Association between inflammatory biomarkers and postoperative acute kidney injury after cardiac surgery in patients with preoperative renal dysfunction: a retrospective pilot analysis.

BACKGROUND: Acute kidney injury (AKI) represents a significant post-cardiac surgery complication, particularly prevalent among individuals with pre-existing renal dysfunction. Chronic kidney disease (CKD) is frequently accompanied by persistent, low-grade inflammation, which is known to exacerbate systemic stress responses during surgical procedures. This study hypothesizes that these inflammatory responses might influence the incidence and severity of postoperative acute kidney injury (AKI), potentially serving as a protective mechanism by preconditioning the kidney to stress. METHODS: This retrospective study enrolled patients with preoperative renal dysfunction (eGFR between 15 and 60 ml/min/1.73 m²) who underwent cardiac surgery between January 2020 and December 2022. Preoperative inflammatory biomarkers were evaluated. The primary outcome was the incidence of postoperative AKI, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Multivariate regression models and sensitivity analyses were conducted to ascertain the relationship between inflammatory biomarkers and AKI. Restricted cubic spines (RCS) was conducted to explore nonlinear associations between inflammatory biomarkers and AKI. RESULTS: AKI occurred in 53.4% (392/734) of patients, accompanied by significant mortality and length of hospital stay increases in cases of AKI (P < 0.005). After full adjustment of confounders, neutrophil percentage-to-albumin ratio (OR = 0.28), systemic inflammation response index (OR = 0.70), systemic immune inflammation index (OR = 0.69), neutrophil-to-lymphocyte ratio (OR = 0.70), monocyte/high-density lipoprotein cholesterol ratio (OR = 0.53), neutrophil/high-density lipoprotein cholesterol ratio (OR = 0.43) demonstrated an inverse association with AKI. Sensitivity analyses revealed that patients in the highest quartile of these biomarkers exhibited a significantly lower prevalence of AKI compared to those in the lowest quartile (p for trend < 0.05). The RCS analysis suggested an "Inverted U-shaped" association of both LnNPAR and LnSIRI with AKI. CONCLUSIONS: This study identified an inverse association between preoperative inflammatory biomarkers and postoperative AKI in patients with preoperative renal dysfunction. The findings implied that preoperative inflammation may play a protective role against postoperative AKI in this patient population undergoing cardiac surgery.

Protective effect of reduced glutathione on acute kidney injury in lung cancer patients treated with cisplatin: a retrospective cohort study.

BACKGROUND: Cisplatin is a common cause of acute kidney injury (AKI) during chemotherapy for lung cancer, and the nephrotoxicity limits its clinical use. Reduced glutathione (GSH) is a major component of the cellular antioxidant defense system and performs important physiological functions. The aim of this study was to analyze the protective effect of GSH on AKI in lung cancer patients treated with cisplatin. METHODS: The clinical data were retrospectively collected from lung cancer patients treated with cisplatin at our hospital between 1 January and 31 December 2019. The patients were divided into AKI group and non-AKI group based on whether AKI occurred, and into GSH group and non-GSH group based on whether GSH was used. Univariate and multivariate logistic regressions were used to analyze the risk factors for AKI. RESULTS: A total of 1372 lung cancer patients treated with cisplatin were enrolled. Of these patients, 231 patients (16.8%) developed AKI. The incidence of AKI was lower in the GSH group compared with the non-GSH group (10.6% vs. 18%, p = 0.009). Multivariate logistic regression analysis indicated that older age (OR = 1.045, 95% CI 1.025-1.065, p < 0.001), anemia (OR = 2.436, 95% CI 1.800-3.298, p < 0.001), higher SUA levels (OR = 1.002, 95% CI 1.000-1.004, p = 0.012), higher total amount of cisplatin per cycle (OR = 1.015, 95% CI 1.004-1.025, p = 0.005), and combination with paclitaxel (OR = 2.099, 95% CI 1.435-3.070, p < 0.001) were independent risk factors for AKI in lung cancer patients treated with cisplatin, whereas GSH (OR = 0.573, 95% CI 0.353-0.931, p = 0.025) and mannitol (OR = 0.229, 95% CI 0.055-0.963, p = 0.044) reduced the risk of AKI. CONCLUSION: GSH was an independent protective factor against AKI in lung cancer patients treated with cisplatin and could be considered for clinical use in these patients to better protect renal function.

