formation mechanism of hard rock spalling failure were statistically summarized and analyzed. Under uniaxial and low confining pressure conditions, when the load reached the rock damage stress, cracks in the rock penetrated to form a failure plane approximately parallel to the axial loading direction, and the strength of rock mass spalling was much smaller than that of intact rock spalling. A triaxial compression test was conducted to analyze the dilatation axial strain and dilatation lateral strain characteristics of gneiss. The results showed that dilatation axial strain gradually increased with the increase of confining pressure, whereas dilatation lateral strain was almost unchanged. Therefore, a safety factor (FS) based on dilatation lateral strain was developed. Through comparison with other strain-based spalling criteria, the establishment and physical meaning of the method were described in detail. In addition, FS was applied to analyze the deep roadway of the Hongtoushan Copper Mine in China and the Rm415 test tunnel in Canada. The results showed that the spalling criterion could accurately indicate the range and depth of the surrounding rock spalling failure, which verified the rationality and applicability of the new spalling criterion. Thus, FS can be utilized as a new theory and analysis tool for the assessment and prevention of spalling failure in deep hard rock roadways.

Population pharmacokinetics of Ainuovirine and exposure-response analysis in human immunodeficiency virus-infected individuals.

BACKGROUND: Ainuovirine (ANV) is a new generation of non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus (HIV) type 1 infection. This study aimed to evaluate the population pharmacokinetic (PopPK) profile and exposure-response relationship of ANV among people living with HIV. METHODS: Plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the PopPK model. Exposure estimates obtained from the final model were used in exposure-response analysis for virologic responses and safety responses. RESULTS: ANV exhibited a nonlinear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (relative standard error [%]) for CL/F was 6.46 (15.00) L/h, and the clearance of ANV increased after multiple doses. The exposure-response model revealed no significant correlation between the virologic response (HIV-RNA <50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure( P value of steady-state trough concentration and area under the steady-state curve were 0.0177 and 0.0141, respectively). CONCLUSIONS: Our PopPK model supported ANV 150 mg once daily as the recommended dose for people living with HIV, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure. TRIAL REGISTRATION: Chinese Clinical Trial Registry https://www.chictr.org.cn (Nos. ChiCTR1800018022 and ChiCTR1800019041).

Fried Soybean Oil Causes Systemic Low-Grade Inflammation by Disrupting the Balance of Gut Microbiota in Mice.

Previous reports have mainly investigated the long-term effects (>30 d), such as gut microbiota dysbiosis and systemic low-grade inflammation, in mice fed fried oil. However, short-term intake of deep-fried oil is more likely to occur in daily life, and such studies are lacking. This study aimed to investigate the short-term effects of fried oil intake on systemic low-grade inflammation. Male Kunming mice were fed non-fried soybean oil or low (25%), medium (50%), or high (100%)-fried oil at 4.4 g/kg for 6 d. Serum and fecal samples were collected on day 7. In all groups fed fried oil, the serum levels of tumor necrosis factor (TNF-α) were significantly elevated 2-4-fold. Among the gut microbiota, the abundance of Alloprevotella significantly decreased by up to 76%, while Lactobacilli significantly increased by up to 385%. The fecal valeric acid content was significantly increased and positively correlated with TNF-α levels. Both valeric acid and TNF-α levels were positively correlated with the abundance of Lactobacilli and negatively correlated with that of Alloprevotella. In summary, a short-term ingestion of even low doses of fried oil alters the gut microbiota Alloprevotella and Lactobacilli and increases fecal valeric acid content, which correlates with increased serum TNF-α levels.

Microbiome and Metabolite Analysis Insight into the Potential of Shrimp Head Hydrolysate to Alleviate Depression-like Behaviour in Growth-Period Mice Exposed to Chronic Stress.