Assessment of urban flood resilience based on the socio-ecological composite index model: a case study in Wuhua District, Kunming City, China.

Global climate change and rapid urbanization have increased the frequency of flooding, making urban flood resilience a critical objective. This article introduces a methodology for assessing urban flood resilience, utilizing a social-ecological synthesis index that integrates geographical and temporal data with Geographic Information System (GIS). The study focuses on ten administrative subdistricts in Wuhua District, Kunming City, China, and selects 18 social-ecological indicators. These indicators, chosen from social and ecological perspectives, are weighted using the entropy weight method to determine their significance in the assessment system. By combining scores for each subdistrict, the study quantifies flood resilience and creates a spatial distribution map using ArcGIS. Key findings reveal that out of the ten administrative subdistricts, five in Wuhua District, particularly in the core urban area of Kunming, demonstrate strong overall flood resilience. Influenced by social-ecological indicators, there is significant spatial differentiation in flood resilience within Wuhua District, with a decreasing trend radiating from the city center to areas farther from the urban core. The research indicates that regions with well-established transportation infrastructure, a wide distribution of government institutions, improved water management facilities, and a substantial population with higher education levels contribute significantly to enhancing urban flood resilience.

Early goal-directed renal replacement therapy in severe pneumonia associated acute kidney injury.

INTRODUCTION: Severe pneumonia is a crucial issue in the development of acute kidney injury (AKI). This study evaluated the efficacy of early goal-directed renal replacement therapy (GDRRT) for the treatment of severe pneumonia-associated AKI. METHODS: In this real-world retrospective cohort study, we recruited 180 patients with severe pneumonia who were hospitalized and received GDRRT in a third-class general hospital in East China between January 1, 2017, and December 31, 2021. Clinical data on baseline characteristics, biochemical indicators, and renal replacement therapy were collected. Patients were divided into Early and Late RRT groups according to fluid status, inflammation progression, and pulmonary radiology. We investigated in-hospital all-cause mortality (primary endpoint) and renal recovery (secondary endpoint) between the two groups. RESULTS: Among the 154 recruited patients, 80 and 74 were in the early and late RRT groups, respectively. There were no significant differences in the demographic characteristics between the two groups. The duration of admission to RRT initiation was significantly shorter in Early RRT group [2.5(1.0, 8.7) d vs. 5.0(1.5,13.5) d, p = 0.027]. At RRT initiation, the patients in the Early RRT group displayed a lower percentage of fluid overload, lower doses of vasoactive agents, higher CRP levels, and higher rates of radiographic progression than those in the Late RRT group. The all-cause in-hospital mortality was significantly lower in the Early RRT group than in Late group (52.5% vs. 86.5%, p < 0.001). Patients in the Early RRT group displayed a significantly higher proportion of complete renal recovery at discharge (40.0% vs. 8.1%, p < 0.001). CONCLUSION: This study clarified that early GDRRT for the treatment of severe pneumonia-associated AKI based on fluid status and inflammation progression, was associated with reduced hospital mortality and better recovery of renal function. Our preliminary study suggests that early initiation of RRT may be an effective approach for severe pneumonia-associated AKI.

A novel model based on protein post-translational modifications comprising the immune landscape and prediction of colorectal cancer prognosis.

Background: Phosphorylation is a critical post-translational modification (PTM) type contributing to colorectal cancer (CRC). The study aimed to construct a nomogram model to predict colon adenocarcinoma (COAD) prognosis based on PTM signatures. Methods: The Cancer Genome Atlas (TCGA) database has been indexed for COAD patients' RNA sequencing, proteomic data, and clinical details. To find potential PTM prognostic signatures, the least absolute shrinkage and selection operator (LASSO) was deployed. Model validation procedures included the use of the Kaplan-Meier (K-M) method, the receiver operating characteristic (ROC) curve, the area under the curve (AUC), and the decision curve analysis (DCA). Additionally, biological enrichment, tumor immune microenvironment, and chemotherapy were also assessed. To validate the model, CRC cells were used in in vitro experiments using western blotting, proliferation assay, colony formation assay, and flow cytometry. Results: The LASSO regression analysis identified 8 PTM sites. Based on the median PTM score, patients were classified into low- and high-risk groups. K-M results showed that high-risk patients had worse prognoses (P<0.001). Our model demonstrated powerful effectiveness and predictive value (TCGA whole group: 1-year AUC =0.611, 2-year AUC =0.574, 3-year AUC =0.627). Additionally, high-risk CRC patients were enriched in KRAS signaling pathways (P=0.01), possessed more robust immune escape capacity (P=0.001, and induced cell-cycle arrest of CRC cells (P<0.01). Conclusions: We established and validated a novel nomogram model related to PTM that can predict prognosis and guide the treatment of COAD.

Cerebral microbleeds in patients with COVID-19: is there an inevitable connection?

The COVID-19 pandemic has underscored the critical interplay between systemic infections and neurological complications, notably cerebral microbleeds. This comprehensive review meticulously aggregates and analyses current evidence on cerebral microbleeds' prevalence, pathophysiological underpinnings and clinical implications within COVID-19 cohorts. Our findings reveal a pronounced correlation between cerebral microbleeds and increased severity of COVID-19, emphasizing the role of direct viral effects, inflammatory responses and coagulation disturbances. The documented association between cerebral microbleeds and elevated risks of morbidity and mortality necessitates enhanced neurological surveillance in managing COVID-19 patients. Although variability in study methodologies presents challenges, the cumulative evidence substantiates cerebral microbleeds as a critical illness manifestation rather than mere coincidence. This review calls for harmonization in research methodologies to refine our understanding and guide targeted interventions. Prioritizing the detection and study of neurological outcomes, such as cerebral microbleeds, is imperative for bolstering pandemic response strategies and mitigating the long-term neurological impact on survivors.

Effect of Delayed Remote Ischemic Preconditioning on Acute Kidney Injury and Outcomes in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

BACKGROUND: Remote ischemic preconditioning (RIPC) has 2 time windows for organ protection: acute and delayed. Previous studies have mainly focused on the organoprotective effects of acute RIPC. We aimed to determine whether delayed RIPC can reduce the occurrence of acute kidney injury (AKI) and postoperative complications in patients undergoing cardiac surgery. METHODS: This prospective, single-center, double-blind, randomized controlled trial involved 509 patients at high risk for AKI who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass. Patients were randomized to receive RIPC (4 cycles of 5-minute inflation and 5-minute deflation on 1 upper arm with a blood pressure cuff) 24 hours before surgery or a sham condition (control group) that was induced by 4 cycles of 5-minute inflation to a pressure of 20 mm Hg followed by 5-minute cuff deflation. The primary end point was the incidence of AKI within the prior 7 days after cardiac surgery. The secondary end points included renal replacement therapy during hospitalization, change in urinary biomarkers of AKI and markers of myocardial injury, duration of intensive care unit stay and mechanical ventilation, and occurrence of nonfatal myocardial infarction, stroke, and all-cause mortality by day 90. RESULTS: A total of 509 patients (mean age, 65.2±8.2 years; 348 men [68.4%]) were randomly assigned to the RIPC group (n=254) or control group (n=255). AKI was significantly reduced in the RIPC group compared with the control group (69/254 [27.2%] versus 90/255 [35.3%]; odds ratio, 0.68 [95% CI, 0.47-1.00]; P=0.048). There were no significant between-group differences in the secondary end points of perioperative myocardial injury (assessed by the concentrations of cardiac troponin T, creatine kinase myocardial isoenzyme, and NT-proBNP [N-terminal pro-brain natriuretic peptide]), duration of stay in the intensive care unit and hospital, and occurrence of nonfatal myocardial infarction, stroke, and all-cause mortality by day 90. CONCLUSIONS: Among high-risk patients undergoing cardiac surgery, delayed RIPC significantly reduced the occurrence of AKI. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2000035568.

Assessing the predictive value of elevated postoperative syndecan-1 levels for progressive acute kidney injury and kidney replacement therapy necessity in adult cardiac surgery patients.