Chronic stress (CS) endangers the physical and mental health of adolescents. Therefore, alleviating and preventing such negative health impacts are a top priority. This study explores the effect of feeding shrimp head hydrolysate (SHH) on gut microbiota, short-chain fatty acids (SCFAs), and neurotransmitters in growing C57BL/6 mice subjected to chronic unpredictable mild stress. Mice in the model group and three SHH groups were exposed to CS for 44 days, distilled water and SHH doses of 0.18, 0.45, 0.90 g/kg·BW were given respectively by gavage daily for 30 days from the 15th day. The results showed that SHH can significantly reverse depression-like behaviour, amino acids degradation, α diversity and ß diversity, proportion of Firmicutes and Bacteroidota, abundance of genera such as Muribaculaceae, Bacteroides, Prevotellaceae_UCG-001, Parabacteroides and Alistipes, concentration of five short-chain fatty acids (SCFAs), 5-HT and glutamate induced by CS. Muribaculaceae and butyric acid may be a controlled target. This study highlights the potential and broad application of SHH as an active ingredient in food to combat chronic stress damage.

Screening, characterization and mechanism of a potential stabiliser for nisin nanoliposomes with high encapsulation efficiency.

The encapsulation efficiency (EE%) reflects the amount of bioactive components that can be loaded into nanoliposomes. Obtaining a suitable nanoliposome stabiliser may be the key to improving their EE%. In this study, three polyphenols were screened as stabilisers of nanoliposomes with high nisin EE%, with curcumin nanoliposomes (Cu-NLs) exhibiting the best performance (EE% = 95.94%). Characterizations of particle size, PDI and zeta potential indicate that the Cu-NLs had good uniformity and stability. TEM found that nisin accumulated at the edges of the Cu-NLs' phospholipid layer. DSC and FT-IR revealed that curcumin was involved in the formation of the phospholipid layer and altered its structure. FT-IR and molecular docking simulations indicate that the interactions between curcumin and nisin are mainly hydrogen bonding and hydrophobic. In whole milk, Cu-NLs effectively protected nisin activity. This study provides an effective strategy for improving the EE% of nanoliposomes loaded with nisin and other bacteriocins.

A Tripeptide (Ser-Arg-Pro, SRP) from Sipunculus nudus L. Improves Cadmium-Induced Acute Kidney Injury by Targeting the MAPK, Inflammatory, and Apoptosis Pathways in Mice.

Cadmium (Cd) is a toxic heavy metal that causes nephrosis, including acute kidney injury. To prevent and treat acute kidney injury (AKI) following Cd exposure, a tripeptide, Ser-Arg-Pro (SRP), from Sipunculus nudus L. was employed, and its potential efficacy in AKI was assessed. Oral administration of SRP significantly alleviated Cd-induced kidney damage, leading to improved renal function and the attenuation of structural abnormalities. A network pharmacology analysis revealed the potential of SRP in renal protection by targeting various pathways, including mitogen-activated protein kinase (MAPK) signaling, inflammatory response, and apoptosis pathways. Mechanistic studies indicated that SRP achieves renal protection by inhibiting the activation of MAPK pathways (phosphorylation of p38, p56, ERK, and JNK) in the oxidative stress cascade, suppressing inflammatory responses (iNOS, Arg1, Cox2, TNF-α, IL-1ß, and IL-6), and restoring altered apoptosis factors (caspase-9, caspase-3, Bax, and Bcl-2). Hence, SRP has the potential to be used as a therapeutic agent for the treatment of Cd-induced nephrotoxicity.

Liberated bioactive bound phenolics during in vitro gastrointestinal digestion and colonic fermentation boost the prebiotic effects of triticale insoluble dietary fiber.

Phenolics in bound form extensively exist in cereal dietary fiber, especially insoluble fiber, while their release profile in gastrointestinal tract and contribution to the potential positive effects of dietary fiber in modulating gut microbiota still needs to be disclosed. In this work, the composition of bound phenolics (BPs) in triticale insoluble dietary fiber (TIDF) was studied, and in vitro gastrointestinal digestion as well as colonic fermentation were performed to investigate BPs liberation and their role in regulating intestinal flora of TIDF. It turned out that most BPs were unaccessible in digestion but partly released continuously during fermentation. 16 s rRNA sequencing demonstrated that TIDF possessed prebiotic effects by promoting anti-inflammatory while inhibiting proinflammatory bacteria alongside boosting SCFAs production and antioxidative BPs contributed a lot to these effects. Results indicated that TIDF held capabilities to regulate intestinal flora and BPs were important functional components to the health benefits of cereal dietary fiber.

Reduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice.