BACKGROUND: The development of acute kidney injury (AKI) post-cardiac surgery significantly increases patient morbidity and healthcare costs. Prior researches have established Syndecan-1 (SDC-1) as a potential biomarker for endothelial injury and subsequent acute kidney injury development. This study assessed whether postoperative SDC-1 levels could further predict AKI requiring kidney replacement therapy (AKI-KRT) and AKI progression. METHODS: In this prospective study, 122 adult cardiac surgery patients, who underwent valve or coronary artery bypass grafting (CABG) or a combination thereof and developed AKI within 48 h post-operation from May to September 2021, were monitored for the progression to stage 2-3 AKI or the need for KRT. We analyzed the predictive value of postoperative serum SDC-1 levels in relation to multiple endpoints. RESULTS: In the study population, 110 patients (90.2%) underwent cardiopulmonary bypass, of which thirty received CABG or combined surgery. Fifteen patients (12.3%) required KRT, and thirty-eight (31.1%) developed progressive AKI, underscoring the severe AKI incidence. Multivariate logistic regression indicated that elevated SDC-1 levels were independent risk factors for progressive AKI (OR = 1.006) and AKI-KRT (OR = 1.011). The AUROC for SDC-1 levels in predicting AKI-KRT and AKI progression was 0.892 and 0.73, respectively, outperforming the inflammatory cytokines. Linear regression revealed a positive correlation between SDC-1 levels and both hospital (ß = 0.014, p = 0.022) and ICU stays (ß = 0.013, p < 0.001). CONCLUSION: Elevated postoperative SDC-1 levels significantly predict AKI progression and AKI-KRT in patients following cardiac surgery. The study's findings support incorporating SDC-1 level monitoring into post-surgical care to improve early detection and intervention for severe AKI.

Normalized lactate load as an independent prognostic indicator in patients with cardiogenic shock.

BACKGROUND: Early prognosis evaluation is crucial for decision-making in cardiogenic shock (CS) patients. Dynamic lactate assessment, for example, normalized lactate load, has been a better prognosis predictor than single lactate value in septic shock. Our objective was to investigate the correlation between normalized lactate load and in-hospital mortality in patients with CS. METHODS: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The calculation of lactate load involved the determination of the cumulative area under the lactate curve, while normalized lactate load was computed by dividing the lactate load by the corresponding period. Receiver Operating Characteristic (ROC) curves were constructed, and the evaluation of areas under the curves (AUC) for various parameters was performed using the DeLong test. RESULTS: Our study involved a cohort of 1932 CS patients, with 687 individuals (36.1%) experiencing mortality during their hospitalization. The AUC for normalized lactate load demonstrated significant superiority compared to the first lactate (0.675 vs. 0.646, P < 0.001), maximum lactate (0.675 vs. 0.651, P < 0.001), and mean lactate (0.675 vs. 0.669, P = 0.003). Notably, the AUC for normalized lactate load showed comparability to that of the Sequential Organ Failure Assessment (SOFA) score (0.675 vs. 0.695, P = 0.175). CONCLUSION: The normalized lactate load was an independently associated with the in-hospital mortality among CS patients.

Roles of AhR/CYP1s signaling pathway mediated ROS production in uremic cardiomyopathy.

PURPOSE: Uremic cardiomyopathy (UCM) is the leading cause of chronic kidney disease (CKD) related mortality. Uremic toxins including indoxyl sulfate (IS) play important role during the progression of UCM. This study was to explore the underlying mechanism of IS related myocardial injury. METHODS: UCM rat model was established through five-sixths nephrectomy to evaluate its effects on blood pressure, cardiac impairment, and histological changes using echocardiography and histological analysis. Additionally, IS was administered to neonatal rat cardiomyocytes (NRCMs) and the human cardiomyocyte cell line AC16. DHE staining and peroxide-sensitive dye 2',7'-dichlorofluorescein diacetate (H2DCFDA) was conducted to assess the reactive oxygen species (ROS) production. Cardiomyocyte hypertrophy was estimated using wheat germ agglutinin (WGA) staining and immunofluorescence. Aryl hydrocarbon receptor (AhR) translocation was observed by immunofluorescence. The activation of AhR was evaluated by immunoblotting of cytochrome P450 1 s (CYP1s) and quantitative real-time PCR (RT-PCR) analysis of AHRR and PTGS2. Additionally, the pro-oxidative and pro-hypertrophic effects were evaluated using the AhR inhibitor CH-223191, the CYP1s inhibitor Alizarin and the ROS scavenger N-Acetylcysteine (NAC). RESULTS: UCM rat model was successfully established, and cardiac hypertrophy, accompanied by increased blood pressure, and myocardial fibrosis. Further research confirmed the activation of the AhR pathway in UCM rats including AhR translocation and downstream protein CYP1s expression, accompanied with increasing ROS production detected by DHE staining. In vitro experiment demonstrated a translocation of AhR triggered by IS, leading to significant increase of downstream gene expression. Subsequently study indicated a close relationship between the production of ROS and the activation of AhR/CYP1s, which was effectively blocked by applying AhR inhibitor, CYP1s inhibitor and siRNA against AhR. Moreover, the inhibition of AhR/CYP1s/ROS pathway collectively blocked the pro-hypertrophic effect of IS-mediated cardiomyopathy. CONCLUSION: This study provides evidence that the AhR/CYP1s pathway is activated in UCM rats, and this activation is correlated with the uremic toxin IS. In vitro studies indicate that IS can stimulate the AhR translocation in cardiomyocyte, triggering to the production of intracellular ROS via CYP1s. This process leads to prolonged oxidative stress stimulation and thus contributes to the progression of uremic toxin-mediated cardiomyopathy.

Case report: Paralytic ileus resulted from nirmatrelvir/ritonavir-tacrolimus drug-drug interaction in a systemic lupus erythematosus patient with COVID-19.

Patients with systemic autoimmune rheumatic diseases are at a high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and effective antiviral treatments including nirmatrelvir/ritonavir can improve their outcomes. However, there might be potential drug-drug interactions when these patients take nirmatrelvir/ritonavir together with immunosuppressants with a narrow therapeutic window, such as tacrolimus and cyclosporine. We present a case of paralytic ileus resulting from tacrolimus toxicity mediated by the use of nirmatrelvir/ritonavir in a patient with systemic lupus erythematosus (SLE). A 37-year-old female SLE patient was prescribed nirmatrelvir/ritonavir without discontinuing tacrolimus. She presented to the emergency room with symptoms of paralytic ileus including persistent abdominal pain, nausea, and vomiting, which were verified to be associated with tacrolimus toxicity. The blood concentration of tacrolimus was measured >30 ng/mL. Urgent medical intervention was initiated, while tacrolimus was withheld. The residual concentration was brought within the appropriate range and tacrolimus was resumed 8 days later. Physicians must be aware of the potential DDIs when prescribing nirmatrelvir/ritonavir, especially to those taking immunosuppresants like tacrolimus.

Achieving Record External Quantum Efficiency of 11.5 % in Solution-Processable Deep-Blue Organic Light-Emitting Diodes Utilizing Hot Exciton Mechanism.

High performance solution-processable deep-blue emitters with a Commission International de l'Eclairage (CIE) coordinate of CIEy≤0.08 are highly desired in ultrahigh-definition display. Although, deep-blue materials with hybridized local and charge-transfer (HLCT) excited-state feature are promising candidates, their rigidity and planar molecular structures limit their application in solution-processing technique. Herein, four novel deep-blue solution-processable HLCT emitters were first proposed by attaching rigid imide aliphatic rings as functional units onto the HLCT emitting core. The functional units not only improve solubility, enhance thermal properties and morphological stability of the emitting core, but also promote photoluminescence efficiency, balance charge carrier transport, and inhibit aggregation-caused quenching effect due to the weak electron-withdrawing property as well as steric hindrance. The corresponding solution-processable organic light-emitting diodes (OLEDs) substantiate an unprecedented maximum external quantum efficiency (EQEmax) of 11.5 % with an emission peak at 456 nm and excellent colour purity (full width at half maximum=56 nm and CIEy=0.09). These efficiencies represent the state-of-the-art device performance among the solution-processable blue OLEDs based on the "hot exciton" mechanism. This simple strategy opens up a new avenue for designing highly efficient solution-processable deep-blue organic luminescent materials.