Whether intestinal Leucine-rich repeat containing G-protein-coupled receptor 4 (LGR4) impacts nutrition absorption and energy homeostasis remains unknown. Here, we report that deficiency of Lgr4 (Lgr4iKO) in intestinal epithelium decreased the proportion of enterocytes selective for long-chain fatty acid absorption, leading to reduction in lipid absorption and subsequent improvement in lipid and glucose metabolism. Single-cell RNA sequencing demonstrates the heterogeneity of absorptive enterocytes, with a decrease in enterocytes selective for long-chain fatty acid-absorption and an increase in enterocytes selective for carbohydrate absorption in Lgr4iKO mice. Activation of Notch signaling and concurrent inhibition of Wnt signaling are observed in the transgenes. Associated with these alterations is the substantial reduction in lipid absorption. Decrement in lipid absorption renders Lgr4iKO mice resistant to high fat diet-induced obesity relevant to wild type littermates. Our study thus suggests that targeting intestinal LGR4 is a potential strategy for the intervention of obesity and liver steatosis.

Changes in blood lipid levels and influencing factors among treatment-naïve adult male HIV/AIDS patients following BIC/FTC/TAF vs . 3TC+EFV+TDF.

BACKGROUND: Antiretroviral therapy (ART) was often associated with dyslipidemia among human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients. This study aimed to assess treatment-naïve adult male patients with HIV/AIDS who initiated ART with either co-formulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) or lamivudine, efavirenz, and tenofovir disoproxil fumarate (3TC+EFV+TDF), monitoring at weeks 4, 12, 24, and 48. METHODS: A case-control retrospective study was conducted. The newly diagnosed HIV-infected individuals attending the sexual transmission disease (STD)/AIDS clinic of Beijing Youan Hospital, Capital Medical University, from January to December 2021. The patients were divided into BIC/FTC/TAF group or 3TC+EFV+TDF group. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and total cholesterol (TC) at different time points over 48 weeks between two groups were compared. A multivariate Cox regression model was used to identify relevant influencing factors for the population at high risk of increased LDL-C. RESULTS: A total of 870 participants, with 510 in BIC/FTC/TAF group and 360 in 3TC+EFV+TDF group. There were no statistically significant differences in median age, baseline CD4/CD8 ratio, median body mass index (BMI) between the two groups. In both two groups, levels of TG, TC, and LDL-C were higher at 4 weeks, 12 weeks, and 24 weeks of treatment (all P <0.05), and there were no statistically significant differences at 48 weeks compared to those at baseline (all P >0.05). In addition, the differences in average changes of the level of TG, TC, HDL-C, and LDL-C from weeks 4, 12, 24, and 48 to baseline between two groups were not statistically significant (all P >0.05). Multivariate Cox proportional risk model analysis showed that initiating ART with HIV RNA ≥10 5 copies/mL (compared with <10 5 copies/mL) was associated with an increased risk of elevated LDL-C (hazard ratio = 1.26, 95% confidence interval: 1.07-1.48, P  = 0.005). CONCLUSIONS: Transient elevations in blood lipid levels (TC, TG, HDL-C, and LDL-C) were observed in treatment-naïve adult male HIV/AIDS patients with BIC/FTC/TAF at 4 weeks, 12 weeks, and 24 weeks of treatment. However, these levels did not differ significantly from baseline after 48 weeks of treatment, regardless of whether patients were in the BIC/FTC/TAF or 3TC+EFV+TDF group.

Investigating the effects and efficacy of self-compassion intervention on generalized anxiety disorders.

BACKGROUND: Generalized anxiety disorder (GAD) is the least successfully treated anxiety disorder. This clinical trial investigated the effects and efficacy of a novel self-compassion intervention in GAD. METHODS: A total of 75 GAD patients were assigned to a self-compassion intervention group (n = 25), a mindfulness intervention group (n = 25), or a treat-as-usual group (n = 25). Patients in the two active groups received eight intervention sessions in two weeks in addition to usual treatment i.e., pharmacotherapy. Primary outcomes were anxiety and worry, assessed at pre-intervention, post-intervention, and three-month follow-up. Secondary outcomes included depression, sleep, as well as self-compassion and mindfulness. RESULTS: Both the self-compassion and mindfulness intervention induced a more rapid decrease in anxiety and depression than pharmacological treatment alone with excellent response and remission rate. Self-compassion intervention also induced a more rapid improvement in sleep quality compared to mindfulness intervention and pharmacological treatment alone. We also presented a mechanism for the self-compassion intervention in which decreased anxiety led to improvement in sleep quality. There was also a higher pleasure, acceptance, and willingness to re-attend in the self-compassion compared to the mindfulness intervention. LIMITATIONS: This study was single blinded and nonrandomized which may bring risks of bias. CONCLUSIONS: Overall, we provided novel evidence that self-compassion intervention is an alternative psychotherapy for GAD with excellent response and acceptability.