Effects of antimicrobial peptides from dietary Hermetia illucens larvae on the growth, immunity, gene expression, intestinal microbiota and resistance to Aeromonas hydrophila of juvenile red claw crayfish (Cherax quadricarinatus).

Antimicrobial peptides (AMPs), which are widely present in animals and plants, have a broad distribution, strong broad-spectrum antibacterial activity, low likelihood of developing drug resistance, high thermal stability and antiviral properties. The present study investigated the effects of adding AMPs from Hermetia illucens larvae on the growth performance, muscle composition, antioxidant capacity, immune response, gene expression, antibacterial ability and intestinal microbiota of Cherax quadricarinatus (red claw crayfish). Five experimental diets were prepared by adding 50 (M1), 100 (M2), 150 (M3) and 200 (M4) mg/kg of crude AMP extract from H. illucens larvae to the basal diet feed, which was also used as the control (M0). After an eight-week feeding experiment, it was discovered that the addition of 100-150 mg/kg of H. illucens larvae AMPs to the feed significantly improved the weight gain rate and specific growth rate of C. quadricarinatus. Furthermore, the addition of H. illucens larvae AMPs to the feed had no significant effect on the moisture content, crude protein, crude fat and ash content of the C. quadricarinatus muscle. The addition of 100-150 mg/kg of H. illucens larvae AMPs in the feed also increased the antioxidant capacity, nonspecific immune enzyme activity and related gene expression levels in C. quadricarinatus, thereby enhancing their antioxidant capacity and immune function. The H. illucens larvae AMPs improved the structure and composition of the intestinal microbiota of C. quadricarinatus, increasing the microbial community diversity of the crayfish gut. Finally, the addition of 100-150 mg/kg of H. illucens larvae AMPs in the feed enhanced the resistance of C. quadricarinatus against Aeromonas hydrophila, improving the survival rate of the crayfish. Based on the aforementioned findings, it is recommended that H. illucens larvae AMPs be incorporated into the C. quadricarinatus feed at a concentration of 100-150 mg/kg.

Comprehensive analysis reveals TSPEAR as a prognostic biomarker in colorectal cancer.

Background: Colorectal cancer (CRC) is one of the most common malignant tumors and has high morbidity and mortality rates. Previous studies have shown that TSPEAR mutations are involved in the development and progression of gastric cancer and liver cancer. However, the role of TSPEAR in CRC is still unclear. Methods: In The Cancer Genome Atlas (TCGA) database, 590 CRC patients with complete survival information were analyzed. We assessed TSPEAR expression in a pan-cancer dataset from the TCGA database. Cox regression analysis was performed to evaluate factors associated with prognosis. Enrichment analysis via the R package "clusterProfiler" was used to explore the potential function of TSPEAR. The single-sample GSEA (ssGSEA) method from the R package "GSVA" and the TIMER database were used to investigate the association between the immune infiltration level and TSPEAR expression in CRC. The R package "maftools" was used to explore the association between tumour mutation burden (TMB) and TSPEAR expression in CRC. CCK-8 assays and cell invasion assays were used to detect the effect of TSPEAR and TGIF2 on the biological behavior of CRC cells. Results: Pan-cancer analysis revealed that TSPEAR was upregulated in CRC tissues compared to normal tissues and that high TSPEAR expression was associated with poorer overall survival (OS) (p=0.0053). The expression of TSPEAR increased with increasing TNM stage, T stage, N stage, and M stage. The nomogram constructed with TSPEAR, age, and TNM stage showed better predictive value than TSPEAR, age, or TNM stage alone. Immune cell infiltration analysis revealed that high expression of TSPEAR was associated with lower immune cell infiltration. Tumor mutation burden (TMB) analysis indicated that high expression of TSPEAR was associated with lower TMB (p=0.005), and high TMB was associated with shorter OS (p=0.02). CCK-8 assays and cell invasion assays indicated that in vitro knockdown of TSPEAR inhibited the proliferation, migration, and invasion of CRC cells. In addition, TSPEAR expression may be regulated by the upstream transcription factor TGIF2. Conclusion: TSPEAR expression was higher in CRC tissues than in normal tissues. Its upregulation was significantly associated with a poor prognosis. Additionally, TSPEAR plays a significant role in tumor immunity and the biological behavior of CRC cells. Thus, TSPEAR may become a promising prognostic biomarker and therapeutic target for CRC patients.

Gene engineered exosome reverses T cell exhaustion in cancer immunotherapy.

Cancer patients by immune checkpoint therapy have achieved long-term remission, with no recurrence of clinical symptoms of cancer for many years. Nevertheless, more than half of cancer patients are not responsive to this therapy due to immune exhaustion. Here, we report a novel gene engineered exosome which is rationally designed by engineering PD1 gene and simultaneously enveloping an immune adjuvant imiquimod (PD1-Imi Exo) for boosting response of cancer immune checkpoint blockage therapy. The results showed that PD1-Imi Exo had a vesicular round shape (approximately 139 nm), revealed a significant targeting and a strong binding effect with both cancer cell and dendritic cell, and demonstrated a remarkable therapeutic efficacy in the melanoma-bearing mice and in the breast cancer-bearing mice. The mechanism was associated with two facts that PD1-Imi Exo blocked the binding of CD8+ T cell with cancer cell, displaying a PD1/PDL1 immune checkpoint blockage effect, and that imiquimod released from PD1-Imi Exo promoted the maturation of immature dendritic cell, exhibiting a reversing effect on the immune exhaustion through activating and restoring function of CD8+ T cell. In conclusion, the gene engineered exosome could be used for reversing T cell exhaustion in cancer immunotherapy. This study also offers a promising new strategy for enhancing PD1/PDL1 therapeutic efficacy, preventing tumor recurrence or metastasis after surgery by rebuilding the patients' immunity, thus consolidating the overall prognosis.

[Fungal luminescence pathways: research and applications].

The fungal bioluminescence pathway (FBP) is a metabolic pathway responsible for the generation of bioluminescence derived from fungi. This pathway utilizes caffeic acid as the substrate, generating a high-energy intermediate, and the decomposition of which yields green fluorescence with a wavelength of approximately 520 nm. The FBP is evolutionally conserved in luminescent fungal groups. Unlike other bioluminescent systems, the FBP is particularly suitable for engineering applications in eukaryotic organisms, especially in plants. Currently, metabolically engineered luminescent plants are able to emit visible light to illuminate its surroundings, which can be visualized clearly in the dark. The fungal bioluminescent system could be explored in various applications in molecular biology, biosensors and glowing ornamental plants, and even green lighting along city streets.

Effects of dietary astaxanthin on growth performance, muscle composition, non-specific immunity, gene expression, and ammonia resistance of juvenile ivory shell (Babylonia areolate).

Astaxanthin is one of the important immunopotentators in aquaculture. However, little is known about the physiological changes and stress resistance effects of astaxanthin in marine gastropods. In this study, the effects of different astaxanthin concentrations (0, 25, 50, 75, and 100 mg/kg) on the growth, muscle composition, immune function, and resistance to ammonia stress in Babylonia areolata were investigated after three months of rearing. With the increase in astaxanthin content, the weight gain rate (WGR), specific growth rate (SGR), and survival rate (SR) of B. areolata showed an increasing trend. The 75-100 mg/kg group was significantly higher than the control group (0 mg/kg). There was no significant difference in the flesh shell ratio (FSR), viscerosomatic index (VSI), and soft tissue index (STI) of the experimental groups. Astaxanthin (75 mg/kg) significantly increased muscle crude protein content and increased hepatopancreas alkaline phosphatase (AKP), superoxide dismutase (SOD), and catalase (CAT) activity. Astaxanthin (75-100 mg/kg) significantly increased the total antioxidant capacity (T-AOC) and acid phosphatase (ACP) of the hepatopancreas and decreased the malondialdehyde (MDA) content of B. areolata. Astaxanthin significantly induced the expression levels of functional genes, such as SOD, Cu/ZnSOD, ferritin, ACP, and CYC in hepatopancreas and increased the survival rate of B. areolata under ammonia stress. The addition of 75-100 mg/kg astaxanthin to the feed improved the growth performance, muscle composition, immune function, and resistance to ammonia stress of B. areolata.

A novel ratiometric fluorescence probe based on the FRET-ICT mechanism for detecting fluoride ions and viscosity.