Efficacy and safety of Trastuzumab Emtansine in treating human epidermal growth factor receptor 2-positive metastatic breast cancer in Chinese population: a real-world multicenter study.

Background: Trastuzumab emtansine (T-DM1) has been approved worldwide for treating metastatic breast cancer (mBC) in patients who have received first-line therapy, shown disease progression, and are human epidermal growth factor receptor 2 (HER2)-positive. T-DM1 received approval in China to treat early-stage breast cancer (BC) in 2020 and for mBC in 2021. In March 2023, T-DM1 was included in medical insurance coverage, significantly expanding the eligible population. Materials and methods: This post-marketing observational study aimed to assess the safety and effectiveness of T-DM1 in real-world clinical practice in China. This study enrolled 31 individuals with HER2-positive early-stage BC and 70 individuals with HER2-positive advanced BC from 8 study centers in Shandong Province, China. The T-DM1 dosage was 3.6 mg/kg injected intravenously every 3 weeks until the disease advanced or the drug toxicity became uncontrollable, whichever occurred earlier. Additionally, efficacy and safety information on T-DM1 were collected. Results: During the 7-month follow-up period, no recurrence or metastases were observed in patients who had early-stage BC. The disease control rate was 31.43% (22/70) in patients with advanced BC. The most common adverse effect of T-DM1 was thrombocytopenia, with an incidence of 69.31% (70/101), and the probability of Grade ≥ 3 thrombocytopenia was 11.88% (12/101). Conclusion: This real-world study demonstrated that T-DM1 had good efficacy and was well tolerated by both HER2-positive early-stage BC and mBC patients.

The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion.

As a strategy to improve the therapeutic success of chimeric antigen receptor T cells (CART) directed against solid tumors, we here test the combinatorial use of CART and IMSA101, a newly developed stimulator of interferon genes (STING) agonist. In two syngeneic tumor models, improved overall survival is observed when mice are treated with intratumorally administered IMSA101 in addition to intravenous CART infusion. Transcriptomic analyses of CART isolated from tumors show elevated T cell activation, as well as upregulated cytokine pathway signatures, in particular IL-18, in the combination treatment group. Also, higher levels of IL-18 in serum and tumor are detected with IMSA101 treatment. Consistent with this, the use of IL-18 receptor negative CART impair anti-tumor responses in mice receiving combination treatment. In summary, we find that IMSA101 enhances CART function which is facilitated through STING agonist-induced IL-18 secretion.

Complement system is overactivated in patients with IgA nephropathy after COVID-19.

IgA nephropathy (IgAN), which has been confirmed as a complement mediated autoimmune disease, is also one form of glomerulonephritis associated with COVID-19. Here, we aim to investigate the clinical and immunological characteristics of patients with IgAN after COVID-19. The level of plasma level of C5a (p < 0.001), soluble C5b-9 (p = 0.018), FHR5 (p < 0.001) were all significantly higher in Group CoV (33 patients with renal biopsy-proven IgAN experienced COVID-19) compared with Group non-CoV (44 patients with IgAN without COVID-19), respectively. Compared with Group non-CoV, the intensity of glomerular C4d (p = 0.017) and MAC deposition (p < 0.001) and Gd-IgA1 deposition (p = 0.005) were much stronger in Group CoV. Our finding revealed that for IgAN after COVID-19, mucosal immune responses to SARS-CoV-2 infection may result in the overactivation of systemic and renal local complement system, and increased glomerular deposition of Gd-IgA1, which may lead to renal dysfunction and promote renal progression in IgAN patients.