Fluoride ion is not only important for dental health, but also a contributing factor in a variety of diseases. At the same time, fluoride ions and cell viscosity are both important to the physiological environment of mitochondria. We developed a dual-response ratiometric fluorescent probe BDF based on Förster resonance energy transfer (FRET) and intramolecular charge transfer (ICT) mechanism for the detection of F- and viscosity. BDF has an outstanding intramolecular energy transfer efficiency of 97.7% and shows excellent performance for fluorine ion detection. In addition, when the system viscosity increases, the fluorescence emission intensity of BDF is greatly heightened, indicating the possibility of viscosity detection. Finally, based on the fluorescence properties of BDF, we used the probe to detect F- in the toothpaste sample and image exogenous fluoride ions in HeLa cells.

Development of fatty acid metabolism score based on gene signature for predicting prognosis and immunotherapy response in colon cancer.

PURPOSE: Metabolic reprogramming is a novel hallmark and therapeutic target of cancer. Our study aimed to establish fatty acid metabolism-associated scores based on gene signature and investigated its effects on immunotherapy in colon cancer. METHODS: Gene expression and clinical information were collected from Gene Expression Omnibus (GEO) database to identify a gene signature by non-negative matrix factorization (NMF) clustering and Cox regression analysis. Subsequently, we constructed the fatty acid metabolism score (FA-score) model by principal component analysis (PCA) and explored its relativity of prognosis and the response to immunotherapy in colon cancer. Finally, the Cancer Genome Atlas (TCGA) database was introduced and in vitro study was performed for verification. RESULTS: The FA-score-high group had a higher level of fatty acid metabolism and was associated with worse patient overall survival. Significantly, FA-score correlated closely with the biomarkers of immunotherapy, and the FA-score-high group had a poorer therapeutic efficacy of immune checkpoint blockade. In vitro experiments demonstrated that ACSL5 may be a critical metabolic regulatory target. CONCLUSIONS: Our study provided a comprehensive analysis of the heterogeneity of fatty acid metabolism in colon cancer. We highlighted the potential clinical utility of fatty acid metabolism-related genes to be biomarkers of colon cancer prognosis and targets to improve the effect of immunotherapy.

Effects of dietary chitosan oligosaccharide on the growth, intestinal microbiota and immunity of juvenile red claw crayfish (Cherax quadricarinatus).

This study aimed to evaluate the potential benefits of chitosan oligosaccharide (COS) on red claw crayfish (Cherax quadricarinatus) and explore its underlying mechanisms. The crayfish were randomly divided into six groups, and the diets were supplemented with COS at levels of 0 (C0), 0.2 (C1), 0.4 (C2), 0.6 (C3), 0.8 (C4), and 1 (C5) g kg-1. Treatment with COS significantly improved the growth performance of the crayfish with a higher weight gain rate (WGR) and specific growth rate (SGR) in the C2 group compared to the C0 group. Additionally, the content of crude protein in the crayfish muscles in the C1 group was significantly higher than that of the C0 group. Regarding non-specific immunity, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and alkaline phosphatase (AKP), and the levels of expression of the genes related to immunity (SOD; anti-lipopolysaccharide factor [ALF]; thioredoxin1 [Trx1]; C-type lysozyme, [C-LZM]; and GSH-Px) in the hepatopancreas and hemolymph increased significantly (P < 0.05) after supplementation with 0.4 g kg-1 of COS, while the content of malondialdehyde (MDA) decreased (P < 0.05). The survival rate of C. quadricarinatus increased (P < 0.05) in the C2, C3, C4, and C5 groups after the challenge with Aeromonas hydrophila. This study found that COS has the potential to modulate the composition of the intestinal microbiota and significantly reduce the abundance of species of the phylum Proteobacteria and the genera Aeromonas and Vibrio in the gut of C. quadricarinatus, while the abundance of bacteria in the phylum Firmicutes and the genus Candidatus_Hepatoplasma improved significantly. This study suggests that the inclusion of COS in the diet of C. quadricarinatus can enhance growth, boost immunity, and increase resistance to infection with A. hydrophila, especially when supplemented at 0.4-0.8 g kg-1.